Shield's General Thoracic Surgery

Volume
One & Two
Shields′
GENERAL THORACIC
SURGERY
8th Edition
EDITED BY
Joseph LoCicero III, MD
Professor Emeritus of Surgery
SUNY Downstate
Brooklyn, New York
Physician Consultant
Mobile County Health Department
Mobile, Alabama
Richard H. Feins, MD
Professor of Surgery
Division of Cardiothoracic Surgery
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Yolonda L. Colson, MD, PhD

Michael A. Bell Distinguished Chair in Healthcare Innovation
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
Gaetano Rocco, MD, FRCSEd

Professor
Chief, Division of Thoracic Surgery
Instituto Nazionale Tumori, IRCCS, Pascale Foundation
Naples, Italy
Acquisitions Editor: Keith Donnellan
Development Editor: Sean McGuire
Development Editor: Brendan Huffman
Editorial Coordinator: Jennifer DiRicco
Editorial Coordinator: Dave Murphy
Marketing Manager: Dan Dressler
Production Project Manager: David Saltzberg
Design Coordinator: Elaine Kasmer
Manufacturing Coordinator: Beth Welsh
Prepress Vendor: Aptara, Inc.
8th edition
Copyright © 2019 Wolters Kluwer.
Copyright © 2009 by Lippincott Williams & Wilkins, a Wolters Kluwer business. Copyright © 2005, 2000 by Lippincott Williams & Wilkins.
Copyright © 1994 by Williams and Wilkins. Copyright © 1989, 1983, 1972 by Lea & Febiger. All rights reserved. This book is protected by
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Printed in The United States of America
Library of Congress Cataloging-in-Publication Data
Names: LoCicero, Joseph, III, 1948- editor. | Feins, Richard H., editor. | Colson, Yolonda L., editor. |
Rocco, Gaetano, MD, editor.
Title: Shields’ general thoracic surgery / [edited by] Joseph LoCicero III, Richard H. Feins, Yolonda
L. Colson, Gaetano Rocco.
Other titles: General thoracic surgery.
Description: 8th edition. | Philadelphia : Wolters Kluwer, [2019] | Preceded by General thoracic
surgery / edited by Thomas W. Shields… [et al.]. 7th ed. c2009. | Includes bibliographical
references and index.
Identifiers: LCCN 2017051947 | ISBN 9781975102241
Subjects: | MESH: Thoracic Surgical Procedures | Thoracic Neoplasms–surgery
Classification: LCC RD536 | NLM WF 980 | DDC 617.5/4059–dc23
LC record available at https://lccn.loc.gov/2017051947
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Dedication to Dr. Thomas W. Shields
This 8th edition of General Thoracic Surgery marks the first time Dr. Shields has not been an
active member of the editorial directors, yet his influence on the text remains strong. His lifelong
interest in lung cancer began in 1951 with a fellowship at the Palmer Memorial Hospital, the
cancer building that was part of Deaconess Hospital, now Beth Israel Deaconess Medical Center.
His experiences with the thoracic surgeon, dynamic and controversial Richard Overholt inspired
him to begin a lifelong study into thoracic lymphatic drainage and lesser pulmonary resections.
He traveled the globe gathering data from leading centers making strong bonds with many
international colleagues. Using this wealth of knowledge, he compiled the first edition of General
Thoracic Surgery published in 1972, updating it every few years.
Dr. Shields was a legend to the surgical students and residents of Northwestern University up to
the time of his death in 2010. His devotion to clear communication of thought made him a tough
taskmaster. His advocacy of evidence-based practice often made him a lightning rod among his
colleagues. We hope that this edition continues the tradition of enhancing our understanding and
practice of thoracic surgery through assimilation of knowledge and expertise from around the
world.
—JLIII
Dedication to Dr. Carolyn E. Reed, MD

This 8th edition of General Thoracic Surgery is dedicated in part to our friend and colleague, Dr.
Carolyn E. Reed who was an editor of the 7th edition and was working on this edition until her
untimely death.
Dr. Reed was an outstanding clinician, teacher, and researcher. Her impact on the field of
thoracic surgery was extraordinary. While maintaining a busy clinical practice at the Medical
University of South Carolina, she made a major impact on our knowledge of diseases of the chest
and how to treat them. She was an NIH-funded researcher and investigator on numerous
important national clinical trials. She served our specialty as the first woman chair of the
American Board of Thoracic Surgery and the first woman president of the Southern Thoracic
Surgical Association. Also, she served as vice-chair of the Residency Review Committee for
Thoracic Surgery, treasurer of the Society of Thoracic Surgeons, treasurer of Women in Thoracic
Surgery, council member of the American Association for Thoracic Surgery, board member of the
Joint Council for Thoracic Surgical Education and the Thoracic Surgery Foundation for Research
and Education. Posthumously, she was unanimously elected the first woman president of the
Society of Thoracic Surgeons.
After her love for providing care to her patients, Dr. Reed’s passion was imparting knowledge to
her students and residents. It is our hope that this edition of General Thoracic Surgery will make
a fitting completion to her obligations, which were such a large part of her life and that those
who use it will continue to experience the wonder of being her student.
—RHF
To my family and to all succeeding generations of knowledge-seeking, innovative healers around

the world to whom we entrust our future health.
—JLIII
To the men and women of Thoracic Surgery who have dedicated their lives to the treatment of
diseases of the chest. It is a specialty that has embraced the research and new technologies
required to serve our patients at the highest level and the spirit of professionalism that is the envy
of all of medicine. And to the teachers of Thoracic Surgery who devote themselves day in and day
out to ensuring that there will always be outstanding chest surgeons.
—RHF
To Gina and Raffaele, sempiternal source of energy and inspiration. Amor gignit amorem.
—GR
To my father for teaching me to dream big, my mother for making hard work and fortitude part of
my DNA, my patients for giving me purpose, my collaborator Mark Grinstaff for the gift of
creativity and friendship, my husband Gray for providing unlimited love and support and
believing in the impossible every day, my two daughters, Karinne and Azuri, and all of my
trainees for opening my eyes to the amazing potential of the next generation, and my special team
that keeps everything running and makes my work enjoyable.
—YLC
Contributing Authors
Ghulam Abbas, MD, MHCM, FACS
West Virginia University School of Medicine
Morgantown, West Virginia
Jay Acharya, MD
Assistant Professor
Department of Radiology
Keck Medicine of USC
Los Angeles, California
Usman Ahmad, MD
Assistant Professor of Surgery
Staff Surgeon, Thoracic Surgery
Cleveland Clinic
Cleveland, Ohio
Marco Alifano, MD, PhD
Full Professor
Department of Thoracic Surgery
Paris Descartes University
Paris Center University Hospital
Paris, France
Mark S. Allen, MD
Division of General Thoracic Surgery
Mayo Clinic
Rochester, Minnesota
Nasser K. Altorki, MB, BCh
Professor of Thoracic Surgery
Department of Cardiothoracic Surgery
Weill Cornell Medical College
New York Presbyterian Hospital
New York, New York
Isabel Alvarado-Cabrero, MD, PhD
Department of Pathology
Mexican Oncology Hospital, IMSS
Mexico City, Mexico
Rafael Andrade, MD, MHA
Associate Professor
Chief, Division of Thoracic and Foregut Surgery
University of Minnesota
Minneapolis, Minnesota
Marco Anile, MD, PhD
Associate Professor
Sapienza University of Rome
Rome, Italy
Beatrice Aramini, MD, PhD
Assistant Professor
Department of Medical and Surgical Sciences for Children and Adults
Division of Thoracic Surgery
University of Modena and Reggio Emilia
Modena, Italy
Saeed Arefanian, MD
General Surgery Resident
Department of Surgery
Washington University in St. Louis
St. Louis, Missouri
Amrita K. Arneja, MD
Neuroradiology Fellow
Mount Sinai Health System
New York, New York
Oscar Arrieta-Rodriguez, MD, MSc
Department Coordinator
Thoracic Oncology Unit
Instituto Nacional de Cancerología
México City, México
Hisao Asamura, MD
Chief
Keio University School of Medicine
Tokyo, Japan
Hugh G. Auchincloss, MD, MPH
Massachusetts General Hospital
Diego Avella Patino, MD
Division of Cardiac and Thoracic Surgery
University of Missouri
Columbia, Missouri
Lea Azour, MD
Assistant Professor
NYU Langone Medical Center
New York, New York
Carl L. Backer, MD
Northwestern University Feinberg School of Medicine
Division Head
Cardiovascular-Thoracic Surgery
Ann & Robert H. Lurie Children’s Hospital of Chicago
Chicago, Illinois
Patrick Bagan, MD
Head of Department
Unit of Thoracic and Vascular Surgery
Victor Dupouy Hospital
Argenteuil, France
Erin E. Bailey, MD
General Surgeon
Graham Health System
Canton, Illinois
Brian P. Barrick, MD, DDS
Professor
Department of Anesthesiology
Thomas L. Bauer II, MD
Associate Professor of Surgery
Hackensack Meridian School of Medicine at Seton Hall University
South Orange, New Jersey
Hackensack Meridian Health Jersey Shore University Medical Center
Neptune, New Jersey
Egidio Beretta, MD, PhD
Department of Medicine and Surgery
University of Milano-Bicocca
Milan, Italy
Edward J. Bergeron, MD
Munson Medical Center
Traverse City, Michigan
Laureline Berteloot, MD
Radiologist
Department of Pediatric Imaging
Necker-Enfants Malades Hospital
Paris, France
Sanjeev Bhalla, MD
Section Chief
Professor of Radiology
Cardiothoracic Imaging
Mallinckrodt Institute of Radiology
Washington University
St. Louis, Missouri
Shanda H. Blackmon, MD, MPH
Associate Professor
Mayo Clinic
Eugene H. Blackstone, MD
Head of Clinical Investigations
The Sydell and Arnold Miller Family Heart & Vascular Institute
Staff member
Department of Thoracic and Cardiovascular Surgery
Quantitative Health Sciences and Transplant Center
Cleveland Clinic
Cleveland, Ohio
Antonio Bobbio, MD, PhD
Praticien Hospitalier
Service de Chirurgie Thoracique
Hôpital Cochin, APHP
Paris, France
Daniel J. Boffa, MD
Associate Professor
Yale School of Medicine
New Haven, Connecticut
Timothy Brand, MD
Alejandro C. Bribriesco, MD
Associate Staff
Cleveland Clinic
Cleveland, Ohio
Lisa M. Brown, MD, MAS
Assistant Professor
UC Davis Health
Sacramento, California
Andrew Brownlee, MD
Fellow
Section of Cardiothoracic Surgery
University of Chicago Medicine
Chicago, Illinois
Alessandro Brunelli, MD
Consultant Thoracic Surgeon
Honorary Clinical Associate Professor
St. James’s University Hospital
Leeds, United Kingdom
Raphael Bueno, MD
Chief
Timothy F. Burns, MD, PhD
Assistant Professor
Department of Medicine
Division of Hematology Oncology
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Peter H. Burri, MD
Professor Emeritus of Anatomy
Institute of Anatomy
University of Bern
Bern, Switzerland
Bryan M. Burt, MD
Baylor College of Medicine
Houston, Texas
Shamus R. Carr, MD, FACS
Assistant Professor
University of Maryland School of Medicine
Baltimore, Maryland
Philip Carrott, MD
Assistant Professor
Section of Thoracic Surgery
University of Michigan
Ann Arbor, Michigan
Ernest G. Chan, MD
University of Pittsburgh Medical Center
Patrick G. Chan, MD
University of Pittsburgh Medical center
John Holt Chaney, MD
Attending Physician
Lexington, Kentucky
Andrew C. Chang, MD
John Alexander Distinguished Professor
Head of the Section of Thoracic Surgery
Ann Arbor, Michigan
Stephanie Chang, MD
Cardiothoracic Surgery Fellow
St. Louis, Missouri
Delphine L. Chen, MD
Associate Professor of Radiology, Medicine, and Biomedical Engineering
Mallinckrodt Institute of Radiology
Washington University School of Medicine
St. Louis, Missouri
Aaron M. Cheng, MD
Associate Professor
Co-Director
UWMC Cardiothoracic ICU
University of Washington
Seattle, Washington
Mala R. Chinoy, PhD, MBA
Professor
Department of Biochemistry and Molecular Biology
Penn State College of Medicine
Hershey, Pennsylvania
Priscilla Chiu, MD, PhD
Assistant Professor
University of Toronto
Staff Surgeon
Division of General and Thoracic Surgery
The Hospital for Sick Children
Toronto, Ontario, Canada
Cliff K. C. Choong, MBBS, FRCS, FRACS
Associate Professor in Surgery
Monash University School of Rural Health
Latrobe Regional Hospital
Victoria, Australia
Anna Maria Ciccone, MD, PhD
Assistant Professor
Rome, Italy
Graham A. Colditz, MD, DrPH
Niess-Gain Professor of Surgery
St. Louis, Missouri
Stéphane Collaud, MD, MSc
Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation
Paris-Sud University
Marie Lannelongue Hospital
Le Plessis-Robinson, France
Willy Coosemans, MD, PhD
Clinic Head
University Hospitals Leuven
Leuven, Belgium
Traves D. Crabtree, MD
Southern Illinois University School of Medicine
Springfield, Illinois
Gerard J. Criner, MD
Professor and Chair
Department of Thoracic Medicine and Surgery
Lewis Katz School of Medicine at Temple University
Philadelphia, Pennsylvania
Richard S. D’Agostino, MD
Assistant Clinical Professor of Cardiothoracic Surgery
Tufts University School of Medicine
Boston Massachusetts
Chair
Division of Thoracic and Cardiovascular Surgery
Lahey Hospital and Medical Center
Burlington, Massachusetts
Walid Leonardo Dajer-Fadel, MD
Associate Professor
General Hospital of Mexico
Mexico City, Mexico
Thomas D’Amico, MD
Gary Hock Endowed Professor of Surgery
Chief, Section of General Thoracic Surgery
Program Director, Thoracic Surgery
Duke University Medical Center
Durham, North Carolina
Gail E. Darling, MD, FRCSC
University Health Network, Toronto General Hospital
Philippe Dartevelle, MD
Professor of Thoracic and Cardiovascular Surgery
University Paris Sud
Hiroshi Date, MD
Professor and Chairman
Kyoto University Graduate School of Medicine
Kyoto, Japan
Jonathan D’Cunha, MD, PhD
Vice Chairman
Research and Education
Chief
Division of Lung Transplantation/Lung Failure
Surgical Director, ECMO
Program Director
Thoracic Surgery Traditional Residency
Program Director
Advanced Lung/Heart Failure Fellowship
Herbert Decaluwé, MD, PhD
Leuven, Belgium
Malcolm M. DeCamp, MD
Fowler McCormick Professor of Surgery
Northwestern Memorial Hospital
Chicago, Illinois
Tracey Dechert, MD, FACS
Boston University School of Medicine
Division of Trauma and Surgical Critical Care
Boston Medical Center
Sebastián Defranchi, MD, MBA
Staff General Thoracic Surgeon
Chair, Patient Safety Department
Chair, Support Services Department
Hospital Universitario Fundación Favaloro
Ciudad de Buenos Aires, Argentina
Pierre Delaere, MD, PhD
Professor
Department of ENT, Head and Neck Surgery
Leuven, Belgium
Paul De Leyn, MD, PhD
Professor
Chief, Department of Surgery
Leuven, Belgium
Lorenzo Del Sorbo, MD
Assistant Professor
Interdepartmental Division of Critical Care Medicine
Steven R. DeMeester, MD
Thoracic and Foregut Surgery
Division of General and Minimally Invasive Surgery
The Oregon Clinic
Portland, Oregon
Todd L. Demmy, MD
Professor of Oncology
Roswell Park Cancer Institute
Professor
University of Buffalo, State University of New York
Buffalo, New York
Willem Adriaan den Hengst, MD, PhD
Resident
Department of Thoracic and Vascular Surgery
Antwerp University Hospital
Antwerp, Belgium
Chadrick E. Denlinger, MD
Associate Professor
Medical University of South Carolina
Charleston, South Carolina
Marc de Perrot, MD, MSc, FRCSC
Lieven P. Depypere, MD, FEBTS
Associate Clinical Head
Leuven, Belgium
Mathieu Derouet, PhD
Scientific Associate
University Health Network
Daniele Diso, MD, PhD
Associate Professor
Department of Thoracic Surgery,
Rome, Italy
Laura Donahoe, MD
Thoracic Surgeon
Toronto General Hospital
Dean M. Donahue, MD
Assistant Professor
Jessica S. Donington, MD, MSCR
Associate Professor
NYU School of Medicine
New York, New York
Frank D’Ovidio, MD, PhD
Associate Professor
Section General Thoracic Surgery
Columbia University
Attending Surgeon
NewYork-Presbyterian Hospital
New York, New York
Nigel E. Drury, PhD, FRCS(CTh)
Clinician Scientist & Consultant in Cardiothoracic Surgery
Birmingham Children’s Hospital
Birmingham, United Kingdom
Lingling Du, MD
Department of Hematology and Medical Oncology
Ochsner Clinic Foundation
New Orleans, Louisiana
Mark R. Dylewski, MD
Chief of Thoracic Surgery
Miami Cancer Institute
Baptist Health of South Florida
Miami, Florida
Janet Edwards, MD, MPH
Assistant Professor
Cumming School of Medicine at University of Calgary
Calgary, Alberta
Melanie A. Edwards, MD
Assistant Professor
Saint Louis University School of Medicine
Saint Louis, Missouri
Dominic Emerson, MD
Fellow
Cardiac Surgery
Cedars-Sinai Medical Center
Elie Fadel, MD, PhD
Chief
Hopital Marie Lannelongue and Université Paris Sud
Pierre-Emmanuel Falcoz, MD, PhD, FECTS
Strasbourg University Hospital
Strasbourg, France
Farhood Farjah, MD, MPH
Associate Professor
Seattle, Washington
Richard H. Feins, MD
Stanley C. Fell†
Professor of Cardiothoracic Surgery
Albert Einstein College of Medicine
Bronx, New York
Mark K. Ferguson, MD
Professor
University of Chicago Pritzker School of Medicine
Chicago, Illinois
Felix G. Fernandez, MD, MSc
General Thoracic Surgery
Emory University School of Medicine
Atlanta, Georgia
Hiran C. Fernando, MBBS, FRCS
Virginia Commonwealth University
Richmond, Virginia
Inova Fairfax Medical Campus
Falls Church, Virginia
Pasquale Ferraro, MD
Professor
Chief
Alfonso Minicozzi and Family Chair in Thoracic Surgery and Lung Transplantation
Centre Hospitalier de l’Université de Montréal
Montreal, Quebec
Raja M. Flores, MD
Chairman and Professor
Icahn School of Medicine at Mount Sinai
New York, New York
Seth Force, MD
Professor
Atlanta, Georgia
Richard K. Freeman, MD, MBA
System Chief Medical Officer
St Vincent Health
Indianapolis, Indiana
Joseph S. Friedberg, MD, FACS
Professor
University of Maryland School of Medicine
Thoracic Surgeon-in-Chief
University of Maryland Medical System
Baltimore, Maryland
Henning A. Gaissert, MD
Visiting Surgeon
Sidhu P. Gangadharan, MD
Chief
Division of Thoracic Surgery and Interventional Pulmonology
Beth Israel Deaconess Medical Center
Perry Gerard, MD, FACR
Professor of Radiology and Medicine
Vice Chairman of Radiology
Director of Radiology IT
New York Medical College
Director of Nuclear Medicine and PET-CT
Westchester Medical Center
Valhalla, New York
Rafael Garza-Castillon, MD
Thoracic Surgery Fellow
Ritu R. Gill, MD, MPH
Assistant Professor
Erin A. Gillaspie, MD
Assistant Professor
Vanderbilt University Medical Center
Nashville, Tennessee
Jason P. Glotzbach, MD
Assistant Professor
University of Utah
Salt Lake City, Utah
Diego Gonzalez-Rivas, MD, FECTS
Director Uniportal VATS Training Program
Shanghai Pulmonary Hospital
Shanghai, China
Andrei-Bogdan Gorgos, MD
Associate Professor
University of Montreal
Montreal, Quebec
Dominique Gossot, MD
Head of Thoracic Department—IMM
Curie-Montsouris Thorax Institute
Paris, France
Ramaswamy Govindan, MD
Professor of Medicine
Anheuser-Busch Endowed Chair in Medical Oncology
Director, Section of Oncology
Division of Oncology
St. Louis, Missouri
Gabriele Simone Grasso, MD
University of Milano-Bicocca
Milan, Italy
Christina L. Greene, MD
Integrated Cardiac Resident
Stanford University School of Medicine
Standford, California
Yosef Jose Greenspon, MD, FACS, FAAP
Assistant Professor
Department of Pediatrics
Division of Surgery
Cardinal Glennon Children’s Hospital
St. Louis University School of Medicine
St. Louis, Missouri
Sean C. Grondin, MD, MPH, FRCSC, FACS
Professor and Head
Calgary Zone Clinical Department Head
Alberta Health Services
Foothills Medical Centre
Calgary, Alberta
Federica Grosso, MD
Department of Oncology
SS Antonio e Biagio General Hospital
Alessandria, Italy
Shawn S. Groth, MD, MS
Assistant Professor
Houston, Texas
Dominique Grunenwald, MD, PhD
Professor Emeritus
Pierre and Marie Curie University
Paris, France
Claude Guinet, MD
Radiologist
Paris Center University Hospital
Paris, France
Julian Guitron, MD
Associate Professor
University of Cincinnati
Cincinnati, Ohio
Jinny S. Ha, MD
Johns Hopkins Hospital
Baltimore, Maryland
Hironori Haga, MD
Kyoto University Hospital
Kyoto, Japan
Semih Halezeroğlu, MD, FETCS
Professor and Chief
Acibadem University School of Medicine
Istanbul, Turkey
Matthew G. Hartwig, MD, MHS
Duke University Health System
Dominik Harzheim, MD
Department of Pneumology and Critical Care
Thoraxklinik, University of Heidelberg
Heidelberg, Germany
Stephen Hazelrigg, MD
Mark W. Hennon, MD
Assistant Professor
University at Buffalo, State University of New York
Assistant Professor of Oncology
Buffalo, New York
Claudia I. Henschke, PhD, MD
New York, New York
Felix J. F. Herth, MD, PhD, FCCP, FERS
CMO
Department of Pneumology and Critical Care Medicine
Thoraxklinik, University of Heidelberg
Heidelberg, Germany
Nicholas R. Hess, MD
Resident
Maxime Heyndrickx, MD
University Hospital of Caen
Caen, France
Wayne Hofstetter, MD
Professor of Surgery and Deputy Chair
University of Texas MD Anderson Cancer Center
Houston, Texas
Young K. Hong, MD
Surgical Oncology and Hepatopancreatobiliary Fellow
Louisville, Kentucky
Yinin Hu, MD
Resident
University of Virginia
Charlottesville, Virginia
James Huang, MD
Associate Attending Surgeon
Thoracic Service, Department of Surgery
Memorial Sloan Kettering Cancer Center
New York, New York
Miriam Huang, MD
Clinical Assistant Professor
Jacobs School of Medicine & Biomedical Sciences
University of Buffalo
Buffalo, New York
Charles B. Huddleston, MD
Professor
St. Louis University School of Medicine
St. Louis, Missouri
Jessica L. Hudson, MD, MPHS
Surgical Resident
St. Louis, Missouri
Mark D. Iannettoni, MD, MBA
W. Randolph Chitwood, Jr., MD, Distinguished Chair in Cardiovascular Sciences
Professor and Chief
Division of Thoracic and Foregut Surgery
Program Director
Thoracic Surgery Residency
Chief
Cardiovascular Service Line
East Carolina Heart Institute at Vidant Medical Center
Greenville, North Carolina
Carlos Ibarra-Pérez, MD
Master and Doctor in Medical Sciences
University of México
Honorary Consultant in Thoracic Surgery
Instituto Nacional de Cardiología Ignacio Chavez
México City, Mexico
Kendra Iskander, MD, MPH
General Surgeon
St. Joseph Hospital
Eureka, California
Dawn E. Jaroszewski, MD, MBA, FACS
Mayo Clinic
Phoenix, Arizona
Leila Jazayeri, MD
Plastic and Reconstructive Surgeon
Kaiser Permanente San Leandro Medical Center
San Leandro, California
Scott B. Johnson, MD
Division Chief, General Thoracic Surgery
UT Health San Antonio
San Antonio, Texas
David W. Johnstone, MD
Medical College of Wisconsin
Milwaukee, Wisconsin
David R. Jones, MD
Professor and Chief
Thoracic Surgery Service
Fiona and Stanly Druckenmiller Chair for Lung Cancer Research
New York, New York
Erkan Kaba, MD
Assistant Professor
Istanbul Bilim University
Istanbul, Turkey
Mohamed K. Kamel, MD
Clinical Fellow
New York, New York
Neil Kapadia, MD
Assistant Professor
Temple University
Brian J. Karlovits, DO
Director of Clinical Operations
Assistant Professor
Department of Radiation Oncology
UPMC Hillman Cancer Center—Shadyside
Shaf Keshavjee, MD, FRCSC, FACS
Professor, Division of Thoracic Surgery
James Wallace McCutcheon Chair in Surgery
Surgeon in Chief
Onkar V. Khullar, MD
Assistant Professor
Atlanta, Georgia
Biniam Kidane, MD, MSc, FRCSC
Assistant Professor
University of Manitoba
Winnipeg, Manitoba
Min P. Kim, MD
Associate Professor
Houston Methodist Hospital
Houston, Texas
Jacob A. Klapper, MD
Duke University Hospital
Patrick Kohtz, MD
Resident
University of Colorado Anschutz Medical Campus
Aurora, Colorado
Rupesh Kotecha, MD
Cleveland Clinic, Taussig Cancer Institute
Cleveland, Ohio
Miami Cancer Institute
Baptist Health South Florida
Miami, Florida
Vasileios Kouritas, MD, PhD, CTh
Cardiothoracic Surgeon
Benjamin D. Kozower, MD, MPH
Professor
St. Louis, Missouri
Seth B. Krantz, MD
NorthShore University HealthSystem
Evanston, Illinois
Clinical Assistant Professor
University of Chicago Pritzker School of Medicine
Chicago, Illinois
Mark J. Krasna, MD
Clinical Professor of Surgery
Rutgers New Jersey Medical School
Newark, New Jersey
Hackensack Meridian School of Medicine at Seton Hall University
South Orange, New Jersey
Daniel Kreisel, MD, PhD
Professor of Surgery, Pathology and Immunology
Surgical Director, Lung Transplant Program
St. Louis, Missouri
Alexander Krupnick, MD
Division of CT Surgery
Kiran Lagisetty, MD
Assistant Professor
Ann Arbor, Michigan
Francesca Lanfranconi, MD, PhD
Research Officer
Institute of Sport, Exercise and Active Living (ISEAL)
Victoria University
Melbourne, Australia
Jacob C. Langer, MD
Pediatric Surgeon
The Hospital for Sick Children
Nathaniel B. Langer, MD, MSc
Michael Lanuti, MD
Director of Thoracic Oncology
Rossano Lattanzio, MD, PhD, Dr.
Researcher
Department of Medical, Oral and Biotechnological Sciences
University “G. d’Annunzio”
Chieti, Italy
Christine Lau, MD, MBA
Kelvin Lau, MA(Oxon), DPhil(Oxon), FRCS(CTh)
St. Bartholomew’s Hospital
London, United Kingdom
Richard S. Lazzaro, MD, FACS
Associate Professor of Cardiothoracic Surgery
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Chief
Lenox Hill Hospital
Director, Robotic Thoracic Surgery
Northwell Health
New York, New York
Dong-Seok Daniel Lee, MD
Assistant Professor
New York, New York
Toni Lerut, MD, PhD
Emeritus Professor of Surgery
Emeritus Chairman, Department of Thoracic Surgery
University Hospitals Leuven, Gasthuisberg Campus
Leuven, Belgium
Gunda Leschber, MD
Head of Department of Thoracic Surgery
ELK Berlin Chest Hospital
Berlin, Germany
Kunwei Li, MD
New York, New York
Moishe Liberman, MD, PhD
Director, CETOC
University of Montreal
Montreal, Quebec
Michael J. Liptay, MD
Department of Cardiovascular and Thoracic Surgery
Rush University Medical Center
Chicago, Illinois
Virginia R. Litle, MD
Boston University
Joseph LoCicero III, MD
SUNY Downstate Medical Center
Brooklyn, New York
Consultant
Mobile County Health Department
Mobile, Alabama
Jason Michael Long, MD, MPH
Assistant Professor
UNC Medical Center
Christine Lorut, MD
Unit of Pneumology
Paris, France
Donald E. Low, MD, FACS, FRCS(C)
Head of Thoracic Surgery and Thoracic Oncology
Department of General, Thoracic and Vascular Surgery
Virginia Mason Medical Center
Seattle, Washington
James D. Luketich, MD, FACS
Henry T. Bahnson Professor and Chairman
Chief, Division of Thoracic and Foregut Surgery
Audrey Lupo, MD, PhD
Hôpitaux Universitaires Paris Centre
Paris, France
Ronson J. Madathil, MD
Acting Assistant Professor
Seattle, Washington
Mitchell J. Magee, MD, MS
Chief
Medical City Dallas Hospital
Dallas, Texas
Raja Mahidhara, MD
Thoracic Surgery
St Vincent Health
Indianapolis, Indiana
J. Shawn Mallery, MD
Associate Professor of Medicine
Division of Gastroenterology, Hepatology and Nutrition
University of Minnesota
Minneapolis, Minnesota
Mirella Marino, MD
Regina Elena National Cancer Institute
Rome, Italy
M. Blair Marshall, MD, FACS
MedStar Georgetown University Hospital
Washington, District of Columbia
Gilbert Massard, MD
Professor
Department of Thoracic Surgery and Lung Transplantation
Strasbourg, France
Douglas J. Mathisen, MD
Hermes C. Grillo Professor of Surgery
Chief
General Thoracic Surgery
Giulio Maurizi, MD
Sant’Andrea Hospital
Rome, Italy
Donna E. Maziak, MDCM, MSc, FRCSC, FACS
Professor
University of Ottawa
Surgical Oncology Division of Thoracic Surgery
Ottawa Hospital—General Campus
Ottawa, Ontario
Daniel P. McCarthy, MD, MBA
Assistant Professor
University of Wisconsin
Madison, Wisconsin
Paul Michael McFadden, MD
Professor of Clinical Cardiothoracic Surgery
Surgical Co-Director of Lung Transplantation
University of Southern California
Rachel L. Medbery, MD
Thoracic Surgery Fellow
Atlanta, Georgia
Robert A. Meguid, MD, MPH, FACS
Associate Professor
Section of General Thoracic Surgery
Aurora, Colorado
Babak J. Mehrara, MD
Professor and Chief, Plastic and Reconstructive Surgery Service
William G. Cahon Chair in Surgery
New York, New York
Steven J. Mentzer, MD
Robert E. Merritt, MD
Director
The Division of Thoracic Surgery
The Ohio State UnviersityWexner Medical Center
Columbus, Ohio
Giuseppe Miserocchi, MD
Professor of Physiology and Biophysics
University Milano-Bicocca
Milan, Italy
John D. Mitchell, MD
Courtenay C. and Lucy Patten Davis Endowed Chair in Thoracic Surgery
Professor and Chief, Section of General Thoracic Surgery
Aurora, Colorado
Kamran Mohiuddin, MD
Director Clinical Research
Einstein Medical Center
Elie Mouhayar, MD
Associate Professor of Medicine
Department of Cardiology
Houston, Texas
Michael S. Mulligan, MD
Chief
Seattle, Washington
Michael S. Mulvihill, MD
Resident in Surgery
Sudish C. Murthy, MD, PhD, FACS, FCCP
Cleveland Clinic
Cleveland, Ohio
Philippe Nafteux, MD, PhD
Clinical Head
Leuven, Belgium
Chaitan K. Narsule, MD
Assistant Professor
Boston University School of Medicine
Basil Nasir, MBBCh
Centre Hospitalier de l’Université de Montréal
Montreal, Quebec
Keith S. Naunheim, MD
The Vallee and Melba Willman Chair of Surgery
St. Louis, Missouri
Calvin S. H. Ng, BSc, MD, FRCSEd(CTh), FCCP
Associate Professor
The Chinese University of Hong Kong
Hong Kong, SAR, China
Daniel G. Nicastri, MD
Assistant Professor
New York, New York
Francis C. Nichols, MD
Consultant General Thoracic Surgery
Mayo Clinic
David M. Notrica, MD, FACS, FAAP
Associate Professor
University of Arizona College of Medicine
Tuscan, Arizona
Mayo Clinic School of Medicine
Division of Pediatric Surgery
Phoenix Children’s Hospital
Phoenix, Arizona
Daniel Ocazionez, MD
Assistant Professor
Department of Diagnostic and Interventional Imaging
University of Texas HSC at Houston
Houston, Texas
Matthias Ochs, MD
Professor and Chair
Institute of Functional and Applied Anatomy
Hannover Medical School
Hannover, Germany
John A. Odell, MBChB, FRCS(Ed), FACS
Emeritus Professor of Surgery
Mayo Clinic
Jacksonville, Florida
Amaia Ojanguren, MD, PhD
University of Lleida
Arnau de Vilanova University Hospital
Lleida, Spain
Institut Catala de la Salut
Barcelona, Spain
Anne Olland, MD, PhD
Associate Professor
Strasbourg, France
Mark Onaitis, MD
University of California San Diego
La Jolla, California
Raymond P. Onders, MD
Professor and Chief of General Surgery
Case Western Reserve University School of Medicine
University Hospitals Cleveland Medical Center
Cleveland, Ohio
Isabelle Opitz, MD
Associate Professor
University Hospital Zurich
Zurich, Switzerland
Asishana Osho, MD, MPH
Clinical Fellow
Berker Özkan, MD
Associate Professor
Istanbul Medical School
Istanbul University
Istanbul, Turkey
Siddharth Padmanabhan, MBBS, LLB, BCom
Resident
Latrobe Regional Hospital
Victoria, Australia
Hao Pan, MD
Chief Resident
San Antonio, Texas
Kostas Papagiannopoulos, MD, MMED THORAX (CTH)
Honorary Senior Lecturer
Leeds University
Nadeem Parkar, MD
Chief
Section of Thoracic and Cardiac Imaging
Assistant Professor of Radiology
Assistant Professor of Internal Medicine
Saint Louis, Missouri
G. Alexander Patterson, MD
Joseph C. Bancroft Professor of Surgery
St. Louis, Missouri
Edoardo Pescarmona, MD
Regina Elena National Cancer Institute
Rome, Italy
Adrienne A. Phillips, MD, MPH
Assistant Professor of Medicine
Division of Hematology and Medical Oncology
New York, New York
Joseph D. Phillips, MD
Assistant Professor
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire
Anthony L. Picone, MD, PhD, MBA
Professor of Oncology
Buffalo, New York
Eitan Podgaetz, MD, MPH, FACS
Associate Professor
Texas A&M University
Director of Minimally Invasive Thoracic Surgery
Center for Thoracic Surgery
Baylor University Medical Center
Dallas, Texas
Cecilia Pompili, MD
Thoracic Surgeon
Leeds Institute of Cancer and Pathology
University of Leeds
St James’s University Hospital
Jeffrey L. Port, MD
Professor of Clinical Cardiothoracic Surgery
Associate Attending
New York, New York
Ciprian Pricopi, MD
Georges Pompidou European Hospital
Paris, France
Varun Puri, MD, MSCI
Associate Professor
St. Louis, Missouri
Joe B. Putnam, Jr., MD, FACS
Medical Director
Baptist MD Anderson Cancer Center
Jacksonville, Florida
Siva Raja, MD, PhD, FACS
Professional Staff, Thoracic Surgery
Surgical Director, Center for Esophageal Diseases
Heart and Vascular Institute
Cleveland Clinic Foundation
Cleveland, Ohio
Arvind Rajagopal, MBBS
Assistant Professor
Department of Anesthesiology
Chicago, Illinois
Ravi Rajaram, MD, MSc
General Surgery Resident
Chicago, Illinois
Pala Babu Rajesh, FRCS Ed, FRCS CTh, FRCS Eng
Regional Department of Thoracic Surgery
Birmingham Heartlands Hospital
Birmingham, United Kingdom
Prabhakar Rajiah, MBBS, MD, FRCR
Associate Professor of Radiology
Associate Director of Cardiac CT and MRI
Department of Radiology, Cardiothoracic Radiology
UT Southwestern Medical Center
Dallas, Texas
Karthik Ravi, MD
Department of Gastroenterology and Hepatology
Mayo Clinic
Rishindra M. Reddy, MD
Associate Professor
Department of Surgery, Section of Thoracic Surgery
Ann Arbor, Michigan
James Regan, MD
Jean-François Regnard
Head
Paris Descartes University
Paris, France
Janani S. Reisenauer, MD
Department of Pulmonary Medicine
Mayo Clinic
Erino A. Rendina, MD
Rome, Italy
Carlos S. Restrepo
Professor of Radiology
Director of Cardiothoracic Radiology
San Antonio, Texas
David Rice, MB, BCh, BAO, FRCSI
Houston, Texas
Thomas W. Rice, MD
Professor
Cleveland Clinic Lerner College of Medicine
Section Head, Department of Thoracic Surgery
Cleveland Clinic
Cleveland, Ohio
Marc Riquet, MD, PhD
Professor
Georges Pompidou European Hospital
Paris, France
Valerie W. Rusch, MD
Professor
Chief, Thoracic Service
William G. Cahan Chair
Memorial Sloan-Kettering Cancer Center
New York, New York
Michele Salati, MD, PhD
Unit of Thoracic Surgery
University Hospital Ancona United Hospitals
Ancona, Italy
Mary Salvatore, MD
Associate Professor
New York, New York
Pamela Samson, MD
Resident Physician
St. Louis, Missouri
Nicola Santelmo, MD
Hôpital Civil de Strasbourg
Strasbourg, France
Inderpal (Netu) S. Sarkaria, MD
Vice Chairman, Clinical Affairs
Giorgio V. Scagliotti
Professor of Medical Oncology
Department of Oncology
University of Turin
Torino, Italy
Eric Sceusi, MD
Thoracic Surgeon
Piedmont Heart Institute
Atlanta, Georgia
Lara Schaheen, MD
Chief Resident
Philip Maximilian Scherer, MD
Assistant Professor of Radiology
University of Central Florida College of Medicine
Florida Hospital
Orlando, Florida
Radiology Specialists of Florida
Maitland, Florida
Colin Schieman, MD, FRCSC
Clinical Associate Professor
Residency Program Director
Calgary, Alberta
David S. Schrump, MD, MBA, FACS
Senior Investigator and Chief
Thoracic and General Surgical Oncology Branch
Center for Cancer Research
National Cancer Institute
Bethesda, Maryland
Matthew J. Schuchert, MD
Associate Professor
Christopher W. Seder, MD
Assistant Professor
Rush University Medical School
Chicago, Illinois
Agathe Seguin-Givelet, MD, PhD
Department of Thoracic
Curie-Montsouris Thorax Institute
Paris, France
Joanna Sesti, MD
Robert Wood Johnson Barnabas Health System
Livingston, New Jersey
Farid M. Shamji, MBBS, FRCSC, FACS
University of Ottawa
Ottawa Hospital—General Campus
Ottawa, Ontario, Canada
Jason P. Shaw, MD
Chief
Department of General Thoracic Surgery
Maimonides Medical Center
Brooklyn, New York
David D. Shersher, MD
Assistant Professor
Cooper Medical School of Rowan University
MD Anderson Cancer Center
Camden, New Jersey
Thomas W. Shields, MD, DSc (Hon.)†
Chicago, Illinois
Joseph B. Shrager, MD
Professor of Cardiothoracic Surgery
Stanford University School of Medicine
Stanford Cancer Institute
Stanford, California
Antonios C. Sideris
Research Fellow
Resident
Department of General Surgery
Cleveland Clinic Foundation
Cleveland, Ohio
Alan D. L. Sihoe, MA(Cantab), FRCSEd(CTh), FCSHK, FHKAM, FCCP
The University of Hong Kong
HKU Shenzhen Hospital
Hong Kong, China
Mark A. Socinski, MD
Executive Medical Director
Member, Thoracic Oncology Program
Florida Hospital Cancer Institute
Orlando, Florida
Joshua R. Sonett, MD
Professor and Chief
Thoracic Surgery
Columbia University
New York, New York
Nathaniel J. Soper, MD, FACS
Loyal and Edith Davis Professor and Chair
Chief of Surgery
Northwestern Medicine
Chicago, Illinois
James E. Speicher, MD
Assistant Professor
Department of Cardiovascular Sciences
Division of Thoracic and Foregut Surgery
East Carolina University
Greenville, North Carolina
Jonathan D. Spicer, MD, PhD, FRCS
Assistant Professor
Dr. Ray Chiu Distinguished Scientist in Surgical Research
McGill University
Montreal, Canada
Laurence N. Spier
Chief
NYU-Winthrop University Hospital
Mineola, New York
Sandra Starnes, MD
John B. Flege Chair in Cardiothoracic Surgery
University of Cincinnati College of Medicine
Cincinnati, Ohio
Kevin L. Stephans, MD
Associate Professor
Cleveland Clinic, Taussig Cancer Center
Cleveland, Ohio
Joel Miller Sternbach, MD, MBA
Bechily-Hodes Fellow in Esophagology
Northwestern University, Feinberg School of Medicine
Chicago, Illinois
Hon Chi Suen, MBBS, FRCSEd, FRCS, RCPS(Glasg), FCSHK, FACS, DABThS, DABS
President
Center for Cardiothoracic Surgery, Inc.
St. Louis, Missouri
David J. Sugarbaker, MD
Professor and Chief
Houston, Texas
Kei Suzuki, MD
Assistant Professor
Boston Medical Center
Scott J. Swanson, MD
Director
Minimally Invasive Thoracic Surgery
Vice Chair
Cancer Affairs
Chief Surgical Office
Dana Farber Cancer Institute
Gunturu N. Swati, MD
Government Medical College Akola
Visiting student
Icahn School of Medicine at Mount Sinai Hospital
New York, New York
Ezra N. Teitelbaum, MD, MEd
Assistant Professor of Surgery and Medical Education
Northwestern University, Feinberg School of Medicine
Chicago, Illinois
Sara Tenconi, MD
Sheffield Teaching Hospitals
United Kingdom
Michael Thomas, MD
Assistant Professor
Pascal A. Thomas, MD
Professor and Chief
North University Hospital–Aix-Marseille University
Marseille, France
Prashanthi N. Thota, MD, FACG
Medical Director
Esophageal Center
Director
Center for Swallowing and Motility Disorders
Digestive Disease & Surgery Institute
Cleveland Clinic
Cleveland, Ohio
Alper Toker, MD
Head
Istanbul University, Istanbul Faculty of Medicine
Istanbul, Turkey
Victor F. Trastek, MD
Director of Science of Healthcare Delivery
College of Healthcare Solutions
Arizona State University
Phoenix, Arizona
Consultant in Leadership and Professionalism
Mayo Clinic
Scottsdale, Arizona
H. Adam Ubert, MD
Attending Cardiothoracic Surgeon
Department of Cardiovascular Medicine
Charleston Area Medical Center
Charleston, West Virginia
Eric Vallières, MR, FRCSC
Surgical Director of the Lung Cancer Program
Medical Director
Swedish Cancer Institute
Seattle, Washington
Victor van Berkel, MD, PhD
Associate Professor
University of Louisville School of Medicine
Louisville, Kentucky
Koen van Besien, MD, PhD
Director, Stem Cell Transplant Program
Division of Hematology/Oncology
New York, New York
Dirk Van Raemdonck, MD, PhD
KU Leuven University
Head of Transplant Center
Leuven, Belgium
Paul E. Y. Van Schil, MD, PhD
Chair
Department of Thoracic and Vascular Surgery
Antwerp University Hospital and Antwerp University
Antwerp, Belgium
Hans Van Veer, MD
Assistant Clinic Head
Leuven, Belgium
Ara A. Vaporciyan, MD, FACS
Houston, Texas
Nirmal K. Veeramachaneni, MD
University of Kansas Medical Center
Kansas City, Kansas
Federico Venuta, MD
Professor of Thoracic Surgery and Chief
Policlinico Umberto I
Rome, Italy
Gregory Videtic, MD, CM, FRCPC, FACR
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Staff Physician
Cleveland Clinic
Cleveland, Ohio
Carlos Vigliano, MD
Associate Professor
Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB)
Favaloro University–CONICET
Chief
University Hospital Favaloro Foundation
Buenos Aires, Argentina
Liza Villaruz, MD
Robin Vos, MD, PhD
Department of Respiratory Medicine, Lung Transplant and Respiratory Intermediate Care Unit University
Hospitals Leuven, Gasthuisberg Campus
Department of Chronic Diseases, Metabolism and Ageing (CHROMETA)
Lab of Respiratory Diseases, KU
Leuven, Belgium
David Waller, FRCS(CTh)
St. Bartholomew’s Hospital
London, United Kingdom
Garrett L. Walsh, MD
Houston, Texas
Saiama N. Waqar, MBBS, MSCI
Division of Oncology
St. Louis, Missouri
William H. Warren, MD†
Professor
Department of Cardiovascular Surgery
Chicago, Illinois
Thomas J. Watson, MD, FACS
Georgetown University School of Medicine
Regional Chief of Surgery
MedStar Washington
Jon O. Wee, MD
Section Chief, Esophageal Surgery
Co-Director of Minimally Invasive Thoracic Surgery
Director of Robotics in Thoracic Surgery
Ewald R. Weibel, MD, DSc(hon)
Professor Emeritus
Institute of Anatomy
University of Bern
Bern, Switzerland
Mark Weir, MBChB
Assistant Professor
Department of Thoracic Medicine and Surgery
Lewis Katz School of Medicine at Temple University
Michael J. Weyant, MD
University of Colorado
Aurora, Colorado
Abby White, DO
Ory Wiesel, MD
Clinical Fellow
Dennis A. Wigle, MD, PhD
Associate Professor
Division of General Thoracic Surgery
Mayo Clinic
Elbert E. Williams, MD
New York, New York
Jennifer L. Wilson, MD
Instructor of Surgery
Douglas E. Wood, MD, FACS, FRCSEd
The Henry N. Harkins Professor and Chair
Seattle, Washington
Neil McIver Woody, MD, MS
Associate Staff
Cleveland Clinic, Taussig Cancer Institute
Cleveland, Ohio
Cameron Wright, MD
Douglas Mathisen Professor of Surgery
Moritz C. Wyler von Ballmoos, MD, PhD, MPH, FACC
Clinical Associate in Surgery
Alexander Yang, MS
MD Candidate, Class of 2020
GW School of Medicine and Health Sciences
Chi-Fu Jeffrey Yang, MD
Resident
Duke University
Stephen C. Yang, MD
The Arthur B. and Patricia B. Modell Endowed Chair in Thoracic Surgery
Professor of Surgery and Oncology
The Johns Hopkins Medical Institutions
Baltimore, Maryland
David Yankelevitz, MD
Professor
Icahn School of Medicine
New York, New York
Anjana Yeldandi, MD
Associate Professor of Pathology
Northwestern Memorial Hospital
Feinberg Pavilion
Chicago, Illinois
Sai Yendamuri, MD, FACS
Professor and Chair
Buffalo, New York
Jonathan C. Yeung, MD, PhD, FRCSC
Assistant Professor
Toronto, Ontario
Akihiko Yoshizawa, MD, PhD
Associate Professor
Department of Diagnostic Pathology
Kyoto University Hospital
Kyoto, Japan
Masaya Yotsukura, MD
Assistant
Keio University School of Medicine
Tokyo, Japan
David S. Younger, MD, MPH, MS
Department of Neurology
School of Medicine and College of Global Public Health
New York University
New York City, New York
Yachao Zhang, MD
Westchester Medical Center
Valhalla, New York
Ze-Rui Zhao, MD
Prince of Wales Hospital
Hong Kong, China
Yifan A. Zheng, MD
Resident
Brittany A. Zwischenberger, MD
Division of Cardiovascular and Thoracic Surgery
Duke University
Joseph “Jay” B. Zwischenberger, MD
Johnston-Wright Professor and Chairman
University of Kentucky
Lexington, Kentucky

†Deceased
Preface to the Eighth Edition
In the foreword to the first edition of General Thoracic Surgery published in 1972, Paul Samson noted
that Shields published a text dedicated to the General Thoracic Surgeon to the exclusion of the heart. That
occurred at a time when the “romance and appeal which have attended the astounding developments in the
surgical treatment of cardiac disease” was skyrocketing.
During the next 40 years of cardiac surgical dominance on the international stage, Shields’ book
remained focused on the diseases of the lungs, esophagus, chest wall, diaphragm, and mediastinum. The
first text, penned by 58 specialists, was encyclopedic in scope and depth. Students and practitioners of
this specialty needed no other book. Through its many editions, it carried the same thorough approach and
served as the de facto bible of the specialty.
Over the decades, other books, atlases and manuals on General Thoracic Surgery have come and gone,
but this book has remained the only comprehensive text in continuous publication for the practitioner of
thoracic diseases, excluding the heart and great arteries.
In the current digital age, seekers of knowledge no longer rely solely on the static text. They often
begin their search for information by scouring the Internet for a variety of media for articles, videos,
meeting reports, videos and other tidbits to understand the nuances of a particular disease or procedure.
While more dynamic than searching the texts of old, these searches often are hampered by search terms,
are disorganized, narrow in scope, and evanescent.
Now, 45 years after the first publication, this edition of Shields’ General Thoracic Surgery is written
by over 150 specialists. It has shed its encyclopedic tradition while maintaining its completeness. It
includes dynamic audio and visual content, color coordinated graphics, and analyses of the world’s
literature and electronic data for the most extensive and concise collection of information for the busy
clinician.
For the first time, the edition includes a retrospective into the past with particular attention to the
milestones of artificial ventilation and the era of minimal invasion, both of which revolutionized the
century-old specialty. It also addresses new topics such as deciphering complex statistical analyses, using
efficiently the new World Health Organization’s International Classification of Diseases (ICD-10), mining
big data sets for specific decision making, and developing and performing effective quality improvement
projects for the surgeon’s practice and hospital setting.
Long-time users of Shields will enjoy the continued comprehensiveness of the chapters. Millennial
practitioners will find this transformed edition less ponderous and intimidating than the tomes of the past,
yet more thorough and meaningful than imprecise, often fragmented individual electronic searches.
Preface to the First Edition
This volume was prepared to present a comprehensive text on the surgical diseases of the chest wall,
pleura, diaphragm, trachea, lung, and mediastinal structures. Initially, an overview of the anatomy and of
the physiology of these structures is given. The investigation of the patient’s disease and the management
of the patient in the perioperative period are considered next. The various operative approaches and the
standard surgical procedures are discussed and these are followed by chapters concerned with the
disease entities of the aforementioned structures. The major objectives are to present a summation of the
current knowledge and the clinical concepts of the surgical management of trauma and diseases of the
thorax. The pathophysiologic alterations produced and the corrections of these by appropriate
intervention are emphasized throughout. Presentations of the clinical features, pathologic changes,
surgical management, operative results, and prognosis of the various disease states are included as an
integral part of the whole.
Outstanding surgeons, physicians, and scientists have cooperated in the preparation of the text. As with
most multi-authored books, repetition could not be completely eliminated; however, I have tried to keep it
at a minimum. In most instances, the repetition serves to emphasize important information relative to the
entire subject. Interestingly, conflicting statements are few, and only an occasional footnote has been
appended to point out such differences in opinion. This book hopefully will serve as a source of
information for the young thoracic surgeon and the person in surgical training. It also should serve as a
reference for surgeons, as well as physicians, outside the field of general thoracic surgery who wish to
ascertain the current views held by the specialty.
TWS
Acknowledgments
Any large textbook such as this one, an army of individuals is required to produce a quality work. The
editors appreciate the efforts of the publishers, the artists, and the printers assigned to this project.
Most of all, it is the volunteers who really make the text worthwhile. We thank the authors and co-
authors who composed the original content and those who updated the old content. In addition, we thank
their administrative assistants who participated in the production of the content.
In particular, the editors wish to acknowledge two volunteers who sacrificed a great deal of personal
time and expended their intellectual energy to improve the quality of the book.
From the inception of this edition, Bryan F. Meyers, MD has been a strong advocate and a driving
force. He participated in the development of the revised table of contents and in the editor discussions of
the revised chapter format. Most importantly, he helped recruit a number of national and international
authors.
Special thanks goes to Martha S. LoCicero, MD, who performed substantial copyediting duties in an
effort to make the text readable and relevant. She also provided the much needed advice and
encouragement over the long development phase of this project.
JLIII
Video List
Video 19.1 Pneumothorax.
Video 19.2 Sonographic signs of a pneumothorax.
Video 20.1 Technique of Videomediastinoscopy.
Video 34.1 Thoracoscopic left upper lobe wedge resection.
Video 34.2 Thoracoscopic right upper lobectomy.
Video 34.3 Thoracoscopic right middle lobectomy.
Video 34.4 Thoracoscopic right lower lobectomy.
Video 34.5 Thoracoscopic left upper lobectomy.
Video 34.6 Thoracoscopic left pneumonectomy.
Video 36.1 Non-intubated uniportal VATS right lower lobe wedge resection for colorectal metastasis.
Video 36.2 Manipulating and division of the left upper lobe bronchus during non-intubated uniportal
VATS left upper lobectomy for early stage non-small cell lung carcinoma.
Video 43.1 Ravitch procedure.
Video 74.1 Preoperative bronchoscopy of an adenoid cystic carcinoma of the lower trachea and carina.
Video 79.1 Correct development of the endarterectomy plane and distal extension of the endarterectomy
such that the specimen releases under gentle tension
Video 83.1 Bronchoscopic view in two patients with bronchiectasis.
Video 83.2 Three-port VATS lobectomy and lingulectomy for bronchiectasis.
Video 83.3 Uniportal VATS lobectomy and lingulectomy for bronchiectasis.
Video 83.4 Virtual bronchoscopy in middle lobe syndrome.
Video 83.5 Uniportal VATS middle lobectomy for middle lobe syndrome.
Video 91.1 Localization of intraparenchymal pulmonary nodules using direct intracavitary thoracoscopic
ultrasonography.
Video 96.1 Anatomy of right paratracheal region.
Video 96.2 VATS dissection of right paratracheal region.
Video 96.3 VATS Subcarinal dissection from the right thoracic compartment.
Video 96.4 VATS inferior mediastinal dissection: Station 8.
Video 96.5 VATS inferior mediastinal dissection: Station 9.
Video 96.6 VATS aortopulmonary window and para-aortic dissection: Stations 5 and 6.
Video 96.7 VATS Subcarinal dissection from the left thoracic compartment.
Video 96.8 TEMLA set up.
Video 96.9 A: Right paratracheal dissection. B: Right paratracheal dissection.
Video 96.10 A: Subcarinal dissection. B: Subcarinal dissection.
Video 96.11 Left paratracheal dissection.
Video 96.12 Aortopulmonary dissection.
Video 108.1 Technique of clinical isolated lung perfusion.
Video 108.2 Technique of clinical isolated lung perfusion as performed at the Antwerp University
Hospital in Belgium.
Video 113.1 Technique of clinical isolated lung perfusion as performed at the Antwerp University
Hospital in Belgium.
Video 134.1 Operative exposure of the proximal esophagus.
Video 134.2 Tracheomalacia before (A) and after (B) aortopexy.
Video 134.3 During the second surgery for repair of EA with TEF in a very small infant, a major chyle
leak was noticed and ended.
Video 134.4 H-type TEF as well as Fogarty catheter placement.
Video 154.1 Division of sternum with lungs deflated.
Video 154.2 Reapproximation of sternum using interrupted sutures.
Video 155.1 Mediastinal exposure using a throw-off grasping forceps.
Video 155.2 Technique for direct aspiration of the liquid component to reduce the volume of a cystic
teratoma.
Video 156C.1 Operative technique of robotic-assisted VATS thymectomy.
Video 174.1 Pus leaking out when infected pericardial cyst being dissected.
Contents
VOLUME ONE
Contributing Authors
Preface to the Eighth Edition
Preface to the First Edition
Acknowledgments
Video List
PART A Evolution of General Thoracic Surgery
SECTION I
History and Pioneers in Thoracic Surgery
1 The History of Thoracic Surgery
John A. Odell
2 Pulmonary Surgery After Mechanical Ventilation
Arvind Rajagopal, David D. Shersher, and William H. Warren†
3 Minimally Invasive Thoracic Surgery
Stephen Hazelrigg, James Regan, and Michael Thomas
PART B The Lung, Pleura, Diaphragm, and Chest Wall
SECTION II
Structure and Function of The Chest Wall and Lungs
4 Anatomy of the Thorax
Anna Maria Ciccone, Federico Venuta, and Erino A. Rendina
5 Embryology of the Lungs
Alejandro C. Bribriesco, Mala R. Chinoy, and Daniel Kreisel
6 Ultrastructure and Morphometry of the Human Lung
Matthias Ochs, Peter H. Burri, and Ewald R. Weibel
7 Cellular and Molecular Biology of the Lung
Steven J. Mentzer
8 Surgical Anatomy of the Lungs
Nirmal K. Veeramachaneni
9 Lymphatics of the Lungs
Marc Riquet and Ciprian Pricopi
10 Mechanics of Breathing and Pulmonary Gas Exchange
Giuseppe Miserocchi, Egidio Beretta, and Francesca Lanfranconi
SECTION III
Thoracic Imaging
11 Standard Radiographic Evaluation of the Lungs and Chest
Dong-Seok Daniel Lee, Mary Salvatore, David Yankelevitz, Claudia I. Henschke, and Raja M.
Flores
12 Computed Tomography of the Lungs, Pleura, and Chest Wall
Mary Salvatore, Kunwei Li, Lea Azour, David Yankelevitz, and Claudia I. Henschke
13 Magnetic Resonance Imaging of the Thorax
Prabhakar Rajiah and Ritu R. Gill
14 Radionucleotide Studies of the Lung
Perry Gerard, Amrita K. Arneja, and Yachao Zhang
15 Thoracic PET CT
Perry Gerard, Neil Kapadia, and Jay Acharya
SECTION IV
Diagnostic Procedures
16 Laboratory Investigations in the Diagnosis of Pulmonary Diseases
Erin A. Gillaspie and Dennis A. Wigle
17 Molecular Diagnostic Studies and Genomic Studies in Pulmonary Disease
Jacob A. Klapper and Chadrick E. Denlinger
SECTION V
Diagnostic Procedures In Pulmonary Diseases
18 Bronchoscopic Evaluation of the Lungs and Tracheobronchial Tree
Dominik Harzheim and Felix J. F. Herth
19 Ultrasound and Endoscopic Bronchoscopic Ultrasound in the Evaluation of the
Lungs, Mediastinum, and Pleura
Basil Nasir and Moishe Liberman
20 Mediastinoscopy
Toni Lerut and Paul De Leyn
21 Transcervical Mediastinal Lymphadenectomy
Gunda Leschber
22 Invasive Diagnostic Procedures
Michael Lanuti
SECTION VI
Preoperative Assessment of the Thoracic Surgical Patient
23 General Risk Assessment of Patients for Thoracic Surgical Procedures
Alessandro Brunelli, Cecilia Pompili, and Michele Salati
24 Pulmonary Physiologic Assessment of Operative Risk
Diego Avella Patino and Mark K. Ferguson
SECTION VII
Preoperative And Anesthetic Management of The General Thoracic Surgical Patient
25 Preoperative Preparation of the General Thoracic Surgical Patient
Traves D. Crabtree and Seth B. Krantz
26 Conduct of Anesthesia
Brian P. Barrick
SECTION VIII
Pulmonary Resections
27 Thoracic Incisions
Dominic Emerson and M. Blair Marshall
28 Technical Aspects of Lobectomy
Stanley C. Fell,† Malcolm M. DeCamp, and Richard H. Feins
29 Pneumonectomy and Its Modifications
Stéphane Collaud, Philippe Dartevelle, and Elie Fadel
30 Sleeve Lobectomy
Paul De Leyn and Herbert Decaluwé
31 Tracheal Sleeve Pneumonectomy
Laura Donahoe and Marc de Perrot
32 Segmentectomy and Lesser Pulmonary Resections
Chi-Fu Jeffrey Yang, and Thomas D’Amico
33 Robotic-Assisted Surgery in Pulmonary Diseases
Richard S. Lazzaro, Andrew Brownlee, Laurence N. Spier, and Mark R. Dylewski
34 Video-Assisted Thoracoscopic Surgery for Wedge Resection, Lobectomy, and
Pneumonectomy
Miriam Huang, Mark W. Hennon, and Todd L. Demmy
35 Uniportal VATS Lobectomy
Diego Gonzalez-Rivas and Alan D. L. Sihoe
36 Awake, Non-Intubated Transpleural Surgery
Ze-Rui Zhao and Calvin S. H. Ng
37 Extended Resection of Pulmonary Carcinoma Including Chest Wall and
Mediastinum
Kelvin Lau
38 Surgical Resection of Superior Sulcus Lesions
Dominique Grunenwald
39 Management of Air Leaks and Residual Pleural Spaces
Cameron Wright
SECTION IX
Postoperative Management of The General Thoracic Surgical Patient
40 General Principles of Postoperative Care
Jason P. Shaw
41 Ventilatory Support of the Thoracic Surgical Patient
Jonathan C. Yeung, Lorenzo Del Sorbo, and Shaf Keshavjee
42 Complications of Thoracic Surgical Procedures
Benjamin D. Kozower
SECTION X
The Chest Cage
43 Chest Wall Deformities
Charles B. Huddleston and Yosef Jose Greenspon
44 Hernias of the Chest Wall
Nigel E. Drury and Pala Babu Rajesh
45 Infections of the Chest Wall
Edward J. Bergeron, Robert A. Meguid, and John D. Mitchell
46 Thoracic Outlet Syndrome
Dean M. Donahue and Asishana Osho
47 Transthoracic Approaches to the Spine
Christopher W. Seder and Michael J. Liptay
48 Chest Wall Tumors
Daniel G. Nicastri, Gunturu N. Swati, Elbert E. Williams, and Raja M. Flores, with contributions
from David R. Jones
49 Chest Wall Reconstruction
Kei Suzuki, Leila Jazayeri, Babak J. Mehrara, and David R. Jones
SECTION XI
The Diaphragm
50 Embryology and Anatomy of the Diaphragm
Thomas W. Shields
51 Physiology of the Diaphragm and Surgical Approaches to the Paralyzed Diaphragm
Raymond P. Onders
52 Congenital Posterolateral Diaphragmatic Hernias and Other Less Common Hernias
of the Diaphragm in Infants and Children
Priscilla Chiu and Jacob C. Langer
53 Foramen of Morgagni Hernia
Federico Venuta, Marco Anile, and Erino A. Rendina
54 Primary Tumors of the Diaphragm
Thoracic Surgery
Min P. Kim and Wayne Hofstetter
Diagnostic Imaging
Daniel Ocazionez and Carlos S. Restrepo
SECTION XII
The Pleura
55 Anatomy of the Pleura
Isabelle Opitz
56 Absorption of Gases Within the Pleural Space
Vasileios Kouritas and Kostas Papagiannopoulos
57 Pneumothorax
Federico Venuta, Daniele Diso, and Erino A. Rendina
58 Mechanics and Fluid Dynamics of Lung and Pleural Space
Giuseppe Miserocchi, Egidio Beretta, and Gabriele Simone Grasso
59 Benign Pleural Effusion
Cliff K. C. Choong and Siddharth Padmanabhan
60 Parapneumonic Effusion, Empyema, and Fibrothorax
David Waller and Sara Tenconi
61 Postsurgical Empyema
Lisa M. Brown and Eric Vallières
62 Tuberculous and Fungal Infections of the Pleura
Gilbert Massard, Anne Olland, Nicola Santelmo, and Pierre-Emmanuel Falcoz
63 Thoracoplasty: Indications and Surgical Considerations
Marco Alifano, Antonio Bobbio, Christine Lorut, and Jean-François Regnard
64 Anatomy of the Thoracic Duct and Chylothorax
Moritz C. Wyler von Ballmoos and David W. Johnstone
65 Solitary Fibrous Tumors and Other Uncommon Neoplasms of the Pleura
Joel Miller Sternbach, Anjana Yeldandi, and Malcolm M. DeCamp
66 Chemotherapy and Alternative Therapies for Malignant Pleural Mesothelioma
Federica Grosso and Giorgio V. Scagliotti
67 Surgical Approaches for Diffuse Malignant Pleural Mesothelioma
Bryan M. Burt, Shawn S. Groth, and David J. Sugarbaker
68 Malignant Pleural Effusions
Jessica L. Hudson and Varun Puri
69 Malignant Pericardial Effusions
David Rice and Elie Mouhayar
SECTION XIII
The Trachea and Bronchi
70 Tracheostomy
Shamus R. Carr and Joseph S. Friedberg
71 Therapeutic Bronchoscopic Procedures
Daniel P. McCarthy and Douglas E. Wood
72 Surgical Anatomy of the Trachea and Techniques of Resection and Reconstruction
Pierre Delaere and Paul De Leyn
73 Management of Nonneoplastic Diseases of the Trachea
Jennifer L. Wilson and Sidhu P. Gangadharan
74 Benign and Malignant Tumors of the Trachea
Henning A. Gaissert
75 Compression of the Trachea by Vascular Rings
Carl L. Backer
SECTION XIV
Congenital, Structural, and Inflammatory Diseases of the Lung
76 Congenital Parenchymal Lesions of the Lungs
Antonio Bobbio, Laureline Berteloot, Claude Guinet, and Marco Alifano
77 Pulmonary Complications of Cystic Fibrosis
Pascal A. Thomas
78 Congenital Vascular Lesions of the Lungs
Antonio Bobbio, Laureline Berteloot, Audrey Lupo, and Marco Alifano
79 Chronic Pulmonary Emboli
Nathaniel B. Langer, Philippe Dartevelle, and Elie Fadel
80 COPD for CT Surgery
Mark Weir and Gerard J. Criner
81 Bullous and Bleb Diseases of the Lung
Alan D. L. Sihoe
82 Lung Volume Reduction
Philip Carrott and Christine Lau
83 Bacterial Infections of the Lungs and Bronchial Compressive Disorders
Semih Halezeroğlu
84 Pulmonary Tuberculosis and Other Mycobacterial Diseases of the Lung
Gilbert Massard, Anne Olland, Nicola Santelmo, and Pierre-Emmanuel Falcoz
85 Surgical Management of Tuberculous and Nontuberculous Mycobacterial
Infections of the Lung
John D. Mitchell
86 Thoracic Mycotic and Actinomycotic Infections of the Lung
Patrick Kohtz and Michael J. Weyant
87 Exotic Infections Requiring Surgical Intervention
Alper Toker, Berker Özkan, and Erkan Kaba
88 Lung Transplantation
Robin Vos, G. Alexander Patterson, and Dirk Van Raemdonck
VOLUME TWO
SECTION XV
Carcinoma of The Lung
89 Lung Cancer: Epidemiology and Carcinogenesis
Pamela Samson and Graham A. Colditz
90 Lung Cancer Screening
Douglas E. Wood
91 Investigation and Management of Indeterminate Pulmonary Nodules
Pasquale Ferraro and Andrei-Bogdan Gorgos
92 Pathology of Carcinoma of the Lung
Akihiko Yoshizawa, Hironori Haga, and Hiroshi Date
93 Ex Vivo Diagnosis of Lung Cancer
Chadrick E. Denlinger and Jacob A. Klapper
94 Staging of Lung Cancer
Joe B. Putnam, Jr.
95 Results of Surgical Treatment of Non-Small Cell Lung Cancer
Ernest G. Chan, Patrick G. Chan, and Matthew J. Schuchert
96 Mediastinal Lymph Node Dissection
Anthony L. Picone, Sai Yendamuri, and Todd L. Demmy
97 Unknown Primary Malignancy Metastatic to Thoracic Lymph Nodes
Marc Riquet and Patrick Bagan
98 Adjuvant Chemotherapy for Non-Small-Cell Lung Cancer
Lingling Du, Ramaswamy Govindan, and Saiama N. Waqar
99 Radiation for Lung Cancer
Kevin L. Stephans, Rupesh Kotecha, Neil McIver Woody, and Gregory Videtic
100 Multimodality Therapy for Non-Small Cell Lung Cancer
Onkar V. Khullar and Seth Force
101 Novel Therapeutic Strategies for Non-Small Cell Lung Cancer
Saeed Arefanian, Stephanie Chang, and Alexander Krupnick
102 Emerging Technologies for Management of Lung Cancer in Patients With Marginal
Physiologic Function
Kendra Iskander and Hiran C. Fernando
103 Small-Cell Lung Cancer
Liza Villaruz, Brian J. Karlovits, Timothy F. Burns, and Mark A. Socinski
SECTION XVI
Other Tumors of the Lung
104 Carcinoid Tumors
Joanna Sesti and Jessica S. Donington
105 Adenoid Cystic Carcinoma and Other Primary Salivary Gland–Type Tumors of the
Lung
Richard S. D’Agostino
106 Benign Tumors of the Lung
Virginia R. Litle and Ghulam Abbas
107 Uncommon Primary Malignant Tumors of the Lung
Sebastián Defranchi and Carlos Vigliano
108 Pulmonary Metastases
Paul E. Y. Van Schil, Willem Adriaan den Hengst, Mark S. Allen, and Joe B. Putnam, Jr.
109 Pulmonary Malignancies in the Immunocompromised Host
David S. Schrump
SECTION XVII
Thoracic Trauma
110 Blunt and Penetrating Injuries of the Chest Wall, Pleura, Diaphragm, and Lungs
Hao Pan and Scott B. Johnson
111 Barotrauma and Inhalation Injuries
Brittany A. Zwischenberger and Joseph B. Zwischenberger
112 Acute Respiratory Distress Syndrome
Ronson J. Madathil, Aaron M. Cheng, and Michael S. Mulligan
113 Management of Foreign Bodies of the Aerodigestive Tract
Sandra Starnes and Julian Guitron
114 Blunt and Penetrating Injuries of the Esophagus
Tracey Dechert and Virginia R. Litle
115 Esophageal Perforation
Raja Mahidhara and Richard K. Freeman
SECTION XVIII
Understanding Statistical Analysis And Medical Decision Making
116 Statistics and Medical Decision Making for the Surgeon
Mark K. Ferguson
117 Clinical Practice Guidelines in General Thoracic Surgery
Robert E. Merritt
118 Rationale for and Use of Large National Databases
Yinin Hu, Varun Puri and Benjamin D. Kozower
119 ICD-10: Implications for Future Clinical Research and Reporting
Melanie A. Edwards and Keith S. Naunheim
120 Instruments and Resources for Quality Improvement in Thoracic Surgery
Farhood Farjah and Douglas E. Wood
PART C The Esophagus
SECTION XIX
Structure of the Esophagus
121 Embryology of the Aerodigestive Tract
Steven J. Mentzer
122 Anatomy of the Esophagus
Thomas J. Watson
123 Lymphatic Drainage of the Esophagus
Thomas L. Bauer II and Mark J. Krasna
SECTION XX
Physiology of The Esophagus
124 Anatomy, Physiology, and Physiologic Studies of the Esophagus
Siva Raja, Prashanthi N. Thota, and Sudish C. Murthy
SECTION XXI
Diagnostic Studies of The Esophagus
125 Radiologic Evaluation of the Esophagus
Beatrice Aramini and Frank D’Ovidio
126 Endoscopy of the Esophagus
Donna E. Maziak and Farid M. Shamji
127 Esophageal Ultrasound
J. Shawn Mallery, Rafael Garza-Castillon, Eitan Podgaetz, and Rafael Andrade
SECTION XXII
Operative Procedures in The Management of Esophageal Disease
128 Operative Strategies for Esophageal Dysmotility Disorders
Chaitan K. Narsule and Hiran C. Fernando
129 Surgical Techniques for the Treatment of Reflux Disease
Antonios C. Sideris, Yifan A. Zheng, Abby White, and Raphael Bueno
130 Techniques of Esophagectomy
Toni Lerut
130A Transthoracic Resection of the Esophagus
Philippe Nafteux, Willy Coosemans, Lieven P. Depypere, Hans Van Veer, and Toni Lerut
130B Extended Resection for Esophageal Carcinoma
Jeffrey L. Port, Mohamed K. Kamel, and Nasser K. Altorki
130C Transhiatal Esophagectomy Without Thoracotomy
James E. Speicher and Mark D. Iannettoni
130D Vagal-Sparing Esophagectomy
Steven R. DeMeester
130E Video-Assisted and Robotic Esophagectomy
Inderpal S. Sarkaria, Lara Schaheen, and James D. Luketich
131 Alternative Conduits for Replacement of the Esophagus
Hugh G. Auchincloss and Douglas J. Mathisen
132 Per-Oral Esophageal Procedures
Ezra N. Teitelbaum and Nathaniel J. Soper
133 Esophageal Stents
Ory Wiesel, Jon O. Wee
SECTION XXIII
Congenital, Structural, and Inflammatory Diseases of the Esophagus
134 Congenital Anomalies of the Esophagus
David M. Notrica and Dawn E. Jaroszewski
135 Inflammatory Diseases of the Esophagus
Joseph D. Phillips and Andrew C. Chang
136 Esophageal Motility Disorders
Janani S. Reisenauer, Karthik Ravi, and Shanda H. Blackmon
137 Gastroesophageal Reflux Disease
Thomas J. Watson
138 Barrett’s Esophagus
Kamran Mohiuddin and Donald E. Low
139 Paraesophageal Hiatal Hernia
Janet Edwards, Colin Schieman, and Sean C. Grondin
140 Esophageal Diverticula
Pamela Samson and Varun Puri
141 Benign Tumors, Cysts, and Duplications of the Esophagus
Kiran Lagisetty and Rishindra M. Reddy
SECTION XXIV
Malignant Lesions of The Esophagus
142 Carcinoma of the Esophagus
Biniam Kidane, Mathieu Derouet, and Gail E. Darling
142 Appendix: 2009 AJCC/UICC Staging of Esophageal Cancer
Thomas W. Rice, Valerie W. Rusch, and Eugene H. Blackstone
143 Staging of Esophageal Cancer
Mark Onaitis
144 Multimodality Therapy for Esophageal Cancer
Abby White and Scott J. Swanson
145 Less Common Malignant Tumors of the Esophagus
Kiran Lagisetty and Andrew C. Chang
146 Palliative Approaches to Inoperable Esophageal Cancer
Jonathan D. Spicer and Garrett L. Walsh
PART D The Mediastinum
SECTION XXV
Structure and Function of The Mediastinal Contents
147 The Mediastinum, Its Compartments, and the Mediastinal Lymph Nodes
Hisao Asamura and Masaya Yotsukura
148 The Thymus
Michael S. Mulvihill, Jacob A. Klapper, and Matthew G. Hartwig
149 Mediastinal Parathyroids
Daniel J. Boffa
150 Neurogenic Structures of the Mediastinum
Ghulam Abbas and Mark J. Krasna
SECTION XXVI
Noninvasive Investigations
151 Radiographic, Computed Tomographic, and Magnetic Resonance Investigation of
the Mediastinum
Nadeem Parkar and Sanjeev Bhalla
152 Radionuclide Studies of the Mediastinum
Philip Maximilian Scherer and Delphine L. Chen
153 Mediastinal Tumor Markers
Mirella Marino, Rossano Lattanzio and Edoardo Pescarmona
SECTION XXVII
Invasive Diagnostic Investigations and Surgical Approaches
154 Sternotomy and Thoracotomy for Mediastinal Disease
Giulio Maurizi, Federico Venuta, and Erino A. Rendina
155 Video-Assisted Thoracic Surgery for Mediastinal Tumors and Cysts and Other
Diseases Within the Mediastinum
Maxime Heyndrickx, Amaia Ojanguren, Agathe Seguin-Givelet, and Dominique Gossot
156 Surgical Techniques for Thymectomy
Joseph LoCicero, III
156A Standard Thymectomy
Francis C. Nichols and Victor F. Trastek
156B Transcervical Thymectomy
Joseph B. Shrager
156C Operative Techniques of VATS and Robotic VATS Thymectomy
Jonathan D’Cunha, Nicholas R. Hess, and Inderpal S. Sarkaria
156D Extended Transsternal Thymectomy With or Without Cervical Incision
Jason P. Glotzbach, Mitchell J. Magee, Alper Toker, and Joshua R. Sonett
SECTION XXVIII
Mediastinal Infections, Mass Lesions in the Mediastinum, and Control of Vascular
Obstructing Symptomatology
157 Acute and Chronic Mediastinal Infections
Ravi Rajaram and Malcolm M. DeCamp
158 Primary Mediastinal Tumors and Cysts and Diagnostic Investigation of Mediastinal
Masses
Francis C. Nichols
159 Lesions Masquerading as Primary Mediastinal Tumors or Cysts
Chadrick E. Denlinger and Jacob A. Klapper
160 Primary Pneumomediastinum
Rachel L. Medbery and Felix G. Fernandez
161 Vascular Masses of the Mediastinum
John Holt Chaney, H. Adam Ubert, and Victor van Berkel
162 Superior Vena Cava Syndrome: Clinical Features, Diagnosis, and Treatment
Paul Michael McFadden and Christina L. Greene
163 Surgical Management of Benign Sympathetic Nervous System Conditions
Stephen Hazelrigg and Erin E. Bailey
SECTION XXIX
Primary Mediastinal Tumors and Syndromes Associated With Mediastinal Lesions
164 Myasthenia Gravis
David S. Younger
165 Evaluation of Results of Thymectomy for Nonthymomatous Myasthenia Gravis
Mitchell J. Magee and Joshua R. Sonett
166 Tumors of the Thymus
Usman Ahmad and James Huang
167 Benign Lymph Node Disease Involving the Mediastinum
Jason Michael Long
168 Diagnosis and Treatment of Mediastinal Lymphomas
Adrienne A. Phillips and Koen van Besien
169 Benign and Malignant Germ Cell Tumors of the Mediastinum
Carlos Ibarra-Pérez, Isabel Alvarado-Cabrero, Walid Leonardo Dajer-Fadel, and Oscar Arrieta-
Rodriguez
170 Benign and Malignant Neurogenic Tumors of the Mediastinum in Children and
Adults
Eric Sceusi and Ara A. Vaporciyan
171 Less Common Mediastinal Tumors
Alexander Yang, Jinny S. Ha, and Stephen C. Yang
172 Mesenchymal Tumors of the Mediastinum
M. Blair Marshall and Young K. Hong
SECTION XXX
Mediastinal Cysts
173 Foregut Cysts of the Mediastinum in Infants and Children
Timothy Brand and Jason Michael Long
174 Foregut Cysts of the Mediastinum in Adults
Hon Chi Suen
Index

†Deceased
Part
A
EVOLUTION OF GENERAL THORACIC

SURGERY
Section
I
HISTORY AND PIONEERS IN

THORACIC SURGERY
1
The History of Thoracic Surgery
John A. Odell
“Let me repeat what history teaches, history teaches.”

—Gertrude Stein
In this chapter important issues of how a correct diagnosis was achieved, how the pleural space needed to
be controlled, and how an ability to control major blood vessels and to close a bronchial stump arose.
For the older surgeons, the story is reasonably well known but for those entering the specialty it needs
retelling. For the sake of brevity and continuity, I have concentrated on the challenges that needed to be
overcome and included within these sections the pioneers who popularized a surgical approach.
Inevitably, there will be some who were involved with more than one approach, and some who will be
left out of the record. I have not attempted to include every pioneer, nor every surgical variation, nor
every surgical first. Many of the early procedures were done in the belief that radical surgery was
necessary to deal with the underlying disease process and many were simply published to show that a
procedure was possible, but with no evidence that the procedure prolonged or improved the quality of
life. It is also difficult to describe the small progressive steps that inevitably take place over a continuum
of time. The first faltering steps are obviously described but the reader will need to imagine the further
progress to the present.
The subject of our surgical history actually deserves space for a book. For those wishing a more
comprehensive tome there are two excellent reviews. Mead’s book1 is almost too comprehensive, and
many will find the description of virtually every operation until the time of publication irksome, yet gems
of information can be found within. Alternatively, the chapter by Molnar2 is excellent and gives a more
inclusive European perspective than other historical chapters, but is limited, as this chapter will be, by
editorial restrictions imposed in a reference book chapter. Nevertheless, both this chapter and Molnar’s
provide references for those wishing to further explore the subject.
Most of the developments that affected thoracic surgery occurred between the World Wars. My
description will stop in approximately 1950, when advances in anesthesia (paralytic agents, halothane,
and pentobarbital [pentothal] all introduced in that decade) enabled routine intratracheal ventilation and
thoracic surgery safer. There will be some overlap with the subsequent chapter. Also, at that time,
antituberculous drugs became widely available and changed the nature of thoracic surgery in a very
dramatic fashion.3 Within a decade and a half of the discovery of antituberculous drugs, specialties of
cardiac surgery and pulmonology, started to form.
INTRODUCTION
It is not known exactly when the first thoracic surgical procedure was performed, but we can readily
understand the chest pathology the early physician had to deal with: traumatic wounds and the
consequences of infection. Two early classic descriptions to set the stage for management of these
pathologic processes are provided.
The first description is that of Hippocrates translated from Fuchs’ edition.4
If as a result of the treatments the pus does not break through, one should not be surprised, for often it breaks into the body, and
the patient seems to be better, because the pus has passed from a narrow space to a larger one. As time goes on, the fever becomes
more severe, coughing begins, the side begins to pain, the patient cannot lie any more on the healthy side but on the diseased side,
the feet and eyes swell.
When the fifteenth day after the rupture has appeared, prepare a warm bath, set him upon a stool, which is not wobbly,
someone should hold his hands, then shake him by his shoulders and listen to see on which side a noise is heard. And right at this
place—preferably on the left—make an incision, then it produces death more rarely.
Those cases of empyema or dropsy which are treated by incision or the cautery, if the water or pus flows rapidly all at once,
certainly prove fatal. When empyema is treated either by the cautery or incision, if pure and white pus flow from the wound, the
patients recover, but if mixed with blood, slimy and fetid, they die.
The second is by Barron Larrey,5 Napoleon’s surgeon, describing a soldier injured during the Egypt
campaign of 1798.
A soldier was brought to the hospital of the Fortress of Ibrahym Bey, immediately after a wound penetrated the thorax, between the
fifth and sixth true ribs. It was about 8 cm in extent. A large quantity of frothy and vermilion blood escaped from it with a hissing
noise at each inspiration. His extremities were cold, pulse scarcely perceptible, countenance discolored, and respiration short and
laborious; in short, he was every moment threatened with a fatal suffocation.
After having examined the wound, the divided edges of the part, I immediately approximated the two lips of the wound, and
retained them by means of adhesive plaster and a suitable bandage around the body. In adopting this plan, I intended only to hide
from the sight of the patient and his comrades, the distressing spectacle of a hemorrhage, which would soon prove fatal; and I
therefore thought that the effusion of blood into the cavity could not increase the danger. But the wound was scarcely closed, when
he breathed more freely and felt easier. The heat of the body soon returned, and the pulse rose. In a few hours he became quite
calm, and to my great surprise, grew better. He was cured in a very few days and without difficulty.
Hippocrates, described a possible lung abscess with rupture either into the bronchus or pleural space;
his description of the symptoms and signs of a bronchopleural fistula was excellent. He knew that early
intervention in the disease process was dangerous and never did drainage until 15 days had passed. In this
setting, Hippocrates was able to differentiate pus of a parapneumonic effusion (commonly Streptococcus
pneumoniae), which tends to be watery and thin (enzymes streptokinase and streptodornase) from that of
a likely staphylococcal empyema (enzyme coagulase results in the formation of a rapid cortex on the
surface of the lung) and to recognize, either an anaerobic or amebic empyema.
What both these famous clinicians described was an open pneumothorax and its consequences.
Hippocrates’ patient with thick white pus has a better prognosis than that with thin watery pus because a
cortex has developed on the pleural surface of the lung, preventing collapse when the sub atmospheric
pleural space was opened and exposed to higher atmospheric pressure.
The lesson was not lost. One of the orders issued in the First World from an Allied Commander about
open chest wounds was one issued by WG MacPherson6 for the Director Medical Service, British
Armies in France.
“An open pneumothorax should be temporarily closed by suture at the earliest opportunity, either in the field ambulance, or at the
Casualty Clearing Station. If for any reason suturing is impossible, the wound should be strapped, so as to render it air tight.”
This issue, collapse of the lung and its consequences when the pleural space is entered, was an
enormous barrier to early surgery within the chest and hindered surgical development, shape, and type
until the first quarter of the 20th century. The history of thoracic surgery has at its core the management of
the pleural space and this problem will rear its head repeatedly in the descriptions that follow. It should
be remembered that this was an era without oximeters, EKG monitors, blood banks, endotracheal tubes,
and antibiotics. Many of the early procedures pursued were designed simply to avoid entering the pleural
space, because it was safer for the patient.
AN ACCURATE DIAGNOSIS
One of the tenets of any planned surgical procedure is an accurate diagnosis. In the 19th century, the
ability to make a diagnosis was limited. A symptomatic empyema necessitans or a traumatic chest wound
was an obvious reason for surgical intervention, but it was difficult to determine if intrathoracic
pathology required intervention. Skoda7 had popularized percussion and Laennec8 auscultation, but the
ability to use these aids were limited by clinical ability. Nevertheless, some clinicians had confidence in
their ability. One such surgeon was Block9 of Danzig, who had performed successful pulmonary
resections in rabbits. Convinced he could do it safely in humans he operated on his cousin in 1883 with
the presumption that she had bilateral apical tuberculosis. She unfortunately died and at postmortem no
evidence of tuberculosis was found. The distraught Block committed suicide. (Authors note: This
description of Block operating on his cousin can be found in numerous textbooks dealing with the history
of thoracic surgery, but none have been referenced [not too surprising as the protagonist had killed
himself].)
In the late 1800s and early 1900s, the most common cause of death was tuberculosis. It was apparent
to many that tuberculosis was a communicable disease. In fact, Villemin,10 a French army surgeon, had
proven so by reproducing the pathologic features of the disease by injecting caseous material from a
deceased patient with tuberculosis into the trachea of rabbits, but his research was largely ignored.
Medical proof had to await Koch’s presentation, entitled “Die Tuberculose” (On Tuberculosis), to the
Berlin Physiologic Society on March 24, 1882. The electrifying atmosphere that developed at the
presentation is vividly described in the book “The Forgotten Plague” by Frank Ryan.11 Present in the
crowded room were Virchow, Loeffler, and Ehrlich, who described “that evening to be the most
important experience of my scientific life.” Three weeks after the presentation, the lecture was
published.12 Twelve days later an English summary was published in the London Times, and a few weeks
later, on May 3, it was published in The New York Times. The rapidity of the spread of the news and its
publication in the lay press testify to how common and threatening tuberculosis was at the time. Naturally
it was thought that surgical resection may have a role in management of such a life-threatening disease.
This was how planned thoracic surgery started. If we study the history of thoracic surgery we study
surgical attempts to control tuberculosis.13
RADIOLOGY
Tuberculosis could now be suspected and proven by examining sputa, but the extent of disease had to wait
until 1895 when Roentgen discovered x-rays.14 The ability to visualize shadows within the chest and
correlate radiographic findings with pathology at autopsy was now at hand.
ESOPHAGOSCOPY
The bronchoscope and esophagoscope were developments that followed laryngoscopy and cystoscopy.
Manoel Garcia, a singer, visualized his own larynx by means of two mirrors.15 This technique was later
modified by Czermack of Budapest who utilized light reflected off a perforated concave mirror.15 In
1853, Desormeaux introduced what he called an endoscope into the bladder. Light was supplied by
burning a mixture of turpentine and alcohol. A condensing lens collected the light rays and rendered them
parallel before reflection into a tube.16
In 1868, Adolf Kussmaul modified the Desormeaux urethroscope by lengthening it to diagnose a
carcinoma of the esophagus and to enter the stomach.17 Mikulicz developed the technique further. He used
a heated platinum wire as illumination at the distal end of the tube.16
In 1902, Max Einhorn18 introduced the idea of an auxiliary channel in the wall of the esophagoscope as
the light carrier. This technology soon transferred itself to the bronchoscope.
BRONCHOSCOPY AND BRONCHOGRAPHY

Bronchoscopy came later than esophagoscopy. Its initial use was therapeutic—the removal of foreign
bodies. Up until the development of the bronchoscope foreign bodies were removed through a
tracheostomy.
In 1882, Weist reported to the American Surgical Association on 1,000 cases of foreign body.
Mortality in the 599 cases not operated on was 23.3% whereas, in those who had tracheotomy for
removal, the mortality was 27.4%. He concluded that unless the foreign body was causing dangerous
symptoms it should be left alone.19
In 1895, Killian20 performed a direct laryngoscopy and was able to visualize the trachea. He later
modified his straight tube by placing lateral openings in the distal end so that respiration could continue.21
In 1897, he was the first to remove a foreign body lodged in the right main bronchus through a
bronchoscope.21,22
Chevalier Jackson started to remove foreign bodies and soon became the leading endoscopist in the
world and was also known for his training courses. Many of these endoscopic procedures were done
under local anesthesia and must have been very uncomfortable for the patient. One of my mentors, an early
pioneer, assisting during his first bronchoscopy, had to hold the patients head and place his thumb
protected by a thimble between the teeth. The operation for removal of a foreign body took all day;
unfortunately the adolescent patient died with extensive surgical emphysema.23
The utility of the bronchoscope broadened to include an aid to diagnosis. Chevalier Jackson24
insufflated barium powder through a bronchoscope to diagnose bronchiectasis. Definition of segmental
anatomy was enhanced by Brock’s work. He instilled barium into cadavers mimicking the positions that
unconscious patients would take and proved that aspiration was the likely cause of lung abscess.25 An
excellent review on the history of bronchography to diagnose bronchiectasis is by Le Roux et al.26 In
1932 Vinson,27 at the Mayo Clinic, established the diagnosis of lung cancer in 71 patients by
bronchoscopy.
CONTROL OF THE PLEURAL SPACE
SAUERBRUCH
Ernst Sauerbruch should be regarded as the prime pioneer of thoracic surgery. Born in 1875, he was 4
years old when his father died of tuberculosis. After qualifying as a medical doctor, he initially worked as
a surgical assistant in Kassel and Erfurt. He realized that if he were to be a surgeon, he would need better
knowledge of anatomy and therefore took up a position with Paul Langerhans in the department of
pathology and anatomy at Berlin-Moabit Hospital. Langerhans encouraged Sauerbruch, who had written a
paper on blunt intestinal injuries, to send a copy of the paper to the famous Polish surgeon von Mikulicz-
Radecki, who read it while visiting the Mayo Clinic.28 Mikulicz was impressed and invited Sauerbruch to
become an assistant in Breslau.
Mikulicz was an autocratic master, an absolute ruler over his clinic, who was disliked by all who
worked with him. What kept his assistants in Breslau was the awareness of Mikulicz’s splendid surgical
and teaching ability; they could learn more from him than other European surgeons. Some of Mikulicz’s
style obviously influenced Sauerbruch because he later became just as autocratic and demanding. As
usual, Mikulicz ignored Sauerbruch for weeks, but then confronted him that scientific results were
expected of him. We can imagine Sauerbruch asking for guidance. The reply given was, “Hundreds of
thousands of people are succumbing to tuberculosis, because as yet no one has been able to operate
within the thorax.”29 This statement must have meant much to Sauerbruch as he repeatedly mentions it in
his book. The statement also emphasizes that surgery and resection was being considered to deal with the
disease of tuberculosis.
The main reason chest surgery was not successful was the problem with intrapulmonary collapse
mentioned at the beginning of the chapter. This stimulated Sauerbruch to find a solution. He enclosed an
animal’s chest in an air-tight, transparent box, which was kept at a negative pressure of 10 cm H2O. Using
gloves built into the box wall, he could now operate on the open chest without collapse of the lung (Fig.
1.1). He proudly showed his mentor, Mikulicz, but unfortunately the apparatus sprung a leak and Mikulicz
was furious that his time had been wasted. The chastened Sauerbruch continued his experimental work
secretly and was later able to convince Mikulicz of its success and the two reconciled. Now with support,
Sauerbruch built a low-pressure chamber with 14 cubic meters of space; the neck of the patient and the
attending anesthesiologist remained outside the chamber. In April 1904, Sauerbruch presented his results
at the annual German surgical congress. But, the concept was to be modified by others (see comments
later on Ludolph Brauer).30
A year later, Sauerbruch anesthetized Mikulicz at his laparotomy where widespread metastatic gastric
cancer was found. After Mikulicz’s death Sauerbruch moved to Greifswald and later to Marburg as first
assistant to Friedrich (see comments later).
He was later appointed Professor of Surgery in Zurich in 1910 on the recommendations of the world-
famous Kocher of Berne and Lucius Spengler of Davos (the site of a famous tuberculosis sanatorium, now
the venue for the world economic forum meetings and from where he was referred many surgical
patients).
In 1911, he performed the first thymectomy for myasthenia gravis using the transcervical approach.31
Then, in 1913, he described phrenicotomy for the treatment of pulmonary tuberculosis.4 He did the first
successful pericardiectomy for constrictive pericarditis. While in Zurich his reputation grew and he was
soon in contact with the famous and elite. His autobiography describes treatment of Lenin, Rothschild, and
King Constantine of Greece, among others. When war broke out in 1914, he volunteered and was
appointed surgeon to the German army. He was exposed to the carnage at Ypres. While treating many
amputees he developed a crude artificial hand.
In 1918, he was offered the chair of surgery at Munich. At that stage, Nissen was his assistant, as was
Lebsche. In 1927, he succeeded Bier (Bier’s block and father of spinal anesthesia) as the chair of surgery
in Berlin. His operating room became a Mecca for thoracic surgeons worldwide. In recognition of his
treatment of Hindenburg, he was given the honorary title of State Councillor by Goering. In 1933, under
the Third Reich, Jews were being persecuted. Following a visit to Turkey, he recommended his assistant
Nissen, a Jew, for a position there. At this stage, the anesthetic management was largely by local
anesthesia, ether, and oxygen. He describes operating on the chest of a 12-year-old boy. The ether vapor
exploded as did an oxygen cylinder. “The patient was killed on the spot, the nursing sister and assistant
were injured and I lost an ear-drum.”29
FIGURE 1.1 Sauerbruch’s experimental negative chamber. The concept of the head, and thus the lungs at atmospheric pressure
and the chest at subatmospheric pressure to maintain lung expansion was transferred to a larger operating chamber. (From
Sauerbruch F. Chirurgie der Brustorgane. Berlin: Julius Springer; 1920:383.)
In Berlin, Sauerbruch became a member of the Mittwochsgesellschaft, the Wednesday Society, a club
founded in the 18th century by Wilhelm von Humboldt, where a limited membership of 16 eminent people
met alternate Wednesdays at one of the member’s houses. At these meetings the host gave a talk on a
subject from his particular field. Five of these members, a third of the society’s members, and close
friends of Sauerbruch’s, were involved with the assassination attempt on Hitler and were executed.32
In the purge that followed the failed assassination attempt, where hundreds were imprisoned, tortured,
and executed, Sauerbruch’s son Peter was arrested because of correspondence discovered between him
and von Stauffenberg, the assassin. Sauerbruch himself was interrogated, but Gebhardt, a former student
of Sauerbruch’s working with the SS and as Himmler’s doctor, convinced Hitler of Sauerbruch’s
innocence, and he and his son were released from prison. Gebhardt was hanged later after the Nuremberg
trials.
Sauerbruch continued working at Charite hospital when it was taken by the Russians in May 1945. His
eminence was well known, but his dementia caused his downfall. He continued operating, even in his
own house, where unfortunately deaths resulted. These poor results did not go unnoticed and unfortunately
were accepted and covered up for some time. “In the coming struggle of the proletariat, in the clash
between socialism and capitalism, millions will lose their lives. In the face of this fact it is a trivial
matter whether Sauerbruch kills a few dozen people on his operating table. We need the name of
Sauerbruch.” Dr. Josef Naas. Administrative Director of the German Academy of Sciences in East
Berlin.33
In 1949, a contemptuous Sauerbruch was summoned before the Denazification Tribunal where his
association with the Nazi regime and his awards were critically examined. Acquittal resulted, most likely
because of his association with the conspirators of the bomb attempt. Although neither an ardent Nazi, nor
a clear opponent, Sauerbruch cannot be considered an innocent bystander. In 1942, he was appointed
Surgeon General to the army and as such accepted experiments with mustard gas on inmates in
concentration camps. Later in 1949, he was ultimately dismissed from his position at Charite Hospital and
died in July 1951.
Despite Sauerbruch’s preeminence in thoracic surgery, his autocratic nature slowed progress in some
fields of the specialty. His rejection of Brauer’s positive head chamber, followed later by rejection of
intratracheal anesthesia, likely slowed the progress of anesthesia in Europe.34 In 1929, Forssmann,35 who
did the first catheterization experiments on himself, visited the eminent Sauerbruch hoping for a position.
Sauerbruch at the meeting stated: “You might lecture in a circus about your little tricks, but never in a
respectable German University. Get out, leave my department immediately.” A dejected, Forssmann
returned to his hospital in Eberswalde and practiced anonymously as an urologist. He later resurfaced,
now famous, when awarded the Nobel Prize with Cournand and Richards in 1954.
LUDOLPH BRAUER
Ludolph Brauer, a physician, had heard of Sauerbruch’s experiments but recognized that the chamber was
expensive and cumbersome. Brauer’s idea was to construct an airtight mask to enclose the face of the
patient. A tube carrying oxygen under pressure would pass through ether and into the mask.30 His second
concept was a chamber enclosing only the head of the animal (or patient). Later, Sauerbruch and Mikulicz
built a chamber with positive pressure around the head of the patient but soon abandoned this concept
because of the effects of anesthesia on the anesthesiologist!
Brauer,36 Sauerbruch’s nemesis, later became a major proponent of collapse therapy by induced
pneumothorax in Germany, following Forlanini’s and Murphy’s work on induced pneumothorax (see
later). In Europe, pneumothorax became the most popular form of treatment for pulmonary tuberculosis for
many years.
Brauer recognized that induced pneumothorax failed because of pleural adhesions and that a more
radical permanent solution was needed. He, also in Marburg at the same time as Sauerbruch, encouraged
Friedrich, Sauerbruch’s chief after Mikulicz, to resect 10 to 25 cm of ribs two to nine on a patient, who
luckily survived. He felt that it was important to emulate as much as possible the collapse obtained by a
pneumothorax. Friedrich later modified the operation to remove, in addition, the 1st and 10th ribs. Of the
first seven patients having the procedure, three died. In 1911, Friedrich37 reported on 27 patients with 8
deaths (30%) in 3 weeks and 2 further within a year.
FIGURE 1.2 Diagrammatic representation of the Brauer–Friedrich thoracoplasty. Note resection of portions of ribs 1 to 10.
(From Alexander J. The Collapse Therapy of Pulmonary Tuberculosis. Springfield, IL: Charles C Thomas; 1937:452.)
Brauer and Friedrich, the surgeon, made several modifications to reduce the high mortality. The team
went through phases, including removing 11 ribs in one stage; performing the procedure in two stages;
resecting ribs subperiosteally to allow regeneration and stabilization; combining the procedure with
pneumothorax and phrenic nerve avulsion; and, lastly, only removing upper ribs.38 These changes are well
documented in Alexander’s book on collapse therapy, the final version known as the Brauer–Friedrich
thoracoplasty (Fig. 1.2).
Brauer continued his interest in intrapulmonary pressures and became involved with aviation medicine
in Germany, establishing in 1927 the first German Institute of Aviation Medicine (GIAM) in Hamburg in
affiliation with the Tuberculosis Research Institute with its two large pneumatic chambers. The GIAM
was active in altitude research and the selection of pilots, as well as educating medical students in
aviation medicine, training Aviation Medical Examiners, and exploring clinical applications of
hyperbaric therapy. Brauer was forced to retire in 1934 for political reasons as the GIAM came under the
influence of the military; in 1939 it was made part of the Aeromedical Research Institute of the
“Reichsluftfahrt” Ministry.
FURTHER PROGRESS WITH VENTILATION AND ANESTHESIA

In 1910, Meltzer and Auer, working with Carrel in the Rockefeller Institute, reported their experience
with ventilation in canine experiments. Via a tracheostomy and a cannula positioned in the trachea, a
continuous stream of oxygen-enriched air was delivered with moderate pressure and maintained the lungs
in an inflated state.39,40
The first case of pulmonary surgery with positive pressure ventilation via an endotracheal tube was
reported by Elsberg41 in 1910 when Lilienthal42 performed a thoracotomy to drain a middle lobe abscess.
Acceptance of this technique was slow as endotracheal intubation was difficult and initially performed
without a laryngoscope, using either ether or cyclopropane as a deep inhalational agent. Many procedures
were instead done with a tight fitting mask or intrapharyngeal airway with hand ventilation. One of the
first reports of a cuffed tube was by Dorrance,43 also in 1910; the cuffed tube was inflated by blowing
into a mouthpiece. Tovell at the Mayo Clinic also described a cuffed tube with the assistance of V
Mueller and company. The best part of this paper was the conclusion: “To design this tube was easy. The
difficulty has been to find a rubber company that was willing to cooperate in the production of an
article that probably would not be salable in large quantities.”44
Pentobarbital (Pentothal) was discovered in 193545 and halothane in 1951.46 Paralytic agents started to
be used in the 1950s. Suxamethonium was discovered in 195147 and pancuronium in 196448 although
cruder paralytic agents were used by some from 1946.49
Magill, the anesthesiologist working at the Brompton Hospital with active thoracic surgeons such as
Tudor Edwards and James Roberts, contributed immensely to improved anesthesia. In fact, the Magill
laryngoscope for intratracheal intubation and the Magill forceps for placement of a throat pack are
instruments with which we are all familiar.50
TUBE THORACOSTOMY
Tube thoracostomy had its origins in the management of empyema. It was well known that empyema pus
needed to be drained,51 although disagreement on how it should be done existed. The grooved needle used
in the 19th century was ineffective for chest drainage, but improved with a hollow needle introduced
through a trocar.52 In 1873, Bowditch,53 in Boston, reported his experience with repeated thoracentesis in
75 cases without seeing “the least permanent evil result.”
Trousseau54,55 also reported on chest aspiration and observed that if a “piece of goldbeaters skin
(Goldbeater’s skin—the outer membrane of a calf’s intestine—a parchment traditionally used in the
process of making gold leaf by beating) or pig bladder is attached to the cannula,” one can prevent the
entry of air, but not the outflow of fluid.
It is difficult to assign priority to which the physician initiated underwater drainage. The method was
likely modified by more than one clinician at the same time. The technique likely started off by placing a
cannula and using it to evacuate fluid daily,56 then using suction and finally attaching the cannula to an
underwater system. In 1876, Croswell Hewett57 introduced a rubber tube through a cannula into the
pleural cavity and then attached it to a glass tube piercing a cork stopper, which reached the bottom of a
glass vessel containing a weak solution of Condy’s fluid (potassium permanganate); von Bülau’s58 method
differed from Hewett’s in that he used lime water.59
Early pulmonary resections were initially managed without chest tube drainage and this approach
likely contributed to the high early mortality. The chest was either simply closed or packed with sponges
that were removed later. The inevitable empyema in these circumstances was managed by prolonged open
drainage or thoracoplasty. In 1929, Harold Brunn60 reported his excellent results with lobectomy which
he attributed to his method of hilar ligation, but the improved results were more likely due to his
management of the pleural space: “the progress of the patient depends on how thoroughly the chest
cavity is kept free from air and fluid for the next five to seven days. If the pedicle is a success, if the
wound does not leak air, and if by constant suction, either with the hand syringe every two hours day
and night or some form of suction apparatus, the chest cavity is kept free of air and fluid and the upper
and middle lobes are allowed to expand, the course of convalescence is usually mild …” Nissen and
Wilson61 thought this approach was one of the most important advances in thoracic surgery.
Pulmonary resections were performed cautiously during the interwar years, but during the Second
World War necessary management of chest wounds and their consequences became standard. Familiarity
with closed underwater chest tube drainage thus became established for management of traumatic
pneumothorax, hemothorax, and postoperative management of the pleural space.62
DRAINAGE OF LUNG CAVITIES AND ABSCESSES

The adult form of pulmonary tuberculosis is characterized by cavities predominantly affecting the apex of
the upper and lower lobes. Abscess cavities elsewhere in the body are managed with simple drainage,
and therefore it is not difficult to imagine that drainage of these tuberculous cavities would be the first
surgical procedures pursued in an attempt to control the disease. Isolated reports of this surgical approach
can be found63,64; some are from an era before the discovery of radiography by Roentgen in 1885,
testifying to the clinical skills of the physicians involved. Until Monaldi65 published a series of cases in
1939, drainage was uncommonly performed; thereafter it had a period of enthusiasm, which waned after
the realization that improvement was usually temporary.
However, not all cavities were due to tuberculosis. At the turn of the 20th century, lung abscess was
common and was associated with a high mortality. The disease was common following surgical
procedures (most often tonsillectomy) and was likely due to aspiration occurring in the absence of a
protected airway. However, at that time the cause of a lung abscess was uncertain. Holman and
colleagues66 believed that postoperative lung complications were due to emboli from the operative field
rather than aspiration of infective material. In order to prove his hypothesis he introduced into the jugular
vein a small segment of femoral vein containing bacteria and a small portion of lead. The lead portion
was to aid with radiographic visualization. Of 17 experiments, lung abscess was produced in 12. Smith,67
a year later, injected into experimental animals scrapings taken from the alveolar borders of people with
moderately severe pyorrhea. Fifty percent of his animals developed pneumonia of which 20% developed
lung abscesses. His conclusions were that aspiration of infectious material from teeth and tonsils
accounted for most lung abscesses. There were many other similar experiments and eventually the
agreement that an abscess could develop either by aspiration or embolization.
In 1936, Neuhof and Touroff discussed their one-stage procedure instead of the usual two-stage
methods. They set great store in location of the abscess by fluoroscopy and bronchoscopy. At this site they
incised a small portion of the rib. The lung was usually adherent; alternatively, it was either sutured to the
edges of the defect, or an iodine-soaked sponge was placed around the periphery of the abscess. In this
area, the sponge was to stimulate adhesion, thus facilitating later drainage. The abscess was then
localized by needle and an incision made through the lung and the abscess drained (Fig. 1.3). In the initial
report, only one of the 37 patients died.68 The authors updated their series in subsequent publications69–71
culminating in their late follow-up where they noted that bronchiectasis was often present. They
recommended bronchography in all cases once recovery had occurred. In one report72 of 45 consecutive
cases, the authors noted a previous surgical procedure: tooth extraction or tonsillectomy in 19 and 17 with
severe gingivodental infection, reinforcing the experimental work of Smith. In nine patients the etiology
was obscure.
FIGURE 1.3 Diagrammatic representation of an early technique of drainage of a lung abscess. After radiographic localization, a
section of rib overlying the area is excised. In this instance the visceral and parietal pleural are not, as usually found, adherent. To
stimulate adherence before incision and drainage, an iodine-soaked gauze is packed around the periphery and the wound closed.
A few days later after the pleura have become fused the wound is reopened, the gauze is removed, and the abscess drained
without spillage of pus into the pleural space. (From Lilienthal H. Thoracic Surgery Vol II. Philadelphia, PA and London: WB
Saunders Co; 1925:245.)
Once antibiotics became available, the incidence of lung abscess decreased. As surgical procedures
became safer a phase of primary surgical resection for lung abscess became popular. However, the
pendulum is swinging back toward Neuhof’s original approach.73 Postma and Le Roux74 clearly showed
that drainage first in the acute phase had a much lower mortality than initial resection.
EMPYEMA
EVARTS GRAHAM AND THE US ARMY EMPYEMA COMMISSION

An untreated empyema is, as a rule, the direct result of the patient’s neglect or of the surgeon’s delay, or of inadequate or useless
surgery.
—Stephen Paget, Surgery of the Chest 1896
Evarts Graham is best remembered as being the surgeon who performed the first successful
pneumonectomy for lung cancer. In my opinion his greater contribution was that of managing
empyema.75,76
The United States initially was neutral when the First World War was declared, but once a decision
was made to become involved in April 1917, large numbers of troops needed to be trained. Large training
camps were set up; these overcrowded camps became fertile ground for the great influenza epidemic that
was ravaging the country at the same time, with approximately 20% to 40% of army personnel being
sickened. Influenza and pneumonia killed more American soldiers and sailors during the war than enemy
action. In fact, more than 30,000 died before leaving US shores.77 Secondary pneumonia and associated
empyema were common. Analysis of a questionnaire sent to the camps documented that a disparity in the
mortality rates between civilians and training soldiers existed: in the camps, mortality varied between
30% and 90%, whereas elsewhere it was approximately 30%.
A US Army Empyema Commission was set up headed by Graham. A previous US Army Pneumonia
Commission had found that the common offending organism in the camps was the β-hemolytic
streptococcus, whereas that in the civilian population was commonly due to an α-hemolytic streptococcus
(S. pneumoniae or pneumococcal pneumonia).78
The universal approach to treatment of empyema at that time was by means of wide open drainage,
usually by resection of one or two segments of the rib. The different organisms causing the empyema
resulted in different qualities to the pus. In the military, the massive pleural serofibrinous exudates arose
concomitantly with the pneumonia; they were synpneumonic, and the pus was thin and watery. The
exudative stage took about 2 weeks to develop and only then did compartmentalization of the empyema
occur. Empyema encountered in civilian settings, secondary most often to pneumococcal pneumonia,
usually developed after the resolution of acute pneumonia. There was early formation of fibrinous
adhesions and the pus was usually thick by the time of drainage. The cortex on the surface of the lung
prevented pneumothorax after drainage, whereas an open pneumothorax developed in the recruits.
Graham and Bell79 concluded that treatment of acute empyema should be the following: drainage, but
avoidance of an open pneumothorax during the period of acute pneumonia; early sterilization and
obliteration of the cavity; and maintenance of nutrition of the patient. However, he was cautious about
using continuous drainage as he was worried that the delirious patient would interfere with the drain and
create an open pneumothorax; instead, repeated chest aspirations became the norm.
In Camp Lee, where Graham was stationed, and using the principles advocated, the mortality rate
decreased to <5%, and other camps reported similar results when they abandoned early open drainage
during the pneumonic stage.80,81
In 1933, Graham82,83 became the first person to perform a successful pneumonectomy using the hilar
tourniquet amputation method for lung cancer on a 48-year-old gynecologist named Dr. Gilmore, who the
day before the operation had his teeth professionally cleaned and had bought a cemetery plot. The tumor
was in the upper-lobe bronchus, but was thought to extend into the main bronchus. The fissure was
incomplete. Seven radon seeds of 1 to 5 mCi each were inserted into various parts of the stump. Tumor
staging today would be T2N1M0. The operation was accompanied by a simultaneous thoracoplasty to
prevent an empyema. The patient resumed his gynecologic practice and died 30 years later at the age of
78, outliving Graham. Graham was one of the first persons to suggest that there was an increased risk of
lung cancer related to tobacco use.84 Graham himself was a smoker, and his own death was the result of
lung cancer.
Graham, in addition to a surgeon, was an innovator. He developed a cardioscope with Allen85 in 1922
and in 1924 with Cole and Copher86 developed a technique for cholecystography.
PERMANENT OPEN DRAIN

Leo Eloesser87 in 1935 described an operation for management of a chronic empyema, associated with
his name, in which he used the term flap, conjuring up visions of a doggy door, or a procedure to allow
air and purulent material to escape, but preventing air from entering the pleural space. The term flap was
no such thing; his use of the term was in the plastic surgical sense and described a skin flap with
subcutaneous tissue or muscle sutured to the inner aspect of the pleural cavity. The lining with skin kept
the drainage site open and obviated the need for use of a drainage tube. I consider the term “permanent
open drain” to be better.
Dr. Eloesser was however not the first surgeon to describe this operation. Samuel Robinson88 of the
Mayo Clinic first reported open pleural drainage in 1916 in a patient with nontuberculous empyema. Even
more amazing is that Dr. Robinson closed and obliterated the pleural cavity with intrathoracic
transposition of the latissimus dorsi muscle.
DECORTICATION
Open drainage with Carrel–Dakin solution washouts were the standard management of an empyema and in
many instances this was effective, but in some patients the space became chronic. Often, this was because
the underlying lung was abnormal (bronchiectasis). Estlander89 proposed resection of ribs overlying the
empyema space, but this only worked for shallow, localized empyemas; Schede elaborated further on this
operation. In addition to the ribs, he also excised the intercostal muscles and parietal cortex so that the
larger chest wall muscles, subcutaneous tissue, and skin fell inward and obliterated the space.90
In 1893, Fowler91 (of Fowler’s position) described a surgical approach to a chronic empyema
managed previously during the acute phase by open drainage. His intention was to excise the chronic
sinus and obtain better drainage, but in removing the fibrosis surrounding the sinus he found that he could
free the cortex from the lung, diaphragm, and pericardium. The cavity was packed with gauze and
irrigated daily. Four weeks later the lung had expanded and obliterated the cavity. Delorme92 in France
and Lambotte93 in Belgium described similar cases the following year. The procedure was reintroduced
by Lilienthal94 two decades later who also started to use the procedure for traumatic hemothorax. In 1923,
Eggers95 reported his large experience of decortication (146 patients) collected from his army service
and civilian service with an operative mortality of 3.4%. His procedure is very similar to the current
operation except that underwater drainage was not used. Eggers should also be remembered as the young
resident surgeon who gave the anesthesia for Torek’s historical esophagectomy.
COLLAPSE THERAPY
James Carson96 of Liverpool is credited with being the first to propose compressive therapy, largely
through creating a pneumothorax for the treatment of apical tuberculous cavities (Table 1.1). His
reasoning was: “the diseased part would be placed in a quiescent state and not be disturbed by the
movements of respiration, and the divided surfaces (the cavity walls) would be brought into close
contact by the same resilient power (air) which before had kept them asunder.” He thought that bilateral
disease could be managed by alternating the pneumothorax.
TABLE 1.1 Variations of Collapse Therapy and Terminology Used

Pneumothorax Therapy
Pneumolysis: the division of adhesions
Open pneumolysis—Done with a thoracotomy
Closed pneumolysis—done blindly, or with fluoroscopy
Intrapleural pneumolysis—done with thoracoscopy
Thoracoplasty: removal of ribs to cause collapse
Apicolysis: mobilization of lung in the extrafascial plane
Extrapleural pneumolysis: mobilization of lung in the extrafascial plane. The space created was filled with either:
Air (extrapleural pneumothorax)
Pedicled muscle
Oil and wax (oleothorax)
Inflatable rubber bags
Polyethylene sheeting
Lucite balls
Phrenectomy: division or crushing of the phrenic nerve
Pneumoperitoneum
CARLO FORLANINI AND PNEUMOTHORAX THERAPY

In 1882 Forlanini97 of Pavia, 60 years after Carson’s proposal, published his first report on artificial
pneumothorax. He had noted that some patients with tuberculosis, who developed a pneumothorax, rather
than a pyopneumothorax, seemed improved. He developed a therapeutic approach of injecting into the
chest small daily volumes of nitrogen, because it tended to get absorbed slowly, until he believed
sufficient quantity was present. He justified his approach by stating: “the lung shrivels … the lung no
longer breathes … the lung that cannot breathe anymore, cannot anymore cough or expectorate.”
Forlanini’s initial report was overshadowed by Koch’s famous lecture12 and report of the same year. The
technique resurfaced in 1894 when Forlanini’s second article98 was published and the results presented in
Rome.
John Murphy, the famous Chicago surgeon, heard of Forlanini’s work and sent his assistant, William
Lemke99 to learn about the procedure. Murphy100 characteristically popularized the procedure so that in
Germany, where it was adopted by Brauer,36 it became known as the Murphy operation.
There existed differences of opinion between Forlanini and Murphy and Lemke. The latter advocated
instilling large volumes of nitrogen in the early stages of disease, before adhesions had formed,101 with
short treatment duration. Forlanini,102 in contrast, was less cavalier and believed that pneumothorax
needed to be maintained for years. These procedures were initially done before radiographs and
depended on clinical ability to determine the diagnosis and extent of treatment. In Europe, pneumothorax
therapy became the dominant form of treatment for many years, but was only used more frequently in the
United States from the mid 1920s.
JACOBEUS AND PNEUMOLYSIS

It soon became apparent that the major problem with induced pneumothorax as a treatment modality was
the presence of adhesions preventing adequate collapse. The frequent inability to completely collapse the
lung with an induced pneumothorax spawned other operations to affect collapse. Pneumolysis procedures
were performed to divide the adhesions so that a pneumothorax would be possible. The open operation
was first performed by Friedrich37 in 1908, but the patient died. Other surgeons also performed the
procedure with poor results and frequent complications, such that the procedure was basically
abandoned. The next attempted step was closed intrapleural pneumolysis where attempts to divide the
adhesions without thoracotomy were made. This procedure was usually done after pneumothorax therapy
had demonstrated on the subsequent radiograph tethering of a portion of lung to the chest wall. Some of
these attempts were made using fluoroscopy but were soon abandoned because of poor definition.103
The procedure that made closed intrapleural pneumolysis possible was thoracoscopy, devised by
Jacobeus of Stockholm,104–106 the forerunner of modern day video-assisted thoracoscopic and
laparoscopic surgery. He used a cystoscope-like instrument introduced through one intercostal space, with
a cautery instrument introduced through another.
JOHN ALEXANDER AND THORACOPLASTY

John Alexander107,108 the 17th president of the American Association for Thoracic Surgery, was himself
afflicted with tuberculosis and wrote two books (Table 1.2), one of which was 700 pages, on the collapse
therapy of tuberculosis, while himself bedbound (therapeutic approach) and recovering from his own
thoracoplasty. His own selected passages are included in an attempt to demonstrate to the reader his, and
others, rationale for lung collapse therapy and strict bed rest enforced in a sanatorium. These concepts are
somewhat difficult to understand given current thinking.
Individual resistance to the disease, which could be influenced by environmental factors or tuberculin therapy, was likely the most
important factor for healing. The next most important factor—the most important one capable of control—is functional rest of the
diseased part. Rest is the keystone of successful treatment of tuberculosis of any organ and the more completely it can be achieved
the better is the result. Compression therapy, whether by artificial pneumothorax or by thoracoplasty or other surgical method
causes partial or complete rest of the more diseased lung. Thereby the most important condition for the repair of the tuberculous
lesion is accomplished.
Next to rest probably the most important clinical effect of compression therapy is the lessening in size of the cavities, ulcers and
other tuberculous lesions and of the alveoli and smaller bronchi.”
He likened the compressed lung being emptied of its waste products being “like a pressed sponge.”
He reported that:
“cavities whose walls are not very stiff are obliterated to mere clefts by thoracoplasty; mechanical compression accomplishes part
of this and secondary fibrous shrinkage the rest. The clefts then fill with granulation tissue rich in blood vessels and become
obliterated, or a smooth clean mucous membrane replaces the previous dirty lining.”
Alexander was clearly passionate about collapse therapy. Collapse therapy and its variations, rather
than excisional therapy, were the prominent means of surgical management of tuberculosis until
antituberculous drugs were discovered. In fact, Alexander,108 in the chapter on the Evolution of Surgical
Therapy in his book, places the description of pulmonary resection into the section “proposed operations
which have not been generally adopted.”
Thoracoplasty was actually initially used to manage empyema90 before being considered for
management of pulmonary tuberculosis. Today it is no longer used as primary therapy for tuberculosis but
is occasionally used to manage a chronic empyema. The circle has been completed. Indeed, de
Cerenville64 of Lausanne was the first to perform the operation for tuberculosis, and reported on four
cases with apical cavitary disease. However, he only removed small portions of anterior ribs.
Subsequently, Brauer37 and Friedrich,38 mentioned earlier, popularized the procedure (Fig. 1.4).
TABLE 1.2 Variations of Thoracoplasty (Main Proponents)

Estlander: localized removal of ribs over an empyema
Schede: removal of ribs, intercostal muscles and cortex over an empyema
Brauer–Friedrich thoracoplasty: a radical thoracoplasty with removal of ribs 1–9 for tuberculosis
Wilms–Sauerbruch or paravertebral thoracoplasty: removal of ribs paravertebrally, done for tuberculosis
Alexander thoracoplasty: a more tailored thoracoplasty where the ribs supplying the upper third to half the chest were removed. Often
done as a staged procedure.
Bjork or osteoplastic thoracoplasty: Often done in association with an upper lobectomy where the remaining lobes were unlikely to fill
the space. Ribs were divided anteriorly and posteriorly and the flap of ribs and intercostal muscles were turned down and sutured in
place.
FIGURE 1.4 Brauer–Friedrich thoracoplasty. Note the large U-shaped thoracotomy. (From Sauerbruch F. Chirurgie der
Brustorgane. Berlin: Julius Springer; 1920:737.)
Meanwhile, Wilms109 of Heidelberg and Sauerbruch, Friedrich’s previous pupil now working in
Zurich and operating on patients with tuberculosis at the tuberculous sanatorium at Davos, independently
developed operations that were a compromise between the earlier limited, low-risk, but less successful
de Cerenville’s procedures and the extensive, high-risk Brauer’s and Friedrich’s procedures. Their
operations were more conservative in that they preferentially resected the posterior portions of the ribs
and transverse processes of the thoracic vertebra. This operation became known as an extrapleural
paravertebral thoracoplasty (Fig. 1.5A–C). Both surgeons modified their procedures over time.
Sauerbruch, in particular, performed hundreds of thoracoplasties. The author’s own mentor, Andrew
Logan, visited Sauerbruch in Berlin before the Second World War and described him performing a
thoracoplasty in approximately half an hour. Logan described that alongside the patient was a metal table
covered in sterile towels. As each portion of the rib was removed, still attached to the rib cutter, the
impatient Sauerbruch would strike the instrument loudly against the metal table, causing the rib fragment
to fly off the instrument around the room. Rib fragments were flying around the room at roughly 1- to 5-
minute intervals.23
FIGURE 1.5 Wilms–Sauerbruch paravertebral thoracoplasty. The procedure was done under local anesthesia using an incision
made between the medial border of the scapular and the vertebra (A,B). (From Sauerbruch F. Chirurgie der Brustorgane.
Berlin: Julius Springer; 1920:371, 741.) The extent is diagrammatically demonstrated in (C). Note the transverse processes are
also removed. (From Alexander J. The Collapse Therapy of Pulmonary Tuberculosis. Springfield, IL: Charles C Thomas;
1937:450.)
FIGURE 1.6 What Alexander called the “modern” thoracoplasty. This operation was staged. Note the removal of the 1st rib
and transverse processes. (From Alexander J. The Collapse Therapy of Pulmonary Tuberculosis. Springfield, IL: Charles C
Thomas; 1937:452.)
The surgeon who popularized the procedure in the United States was Alexander. The number of ribs
resected usually was not more than seven to nine and tended to be of the same extent as the Brauer–
Friedrich operation. Portions of the posterior and lateral ribs are removed, but usually no more than two
to three ribs at one time, requiring staged procedures (Fig. 1.6). In Alexander’s108 hands, the mortality
was approximately 10%, with sputum negativity accomplished in approximately 75% of survivors. This
figure compared favorably with the Brauer–Friedrich mortality of approximately 30%, with 35% sputum-
negative patients.
Up until the Second World War, thoracoplasty was a predominant operation for tuberculosis in the
United States. Conversely, in Europe, it was probably pneumothorax therapy that was predominant,
although thoracoplasty was commonly performed. It is not difficult to imagine why thoracoplasty was
popular. The operation involved the chest wall, and efforts were concentrated on keeping extrapleural;
intrapleural operations were more difficult because of the extensive adhesions generally present. Almost
all operations were performed using local anesthesia in order that the patient could cough and expectorate
during the operation and so prevent contralateral spread. During those early four decades of the 20th
century, there were no antibiotics, blood banks, double-lumen endotracheal tubes, or accurate monitoring
of oxygen saturation or continuous arterial blood pressure. A thoracoplasty was obviously a safer
procedure for most surgeons.
In many of the patients undergoing a thoracoplasty, the apex did not adequately collapse, and some
surgeons added pneumolysis to the procedure. Carl Semb,110,111 instead of mobilizing the lung in the
intrapleural plane, did it in the extrafascial plane and this part of the procedure became known as
apicolysis (Fig. 1.7A–C).
PHRENICECTOMY
Alexander108 devoted three chapters of over 60 pages in his book on collapse therapy to this subject. The
procedure likely did more harm than good, but the reader needs to appreciate the context in which this
largely irreversible procedure took place.
The procedure was first advocated by Stuertz112 in 1911 who felt that phrenicectomy could release a
diseased lower lobe, constrained by pleural adhesions, which could not be otherwise collapsed by an
induced pneumothorax. He felt it might be useful when tuberculosis involved the lower lobe or where
there was a bronchiectatic cavity.
Two years later, Sauerbruch,113 apparently without knowing Stuertz’s proposal, reported on five cases
(three with tuberculosis and two with bronchiectasis) of phrenicectomy with postoperative improvement.
The operation could be simply done in the neck and became soon popular throughout the world.
Phrenicectomy was even preferred to pneumothorax therapy, which was often unsuccessful due to
adhesions and the repeated need for refills. As phrenic nerve division often did not result in complete
collapse because of regeneration of the nerve or the presence of an accessory phrenic nerves, fiber
avulsion (Fig. 1.8)114,115 or a more radical resection were pursued.116 Others, such as Friedrich,117 simply
crushed the phrenic nerve hoping that recovery would occur.
Alexander clearly believed the procedure had a role and used it as a first choice over pneumothorax
therapy in 63% of cases.118 He did however attempt to categorize patients who would respond to either
pneumothorax or phrenicectomy.108
EXTRAPLEURAL APICAL PROCEDURES

The following procedures are included under collapse procedures because they were devised according
to the apicolysis technique popularized by Semb.110,111 In addition, many of the procedures were also
performed in combination with thoracoplasty. The rationale for these procedures, if done alone without
thoracoplasty, was the desire to avoid disfigurement and paradoxical movement of the chest wall.
In 1891, Tuffier119 performed an extrapleural dissection before his apical resection. Two years later he
performed a successful extrapleural apical dissection (apicolysis) for severe hemoptysis. In 1910, he
performed a similar procedure in which he filled the space with body fat, hoping to establish a permanent
collapse.120 Thereafter, a series of different collapse procedures in which the apex of the lung was freed
extrapleurally (called extrapleural pneumolysis) were described. In these procedures, the space between
the extrapleurally mobilized lung and the unresected chest wall was filled with either air (extrapleural
pneumothorax),121,122 pedicled muscle (Fig. 1.9A,B),123–125 fat (Fig. 1.10A–C), oil and wax (oleothorax)
(Fig. 1.11),126 inflatable rubber bags (the forerunner of tissue expanders),127 polyethylene sheeting,128 or
hollow spheres of polymethyl methacrylate (Perspex).129
FIGURE 1.7 Extrafascial apicolysis with thoracoplasty. A, B: After the apical ribs have been resected, the fibrous attachments
on the medial aspect are divided and swept downwards. Intercostal bundles are divided posteriorly to allow the extra fascially
mobilized upper lung to be displaced inferiorly. C: Demonstrates, using other views what is achieved. (From Semb C.
Lungenchirugie. Berlin und Wien: Urban and Schwarzenberg; 1944:274, 275, 262.)
Despite attempts at sterilizing the foreign material, in most patients infection ensued with the
subsequent creation of chronic sinuses, empyema, and fistulous tracts. Occasionally, patients survived and
decades later their chest radiographs became the subject of interesting historical teaching.130
FIGURE 1.8 Phrenicectomy. The phrenic nerve may be simply cut, or, in this instance avulsed by twisting the nerve around a
hemostat. Done in this manner the patient “will complain of thoracic and abdominal pain.” (From Lilienthal H. Thoracic Surgery
Vol II. Philadelphia, PA and London: WB Saunders Co; 1925:516.)
UNUSUAL OPERATIONS UNDERTAKEN IN AN EFFORT TO CONTROL

TUBERCULOSIS
At the turn of the 20th century, tuberculosis was the commonest cause of death and attempts to treat this
disease prompted use of many unusual bizarre medications and surgical approaches. Some of these
surgical approaches will be briefly described.
In 1858, as reported by others4,131 (no original report can be found), Freund concluded, on the basis of
necroscopy observations, that active apical tuberculosis was more common in those patients whose first
rib was shorter or whose first cartilage was stiffer than normal. He also noted evidence of healed
tuberculosis in cadavers where there had been spontaneous rupture of the first costal cartilage and false-
joint formation. The absence of apical tuberculosis in children was explained by the apex of the lung
being inferior to the 1st rib, and therefore uninfluenced by abnormalities of the 1st rib. He advocated
subchondral resection of about 0.5 cm of the 1st rib cartilage and interposition of a portion of pectoralis
major. This bizarre operation with illogical basis was popular for some time but was the first attempt at
managing pulmonary tuberculosis by a surgical procedure involving the chest wall.
Scaleniotomy and scalenectomy, that is, the division or excision of the scalene muscles in the neck,
were advocated to lessen respiratory movements of the upper lung.132 These procedures were usually
performed in association with a collapse procedure or to assist the resection of the anterior portion of the
1st rib during a subsequent thoracoplasty.
In 1913, Alvarez133 operated on four patients with advanced tuberculosis. He stretched the 2nd, 3rd,
and 4th intercostal nerves in order “to paralyze by excess of stimulation via the rami communicantes,
the vasoconstrictor fibers supplying the lung.” He hoped that congestion of the lung would be produced
and that the hyperemia would influence the disease. The dyspnea and dullness that lasted 3 to 6 days was
attributed to encroachment upon the alveolar spaces by the dilated blood vessels, rather than the likely
pneumothorax or hemothorax. As a consequence, three of the four patients soon died. He later reported on
a further 12 patients, who were improved, but not cured, because they did not complete the sanatorium
treatment134!
Alexander135 continued the theme of operating on the intercostal nerves and devotes a whole chapter
on this in his book. The basis for his operation was to further promote pulmonary rest as stressed earlier
in the chapter. In an effort to prevent paralysis of the upper abdominal muscles, he only paralyzed the 2nd
to 9th nerves. Others attempted to perform the same procedure using alcohol injections.136
FIGURE 1.9 Extrapleural pneumolysis using pedicled pectoralis major muscle. The pectoralis is major muscle with its humeral,
sternal and rib attachments divided, but with the vascular pedicle preserved, is slipped into the space created extrapleurally
beneath the upper ribs. (From Alexander J. The Collapse Therapy of Pulmonary Tuberculosis. Springfield, IL: Charles C
Thomas; 1937:408.)
FIGURE 1.10 Autogenous fat utilized for extrapleural pneumolysis. Fat removed from the abdomen or buttock, or “a lipoma, if
available” is placed in the space created (A, B). The intended collapse of the cavity is also shown (C). (From Lilienthal H.
Thoracic Surgery Vol II. Philadelphia, PA and London: WB Saunders Co; 1925:448, 455.)
In 1921, Sayago137,138 proposed placement of a bone graft removed from the tibia and placed in a
subpleural position between the 1st and 4th ribs. The presence of the graft was to stimulate a reaction in
the lung, increasing blood supply and causing growth of fibrous tissue which would encapsulate the
tuberculous lesions. Three patients had the procedure: one died, “one improved,” and one had a
thoracoplasty at a later date.139
Ligation of the pulmonary artery was initially reported by Sauerbruch4 and later by Schlaepfer,140,141
who also did animal experiments in order to assess effectiveness. The lungs shrunk to approximately half
their normal size; collateral bronchial arteries enlarged and the alveoloar walls became thickened. Based
on these experiments, Schlaepfer141 recommended ligation of the lobar branches in conjunction with
phrenic paralysis, in preference to collapse therapy using pneumothorax or thoracoplasty. As reported by
Alexander,108 Baumgartner and also Eloesser proposed ligation of the pulmonary artery and veins in
patients with severe hemoptysis. Blood supply from pleural adhesions was expected to keep the lung
viable. Others proposed simply ligating the pulmonary veins to the affected lobe.142 Significant pleural
adhesions made the surgical intent difficult and only a small series of patients were reported.
The vascular approach to tuberculous surgical treatment was even more unbelievable. In 1929,
Babcock143 divided the common carotid artery and jugular vein on the side of the involved tuberculous
lung and anastomosed their proximal ends. His theory was that diversion of blood would decrease the
rate and amplitude of respiratory movements as well as produce a hyperemia around the tubercles. After
17 days he claimed that the reduction of the respiratory rate to 11,500 respiratory cycles per day had
saved the 28-year-old patient, who was discharged with a less productive cough.
The resort to induced bronchial stenosis to cure tuberculosis was suggested by Adams.144,145 In
experimental animal models, he had induced bronchial stenosis by application of 35% silver nitrate
through a bronchoscope. After injecting tubercle bacilli into the blood stream and thereby inducing
bilateral pulmonary lesions, these healed quicker in the atelectatic lobes.145 Of the five patients he
reported on, only one had questionable benefit.145
FIGURE 1.11 Ladles used to instill heated liquid paraffin wax into the apical space. The wax solidified at body temperature.
(From Sauerbruch F. Chirurgie der Brustorgane. Berlin: Julius Springer; 1920:363.)
EMPHYSEMA
The clinical features of emphysema were well known and some of these were thought to be responsible
for the patient’s symptoms. For example, it was noted that emphysematous patients leaned forward when
breathing. This was believed to be an adaptive process to increase the curvature of the diaphragm. In fact,
abdominal compression belts were successfully used in the 1930s in an attempt to restore diaphragmatic
curvature.146 In similar context, others used pneumoperitoneum in the acute moribund states with some
patients obtaining symptomatic relief.147–149
The large barrel-shaped chests of patients with emphysema resulted in speculation that the lungs had
grown too large and that the chest cavity needed to be made bigger to accommodate the lungs. Freund150
(Fig. 1.12) advocated costochondrectomy or transverse sternotomy to provide more room. In complete
contrast, others thought the chest had grown too large and advocated thoracoplasty to reduce the size of
the chest!
Other bizarre procedures were also advocated, such as pleurodesis, to improve the blood supply of the
lung (because emphysema results from alveolar wall ischemia): phrenectomy, because overvigorous
inspiration was ripping alveolar walls and hilar denervation in an attempt to decrease
bronchoconstriction and mucous production mediated by the parasympathetic nervous system.151
FIGURE 1.12 Freund’s operation for emphysema. He divided the costal cartilages in the belief that this would enlarge the chest
cavity to better accommodate the large lungs. (From Sauerbruch F. Chirurgie der Brustorgane. Berlin: Julius Springer;
1920:457.)
Whole lung irradiation did have some success152; its rationale was that induced fibrosis would result
in increased elastic recoil. Brantigan153 showed that multiple wedge resections resulted in some
symptomatic improvement in patients with emphysema. This report prompted Joel Cooper et al.154 to
initiate what has become known as lung volume reduction surgery.
PULMONARY RESECTIONS
The early pioneers of thoracic surgery had many concerns, which are listed in Table 1.3, and which will
serve as a framework for this section of the chapter.
Paget’s book of 1896155 is famously quoted by cardiac surgeons: “Surgery of the heart has probably
reached the limits set to nature,” but he was just as pessimistic with regard to pulmonary resection for
tuberculosis, “the indications for the operation are so doubtful, the advantage of it so uncertain, and
the proportion of deaths from it so large, that at present there is no clear reason why the surgeon
should undertake it.”
TABLE 1.3 Concerns Regarding Pulmonary Resection

1. How to enter the chest.
2. What will happen when large vessels are suddenly ligated?
3. How to avoid infection within the pleural space.
4. How to avoid spillage of pus into the contralateral lung.
5. How to close the bronchial stump.
6. How to seal the raw surface of the lung.
7. What will happen to the space previously occupied by lung?
8. How extensive should the surgical procedure be?
ENTRY INTO THE CHEST

Initial entry into the chest was simply by rib division. Later, rib spreaders were devised by von Mikulicz
with Sauerbruch and Lilienthal with minor modifications by others.156 The rib spreader used currently by
the majority of thoracic surgeons was devised by the Argentinian surgeon, Finochietto.157 In addition to
the problem with an open pleural space, there were no vascular clamps—the only clamps remotely
resembling current vascular clamps were Wertheim right-angle hysterectomy clamps, the only suture
materials were silk and catgut, there were no swaged needles, and most of the suturing was done with
handheld large needles.
LIGATION OF PULMONARY ARTERIES

Although experimental surgeons had described individual ligation of hilar vessels,158,159 it was not
initially considered safe to encircle the large vessels found in the hila of human lungs, nor to ligate these
vessels with silk. There existed concern that sudden ligation of a major pulmonary artery would produce
the clinical picture seen with acute pulmonary embolism. Even Graham in his famous pneumonectomy
case, temporary occluded the main pulmonary artery and observed the patient before ligating the artery.
Why was individual vessel ligation not pursued? Did surgeons forget what experimental surgeons had
described? In pondering these answers one must recognize that there was a marked discrepancy in size of
experimental animals’ hilar vessels compared to that of a human’s. The experimental animal was healthy,
whereas the patient at the time needing surgery (usually inflammatory lung disease) had marked
lymphadenopathy and fibrosis around the hilar vessels making encirclement difficult and hazardous. Willy
Meyer,160 who attempted the first pneumonectomy, lost a patient intraoperatively when attempting to pass
a ligature around the artery. Anesthetic practice at the time also required that the operation be performed
rapidly. Instead, the whole hilum was encircled with a serrenoeud, Shenstone snare161 or variation
(similar to a Rummel tourniquet). The vessels hopefully thrombosed, the lung infarcted and was then
removed a few days later. Some surgeons utilized the snare to control the hilum, then transected the distal
lung and individually sutured the vessels and bronchus with chromic catgut (Fig. 1.13). The inevitable
empyema was usually managed by open drainage or thoracoplasty. In a similar fashion, some surgeons left
clamps on the hilum and removed them a few days later. This tourniquet technique may seem barbaric
when viewed from current experience, but it did offer some benefit in that spillage of infected material
was somewhat reduced by placing the tourniquet early in the procedure.
Lilienthal’s162 technique of lobectomy is shown. Only the lobe to be removed was dissected free. If the
pleural space overlying other lobes was nonadherent he placed iodoform gauze strips over them and
removed the strips 48 hours later (Fig. 1.14A,B). A week later, he proceeded with the lobectomy, leaving
the now adherent lobe in place (Fig. 1.15A–E). He sutured the hilar structures en masse with individual
sutures and left the ends of the sutures long and attached to a safety pin positioned under the skin, so that
tension was placed on the pedicle, to steady the mediastinum when the patient coughed or strained. He
also enclosed the stump in a “rubber dam” so that the inevitable fistula and empyema would localize.
Between 10 and 18 days after lobectomy the stump sloughed, the rubber dam and sutures were removed.
Further healing was followed by granulation tissue and contraction of the wound. Almost every
pulmonary resection was accompanied by phrenicotomy, to keep the diaphragm immobile.162
AVOIDANCE OF SPREAD TO THE CONTRALATERAL LUNG

Surgical resections were initially done for bronchiectasis and tuberculosis; it was rare to do an operation
for lung cancer. Spinal anesthesia was used in the beginning of surgical resections to preserve the cough
reflex so that any pus expressed during manipulation would be coughed up. Archibald, in 1934, utilized,
to block the bronchus, a coude catheter to which a balloon was attached. The patient was initially deeply
anesthetized with chloroform and the catheter was then manipulated blindly, as best as possible, into the
lobe to be excised and the balloon inflated.163 Once positioned anesthesia proceeded with a nitrous
oxide–oxygen mix. Overholt initially advocated the prone position to avoid spillage.164 Double-lumen
tubes to protect the contralateral lung from spillage and the development of pneumonia did not exist, until
Carlen, the otolaryngologist working with Viking Bjork165 devised in 1950, a double-lumen tube.
FIGURE 1.13 Roberts tourniquets used to control the hilum of the lung (A). A ratchet mechanism kept the snare tightened.
Some surgeons closed the chest around the metal tube and tightened the snare over days leading to infarction of the lung. In (B)
two tourniquets are used to control the hilum during a lobectomy. (From personal collection (A) and Semb C. Lungenchirugie.
Berlin und Wien: Urban and Schwarzenberg; 1944:189.)
FIGURE 1.14 Lilienthal’s technique of creating adhesions over the lobe that is nonadherent and to be retained. Iodoform gauze
strips are placed in the space and with safety pin attached (A) are left in place and buried subcutaneously for 48 hours (B) and
then removed. Lobectomy follows a week later. (From Lilienthal H. Thoracic Surgery Vol II. Philadelphia, PA and London: WB
Saunders Co; 1925:162–163.)
HOW TO CLOSE THE BRONCHIAL STUMP

A major problem was management of the bronchial stump. Management of the bronchus was variable;
some simply ligated the bronchus with silk sutures, but others covered the bronchus with pericardium or
lung tissue and some even managed it similar to an appendix by inverting the crushed bronchial stump
(Fig. 1.16). Quinby and Morse166 working in the laboratory of the Harvard Medical School did numerous
experiments relating to lung resection and found that healing of the cut bronchus depended on the amount
of peribronchial tissue that happened to be present. Reinhoff et al.167 at Johns Hopkins did further
research and his technique was adopted by others. He stressed three important rules: avoid devitalization,
preserve blood supply around the bronchus by using a minimum of sutures, and cover the bronchus with
adjacent tissue.
In these early days mortality was extremely high. Gaensler168 described the not uncommon horrific
postoperative event: “Either the patient suddenly turned blue and died because the bronchial stump
had blown, or the patient suddenly turned white and dies when the artery had blown.”
HOW TO SEAL THE RAW SURFACE OF THE LUNG

Today, we have staples to separate lobes and segments and have hemostatic and other agents to seal the
raw surface of the lung. The early surgeon had basically nothing but some attempted to use a large
soldering iron to perform lobectomies (Fig. 1.17); indeed, a better term to define this procedure would be
lobe destruction as no specimen was available to send to the pathologist and to seal the raw
surfaces.169,170
WHAT WILL HAPPEN TO THE SPACE PREVIOUSLY OCCUPIED BY LUNG

Another more theoretical concern was compensation after removal of a lobe or lung. Will the remaining
lung fill the space? How will it happen? In the experimental animal model with a flaccid mediastinum, the
remaining lung filled the empty pleural space. Mollgard171 believed compensatory emphysema occurred:
“if the heart is strong, the distension is much less, but if it is weak, the emphysema may reach a
marked degree.”
When Graham did his pneumonectomy he did not know, as we know today, that the space fills with
fluid. He combined his operation with a thoracoplasty. This decision was correct at the time because a
bronchial fistula was the norm rather than the exception. It was only once control of the bronchus became
routine that the space was left to fill with fluid—but who decided that this approach was safe is still
uncertain.
Space problems after pulmonary resections were common and likely contributed to the high mortality
associated with early pulmonary resections because drainage was not routinely practiced (see comments
in section on underwater drainage).60 This was the likely reason that Lilienthal attempted mediastinal
stabilization with long hilar sutures (Fig. 1.15E).
As surgical procedures evolved, the issue of the residual space after lobectomy and its effects on
morbidity were commonly recognized, particularly in patients having upper-lobe resection for
posttuberculous cavities or bronchiectasis. The fibrotic lower lobe/lobes often did not expand to fill the
remaining space. Viking Bjork172 introduced “osteoplastic thoracoplasty” as a complement to upper
lobectomy. He created a flap of chest wall by resecting posterior portions of ribs two to four and then
attaching the flap of chest wall to the 5th rib.
FIGURE 1.15 Lilienthal’s technique of lobectomy. A: The tourniquets similar to (B) are not shown. Sutures are being placed in
the hilum of the lung remaining. The stump to be left behind appears smaller than usual. Note that the sutures are not swaged. B:
Note the long stump in relation to the lobe remaining and the multiple sutures kept long. C: A rubber dam encircles the stump and
sutures. D: The stump within the dam is washed with iodoform; then the sutures and dam are directed through one side of the
closed wound and buried subcutaneously. E: The sutures are attached to a safety pin and anchored in the subcutaneous tissues in
order to stabilize the mediastinum. When the stump sloughed 10 to 18 days later, the wound was reopened in the area of the pin
and the sutures and rubber dam removed to create a controlled fistula, which hopefully healed over time. (From Lilienthal H.
Thoracic Surgery Vol II. Philadelphia, PA and London: WB Saunders Co; 1925:154–159.)
FIGURE 1.16 Sauerbruch’s technique of bronchial closure. He closed the stump in a similar fashion to an appendix stump.
(From Sauerbruch F. Chirurgie der Brustorgane. Berlin: Julius Springer; 1920:424.)
FIGURE 1.17 Lobe destruction for bronchiectasis using a soldering iron. The image this description portrays is the smell of a
burning lung and the device that heated the soldering iron. (Reprinted from Ballon H, Singer JJ, Graham EA. Bronchiectasis. J
Thorac Surg 1931–1932;1:502–561. Copyright © 1931 The American Association for Thoracic Surgery. With permission.)
EVOLUTION OF SURGICAL PROCEDURES AND THE EXTENT OF SURGERY

As stressed repeatedly, the first pulmonary resections were in the hope that tuberculosis could be
controlled. Block’s disastrous operation on his cousin was described earlier. Other early attempts at
resection were made, with similar poor results. Tuffier120 in 1891 and Doyen173 in 1895 reported
sporadic success with wedge excisions of apical lesions approached in an extrapleural manner.
In 1907, Gluck174 successfully performed a lobectomy on a 5-year-old. The first lobectomy for
tuberculosis in the United States was performed by Babcock175 in 1908. The right lower lobe was
delivered through the chest wall and clamped sequentially and oversewn. The patient died and, at
postmortem, the remaining lobes were atelectatic and had tuberculosis. A hiatus of 27 years followed
before the next reported lobectomy for tuberculosis in the United States.176
In 1912, Morriston Davies177 in England operated on a patient with a right lower-lobe squamous
carcinoma. The lower lobe vessels were ligated individually and the bronchus was oversewn and
covered with an adjacent portion of lung. The patient died with an empyema on the eighth day. Since then,
the technique of individual vessel ligation seemed to be forgotten; in 1940, when Kent and Blades178
described the technique, they intimated that it was new.
During the next several years, resections were performed sporadically and in small numbers. At the
meeting of the American Association of Thoracic Surgery in 1938, 18 cases were reported; at the 1940
meeting, 50 cases were reported, with 16 deaths.179 In the discussion, resection was suggested to be
better after thoracoplasty to diminish the dead space and possibility of infection; others emphasized that
resection was dangerous. Resection was not actively pursued as a means of managing tuberculosis,
because collapse therapy and its variations were the preferred treatment options. Surgical resection
tended to be performed in patients in whom collapse therapy had failed, those whose cavities had not
collapsed, those who had a stenotic bronchus, and, those who experienced recurrent hemoptysis—all
patients who would be expected to have a high mortality.
In 1943, Churchill and Klopstock180 challenged the prevailing view of resection following collapse
therapy and once all other options had failed. They published a small series in which patients with lobar
involvement underwent lobectomy using the individual vessel ligation technique rather than thoracoplasty.
They believed that lobectomy was more conservative of pulmonary function than a seven-rib
thoracoplasty. After this report,181 the surgical attitude swung to some degree against collapse therapy and
toward surgical resection primarily. However, mortality was still high in the prestreptomycin era; in
1946, Overholt and colleagues181 reported 200 cases with a mortality of 25%. Four years later, after
several years of streptomycin use, the picture was different; the morbidity and the mortality after surgical
procedures performed for tuberculosis had decreased dramatically.
Chamberlain182 of New York proposed segmental resection to control the disease. He noted that
tuberculosis was commonly localized to three segments: the apical and posterior segments of the upper
lobe and the superior segment of the lower lobe; by 1953, he had performed 300 cases with a low 3%
mortality.
Resectional lung surgery was very infrequently performed for carcinoma because of the advanced
presentation of disease. In the event of early diagnosis, resection was regarded as a simpler technical
procedure than for tuberculosis.183 In this setting, surgery for bronchiectasis mirrored the experience of
that for tuberculosis in as much as, at the beginning, the mortality was extremely high. In 1923, when
Ballon et al.169 reviewed the literature on lobectomy for bronchiectasis, he found a success rate of only
17% with an operative mortality of 52%. In 1940, pneumonectomy and lobectomy for tuberculosis had a
mortality of 40% to 50% and 20% to 25% for lobectomy, respectively.183 Surgeons also started to
advocate staged operations.183–185 Coryllos’s approach included in increasing order of invasiveness,
artificial pneumothorax, phrenicotomy, thoracoplasty, and lobectomy by cauterization (as advocated by
Ballon et al.169) or exteriorization. For these procedures, he also recommended spinal anesthesia.
In 1931, Ballon et al.169 described 212 patients operated on for bronchiectasis with a two-stage
operation and reported a 34% mortality (72 deaths). The initial removal of several ribs was followed 10
days later by repeated cauterizations taking place several weeks apart using a large soldering iron.
Postoperative infection was regarded as a normal consequence of the operation and was managed by
prolonged drainage or thoracoplasty. Numerous bronchial fistulae were left allowing the pus to drain via
the wound rather than be coughed up. In Lilienthal’s book162 he emphasizes: “the skin wound should not
be sutured. This is a rule without exception.” The italics are his words.
Graham and Singer’s82,83 successful pneumonectomy for lung cancer to some extent influenced
surgeons to view pneumonectomy as the appropriate standard procedure for lung cancer. In 1950, the
presentation by Churchill and colleagues186 at the AATS meeting, in which they compared results of 31
lobectomies with 87 pneumonectomies with comparable survival, engendered considerable discussion.
Many considered lobectomy, in situations where pneumonectomy would have been tolerable, somewhat
heretical. Graham stated: “We should distinguish between the ideal operation for cancer and one which
theoretically is not ideal but will sometimes work.” Alton Ochsner stated: “Lobectomy should be
limited to those cases in which pneumonectomy is contraindicated, not those in which lobectomy can
be done.” However, within a year or 2, the principle of lobectomy for lung cancer became standard.
ESOPHAGEAL SURGERY
Many of the pathologic processes affecting the esophagus are named after their discoverers (Zenker,
Barrett, Boerhaave, etc.) as are many of the surgical procedures named after their proponents (Belsey,
Collis, Ivor Lewis, Heller, etc.).187
The first interventions on the esophagus were performed to remove foreign bodies. If induced vomiting
was unsuccessful a stiff rod or bougie was introduced and pushed in the hope of forcing the object into the
stomach. Clark188 in 1803 described a tube made of elastic gum through which a whale bone with four
elastic hooks attached was passed into the esophagus to surround and catch the foreign body.
DIAGNOSIS
Within months of Roentgen’s announcement there were attempts at opacifying the esophagus and
gastrointestinal tract using iron oxide, bismuth, and lead solution.189–194 Bismuth had some toxicity and
because barium could be purified to a greater degree and was cheaper, this became the preferred contrast
agent.195,196 In 1917, Dr. Carmen,197 chair of Radiology at Mayo Clinic, published a classic text The
Roentgen Diagnosis of Diseases of the Alimentary Canal. Radiologic features like SES of the
“stomach,” “niche,” “filling defect,” and the “incisura” are all attributed to him.
In 1910, the upper and lower sphincters were identified by Keith,198 albeit pressure manometry was
only performed 50 years later.199
ESOPHAGEAL STRICTURE
Most esophageal strictures, until 1927 when a federal law was passed requiring proper labeling of
caustic alkalis, were due to the accidental swallowing of lye or sulfuric acid.200 Once the incidence of
accidental ingestion lessened, increased recognition of strictures consequent on gastroesophageal reflux
occurred.
Many of the patients with caustic stricture were young and surgical relief was attempted largely by
bypassing the obstruction without entering the chest. The strictured esophagus was simply left in situ to
drain mucous into the stomach. Contrast this to esophageal carcinoma where management required entry
into the chest—a situation to be avoided at the time. The patients with esophageal carcinoma were older
and the disease often advanced at the time of presentation. It is not surprising that a nihilistic attitude to
esophageal carcinoma initially existed and that surgery for carcinoma lagged behind that of management
of strictures, but the lessons learnt from management of strictures were not forgotten.
Earlier, the development of esophagoscopes and esophagoscopy were described, but these instruments
were not widely available. Strictures were initially dealt with using bougies passed blindly, but blind
dilatation was a hazardous procedure and perforation was common and resulted in death.201 In an effort to
reduce this complication, Frazier202 described the use of metal balls. The balls varied in size from 2 to 7
mm and were perforated so that a thread could pass through them. The patient initially swallowed the
smaller ball with string attached. If it passed into the stomach by the next day, it was withdrawn and a
larger ball attached and the process repeated until the largest had passed.
FIGURE 1.18 String sawing through a stricture. A fishing line is used. The mouth and the gastrostomy site are protected by
metal guards. (From Lilienthal H. Thoracic Surgery Vol I. Philadelphia, PA and London: WB Saunders Co; 1925:327.)
Later, others tried management of the stricture in a similar fashion to urethral strictures. A custom-
made esophagotome fashioned on a narrow whale bone shaft was followed by dilation.203 Others used a
heavy string, much like a Gigli saw, with one end introduced through a gastrostomy, the other end through
a cervical esophagostomy (Fig. 1.18).204,205
It was realized that if a hollow bougie followed a guide the risk of perforation would be less. In 1903,
Dunham206 described a technique where a string was swallowed and then recovered through a
gastrostomy. This served as a guide to pass a wire over which aluminum bougies were passed. In some
patients string was left in situ for months. Vinson207 later used a perforated bougie that followed a
swallowed string.
In 1907, Roux208 of Lausanne described the use of jejunum to bypass the stricture, bringing the upper
end of the jejunum to a subcutaneous anterior chest wall position. It was left to Lexer209 to connect the
subcutaneous jejunum to the cervical esophagus by using a skin tube to bridge the gap (Fig. 1.19). These
procedures were not without risk. Saint,210 reviewing the literature (144 esophagoplastic operations for
benign stricture) in 1929 found a total mortality of 29%; Ochsner and Owens211 4 years later in their
review of 240 patients found a 33% mortality. The use of long lengths of jejunum as a bypass was limited
by the inadequacy of the blood supply. Longmire and Ravitch212 described the anastomosis of the internal
mammary artery to the mesenteric artery—the supercharged jejunum of today.
In 1923, Roith213 of Baden-Baden used the right colon brought up subcutaneously to bypass the
esophagus. This patient survived 3 years.
Entry into the chest with resection of the stricture and replacement with stomach was introduced by
Oshawa214 in Japan followed by jejunal interposition215,216 and then by colon interposition.217,218
FIGURE 1.19 Skin tube created to bridge the gap between the stomach and the esophageal neck remnant. This procedure was
often done in stages. (From Lilienthal H. Thoracic Surgery Vol I. Philadelphia, PA and London: WB Saunders Co; 1925:330.)
PHARYNGOESOPHAGEAL DIVERTICULUM
The abnormality was first described by Ludlow219 in 1767, and the specimen is still preserved in the
Hunterian Museum in Glasgow, but has always been associated with the German pathologist Zenker.220
Zenker, a pathologist, and von Ziemssen correlated symptoms with pathologic findings (postmortem
examination in 22 of their 34 cases) and classified diverticula into four types: a true pharyngeal
diverticulum, the most common; that arising from the pharyngoesophageal junction; that arising from the
middle third of the esophagus near the bifurcation of the trachea; and the epiphrenic diverticulum.
Importantly, the authors noted that in none of the typical pulsion diverticula is there a complete muscular
layer. The best description of the symptoms and clinical signs that has not been bettered since is by
Moynihan.221
Early surgical attempts of excision were associated with mortality, leakage, and infection, likely due to
the considerable overgrowth of bacteria present in the sac, as well as failure to deal with the spasm of the
cricopharyngeus. Niehans’222 patient died of a secondary hemorrhage from the superior thyroid artery 2
weeks after excision. Burchardt’s patient died on the sixth day of pneumonia. Kocher’s patient, the first
surviving, operated on in 1892, had leakage for 13 days.223
Others attempted correction by invaginating the sac into the esophagus without opening it.224 Zesas,222
in an effort to prevent contamination, did a two-stage operation in which the neck of the sac was initially
closed. The diverticulum was sutured to the skin and resected 8 days later. This two-stage operation was
taken up by the Mayo Clinic, who reported in 1923, experience with 74 cases.225 Eventually it was
recognized that a Zenker diverticulum needed a cricopharyngeal myotomy as part of surgical
management.226
Mondiere227 as early as 1833 postulated that pulsion diverticula were mucosal herniations associated
with some sort of obstruction to swallowing. The role of a motility disorder in its pathogenesis was only
appreciated a century later.228 Epiphrenic diverticula were initially managed by anastamosing the stomach
and the sac through an abdominal approach.229 The first successful excision was done by Clairmont230 via
a transabdominal, transdiaphragmatic approach, followed later by Barrett231 in 1933 done via a
transpleural approach.
ACHALASIA
The condition was first described in 1672 by Thomas Willis.232 His patient self-dilated himself using a
fashioned rod of whale bone for 15 years. Russel233 in 1887 introduced the use of an inflatable bag. He
constructed “an instrument consisting of a sausage shaped silk bag, rendered airtight by a very thin
rubber bag within and mounted on the end of a tube, or hollow bougie.” This was passed through the
stricture in a collapsed state and blown up with air in a syringe when in position. Plummer234 of the Mayo
Clinic later popularized this technique of using an inflatable balloon. In some of his cases the patient
swallowed 6 yards of silk string beforehand: 3 yards in the afternoon and 3 the next morning.235 Over the
string he passed a sound. His dilator was constructed in similar manner to Russel’s except that dilation
was achieved with water. The pressure used was gauged by the amount of pain produced. Pressures of
100 to 50 mm Hg were generally used. If a pressure of 500 mm Hg was not able to “paralyze the
sphincter” he used dilators of increasing size. Plummer initially considered the problem as being due to
spastic contraction of the cardia, and he described the stages of the disease. Mikulicz236 popularized
manual dilation of the cardia through the stomach.
Initial surgical attempts on the area “of obstruction” were done in fashion similar to a Heineke–
Mikulicz or Finney’s pyloroplasty.237–239 Lambert’s operation240 consisted of making a gastrostomy and
passing a clamp through the gastrostomy into the dilated esophagus. One blade was then passed through
the cardia and then into the redundant mega esophagus which had been pulled into the abdomen and
closed, similar to an enterotribe. Sutures of chromic catgut united the contiguous portions of stomach and
esophagus. The clamp was left for 4 days then tightened crushing all tissue between. The clamp was
removed on the ninth day. The patient eventually recovered and was reported to eat anything with ease.
Almost all of these procedures were done via a laparotomy. Unfortunately these procedures resulted in
significant reflux esophagitis highlighted by the 1949 paper of Barrett and Franklin.241 It was publication
of these dismal results of esophagogastrostomy that prompted return to the Heller procedure described
almost four decades earlier.
The German surgeon Heller242 performed the first myotomy, done transabdominally, in 1913. His
initial intention was to create an esophagogastrostomy as described by Heyrovsky238 in the previous
paragraph, but decided, because the esophagus was dilated and hypertrophied, that this procedure was
unwise. Instead he made two longitudinal incisions, one anterior and one posterior, 8 cm in length starting
2 cm above the constriction and down onto the cardia of the stomach. The patient was able to eat anything
immediately after the operation. Groeneveldt243 modified the procedure by doing a single myotomy, the
procedure later universally adopted and the one done today.
Rake244,245 of Guy’s Hospital described pathologic changes in and around the ganglia and connecting
nerves of Auerbach’s plexus. It was left to Hurst, working with Rake246 in 1930 to define the cause, a
failure of relaxation of the cardia.
CONGENITAL ESOPHAGEAL ATRESIA

This atretic condition alone was described in the late 17th century in a conjoined twin247 and later in the
same century, its association with a tracheal fistula.248 Vogt249 was the first to classify the types of atresia,
but did not describe the rarest form, a tracheoesophageal fistula without atresia. This had been first
described by Lamb250 in 1873.
The first procedure done for the condition was by Steele.251 At the time of making a gastrostomy he
attempted, using bougies placed in the mouth and a retrogradely slender steel probe introduced via the
gastrostomy “in the hope that the lower esophagus if twisted or narrowed might be rendered pervious.”
The neonate died of pneumonia the following day.
Thereafter surgical attempts were uniformly fatal well described in Mead’s book.1
In 1939, Ladd did the first multiple-stage repair (fistula ligation, esophagostomy, gastrostomy, and
subsequent antethoracic esophagoplasty, using a skin tube).252 The surgeon whose name is associated with
surgical repair is Cameron Haight, who succeeded Alexander at Ann Arbor. He did the first primary one-
stage repair with survival in 1941.253 In 1944, he had done 16 such procedures with six survivors.254 All
operations were done by an extrapleural route.
HIATAL HERNIA SURGERY

Allison255 in 1951 published one of the first descriptions of sliding hiatal hernia, describing the typical
symptoms, the endoscopic appearance, biopsy showing gastric mucosa, and esophageal tissue, and
speculated on why the hernia developed. His surgical technique was “achieved by two main steps: first
by division of the extended phrenoesophageal ligament and peritoneal reflection close to the cardia,
and the resuturing of these to the under surface of the diaphragm, and second, by the application of
the vertical fibers of the right crus to one another behind the esophagus, their retention there, by such
light suturing as will enable them to continue to act as muscle.” He did 33 procedures on patients with
esophagitis with one death and 30 excellent results. On 15 patients with strictures he resected the stricture
and did an esophagojejunostomy, with cure in all.255 In 1973, he reported long-term follow-up with a
recurrence rate of 50%.256
Barrett257 described the paraesophageal hernia as well as the mucosal changes258 that bear his name.
Nissen,259 while in Istanbul, resected the cardia in a young patient with an ulcer and wrapped the
fundus around the anastomosis, similar to a Witzel gastrostomy. Sixteen years later the patient had no
problems with reflux and he used the same principle in another patient with reflux esophagitis. In 1956, he
described the operation of fundoplication for reflux that we recognize today.260 At Frenchay Hospital in
Bristol, Ronald Belsey developed a reputation for esophageal surgery and many thoracic surgeons,
including Griff Pearson and Mark Orringer, spent some time training with him. He developed his own
antireflux procedure called the Belsey Mark IV.261
Collis262 described in 1957 his lengthening operation and called the portion of stomach left above the
diaphragm the connecting tube.
FRANZ TOREK AND THE FIRST TOTAL ESOPHAGECTOMY
Early attempts at esophagectomy for carcinoma were limited to the cervical esophagus, with creation of a
salivary fistula and a distal esophageal stoma.263 Later, attempts on managing involvement by cancer of
the intrathoracic esophagus concentrated on an extrapleural approach with avoidance of damage to the
vagal nerves and thoracic duct. The tumor was excised, the proximal end of the esophagus was brought
out as a salivary fistula and the distal end was ligated. A gastrostomy was done for feeding. Mortality was
high. There were few attempts at restoring gastrointestinal continuity; mainly by the use of skin tubes.
There was considerable concern regarding the vagal nerves as it was believed that if the branches
supplying the cardiac plexus were divided, or if the nerves were stimulated by dissection, then syncope
and vagal collapse would result. An intrathoracic anastomosis was avoided for two reasons such as
difficulty in managing the patient with an open chest and also concerns of leakage.
In 1913, Torek,264 at Lenox Hill hospital, New York did a left thoracotomy and excised the esophagus
in a patient with carcinoma—he had previously done a gastrostomy. There were extensive adhesions
present and the tumor was fixed just below the aortic arch to the left bronchus. Mobilization behind the
arch was achieved by ligating intercostal arteries and lifting the aorta forward. A hole in the bronchus
created during dissection was sutured with silk. Resection was completed in 1 hour and 45 minutes.
Torek stated: “To my great satisfaction, the pulse never wavered during the procedure, remaining
between ninety-three and ninety-six. The dreaded vagal collapse had therefore, been safely avoided.”
The distal esophagus was invaginated like an appendix stump. No attempt was made to restore
gastrointestinal continuity; instead the proximal esophagus was tunneled to approximately the 2nd
interspace and a rubber tube connected the remaining proximal esophagus to the previously placed
gastrostomy. Eggers gave the anesthesia and the Meltzer–Auer intratracheal apparatus was used. At the
end of the operation, a hot whisky enema with strychnine was given. The patient milked food along the
rubber tube and refused any plastic procedure being performed. She lived for 13 years.
Torek, similar to Souttar and his mitral commissurotomy, never did another esophagectomy! Of the next
25 cases done at the hospital only one patient survived.
In the same year as Torek, Auch,265,266 interim Chief of Surgery in Munich prior to Sauerbruch’s
appointment, performed a transhiatal esophagectomy using an instrument to which the distal esophagus
was tied; this instrument was introduced perorally by the anesthesiologist. The esophagus was removed
through a separate incision in the neck from above (Fig. 1.20A,B). This patient died as did the next two.
Denk,267 also in the same year, described his operation where the esophagus was mobilized digitally from
the abdomen and neck digitally, and avoiding pleural entry, similar to the transhiatal esophagectomy as it
is done today. In this context, he occasionally used a vein stripper to aid mobilization. Then, the
esophagus was divided at the cardia and removed through the neck wound. The proximal stomach was
sutured to the skin. The diaphragm was closed and a gastrostomy performed. After healing, continuity was
restored with a skin tube. Grey Turner268 described a similar procedure by which he divided the
esophagus in the neck and proceeded with dissection from the abdomen. Because of adhesions, “it was
necessary to introduce the whole hand into the posterior mediastinum and to practice the maneuvers
of the obstetrician separating a retained placenta.” The withdrawal of the esophagus “was followed by
a gush of blood, but this soon stopped.” My mentor, Andrew Logan, assisted Turner at these operations
and described them as being “horrendous.”
Gastrointestinal continuity was initially achieved using the thoracic route using jejunum,269 colon,270
and gastric tubes.271 Kirschner272 described mobilization of the stomach as is done today. The first
intrathoracic esophagogastric anastomosis for a distal esophageal carcinoma was done in 1933 by
Oshawa,214 a Japanese surgeon. Others soon followed but it was left to Sweet273 to popularize the
technique and, in particular, the anastomotic technique. To this purpose, he favored a left-sided
thoracolaparotomy approach with a vertical incision through the diaphragm toward the hiatus. This
approach was then changed by Belsey to a circumferential detachment at the costal margin, thus
preserving the phrenic nerve and the diaphragmatic function.
FIGURE 1.20 A: Diagrammatic representation of Auch’s transhiatal esophagectomy. The upper ellipse, labeled b represents
the neck incision. B: The extent of von Ach’s patient’s cancer. (From Dubecz A, Levente K, Stadlhuber RJ, et al. The origins of
an operation: A brief history of transhiatal esophagectomy. Ann Surg 2009;249:535–540.)
In 1946, Ivor Lewis274 popularized a right thoracotomy approach arguing that dissection in the mid
esophagus could now be done under direct vision and that the absence of a diaphragmatic incision
lessened respiratory complications. Changing the position of the patient after mobilization of the stomach
through a laparotomy was regarded as a minor inconvenience. Surgeons then reserved the
thoracolaparotomy approach for distal esophageal cancers and Ivor Lewis approach for the mid and
proximal esophageal cancers.
Many patients with esophageal carcinoma were simply not treated. Souttar275 developed a flexible
spiral tube made of gilded German silver wire, which he passed across the cancerous stricture for
palliation.
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268. Turner G. Excision of the thoracic esophagus for carcinoma with construction of an extrathoracic gullet. Lancet 1933;33, ii:1315–1316.
269. Wullstein L. Ueber antethorakale oesophago-jejunostomie und operationen nach geichen prinzip. Dtsch Med Wschr 190;31:734–736.
270. Vulliet H. de l’oesophagoplastie et de ses diverse modifications. Semaine med 1911;45:529–530.
271. Beck C, Carrell A. Demonstration of specimens illustrating a method of formation of a prethoracic esophagus. Illinois Med J
1905;7:463.
272. Kirschner M. Eines neues verfahren der oesphagoplastik. Arch Klin Chir 1920;114;606–626.
273. Sweet RH. Surgical management of carcinoma of midthoracic esophagus. Preliminary report. New Eng J Med 1948;233:1–7.
274. Lewis I. The surgical treatment of carcinoma of the oesophagus, with special reference to a new operation for growth of the middle
third. Br J Surg 1946;34:18–31.
275. Souttar H. Carcinoma of the esophagus. Brit Med J 1935:11:777–779.
2
Pulmonary Surgery After Mechanical
Ventilation
Arvind Rajagopal ■ David D. Shersher ■ William H. Warren
“We are like dwarfs perched on the shoulders of giants, and thus we are able to see more and farther than the latter. And this is not at all
because of the acuteness of our sight or the stature of our body, but because we are carried aloft and elevated by the magnitude of the
giants.”
—Bernard of Chartres
The development of thoracic surgery as a surgical specialty was inextricably interwoven with the
development of general anesthesia, surgical pathology, and infectious disease. To illustrate this point,
several of the founding members of the American Association for Thoracic Surgery (founded in 1917)
were not surgeons. The organization’s first president, Samuel James Meltzer, was the head of the
Department of Physiology at Rockefeller Institute. He and his son-in-law, John Auer, were instrumental in
the development of anesthesia with their seminal publication in 1909 entitled “Continuous respiration
without respiratory movements.”1 In the following year, Charles A. Elsberg of New York published the
first clinical application of this respiratory model, using cocaine to topically anesthetize the throat,
passing an orotracheal tube by touch only, and allowing the patient to ventilate an ether/oxygen mixture
spontaneously against a positive airway pressure ranging from 15 to 25 mm Hg.2 The first surgical patient
was a 55-year-old butcher who had developed a right middle lobe abscess. The procedure, which was
essentially an open and closed thoracotomy without finding the abscess, lasted 45 minutes. The patient
survived the procedure and the abscess, presumably drained spontaneously during or prior to the second
procedure, resolved completely. (The procedure had been attempted weeks before, but was postponed
due to the patient coughing up copious secretions and could not be intubated.) It is with these two
publications that we pick up the story of the development of surgery of the lung and the pleural space. It
should be acknowledged that choosing these milestone papers as the beginning of this chapter is as
arbitrary as it is practical. The references provided are a catalogue of arguably the landmark publications
of history of early 20th century thoracic surgery.3–6 The development of esophageal and tracheal surgery
are equally interesting, but to include these would render this chapter encyclopedic. Nor will we attempt
to trace the origins of cardiac and vascular surgery. These topics can be described elsewhere for an
interested reader.
Thoracic surgery was one of the surgical specialties to progress relatively slowly at the end of the 19th
century. This was primarily due to what was known as the “pneumothorax problem.” Early attempts at
operating in the pleural space were limited by the collapse of the lung on the side undergoing surgery.
Unless there were extensive adhesions, such as in the case of an empyema, patients who were breathing
spontaneously would only tolerate short procedures before they became hypoxic and hemodynamically
unstable. Normally, intrapleural pressure is slightly negative. Without adhesions, in a spontaneously
breathing patient, the lung tends to collapse under its own elastic forces when the pleural space is
exposed to atmospheric pressure. The immediate hemodynamic changes require urgent closure of the
chest. Rudolph Matas from New Orleans, one of the pioneers of thoracic surgery, stated, “until a solution
for lung collapse after opening the chest is found, an analogy between the pleural space and peritoneum,
from a surgical point of view, will never exist.”7 Thus, although thoracic surgery was in many ways born
out of general surgery, the “pneumothorax problem” was one of many to limit the application of surgical
principles learned in abdominal surgery and elsewhere.
In Breslau, Johann Anton von Mikulicz-Radecki, a disciple of Billroth, placed his junior associate,
Ferdinand Sauerbruch, in charge of a research project to investigate this matter. Mikulicz had tried a
method of positive pressure ventilation using a tight-fitting face mask, but with poor outcomes. They had,
therefore, proposed a complicated arrangement, whereby the patient and the entire operating team were
crammed into a tiny hermetically sealed operating room except for the patient’s head and the
anesthesiologist. Upon applying a negative pressure to the chamber, the lung remained expanded.
At a surgical congress in Berlin in 1904, Mikulicz presented a paper entitled “Uber Operatione in der
Brusthohle mit Hilfe der Sauerbruchschen Kammer.”8 With this apparatus, which came to be known as the
“Sauerbruch chamber,” he was, for the first time, able to perform an open thoracotomy on a patient who
was breathing spontaneously (Fig. 2.1). Herbert “Willy” Meyer, who received his medical training at the
University of Bonn, witnessed the use of such a chamber in Germany in 1904. In 1908, Sauerbruch, by
invitation, demonstrated a portable version of the chamber at the Surgical Section of the AMA in Chicago.
Passing through New York on his way back to Europe, he left the chamber with Meyer, who experimented
with it at Rockefeller Institute. Willy Meyer, working with his brother, Julius Meyer, modified it to have
both positive and negative pressure chambers. He named it the Universal Chamber9 (Fig. 2.2). Although
this was awkward, it was technically portable and reconstructed for demonstration at the American
Surgical Association in Philadelphia in 1911. This was the only such negative pressure chamber ever
used in the United States.
FIGURE 2.1 Sauerbruch chamber. The patient’s head was placed through an aperture in the wall of the chamber, while the
operating team was sealed within the chamber where negative pressure was applied. The patient was induced, usually breathing
spontaneously under ether/oxygen facemask. (From Kozuschek W. Johann von Mikulicz-Radecki 1850–1906. Mitbegründer der
modernen Chirurgie. In Erinnerung an den großen Chirurgen der Deutschen Gesellschaft für Chirurgie und der
Gesellschaft der Polnischen Chirurgen gewidmet, 2. poln.-dt. Auflage. Acta Universitatis Wratislaviensis No. 2555, gefördert
von der Alfried Krupp von Bohlen und Halbach-Stiftung, Breslau 2005.)
A second approach was proposed by Ludoph Brauer from Hamburg which consisted of placing the
patient’s head in a positive pressure chamber while the rest of the body remained outside10 (Fig. 2.3).
Both techniques were limited by the inability to eliminate carbon dioxide leading to hypercapnia. Such
pressure chambers were the state of the art until the 1930s, despite the development of positive pressure
ventilation techniques. This was partially due to Sauerbruch’s zealous advocacy of his method of negative
pressure chambers.11
DEVELOPMENT OF POSITIVE PRESSURE VENTILATION

It is supremely ironic that the three components required for positive pressure ventilation had existed for
many years prior to their routine use in anesthesia. These were (1) the development of the endotracheal
tube, (2) the development of the laryngoscope, and (3) the development of a bellows mechanism to
provide positive pressure ventilation.
In 1878, more than 15 years preceding the development of the laryngoscope, William MacEwen in
Glasgow inserted an endotracheal tube by touch to protect the airway in cases of edema of the glottis and
oral surgery.12 This was intended to provide an alternative to a tracheostomy (which had been known for
years dating back to Egyptian times). In 1871 Freidrich Trendelenberg had advocated for placement of an
endotracheal tube for elective general anesthesia.13
In 1885, Joseph O’Dwyer from the New York Foundling Asylum developed a hooked metal
endotracheal tube which was blindly passed to successfully maintain the airway of a 2-month-old infant
and a 3½-year-old child with diphtheria.14 In 1895, Theodore Tuffier from Paris introduced an
endotracheal tube with an inflatable cuff, but this was not immediately adopted.15 In 1929, Sir Ivan Magill
and E. Stanley Rowbotham from London used similar endotracheal tubes to protect the airway during
maxillofacial surgery.16,17 These tubes were blindly placed using an orotracheal and nasotracheal route.
FIGURE 2.2 Universal chamber. In this chamber, both positive and negative pressures could be applied to the head and the
body separately. This chamber was also used exclusively by Dr. Willy Meyer for animal experiments at Rockefeller Institute.
(Meyer W. Pneumonectomy with the aid of differential air pressure: an experimental study: the new type of apparatus used.
JAMA 1909;53:1978–1987.)
FIGURE 2.3 Bauer positive pressure chamber. As an alternative to the bulky negative pressure chambers, where the body was
exposed to negative pressure, this chamber consisted of placing the head in a box where the patient was able to breathe
spontaneously under positive pressure. (Brodsky JB, Lemmens JM. The history of anesthesia for thoracic surgery. Minerva
anestesiol 2007;73(10):513–524. Reprinted by permission of Edizioni Minerva Medica from Minerva Anestesiol 2007;73:513–
24.)
In 1895, Alfred Von Kirstein from Berlin published the first known report on the laryngoscope for
direct examination of the larynx under anesthesia,18 which, in 1913, was modified by Chevalier Jackson
from Pittsburgh for the safe passage of endotracheal tubes.19 Its utilization helped pass endotracheal tubes
safely, but it was only slowly adopted in clinical practice preferring instead passing tubes per os and per
nares by touch only. Until the 1930s, concern about placing endotracheal tubes per os or per nares was
based, in large part, on the potential for contamination of the airways.
In 1893, George E. Fell of Buffalo developed a set of foot-driven bellows connected to a mask to
provide positive pressure to maintain respiration in patients with opium poisoning.20 O’Dwyer modified
the Fell apparatus by using an endotracheal tube21 (Fig. 2.4). He was among the first to recognize that
expiration was almost entirely a passive act. In 1899, Rudolph Matas used the Fell–O’Dwyer apparatus
together with an endotracheal tube for an open thoracotomy, later writing “it is curious that surgeons
should have failed to apply for so long a time the suggestions of the physiology laboratory, where the
bellows and tracheal tubes have been in constant use from the days of Magendie to the present, in practice
artificial respiration on animals.”7
Despite the availability of these techniques and tubes, open mask anesthesia using ether remained
widely used in thoracic anesthesia until almost 1930. Ether, nitrous oxide, and chloroform had all been
known for many years, before their use in dentistry and subsequently in surgery. They had all been used as
agents for entertainment in traveling shows and social gatherings known as “ether parties.” In fact, it was
Oliver Wendell Holmes, a physician and father of the Supreme Court Justice, who proposed the term
“anesthesia” (Gr. to render insensible) in a letter dated November 21, 1846, addressed to William T.G.
Morton, who was experimenting with the use of sulfuric ether in his dental practice and advocating its use
in general surgery.
FIGURE 2.4 Fell–O’Dwyer respirator. (Illustration in Transactions of the Southern Surgical and Gynecological
Association. pg 80 Google: Hallion and Tuffier.) This apparatus consists of a foot-driven pump to generate the flow of anesthetic
gases through a tube placed in the trachea. (From “Medical and Surgical Reports of the Presbyterian Hospital,” for 1896.)
Arthur Ernest Guedel, an anesthesiologist from Indianapolis, is credited to be the first to use a cuffed
endotracheal tube in a clinical setting in 1928.22 This allowed the patient to be ventilated by hand and
allowed deeper levels of anesthesia not possible in the spontaneously breathing patients undergoing ether
anesthesia. Previously, the goal was to intentionally keep a patient lightly anesthetized in order to
maintain airway reflexes, protecting the airway from contamination. With the advent of a cuffed
endotracheal tube, a patient could be placed in deeper anesthetic levels, ventilated by hand providing a
route for suctioning secretions as well as deeper level of anesthesia during the procedure. The ability to
provide positive airway pressure was the solution for the “pneumothorax” problem, which we know
today as respiratory acidosis from hypoventilation and retention of CO2.
In 1934, Paul Frenckner, an ear nose and throat endoscopist, and Emil Anderson, an engineer by
training, developed the “Spiropulsator” in Stockholm, a prototype for mechanical ventilation built by
Aktiebolagel Gasaccumulator (AGA).23,24 Although this was a giant step in the right direction, this was
hampered by the patient’s own breathing efforts. This prototype was modified in 1938 with the help of
Clarence Crafoord, a thoracic surgeon in Stockholm, and its use ushered in the dawn of the modern era of
mechanical ventilation.24 In 1939, Frederich R. Mautz, another cardiac surgeon from Cleveland, modified
the Heidbrink anesthetic apparatus (a modification of the spiropulsator) to provide rhythmic compression
of a rebreathing bag.25 Thus, in another twist of irony, the first mechanical ventilators were developed by
an otolaryngologist, and two cardiac surgeons with the help of a mechanical engineer. A nitrous
oxide/oxygen mixture was administered through an endotracheal tube in these early cases. Controlled
positive pressure ventilation with an endotracheal tube became routinely used in thoracic surgery only in
1942, after the first successful clinical use of curare by Harold Griffith and his resident G. Enid Johnson
at the Montreal Homeopathic Hospital (later Queen Elizabeth Hospital).26
THORACIC SURGERY FOR TUBERCULOSIS

From the development of mechanical ventilation until 1944, the year of the introduction of streptomycin
(the first effective antituberculous antibiotic), the story of thoracic surgery was largely dominated by the
management of tuberculosis. Although sanatoria were developed with the goal of rest and isolation in a
healthy environment, the medical doctors in charge of running these sometimes remote facilities were
instrumental in early operative intervention. This is yet another example of doctors without formal
surgical training providing valuable contributions to the development of thoracic surgery. These included
E. Stuerz from Koln who suggested division of the phrenic nerve in the neck to collapse lower lobe
cavities through diaphragmatic paralysis; Carlo Forlanini from Pavia for the introduction of iatrogenic
pneumothorax; Hans Christian Jacobaeus from Stockholm who invented pleuroscopy and division of
intrapleural adhesions; Edouard de Cereville from Lausanne who was the first to recommend rib
resections for draining tuberculous empyema; and Ludolph Brauer from Hamburg who developed the
concept of thoracoplasty.27–31 All of these physicians were trained in internal medicine and had no formal
surgical training. It would be remiss not to acknowledge that these pioneers tragically themselves
frequently became victims of tuberculosis.
TUBERCULOUS EMPYEMA
In 1890, Max Shede from Hamburg introduced a version of thoracoplasty in which the entire chest wall
including the ribs, intercostal muscles, and the thickened parietal pleural were resected in cases of
chronic tuberculous empyema over a destroyed lung ravaged by tuberculosis.32 The remaining chest wall
musculature along with subcutaneous tissue and skin was used to fill the remaining space. To consider that
this operation was accomplished without deep endotracheal anesthesia, with massive blood loss, and an
operative mortality close to 50% is staggering to understand today. If the patient survived, there was
paradoxical chest wall motion, weakness of the abdominal wall not to mention a grotesque final
appearance of the thorax. In 1935, Leo Eleosser in San Francisco described a flap created in the chest
wall to drain a tuberculous effusion as an alternative to thoracoplasties, a technique which would prove
valuable in managing empyemas of all types, including postpneumonectomy empyemas, in the years to
come.33 In 1946, Col. John B. Grow in Denver and subsequently in 1953 Frederick B. Kergin in Toronto
independently described procedures whereby the ribs were resected subperiosteally together with the
thickened parietal pleura but sparing the neurovascular bundles.34,35 These intercostals bundles were then
allowed to collapse the cavity. Since only the ribs over the empyema cavity (plus one above and below)
were resected, and due to advances in anesthetics techniques, the results were better, but far from
cosmetically acceptable.
COLLAPSE THERAPY FOR TUBERCULOSIS

What followed is one of the more spectacular and inventive periods of thoracic surgery. Based on the
clinical observation that patients with pulmonary tuberculosis who had a spontaneous pneumothorax
showed improvement in dyspnea and fever, and aided in their recovery, a variety of techniques were then
used to induce what came to be known as “collapse therapy.” In 1913, H. Morriston Davies in London
summarized the experience with “artificial pneumothorax” with insufflations of 200 to 1,000 cc of various
gases noting the risk of air embolus.36 In 1934, Emil Bunta from the Municipal Tuberculosis Sanatorium,
Chicago, proposed monitoring the intrapleural pressure as a means of avoiding clinical
decompensation.37 One of the limitations of artificial pneumothorax was the presence of adhesions,
leading Jacobeus to introduce the concept of thoracoscopy to divide adhesions.38
In an effort to avoid “artificial pneumothorax,” phrenic nerve division (“phreniectomy”) performed to
collapse tuberculous cavities was summarized by Oren Beatty from Waverly Hills Sanatorium, Kentucky,
in 1935 concluding that in 25% of selected cases, the cavities would close.39
In 1891, Theodore Tuffier is credited with introducing the concept of dissecting out an extrapleural
plane, filling the space with omentum creating what he described as a “plombage.”40 In 1935, F.S. Dolley
explored the utility of apical thoracoplasty, but the benefits were short-lived.41 In 1937, John Alexander
in Ann Arbor wrote a book regarding the virtues of collapse therapy for pulmonary tuberculosis, wherein
a limited thoracoplasty was performed to collapse an apical cavity.42 After this, several other authors
used various other materials including paraffin packs, polystan sponge, and gauze packing each able to
successfully cause long-term lobar collapse with improvement in the patient’s clinical condition. In 1946,
David Wilson from Greenville, South Carolina, presented his experiments with Lucite balls inserted into
the subpleural space of dogs to achieve a plombage, followed 2 years later with the early clinical
experience.43,44 In 1949, Harry E. Walkup from Oteen, NC, in 1950 Frances M. Woods, and in 1956
Norman Wilson, both from Boston, all summarized their own experiences of creating an extrapleural and
subsequently an extraperiosteal space filled with a “plombage” of Lucite balls45–47 (Fig. 2.5). Similarly,
William E. Adams from Chicago summarized his experience with paraffin wax seeking to find the ideal
plombage material.48 While the cosmetic appearance was better than a thoracoplasty, there was an
unacceptable incidence of septic and hemorrhagic complications and erosions sometimes into the contents
of the axilla or extrusion through the chest wall.49,50
Controversy arose over whether collapse therapy (whether by artificial pneumothorax, phrenic nerve
resection in the neck, intraperitoneal insufflations, or plombage) was better than resection of the diseased
lung either by lobectomy or pneumonectomy (with or without thoracoplasty).
The first publications on pulmonary resection for tuberculosis, published in 1935 to 1940, were met
with derision. In 1935, S.O. Freedlander of Cleveland bravely presented an unsuccessful attempt to
perform a lobectomy leading John Alexander, in the discussion of the paper, to doubt whether “lobectomy
will ever be widely accepted for uncomplicated cavernous tuberculosis.”51,52 Five years later, Frank
Dolley and John Jones from Los Angles presented their paper on the same topic.53 In the discussion of this
presentation, 18 other surgeons volunteered their results, including 19 pneumonectomies (operative
mortality 40.2%) and 31 lobectomies (operative mortality 20.5%).53 Although patients’ outcomes were
rarely improved, these papers mark the early beginnings of the development of the techniques of
pulmonary resections.
On October 19, 1943, streptomycin was isolated by Albert Schatz, a graduate student working in the
laboratory of Selman Abraham Waksman, a soil scientist at Rutgers University. It subsequently proved to
be the first effective antituberculous antibiotic and thereafter, a struggle for credit ensued.54,55 This was
soon followed by the introduction of other antituberculous drugs, bringing to an end to an era which
dominated the field of pulmonary surgery during which pulmonary resections were attempted with mixed
results.
TECHNIQUES OF EARLY PULMONARY RESECTIONS

As early as 1882, apparently independently, Theodur Gluck, H. Schmid, and H.M. Block, three German
surgeons from Danzig, experimented with lung resections. Based on animal experiments, Block tempted to
perform an apical wedge resection on a young woman.56 In a letter to the editor of the Boston Medical
and Surgical Journal March 15, 1883, Walton, an acquaintance of Block, wrote: “It seems that he
operated on a young lady, I am told a relative, at her own request. The lungs are said to have been found
healthy but the patient died according to one report during the operation, according to another, shortly
after. Legal procedures were instituted but the unfortunate operator took his own life, shooting himself
through the head.” Resulting in the death of the patient.56 This is the first attempt at a lung resection
recorded in modern history.
At this period in time, pulmonary resections were performed under primitive conditions both with
respect to anesthesia and surgical technique. As a result, resections were performed in two stages with
mass ligations of the lobar structures and subsequent resection of necrotic lung with the expected high
incidence of bronchopulmonary fistula and an unacceptable incidence of perioperative death. Pulmonary
resections were accomplished, mostly for bronchiectasis, by crude dissections of the hilum, applying
mass ligatures and two-stage resections of the necrotic lung. At the second operation when the necrotic
lung is resected, sometimes with a cautery iron (leading to the term “cautery pneumonectomy”), the
inevitable bronchial stump fistula was managed by chronic chest tube drainage.
In 1922, Howard Lilienthal from New York published a series of 30 lobectomies that were mostly
performed in one stage.57 These were performed with ether/nitrous oxide through an intrapharyngeal tube
placed through a nostril, not with an endotracheal tube, stating “I have abandoned the intratracheal tube
for the simple and less dangerous intrapharyngeal method.” Lilienthal’s pivotal contribution was
performing a lobectomy in one stage, while still using a mass ligature, but this went largely unrecognized
since he had an operative mortality of 43%. In 1929, Harold Brunn of San Francisco published his
experience with pneumonectomy, attributing his excellent results to his method of controlling hilar
vessels.58 In fact, the most important difference in his technique was the vigorous use of intrapleural
suction “either by hand syringe every two hours day and night, or some form of suction apparatus” to
remove postoperative fluid and air. For years, chest tube drainage had been used for empyema or
pneumothorax, but this was the first account of advocating drainage of the pleural space postoperatively.
Credit must be paid to H. Morriston Davies in London who, in 1913, described in his report “Recent
advances in the surgery of the lung and pleura,” the technique of individual dissection of the structures to
perform a lobectomy for carcinoma.36 This momentous contribution is often overlooked because the
patient died on the eighth postoperative day. This, however, should not diminish the landmark paper of
Edward Churchill of Boston in 1931, who is often quoted as performing the first “modern” lobectomy.59
In this case, the patient survived after a lobectomy with individual ligation of the vessels and bronchus for
a “bronchial adenoma.” William F. Reinhoff Jr. of Baltimore must be recognized as the first surgeon to
propose closure of the bronchial stump not with a ligature, but with “cutting the cartilages at various
points in order to do away with their spring-like action” and “sutured the bronchial with interrupted
medium silk sutures.”60 However, regarding anesthesia, he stated “whether or not an intratracheal tube
should be used is still an unsettled question” citing concerns about contaminating the airway with oral
organisms and damage to the tracheal mucosa.
FIGURE 2.5 Lucite plombage. Plain AP chest x-ray, CT image, and recovered Lucite balls placed in the extrapleural space of a
29-year-old male with a tuberculous cavity in the right upper lobe, some of which became infected 57 years after implantation.
(From Gotoh S, Chohnabayashi N. Infection 57 years after plombage. N Engl J Med 2009;360:e29. Copyright © 2009
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)
In 1932, Norman Shenstone and Robert Janes in Toronto published their experience with a tourniquet
devised on the basis of a tonsillar snare, allowing the surgeon to expeditiously control the hilar vessels.61
The patient would return to the operating room for a second stage after hilar structures were (presumably)
less edematous, in order to better dissect out the hilum. It is unlikely that this technique was necessary in
the majority of cases and may have served to delay the surgical techniques of hilar dissection.
However, it is the 1942 publication of Edward Kent and Brian Blades in St. Louis entitled “Surgical
anatomy of the pulmonary lobes” that is most often quoted as the basis of dissection of hilar dissection of
individual vessels and bronchi.62 In 1968, Frank J. Milloy and Lawrence E. Wragg in Chicago would
describe the vascular structures of the lung including the many variants from cadaver and surgical
dissections.63–65
PNEUMONECTOMY
In 1931, Rudolf Nissen, who at the time worked as a surgical assistant to Dr. Sauerbruck in Berlin,
successfully performed a two-stage left pneumonectomy on a 12-year-old girl with bronchiectasis.66 In
this case, the lobes were separately strangulated and the chest was packed. The resulting necrotic lungs
sloughed off in 14 days apparently without a bronchial stump leak.
This was followed by Cameron Haight in Ann Arbor who, in 1932, performed a very similar
procedure on a 13-year-old girl.67 In this case, the patient had aspirated a portion of a tooth guard that
was lodged in the left mainstem bronchus, ultimately causing an empyema. On November 8 and 14, 1932,
she underwent the same two-stage technique as Nissen, with strangulation of the left upper and lower
lobes individually and packing of the left pleural space, followed by, in four stages, an 11 rib
thoracoplasty! This patient, too, survived, more a testament to the healing powers of youth than what we
today would consider good surgical technique.
The year 1933 was a momentous one for pulmonary resections. During this year, three great thoracic
surgeons Edward Archibald in Montreal, William F. Reinhoff Jr. in Baltimore, and Evarts Ambrose
Graham in St. Louis each performed their first successful pneumonectomy.
On July 7, 1933, Edward Archibald in Montreal performed a successful “dissection” left
pneumonectomy which was preceded by an exploratory thoracotomy simply to exclude mediastinal or
pleural metastases.68 In this case, the bronchus was ligated but not sutured. The surgeon noted “mass
ligation of the bronchus is always followed by a fistula.” He cauterized the mucosa with phenol and
ligated the bronchus with catgut and silver wire. The patient, however, died on March 16, 1934, from
disseminated carcinoma.
On July 24, 1933, Reinhoff published his results of two left pneumonectomies. The first case was a
3½-year-old girl with a fibrosarcoma which was resected through an anterior thoracotomy.69 In this case,
he describes bronchial closure using interrupted silk sutures. His patient, however, died “accidentally”
4½ years later. In the second case, a 24-year-old girl with undisclosed pathology underwent a successful
left pneumonectomy using the same surgical technique. Hilar vessels were individually ligated, the
bronchial stump was sutured, and a thoracoplasty was avoided. All these were revolutionary ideas and
the importance of this publication cannot be overestimated. Curiously, however, in both cases,
“intratracheal anesthesia” was not used. According to this report, he stated, “the patient having been
accustomed to breathing with one lung (due to (an induced) preoperative pneumothorax on the operative
side), experienced no difficulty when the chest was opened. This obviated the necessity and nuisance of
introducing a tube in the trachea and otherwise unavoidable introduction of infection into the trachea.”
The most cited accomplishment is that of Graham who, on April 5, 1933, performed a first
pneumonectomy in one stage for lung cancer on James Gilmore, a 48-year-old gynecologist.70 The patient
had a left upper lobe carcinoma thought preoperatively to be resectable by lobectomy. The procedure was
performed with a single lumen endotracheal tube using nitrous oxide. Intraoperatively, it was determined
that the tumor was too close to the hilar structures, and a left pneumonectomy had to be performed. The
pulmonary artery was ligated with catgut. Graham latter admitted that the main pulmonary artery was
ligated with considerable trepidation, citing concerns analogous to the sudden death caused by a
pulmonary embolism. Seven radon seeds of 1.5 millicuries were inserted into various parts of the stump
which was then cauterized to destroy the mucosa, then ligated with two separate suture ligations of no. 2
catgut. Since it was anticipated that the patient would develop an empyema, ribs 3 to 9 were resected
after the lung was removed to obliterate the pneumonectomy space. As predicted, an empyema did occur
but the stump closed over time. The patient survived and, in a twist of fate, was alive and still smoking 24
years after this operation, at the time of the death of Graham. Graham himself was a lifelong smoker and
he died of small cell cancer in 1957. James Gilmore, having become a close personal friend, attended the
funeral of his surgeon. Upon reviewing the pathology of Dr. Gilmore’s specimen, several years after
Graham’s landmark surgical resection, Lauren Ackerman, at that time a pathologist at Barnes Hospital,
confirmed the diagnosis to be “undifferentiated carcinoma” with nodal metastases.71
LOBECTOMY VS. PNEUMONECTOMY

Over time, it became clear that both lobectomy and pneumonectomy were feasible operations on carefully
selected patients. However, while lobectomy had a significantly lower operative morbidity and mortality,
controversy arose regarding whether or not lobectomy was an adequate operation for cure. In order to
compare these two procedures, several issues had to be addressed. First, there had to be a comprehensive
histologic classification of primary pulmonary carcinoma. Second, there had to be a widely accepted
staging system. Third, there had to be a better way to identify and assess the perioperative risk factors.
HISTOLOGIC CLASSIFICATION OF PULMONARY CARCINOMA

In 1879, F.H. Harting and W. Hesse identified a fatal pulmonary condition in the miners of Schneeberg, a
town in Saxony, Germany, originally called a “round cell—or oat cell sarcoma.”72 At the time, the miners
were mining for cobalt and bismuth. However, in the 1940s, uranium was found at this site and it was
postulated that these early miners probably had significant radioactive exposure. For almost 50 years, the
pioneers of pathology more or less accepted the fact that this entity was not a carcinoma. In 1926, W.G.
Barnard in London determined that this so-called “oat cell sarcoma” was actually an aggressive primary
carcinoma of the lung.73
It must be remembered that pathology of this era was largely confined to the examination of autopsy
specimens and lung cancer was widely viewed as uncommon and relatively unimportant. This was
exemplified when, in 1904, Frank B. Mallory published the first American textbook on histopathology,
The Principles of Histologic Pathology; in it only a nine-line paragraph was dedicated to the subject of
lung cancer.74 No illustrations were included.
In addition to pathologic relevance, the etiology of lung cancer was also in question. James Ewing,
Professor of Pathology at Cornell, is widely regarded as the father of American tumor pathology. In his
textbook, published in 1909, a nine-page chapter is devoted to the subject of lung cancer with three gross
photographs, but no micrograph.75 Within the first four editions of his textbook, the last being 1940, the
statement appears, “The chief etiological factor (of lung cancer) is tuberculosis.”
Although there were several classic textbooks of tumor pathology, the entity of lung cancer continued
to be largely neglected until Robbins proposed in 1957, in his textbook, Textbook of Pathology, that
squamous carcinoma, adenocarcinoma, and undifferentiated large cell carcinomas existed and that they
had to be distinguished from small cell carcinoma.76 He also concluded that localized tumors respond
reasonably well to resection, with the exclusion of small cell carcinoma which did not benefit from
surgery. With great insight, he was among the first to acknowledge that admixtures of cell types
(heterogeneity) frequently occurred.
In 1952, Averill Abraham Liebow, Associate Professor of Pathology at Yale, New Haven, proposed in
the first Armed Forces Institute of Pathology, Fascicle 17, a classification of lung cancer.77 In this he
recognized, for the first time, bronchiolar (alveolar cell) carcinoma which could be distinguished from all
the other histologic types.
THE TNM STAGING SYSTEM

The first widely agreed upon staging of lung cancer was provided in 1979 when the American Joint
Committee for Cancer Staging and End Results Reporting (AJC) offered the TNM system, subsequently
adopted by the International Union Against Cancer (UICC). Although this has undergone several changes
over the years, it marked a milestone by providing a standard staging against which all surgical (and
nonsurgical) outcomes could be measured. Prior to this, the size and location of the primary tumor and the
involvement of the chest wall and mediastinal structures had been recognized as important prognostic
factors.
The first account of a rigid bronchoscope was attributed to Gustav Killian, when he was assistant
professor in the Department of Otolaryngology, University of Mainz, Germany. He used a modified rigid
esophagoscope in order to retrieve an aspirated bone from the right mainstem bronchus on March 27,
1897.78 This was no small feat since he used reflected light from a head lamp for illumination. In 1905,
Chevalier Lawrence Jackson in Pittsburgh, destined to become this nation’s preeminent
bronchoesophagoscopist, was using a similar instrument modified with a light carrier to retrieve
aspirated foreign bodies.79 In 1934, his son, Chevalier Lawrence Jackson Jr. in Philadelphia reported on
32 lung cancers and effectively introduced the merits of rigid bronchoscopy in the evaluation of lung
cancer.80
Henry Khunrath Pancoast was an anesthetist at the University of Pennsylvania when, in 1902, he was
appointed to succeed Charles Lester Leonard, who died from a radiation-induced cancer. Pancoast,
destined to become the nation’s first Professor on Roentgenology, is credited with recognizing a tumor
occurring at the apex, or superior sulcus, of the chest in his 1924 landmark publication of three such
cases.81,82 The tumor was not immediately recognized to be of lung origin, but rather a sarcoma
secondarily invading the lung from the chest wall. (Historians will later point out that this tumor had been
previously described by Edward Selleck Hare in 1839, more than 60 years earlier but the eponym
nevertheless has been given to Pancoast.83)
The significance of the involvement of regional and mediastinal lymph nodes had been suspected, but
not uniformly agreed upon. Recall that the patient who underwent Graham’s first pneumonectomy had
nodal metastases. The recognition that the involvement of mediastinal nodes was important, even in the
absence of recurrent laryngeal palsy or superior vena cava obstruction. In 1949, Albert Daniels of San
Francisco described the early technique of performing a scalene node biopsy “following the subclavian
and internal jugular vein into the upper mediastinum” for the purpose of staging lung cancer.84 In 1954,
Dwight E. Harken in Boston published his experience with the first cervical mediastinoscope (a Jackson
laryngoscope), through the bed of a scalene node biopsy but this was not widely accepted due to a high
incidence of hemorrhage, pneumothorax, and marginal exposure.85 A midline incision and modification of
this instrument introduced by Eric Carlens, a “clinical physiologist” in the Department of Otolaryngology
at the Karolinska Institute in 1959, led to the wide acceptance of this as a way to safely biopsy the
mediastinal nodes.86
Scans to detect distant metastases were in their infancy. Even aspiration cytology of pleural fluid was
criticized in some quarters due to the experience with tumor seeding in the chest wall. It took
developments and improvements in imaging to accurately exclude patient with distant metastases.
ASSESSING PERIOPERATIVE RISK FACTORS

The importance of pulmonary function testing in the evaluation of patients being considered for pulmonary
resection was first summarized by Fredrick Warring from Laurel Heights State Tuberculosis Sanitarium,
Shelton Connecticut as early as 1945.83 Subsequent papers in early 1950s by G. Birath from Stockholm,
John J. Curry from Washington, DC, and Warriner Woodruff from Saranac Lake, New York, all drew
attention to the importance of preoperative evaluation of pulmonary function.87–90
As described below, the double lumen tube was introduced in the 1940s in part as a method to
accurately determine split lung function studies. While in some cases considered to be reasonably
accurate in predicting postpneumonectomy FEV1, it was not well tolerated by patients having been
inserted under topical anesthesia and a new solution was sought. Subsequently, spirometry was performed
placing patients in the lateral decubitus position. The results were variable and difficult to reproduce. In
1974, Sven Kristersson in Malona, Sweden, introduced xenon-133 ventilation radiospirometery as a
means to predict postpneumonectomy status, followed by Phillip Boysen in Gainsville who, in 1977,
introduced the use of technetium-99m perfusion scans for the same purpose.91,92 Today, a combination of
these two scans is routinely used by many in selected patients who are considered to be marginal
candidates for major pulmonary resections and by most in patients prior to a pneumonectomy.
Pulmonary reserve was not the only important consideration. Early on, studies showed that some
patients after a pneumonectomy had high pulmonary arterial pressures at rest and after exercise.
Postoperative performance limitations seemed to correlate with poor pulmonary hemodynamics. A series
of papers then appeared using balloon occlusion of a pulmonary artery in order to predict postoperative
PA pressure. The basic conclusions were the same, namely, if the patient has a PA pressure of over 35 mm
Hg and a PaO2 of less than 45 mm Hg, the patient is not a good candidate for a pneumonectomy. Today,
this procedure is seldom used due to echocardiography assessments of marginal patients and the
recognition that while the hemodynamic model may be accurate, it fails to take into account the volumetric
changes of resecting the diseased lung. In 1984, Thomas P. Smith in Shreveport recognized the value of
the age-old practice of exercising the patient to predict the overall post-thoracotomy morbidity.93
SIGNIFICANT ANESTHESIA DEVELOPMENTS AFFECTING THORACIC

SURGERY
The first clinical use of curare was reported in 1942 by Harold Griffith from the Montreal Homeopathic
Hospital (subsequently renamed Queen Elizabeth Hospital), and for the first time deeper levels of
anesthesia could be used safely along with ether to achieve temporary muscle paralysis.26 This
accomplishment, along with the ability to provide mechanical ventilation, significantly changed the course
of thoracic surgery. Volatile anesthetic agents such as cyclopropane, ether, and nitrous oxide were the
mainstay of anesthesia until the development of noninflammable halogenated agents such as halothane.
Halothane was a less toxic agent, which allowed for a smoother induction and wake up. One of the main
advantages was that it allowed the unlimited use of electrocautery along with the delivery of higher
concentrations of oxygen without fear of explosion. This meant that even patients with decreased
respiratory reserves could tolerate thoracic procedures.
The diagnosis of thoracic tumors in surgical patients was greatly aided by the introduction of rigid
bronchoscopy in the 1920s, but it was very operator dependant. Fiberoptic bronchoscopy had to wait for
Shigeto Ikede from Tokyo to introduce fiberoptic technology in 1968.94 Flexible bronchoscopy also
assisted with more accurate placement of double lumen tubes and bronchial blockers. Improvements in
ventilation techniques have also influenced the management of thoracic surgical patients. Positive end-
expiratory pressure (PEEP) to the dependent lung or continuous positive airway pressure (CPAP) to the
operative lung has been used intraoperatively to optimize oxygenation during one-lung ventilation.
Nevertheless, it may come as a surprise to the new trainee that pulmonary isolation, a technique routinely
used today, was not always readily available.
DEVELOPMENT OF ENDOBRONCHIAL BLOCKING DEVICES

The ability to provide positive pressure ventilation and suction endotracheal secretions was achieved by
the late 1920s with the development of the cuffed endotracheal tube. This, however, did not allow for the
selective ventilation of the nonoperative lung nor protection of the dependant lung of contamination from
the operative side. Endobronchial blocking devices were developed to perform selective one-lung
ventilation and aid in controlling cross contamination.
In 1932, Joseph Gale from Madison was credited to be the first to report the clinical use of a single
lumen endobronchial tube to provide one-lung anesthesia for thoracic surgery.95 This was performed with
a red rubber Guedel–Waters endotracheal tube with an inflatable cuff. The tube was inserted into the
trachea with the tip pointing into the bronchus to be entered and the bevel toward the carina. The cuff was
inflated until the first feeling of resistance. The advantages claimed were providing an immobile
operative field with quiet respirations, while providing adequate ventilation, and limiting cross
contamination into the nonoperative lung. However, the placement of this tube into the bronchus of the
nonoperative lung, especially the left, was problematic.
In 1935, Archibald warned of the dangers of spillage down the bronchus into the dependant lung.96 To
address this, he used a gauze or a balloon across the operative field to block a mainstem bronchus and
limit contamination. In 1936, Magill presented his experience placing endobronchial blockers either
beside or through the endotracheal tube.97 These blockers were placed either blindly using x-ray
confirmation or under direct vision using a telescope.
In 1981, Robert Ginsberg in Toronto used a Fogarty catheter through an endotracheal tube guided into
the mainstem bronchus of the operative lung using fiberoptic bronchoscopy.98 In 1985, Hiroshi Kamaya
from Salt Lake City introduced the Univent tube, which is a silicone single lumen endotracheal tube
within which is a bronchial blocker balloon which could be guided into the bronchus of the operative
lung.99 The catheter could be deflated during the case to allow reinflation of the operative lung and testing
of the bronchial stump. If postoperative ventilation should be required, the endotracheal tube could be left
in place for up to 24 hours. However, atelectasis of the operative lung takes place only by absorptive
atelectasis and secretions could not be adequately suctioned from the bronchus of the operative lung.
Moreover, there was no ability to perform intraoperative flexible bronchoscope.
Bronchial blockers, however, are useful in cases where double lumen tubes are impossible to place
such as in difficult airways or in children with smaller airways as advised by Gregory Hammar from
Stanford.100
DOUBLE LUMEN ENDOTRACHEAL TUBES

Double lumen tubes provided many advantages over endobronchial blocking devices for intrathoracic
procedures. It allows for isolating the operative lung which provides for a quiet operative field and also
protects the nonoperative lung from contamination. Intraoperative suctioning and re-expansion of the
operative lung can be performed as needed but perhaps the greatest advantage is the ease of deflation and
reinflation of the operative lung which was a vast improvement over bronchial blocking balloons which
relied on absorptive atelectasis for deflation. Initially, however, there was difficulty with correct
placement of these tubes.
In 1946, Eric Carlens introduced a double cuffed left-sided double lumen tube to be used for
differential bronchial spirometry.101 It consisted of two tubes of unequal length molded together. The
shorter tube remains in the trachea while the longer one ends up in the bronchus. When the proximal cuff
is inflated, breaths are delivered to both lungs under positive pressure. When the distal cuff is up
ventilation can be delivered selectively to either lung by clamping gas flow to the tracheal or bronchial
lumen.
In 1950, Viking Bjork presented his experience with this tube to limit contamination of the
nonoperative lung.102 While the hook may have been helpful for placement, it was associated with serious
injuries to the airway. High airway resistance was encountered which was due, in part, to the size of the
tube and correct placement was difficult to confirm. In 1959, G.M.J. White from Middlesborough
recognized the limitation of having only a left-sided tube and created left- and right-sided tubes with a D-
shaped side hole to allow ventilation of the upper lobe bronchi, but retaining the Carlens carinal hook.103
In 1962, Frank L. Robertshaw from Manchester introduced a tube intended to solve some of the
problems because it lacked the carinal hook of the Carlens tube.104 Its molded curvature and wider
lumens helped to reduce kinking and improve gas flow during one lung ventilation. In addition, it had a
side hole in the right-sided tube to allow for ventilation of the right upper lobe.
Some of these early double lumen tubes were made of latex. The currently available double lumen
tubes are made of polyvinyl chloride which has allowed the walls of the tubes to become thinner as well
as transparent.105 This allows for less resistance to air flow as well as better visualization.
The cuffs used in these double lumen tubes have also undergone modifications. As with single lumen
tubes, the original cuffs were low-volume high-pressure, which were associated with tissue necrosis.
Current cuffs are high-volume low-pressure cuffs which have reduced the risk of airway injury. Today,
double lumen tubes are available for either right or left mainstem bronchus in sizes ranging from 26 to 41
French. The majority of double lumens inserted are left-sided tube, since right-sided tubes carry the risk
of occlusion of the right upper lobe bronchus.
The first half of the 20th century proved to be instrumental in amassing a body of literature and
techniques to allow for safe pulmonary resections. From the early success of Evarts Graham to today’s
reproducible low-morbidity and low-mortality pulmonary resections, the field of thoracic surgery became
an endeavor which is safe, effective, and technically achievable. A more robust version of the TNM
classification, advancements in histologic characterization, and improved technologies to assist in staging
helped identify appropriate operative candidates who would benefit from pulmonary resection.
Additionally, developments in chemotherapies and radiotherapeutics are instrumental in improving
overall oncologic outcomes.
The development of the disciplines of general anesthesia and pulmonary surgery has progressed hand
in hand, with innovations in one spurred on by the needs of the other. Likewise, the fields of pulmonary
medicine, infectious disease, and pharmacology have also shaped—and in turn been shaped—over the
course of time. There is no better example of the positive effects of medical subspecialty cross-
pollination targeted toward making the impossible aspirations of yesterday’s physicians and surgeons
possible today.
“The farther backward you can look, the farther forward you are likely to see.”
—Winston Churchill
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3
Minimally Invasive Thoracic Surgery
Stephen Hazelrigg ■ James Regan ■ Michael Thomas
INTRODUCTION
Minimally invasive thoracic surgery is a descriptive term that can refer to many things depending on the
context of the time it is used. Presently it refers to the performance of thoracic surgery using endoscopes
or small incisions, typically no rib spreading, and now almost always with scopes for visualization.
Minimally invasive changes have occurred in many different technical areas including mediastinoscopy,
bronchoscopy, video-assisted thoracic surgery (VATS) techniques, as well as areas like peroral and
esophageal techniques.
THORACOSCOPIC PROCEDURES
Initially, it was thought that using any scope, including the cystoscope, as done by Dr. Jacobeus to look
into the chest cavity was deemed minimally invasive at the time. Now very complex intrathoracic
procedures are performed routinely using small incisions and advanced instrumentation. Historically,
scopes were used to address fluid issues and pleural abnormalities dating back 100 years.1 In the early
1990s on the heels of laparoscopy, these rigid scopes, with better resolution, projected onto screens,
started to make their way into chest procedures. Again the most common early procedures were pleural
based to evaluate fluid, perform pleural biopsies, or deal with simple lung issues like spontaneous
pneumothoraces. Simple procedures with vessel loops could be used to ligate apical blebs, and lasers
were occasionally used to resect small peripheral lung lesions.2,3 These resections were often time
consuming. It was the advent of the endoscopic stapling device that really accelerated the magnitude of
procedures done thoracoscopically. Thoracoscopy took on the term video-assisted thoracic surgery VATS
as many procedures were hybrid types, using small thoracotomies with scope assistance. Wedge resection
became quite easy and reliable with less pain and morbidity when done using VATS. These minimally
invasive procedures often extended the ability to offer surgery to patients that might have been refused
surgery before due to their high risk with open surgery. Early studies then applied VATS to attempt
anatomic resections such as lobectomy. This procedure evolved from mini-thoracotomies with rib
spreading, to eventually elimination of the rib spreading and using the projected picture (no longer
looking through the open incision into thoracic cavity) to guide the entire procedure. After many years of
proving that oncologic principles were followed including adequate nodal dissection, VATS lobectomy
became accepted. Instrumentation continues to improve, making procedures both safe and quicker. We
now face debates about whether or not to use robotics. Is it safer and better, and what are the cost
implications? These represent the next questions to be answered. In the following pages we will
chronicle in a little more detail with regard to some of the history and advances in several procedures.
Clearly, this is a moving and ever-changing target.
MEDIASTINOSCOPY
The main advances in this area have been in the use of video scopes that project a clear and often
magnified image onto a screen. This allows all in the room to view the operative field as opposed to the
old scopes where only the surgeon was able to see by looking through a lighted tube.
BRONCHOSCOPY
The original bronchoscopes were all rigid; but with the advent of the flexible scopes it did not take much
time until almost all bronchoscopies were done with the flexible scopes. Instrumentation for the flexible
system had extended its use such that even complicated endobronchial resections can be performed. The
rigid scope still has some role for the thoracic surgeon. It can be done with JET ventilation and when
energy sources (i.e., laser, argon beam coagulation, etc.) are used the fire risk is significantly diminished.
The rigid scopes still allow larger and better suctioning and this is useful with significant bleeding in the
airway.4 Presently, endobronchial procedures are being performed more frequently with the development
of endobronchial valves and more user-friendly stents. There are different types of endobronchial valves
but they are all designed to obstruct inflow to the portion of the lung where they are deployed and to
allow air and fluid to come out of that segment. They are used either to obstruct air leaks or to restrict
flow into emphysematous areas to attempt to create volume reduction.5–7 In case of air leaks these valves
have been used most frequently for postoperative lung resection patients that have a prolonged leak.
Bronchoscopy with balloon occlusion is used to see if the leak can be stopped by obstruction of a limited
number of segments. When a chest tube is present it is reasonably easy to determine if valve placement
will stop or significantly diminish the leak. Unfortunately, in many of these patients they suffer from
emphysema and have collateral ventilation such that the valve placement will not work. Valve patient is
technically easy and rapid.
Endobronchial techniques continue to evolve to treat end stage emphysema patients. Valves, coils, and
obstructing substances are all in various experimental stages. The valves are designed to attempt to
restrict airflow into the most emphysematous areas and thus cause both redistribution of inhaled air to the
better lung and to cause the lung size to diminish allowing better diaphragmatic function. Endobronchial
resection of tumors has been enhanced with several options with regard to energy sources. These include
lasers, argon plasma coagulation (APC), and cryoprecipitation.8 These are all easily used with the
flexible scope but with lasers and APC precautions to prevent and potentially deal with airway fires (low
inhaled oxygen) must be considered. Fires are rare but obviously devastating if they occur. Cryo does not
have any fire risk and works by freezing the tissue which is then mechanically debrided. Each of the
energy sources mentioned can be used with excellent results. All this can take some time compared to
rigid techniques. Endobronchial stents come in both silastic and nitinol (metal) varieties. The metal ones
are both covered and uncovered and can now be delivered fairly easily with a flexible scope typically
using fluoroscopy. These stents often lead to granulation tissue and potentially long-term airway issues.
Silastic stents are relatively inert in the airway but are more easily dislodged than their metal
counterparts. The silastic stents require rigid placement.9 Appropriate judgment needs to be used in using
them. Stents may be used for stenotic areas and are being used more in carefully selected patients with
tracheomalacia malaise.
VATS ANATOMIC LUNG RESECTIONS

Both lobectomies and segmentectomies are now performed using video-assisted techniques. The
evolution to lobectomy preceded segmental resections but the instruments and skills required are similar.
Many of the early reports of VATS lobectomy, such as Kirby et al.10 were efforts to prove that it could be
done safely. The evolution was from limited thoracotomy with rib spreading and using the scope as a light
source to allow better visualization through the incision to the gradual elimination of any rib retraction
and doing the procedure looking at the monitor screen. Ultimately, large series, such as McKenna et al.,11
began to prove safety, and then oncologic equivalence to open techniques. Instrumentation evolved and
skills improved. There have even been some papers suggesting less inflammation with VATS lobectomy
and that could translate into better oncologic outcomes. While this is unclear, it is very clear that VATS
lobectomy is now common and clearly produces less pain than open thoracotomy. The less pain translates
into fewer lung-related problems, that is, pneumonia, and while certainly not the number one priority, the
cosmetics are better. Now, questions are arising about whether there is any advantage to use of the robotic
system for lobectomy.
ROBOTIC SURGERY
The newest phase in minimally invasive thoracic surgery has occurred with the introduction of robotic
surgery. The development of the robot has occurred over the past two decades. The original robots first
used in surgery were quite primitive and played limited roles. They performed simple functions such as
positioning systems to assist with procedures. While primitive, this robot has led to or inspired the
development of more complex surgical systems. However, it was not until NASA and the U.S. Army
became involved that surgical robotics became more complex. One of the driving forces behind this was
the concept of telepresence, the utilization of virtual reality technology to remotely control machinery to
participate in distant events.12 Their extensive work and research eventually led to the development of
commercially available surgical systems. These systems are complex master-slave machines with a
remote console utilizing video-assist visualization and computer enhancement to operate multiple robotic
arms. The original da Vinci system had a master console where the surgeon sits, a mobile charted mount
with two operating instrument arms and a camera arm, and a vision chart with a dual light source and dual
3-shp cameras.12 Technology has advanced, so has this system, and several generations have been
produced. Much of the initial interest in robotics for thoracic procedures stems from the difficulties
associated with VATS. Several of these drawbacks include having to instruct an assistant to drive the
endoscope, amplification of physiologic tremor with long instruments, limited mobility and angles due to
rigid instruments, and an instrument fulcrum effect and counterintuitive hand movements to manipulate the
instruments. There is also a loss of depth perception and limited magnification possibilities with the two-
dimensional images of the majority of endoscopes. Many of these concerns may be alleviated with the
advent of the robotic surgical system. First, the robotic instruments are designed after the human hand
having seven degrees of freedom. The movements of the robotic arms are precise as they mirror the
surgeon’s natural movement, filter up to 6 Hz of tremor, and can scale large movements into micro
movements within the patient. Finally, the endoscope is manipulated by the surgeon at the console, and
provides improved three-dimensional visualization with depth perception and magnification of the
operative field. The number of surgeries performed with the robot are numerous. Its use has spread among
several surgical specialties including general surgery, transplant, urology, gynecology, and cardiac
surgery. However, the early use of the robot in thoracic surgery was in the early 2000s when thymectomy
was performed.13 This was followed in 2002 by a report by Melfi et al.14 reporting the use of the robot to
perform 17 cases including five lobectomies, three tumor enucleations, three tumor excisions, and one
bulla stitching completed with fibrin glue for spontaneous pneumothorax. Since this time the robot has
been used to perform several different thoracic surgeries including lobectomy, segmentectomy, and
resection for anterior and posterior mediastinal masses. Over time it has become clear that robotic
lobectomy can be done safely and with good oncologic principles. In 2009, Gharagozloo et al.15 reported
on a series of 100 patients with stages I and II NSCLC. They performed a hybrid approach, utilizing the
robot for nodal dissection and a standard VATS lobectomy. They had a mortality rate of 3% but did not
have a death in the last 80 patients. In addition, they reported a 17/100 nodal upstaging. They concluded
that the robot was useful for dissection of the nodal basins and pulmonary hilar dissection. Cerfolio et
al.16 in 2001 published a series, but was comparing robotic lobectomy to muscle sparing thoracotomy. He
compared 106 robotic lobectomies to 318 muscle/nerve sparing thoracotomies. They found that
robotically they were able to achieve an RO resection with good hilar lymph node dissection. In addition,
they were able to show that the robotic lobectomy had a better quality of life with a shorter hospital stay.
The one disadvantage was a higher operative time for the robotic arm. In 2011, Augustin et al.17 showed
similar results, showing that this was a safe and feasible operative approach. In 2011 as well, Louie et
al.18 showed similar results with robotic lobectomy versus traditional VATS. They discussed that
potential benefits of robotic surgery versus VATS was less pain. In the same year, Jang et al.19 showed
comparable results as well. Then in 2012, Park et al.20 showed a long-term series of 325 patients over 10
years and compared to prior VATS and open procedures. They were able to show comparable long-term
survival results from robotic lobectomy. The main drawback of robotic lobectomy will be the time
required for setup and the cost factor. In 2008, Park and Flores21 showed that robotic lobectomy was
higher in cost than traditional VATS, but less than open thoracotomy. Swanson et al.22 in 2014 showed
similar results when comparing robotic lobectomy and wedge to traditional VATS lobectomy and wedges.
They were able to show that there were similar outcomes, but robotic surgery was associated with a
higher cost and longer operative times. In the mediastinum, the most common indications for resection are
in the anterior mediastinum and include thymectomy for myasthenia gravis and thymoma. The purported
benefits of a robotic approach are related to its narrow nature and the rigid chest wall. With the use of
CO2 this space is widened, resulting in improved visualization and operability.23–25 In comparison to
VATS, the complications are similar. With regard to clinical outcomes, there appears to be no significant
difference, although some suggest that there is a quicker improvement in quality of life and shorter
hospital stay.26–28 In the posterior mediastinum, the most common tumors requiring resection would be
neurogenic tumors, followed by esophageal cysts and lymphatic tumors. However, the overall experience
with the robot in this area is limited in several studies.29–33 A robotic approach may provide some
advantage over a thoracoscopic approach in the narrow areas at the apex and near the diaphragm due to
its increased maneuverability. However, currently there are no studies comparing the two approaches and
further research needs to be completed to determine if there are true advantages to the robot. Robotics
represents new technology that continues to advance. At this time, it appears more costly without major
advantages over VATS but this certainly could change over time.
PERORAL TECHNIQUES
Peroral techniques refer to esophageal endoscopic surgeries which have been increasing substantially.
They range from techniques used to address Zenker diverticuli and achalasia to mucosal resections done
in Barrett’s patients and those with early cancers as well as esophageal stents. Like the endobronchial
stenting, stents have become very user-friendly with the flexible endoscopes and are used more
frequently. Over the last several years, these have been used for esophageal perforations with success.
There are now a wide assortment of lengths and diameters which have helped to try to keep the stents
from migrating, which is a particular problem when there is no mechanical lesion (i.e., cancer or
stenosis). There also exists endosuturing devices. These can be used to attempt to suture esophageal tears
or to stitch and anchor stents to prevent migration. Zenker diverticuli can be addressed endoscopically.
This has been available for quite a while with publications using a Weerda diverticuloscope to view the
diverticulum and introducing and firing an endoscopic stapler to connect the esophageal true lumen with
the diverticulum and perform a cricopharyngeal myotomy simultaneously (Fig. 3.1).34
FIGURE 3.1 Peroral diverticulum procedure. A,B: Demonstrate ablation of septum. C,D: Demonstrate healed esophagus with
no evidence of residual diverticulum.
FIGURE 3.2 Peroral esophageal myotomy procedure. Panel A demonstrates mucosal incision; active myotomy (Panel B);
completed myotomy (Panel C); reapproximation of mucosa (Panel D).
Achalasia has been an area of recent intense interest. A Heller myotomy is performed endoscopically
by incising the mucosa and incising the circular muscle layer. The mucosa is then closed. This procedure
is called peroral esophageal myotomy (POEM) (Fig. 3.2).35,36
Early studies have shown considerable success such that ongoing debates are being made over
outcomes of this versus laparoscopic myotomy and antireflux procedure. Endoscopic mucosal resections
(EMR) are performed for localized Barrett and small early esophageal tumors. The endoscopic tools and
skills continue to increase, allowing advanced endoscopic surgeons and gastroenterologists to do these
procedures. In some cases, these are diagnostic and some therapeutic. Obviously, the more extensive
resections may cause stenosis and other issues.
CONCLUSION
Minimally invasive thoracic surgical techniques have come a long way and continue to evolve. It is now
fairly well accepted as a standard therapy to perform VATS for most intrathoracic abnormalities including
lobectomies. In fact, many feel VATS is better than thoracotomy for most thoracic procedures because of a
lower morbidity. Robotics is continuing to develop. Presently, it clearly is safe and effective. Questions
about cost-effectiveness and operative times and true advantages will need to be evaluated. We look
forward to new developments and advances in the future. Endoscopic skills, instruments, and vision
continue to advance. Many esophageal abnormalities lend themselves to minimally invasive treatment
with a lower postoperative risk profile.
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11. McKenna RJ, Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: experience with 1100 cases. Ann Thorac Surg
2006;81:421–426.
12. Satave RM. Surgical robotics: the early chronicles: a personal historical perspective. Surg Laparosc Endosc Percutan Tech
2002;12(1):6–16.
13. Yoshino I, Hashizume M, Shimada M, et al. Thoracoscopic thymectomy with the da Vinci computer-enhanced surgical system. J
Thorac Cardiovasc Surg 2001; 122(4):783–785.
14. Melfi FM, Menconi GF, Mariani AM, et al. Early experience with robotic technology for thoracoscopic surgery. Eur J Cardiothoracic
Surg 2002;21(5):864–868.
15. Gharagozloo F, Margolis M, Tempesta B, et al. Robot-assisted lobectomy for early-stage lung cancer: a report of 100 consecutive cases.
Ann Thorac Surg 2009;88(2):380–384.
16. Ceroflio RJ, Bryant AS, Skylizard L, et al. Initial consecutive experience of completely portal robotic pulmonary resection with 4 arms. J
Thorac Cardiovasc Surg 2011;142(4):740–746.
17. Augustin F, Bodner J, Wykypiel H, et al. Initial experience with robotic lung lobectomy: a report of two different approaches. Surg
Endoscopy 2011;25(1):108–113.
18. Louie BE, Farivar AS, Aye RW, et al. Early experience with robotic lung resection results in similar operative outcomes and morbidity
when compared with matched video-assisted thoracoscopic surgery cases. Ann Thorac Surg 2012;93(5):1598–1604.
19. Jang HJ, Lee HS, Park SY, Zo JI. Comparison of the early robot-assisted lobectomy experience to video-assisted thoracic surgery
lobectomy for lung cancer: a single-institution case series matching study. Innovations (Philo) 2011;6(5):305–310.
20. Park BJ, Melfi F, Mussi A, et al. Robotic lobectomy for non-small cell lung cancer (NSCLC): long-term oncologic results. J Thorac
Cardiovasc Surg 2012;143(2):383–389.
21. Park BJ, Flores RM. Cost comparison of robotic, video-assisted thoracic surgery and thoracotomy approaches to pulmonary lobectomy.
Thorac Surg Clinics 2008;18(3):297–300.
22. Swanson SJ, Miller DL, McKenna RJ Jr, et al. Comparing robot-assisted thoracic surgery lobectomy with conventional video-assisted
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23. Castle SL, Kernstine KH. Robotic-assisted thymectomy. Semin Thorac Cardiovasc Surg 2008;20(4):326–331.
24. Limmer KK, Kernstine KH. Minimally invasive and robotic-assisted thymus resection. Thorac Surg Clin 2011;21(1):69–83.
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27. Ruckert JC, Swierzy M, Ismail M. Comparison of robotic and nonrobotic trhoracoscopic thymectomy: a cohort study. J Thorac
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30. Al-Mufarrej F, Margolis M, Tempesta B, et al. Novel thoracoscopic approach to difficult posterior mediastinal tumors. Gen Thorac
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31. Cerfolio RJ, Bryant AS, Minnich DJ. Operative techniques in robotic thoracic surgery for inferior or posterior mediastinal pathology. J
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Laparoendosc Adv Surg Tech A 2015;25(2):123–129.
Part
B
THE LUNG, PLEURA, DIAPHRAGM,

AND CHEST WALL
Section
II
STRUCTURE AND FUNCTION OF THE

CHEST WALL AND LUNGS
4
Anatomy of the Thorax
Anna Maria Ciccone ■ Federico Venuta ■ Erino A. Rendina
Because of the special functions of the heart and lungs, the chest cage simultaneously must provide
significant protection for its contents and unique support for the lungs. The chest wall is a set of soft and
bony tissues that contains the thoracic viscera. It provides two basic functions: the rib cage delimits
inside and protects the heart, great vessels, and lung from damage; and it takes part in respiration with the
diaphragm and the extrathoracic muscles. This chapter discusses the anatomical relationships between the
soft tissues and bones of the thoracic wall, and their intertwined functions during respiratory movements.
SURFACE ANATOMY OF THE THORAX

The anterior chest wall has several significant landmarks. In the majority of subjects, the superior aspect
of the sternum is easily identifiable. It is slightly concave and forms the jugular or suprasternal notch. In
the vertical midline of the chest the outline of the sternum can be recognized.
From the suprasternal notch, the uppermost boundary of the thorax extends laterally and slightly
upward along the edge of the clavicles and then curves backward toward the shoulders.
Where the sternal angle articulates with the 2nd costal cartilages, there is a palpable prominence,
generally defined “angle of Louis.” This is a significant landmark and defines the upper one-third of the
thoracic cage. The outline of the sternocleidomastoid muscles may be seen extending diagonally: they
originate on the temporal bone of the skull and course inferiorly and anteriorly to insert on the manubrium
of the sternum and on the medial third of the clavicle.
The lower border of the rib cage is palpable, especially in the thin subjects, from the apex of the
xiphoid extending at a downward angle, reaching its lowest level in the lateral aspect at the midaxillary
line.
In men, the nipple lies on the lower border of the pectoralis major muscle over the 4th intercostal
space or on the 4th or 5th rib, just lateral to the midclavicular line. In women, the nipple position is
variable because of the variable size of the mammary glands. They differ in size and shape but generally
lie over the 2nd to 6th ribs. The axillary tails extend upward into the axilla along the lower border of the
pectoralis major muscle.
A few bony landmarks are also identifiable on the posterior aspect of the thorax, which is covered
almost completely by the superficial muscles of the back.
The vertebra prominens is a steady anatomic landmark that corresponds to the spinous process of the
7th cervical vertebra and it stands out clearly in the midline. Below this process, only the spine of the
first thoracic vertebra is visible, while the remaining 11 thoracic vertebrae are less prominent.
The medial edge of each scapula lies laterally to the midline from rib two to seven. The spine of the
scapula extends diagonally upward from the medial border at about the third thoracic vertebra to end in
the acromion in the shoulder.
Several common vertical lines of reference are used to describe positions on the chest wall from the
sternum toward the column (Figs. 4.1 and 4.2). The midsternal line runs down the middle of the sternum.
The lateral sternal line runs along the lateral edges of sternum. The midclavicular line extends downward
from the middle of the clavicles; it defines the midpoint of the anterior chest wall. The anterior axillary
line describes a course extending caudally from the anterior axillary fold. The midaxillary line defines the
midpoint of the lateral aspect of the chest wall, between the anterior and posterior axillary lines. The
posterior axillary line runs downward along the posterior axillary fold. The scapular line lies on a plane
passing through the inferior angle of the scapula. The vertebral line extends over the spinous processes of
the vertebral column in the midline.
FIGURE 4.1 Surface features and superficial musculature of the anterior chest wall. Midsternal line (A), Lateral sternal line (B),
Midclavicular line (C), Anterior axillary fold (D), Posterior axillary fold (E).
CUTANEOUS INNERVATION
Supraclavicular nerves, arising as terminal branches of spinal nerves C3 and C4, supply the skin
innervations above, overlying, and just below the clavicle. The remaining anterior thoracic wall skin is
supplied by the anterior and lateral cutaneous branches of thoracic spinal nerves.
FIGURE 4.2 Surface relations of pleura and lungs (anterior view).
FIGURE 4.3 Surface relations of pleura and lungs (lateral view).
Dorsal rami of C4, C5, C8, T1, and T2 innervate the skin over the back by their medial cutaneous
branches. The skin over the inferior portion of the back is innervated by medial and lateral cutaneous
branches of T3 through T10.
The knowledge of the topography of the various fissures and lobes of the lungs related to the chest wall
surface, as observed by Brock,1 is essential for clinical examination (Figs. 4.3 and 4.4).
SUPERFICIAL CHEST WALL MUSCULATURE

The anterior aspect of the thorax is covered almost completely by the superficial muscles of the chest
(Fig. 4.1). The pectoralis major muscles are evident just below the clavicles bilaterally. They arise from
clavicular and sternocostal fibers; they converge on each side toward their insertion ending in a flat
tendon, which is inserted into the intertubercular sulcus of the humerus. The lower edge of each pectoralis
major muscle forms the anterior fold of the axilla. Their fibers are supplied by medial and lateral pectoral
nerves from the brachial plexus. The clavicular portions of these fibers flex, adduct, and rotate inward the
humerus and elevate the arm. The sternocostal portions antagonize the previous actions contributing to
downward and forward movement of the arm. Furthermore, these muscles may elevate the upper ribs in
forced respiration if the shoulder girdle is in a fixed position.
FIGURE 4.4 Posterior view of the chest wall. Surface features (left) and superficial muscles (right).
Deeper to the major pectoralis muscles are the pectoralis minor muscles. They arise from the upper
borders and outer surfaces of the 2nd, 3rd, 4th, and 5th ribs and form a flat tendon that inserts on the
coracoid process of the scapula. These muscles also depress and rotate the shoulders downward when
supplied by the medial and lateral pectoral nerves.
The serratus anterior muscles lie along the anterolateral aspects of the thoracic wall and, in thin or
muscular subjects, can be easily visible. They originate from the 1st to the 8th ribs and insert along the
anterior surface and medial border of the scapula. On each side, the muscle is supplied by the long
thoracic nerve which passes on their external surface, downward in the midaxillary line. These muscles
hold the scapulae toward the thoracic wall and participate in adduction and elevation of the arms above
the horizontal position. Muscles of the posterior chest wall (shoulder and scapular region) form the
surface features of the back of the thorax and help move the upper extremity (Fig. 4.2).
The posterolateral contours of the neck and uppermost limits of the shoulders are formed by the
trapezius muscles. On each side they arise from the superior nuchal line of the occipital bone, the
ligamentum nuchae of the neck, the spine of the 7th cervical vertebra, and spines and supraspinous
ligaments of all thoracic vertebrae. The superior fibers reach the lateral third of the clavicle. The middle
fibers insert into the acromion of the scapula and the spine. The inferior fibers converge near the scapula
and end in an aponeurosis. These muscles are supplied by spinal accessory nerves and filaments from
cervical spinal levels C3 and C4. They can elevate, depress, or adduct the scapulae aiding
scapulohumeral movements and are powerful stabilizers of the shoulders.
Lower and lateral parts of the back are covered by the latissimus dorsi muscles. These muscles arise
by broad aponeurotic origins from spines of lower thoracic vertebrae, the lumbodorsal fascia, the iliac
crests, and some slips from the outer surfaces of the lower three or four ribs. Their fibers converge
frontward and upward to insert on the intertubercular groove of the humerus. Moreover, some fibers of
their upper thirds enter to form the posterior folds of the axillae. Each is supplied by a thoracodorsal
nerve from the brachial plexus. They allow movements of adduction, extension, and medial rotation of the
arms and are considered accessory muscles of respiration as part of their slips are attached to the lower
ribs.
Deep to the trapezius and the latissimus dorsi lies the scapular muscles involved in scapular
movements: the levator scapulae, the rhomboid major, and the rhomboid minor muscles. They elevate,
adduct, and retract the scapula. They are also involved in movements of the ribs in a lesser degree.
The levator scapulae is a thin long muscle located laterally on each side of the neck and that originates
from the first three to four cervical vertebrae (transverse processes). Its fibers lie diagonally down to the
superior angle of the scapulae.
The rhomboid minor muscles originate from the last cervical vertebra and from the first thoracic
vertebra. It goes to form the internal border of the scapulae, bilaterally.
The rhomboid major starts from 2nd, 3rd, 4th, and 5th thoracic vertebrae, and it extends to the medial
border of the scapulae, just below the spine. These two muscles may be fused.
They are all supplied by the dorsal scapular nerve, but the levator scapulae are also supplied by
branches from C4 and C5.
The triangle of auscultation is a limited portion of the back almost free of interposed muscle tissues
(save for lower fibers of the rhomboid muscles) which allows to perceive respiratory sounds relatively
free of distortion. It is bounded by the lateral edge of the trapezius, the upper margin of the latissimus
dorsi, and the vertebral border of the scapula.
Thorough knowledge of the anatomy of the chest wall muscles is mandatory before selecting the best
surgical incision to perform in a given situation. Moreover, the superficial chest wall muscles can be of
great aid in managing different situations both within and on the surface of the thorax.
Muscle flaps can be utilized in the repair of a bronchopleural fistula to bring healthy, vascularized
tissue into an infected field and promote closure. Furthermore, after a skeletal thoracic resection and
reconstruction, if primary closure cannot be performed, muscle transposition is best to accomplish soft
tissue reconstruction. The most commonly used muscle flaps are the pectoralis major and latissimus dorsi.
Size and location of the chest wall defect and preservation of the blood supply to the flap dictate the
appropriate reconstruction.
Pectoralis major is the most frequent flap used in sternal region defects. The pectoralis can be taken as
a muscle flap or as a myocutaneous flap because of the multiple perforators entering the skin through the
muscle from the internal mammary arteries. The pectoral branch of the thoracoacromial artery is the major
blood supply. Release of the humeral tendon of the muscle provides a wider mobilization and rotation.
For larger defects located over the mid sternum, pectoral muscle can be used bilaterally.
The latissimus dorsi is the flap of choice to harvest in anterior and lateral defects. It can be used as a
myocutaneous flap or as a muscular flap. The major blood supply is usually the thoracodorsal artery, a
terminal branch of the subscapular artery, but it may also be the serratus collateral vascular plexus.
Because of its long pedicle, a latissimus dorsi flap can be used to cover any area of the chest.
As an alternative, the serratus anterior may be used and rotated into the chest to fill a small residual
space, since it provides only a moderate amount of tissue.
Furthermore, the intercostal muscle of the 5th intercostal space can be prepared, preserving its
posterior vascular supply, which requires a wide musculopleural flap. It can be tailored for protection of
the bronchial stump or anastomosis during bronchoplastic procedures. This flap may be utilized to repair
a bronchopleural fistula and/or fill small residual spaces providing vascularized and healthy tissue.2
THE THORACIC SKELETON

The skeletal structure of the chest consists of the sternum anteriorly, 12 thoracic vertebrae forming the
vertebral column posteriorly, and 12 pairs of costae.
The thoracic inlet is the uppermost extent of the thoracic cavity. It is surrounded front to back by the
manubrium of the sternum, the 1st ribs, and the 1st thoracic vertebra (Fig. 4.5). The anterior border lies
about 2 to 3 cm below its posterior limits. The apical boundary of the pleural cavity is demarcated by a
thickened endothoracic fascia, the Sibson fascia, which roofs the apex of the lung, and the parietal pleura
on each side. Major structures passing through this aperture include the major arterial branches of the
aortic arch, the great venous vessels of the head and upper extremities, as well as, the trachea, the
esophagus, and the major trunks of the brachial plexus bilaterally.
FIGURE 4.5 Thoracic skeleton (lateral view).
The outlet of the thorax lies at the boundary between the chest and the abdominal cavity and is much
larger. It is bordered by the xiphoid process, fused costal cartilages of ribs 7 through 10, the anterior
portions of the 11th ribs, the arches of the 12th ribs and the 12th thoracic vertebra. The anterior margin of
this aperture is at the level of the 10th thoracic vertebra and the posterior margin is at the 12th; the outlet
reaches its lowest level in the lateral aspect near the midaxillary line, which corresponds to the level of
the 2nd lumbar vertebra.
The diaphragm is a sheet of internal skeletal muscle that lies on the floor of the thoracic cavity.
Through the hiatus of the diaphragm several vital structures traverse the outlet to enter the abdomen,
including the esophagus and the descending thoracic aorta on the left side and the inferior vena cava on
the right side which passes through the diaphragm to reach the right atrium.
The sternum is a flat, sword-shaped bone that lies in the anterior midline of the thorax and extends
longitudinally from the base of the neck down to about 15 to 20 cm. It consist of three distinct portions
that ossify separately from three distinct cartilaginous precursors: the manubrium, the body, and the
xiphoid process (Fig. 4.6).
The manubrium forms the top portion of the sternum. It is about 5 cm wide in its upper half and 2.5 to
3 cm wide in its lower half. Centrally on the upper border, an indentation is present which, together with
the sternal ends of each clavicle, forms the suprasternal notch. Clavicles articulate with the manubrium on
each side by a joint. The widest portion of the manubrium has indentations on each lateral surface, the
costal incisura, to accommodate articulation of the first costal cartilages. At the lower edge of the
manubrium, each lateral margin has a curved indentation for articulation of the upper half of the second
costal cartilages. The lower margin of the manubrium articulates with the body of the sternum at the
sternomanubrial joint, which is a synchondrosis, sufficiently flexible to allow movements of the body on
the manubrium during respiratory movements.
The joint between the lower border of the manubrium and the upper margin of the body forms an angle,
where the 2nd cartilage articulates with the sternum. It is called the angle of Louis (or sternal angle). This
identifies a readily palpable surgical landmark that corresponds to the level of the aortic arch and the
tracheal carina and posteriorly to the level of the 4th to 5th thoracic vertebrae.
The body represents the longest segment of the sternum. On each side, just beneath the sternubrial joint,
there is the lower half of the 2nd costal cartilage’s articulation that matches up to the corresponding
indentations on the manubrium to form a complete facet. Along the sides of the body are additional paired
facets, which form a joint with the corresponding costal cartilages, from 3rd through 7th. The lower
border of the body ends with a cartilaginous facet to form the joint with the xiphoid process.
The xiphoid is the most inferior, shortest (2 to 3 cm), and thinnest part of the sternum, that originates
from a cartilaginous appendix which often ossifies partially or completely by middle age. It may be
occasionally bifid or perforated. It extends downward to end in the sheath of the rectus abdominis muscle.
It generally moves with the sternum during respiratory movements but its backward displacement due to
the contractions of the diaphragm is prevented by the costoxiphoid ligaments which extend from its
anterior surface to the front of the 7th costal cartilage.
The ribs and their costal cartilages form the greater part of the thoracic skeleton and widely define the
size and the shape of the rib cage. A single rib with its cartilage are properly termed a costa. There are 12
pairs of costae which articulate dorsally with the 12 thoracic vertebrae on the vertebral column, and
ventrally with the sternum. The upper seven ribs form a complete loop to articulate by way of their
cartilages with the sternum on the midline, and they are so called “true ribs” or vertebrosternal ribs. The
lower five ribs do not articulate directly with the sternum. The costal cartilages of the 8th, 9th, and 10th
ribs attach to the cartilage of the ribs immediately above them (“false ribs” or vertebrocostal ribs). And,
the anterior extremities of the 11th and 12th ribs are free (“floating ribs” or vertebral ribs) and their
costal cartilages are short, have no sternal attachment and end in the muscle of the posterolateral
abdominal wall.
FIGURE 4.6 Skeleton and bones of the pectoral girdle (anterior view).
The angle of costal elements of the thoracic wall relative to the vertebrae and the sternum is therefore
the result of cephalic migration of the vertebral ends and the relative retention of the sternal ends at their
original levels.
Ribs exhibit many similar characteristics, but their form is variable at different levels. They
progressively increase in length from the 1st to the 7th and then decrease to the 12th. Several features are
in common among ribs three through nine, also called typical ribs. Each single rib, from vertebral to
sternal ends, has a head, a neck, and a body or shaft (Fig. 4.7). The head articulates with the vertebral
column (costovertebral joint) by means of two facets: the inferior facet attaches on the adjacent vertebral
body; and, the upper one articulates with the body of the vertebra above it.
The neck extends dorsolaterally for about 2.5 cm. The end of the neck is marked on the side by a
tubercle which articulates with the transverse process of the lower vertebra with which the head
articulates. The body extends dorsolaterally for 5 to 7.5 cm and then turns gradually forward and
downward. At this level the curvature accentuates to form the angle of the rib that marks the lateral extent
of the erector spinae muscles of the back. At the lower border on the inner aspect of the body is the
subcostal groove, which houses the intercostal nerve bundles and vessels and is better defined on the
posterior half of each rib. Each rib is continued through a joint by its costal cartilage which is attached to
the sternum. Exceptions are the floating ribs, which have no direct skeletal attachment.
The 1st and the 2nd ribs differ from other typical ribs. The 1st rib is the shortest one and is wider and
more curved than the rest. Its head articulates with a single facet of the 1st thoracic vertebral body. This
rib is flat forming a lower and an upper surface, furrowed in the middle by the intertubercular grooves for
the subclavian artery and the subclavian vein. This separation by the tubercle allows for the attachment of
the anterior scalene muscle. The 2nd rib has a similar curvature but is nearly twice the length of the 1st.
Its angle is poorly defined and the body is marked by a tubercle for the serratus anterior muscle. The
articulation of its cartilage to the sternum forms the angle of Louis. The 11th and 12th ribs are different in
shape as they have almost absent necks, angles, and costal grooves and are sequentially shorter than the
ribs above. Furthermore, they present only one articular facet for their corresponding vertebra.
FIGURE 4.7 Typical rib. A: Inferior view. B: Superior view.
Rib structure and number may vary: the 1st rib may be fused with the 2nd and this may be associated
with other variations of sternum or thoracic vertebrae. The sternal extremity of the 3rd or 4th rib may be
bifid and the 8th may reach the sternum on one or both sides. A lumbar rib may be present associated with
the first lumbar vertebra. However, the most clinically relevant variation is the presence of a cervical rib.
This is a cartilaginous or ossified rib born by the 7th cervical vertebra, which may be shorter or longer
and attached to the 1st costal cartilage or to the manubrium. This variation of the thoracic inlet may lead
to the compression of the subclavian vessels and/or the brachial plexus, thus compromising the
neurovascular supply to the upper extremity.
THE INTERCOSTAL SPACE

The space between the adjacent ribs, the intercostal space, is filled by the intercostal muscle and
membrane. Since there are 12 ribs on each side, there are 11 intercostal spaces. In the intercostal spaces
lie different structures: several kinds of intercostal muscles, intercostal arteries and associated veins,
lymphatics, and nerves (Fig. 4.8). Comprehensive insight into the anatomy of the intercostal spaces is
mandatory for everyone who practices medicine.3
THE INTERCOSTAL MUSCLES

The intercostal muscles are three thin planes of muscular and tendinous fibers occupying each of the
intercostal spaces. They are named external, internal, and innermost from their surface relations, and are
all innervated by intercostal nerves (Figs. 4.9 to 4.11).
FIGURE 4.8 Relationships of structures within the intercostal space. A: Intercostal vessels and nerves. B: Collateral vessels.
A, artery; V, vein; N, nerve.
FIGURE 4.9 Thoracic wall and muscles of the intercostal spaces (anterior view). The anterior half of the right side has been
removed to demonstrate the inner aspect of the posterolateral thoracic wall.
The external intercostals are 11 on either side. They extend from the tubercles of the ribs dorsally, to
the cartilages of the ribs ventrally, where they end in thin membranes. The external intercostal membranes
continue forward toward the sternum. Each external intercostal muscle arises from the lower border of a
rib, and is inserted into the upper border of the rib below. In the two lower spaces they extend to the ends
of the cartilages, and in the upper two or three spaces they do not reach the ends of the ribs. They are
thicker than the internal intercostals and their fibers are directed obliquely downward and lateral on the
back of the thorax, and downward, forward, and medial on the front.
FIGURE 4.10 Anterior view of the left half of the thorax showing the course of the external intercostal muscles, directed
obliquely downward, forward, and medialward on the front, which is the opposite of the course of the internal muscle fibers.
FIGURE 4.11 Posterior view of the thoracic wall and muscles of the intercostal spaces. The posterior half of the left side has
been removed to demonstrate the inner aspect of the anterolateral thoracic wall.
The internal intercostals are also 11 in number on each side. They begin ventrally at the sternum in the
interspaces between the cartilages of the true ribs and at the ventral extremities of the cartilages of the
false ribs. They extend downward as far as the angles of the ribs, where they continue to the vertebral
column as thin aponeuroses called the internal (or posterior) intercostal membranes. Each internal
intercostal muscle arises from the inferior border on the inner surface of the rib that lies superiorly, as
well as from the corresponding costal cartilage, and is inserted into the upper border of the rib below.
Their fibers are also directed obliquely, but pass inferiorly and posteriorly, in a direction opposite to
those of the external intercostals.
It is conventionally considered that because of their fiber orientations, the external intercostal muscles
elevate the ribs, whereas the internal interosseous intercostals lower the ribs.
The innermost intercostals are incomplete and variable. They pass from rib to rib, deep to the internal
intercostals. The fibers of the innermost intercostals pass in the same direction as those of the internal
intercostals, the only difference being that they lie deep to the intercostal neurovascular bundle. They are
actually separated from the internal intercostals by only the intercostal nerves and vessels.
The subcostalis (or infracostal) muscles are combined muscular and aponeurotic slips that vary in size
and number and lie on the internal surface of the lower ribs. They are usually well-developed only in the
lower part of the thorax. Near the angles of the ribs they may be considered as parts of the innermost
intercostals which span two intercostal spaces. Each subcostal muscle arises from the inner surface of
one rib near its angle and inserts into the inner surface of the 2nd or 3rd rib below. Their fibers run in the
same direction as those of the internal intercostals.
In each intercostal space thin but firm layers of fascia cover the outer surface of the external
intercostals and the inner surface of the internal intercostals. A third fascial layer is interposed between
the two planes of muscular fibers and, in those situations where the muscular fibers are deficient, as
between the external intercostals and the sternum ventrally, and the internal intercostals and vertebral
column dorsally.
THE NEUROVASCULAR BUNDLE

Lying between the innermost fascia and the inner intercostal muscles is the neurovascular bundle. When
they are not covered by the innermost intercostal muscles, the intercostal nerves and vessels run just
behind the internal intercostal muscles. Thus, they are generally covered on the inside by the parietal
pleura, subcostal muscles, or the transversus thoracis muscle. One particular concept is that the
neurovascular bundle has a strict order: the intercostal vein is most cephalad, followed progressively by
the intercostal artery and finally the intercostal nerve (Fig. 4.12). This neurovascular bundle runs high in
the intercostal space. Because of this the intercostal space should be penetrated as low as possible by
invasive procedures.
INTERCOSTAL VESSELS
In each intercostal space there are two sets of arteries, posterior and anterior, that anastomose with each
other (Fig. 4.13). The posterior intercostal arteries of all but the first two interspaces are from the
descending thoracic aorta. The arteries of the first two spaces posteriorly come from the highest (or
supreme) intercostal branch of the costocervical trunk. Each posterior intercostal artery gives off a
collateral branch in the intercostal space. They supply the lateral and posterior portions of the intercostal
space. Anterior intercostal arteries are branches of the internal thoracic artery (upper six intercostal
spaces) and one of its terminal branches, the musculophrenic artery (7th to 10th intercostal spaces). They
are much smaller than the posterior ones. The upper two intercostal spaces are supplied anteriorly by the
supreme thoracic artery, the first artery to arise from the axillary artery. There are two anterior intercostal
arteries per side per intercostal space, one coursing above and one coursing below each rib. Anterior
intercostal arteries supply the anterior portions of the intercostal spaces.
The intercostal veins having similar names generally follow the distribution of the intercostal arteries
with the exception of posterior intercostal veins that drain into the azygos system. On the right side, the
azygos vein collects intercostal veins from all of the intercostal spaces except the first, and by the
hemiazygos and accessory hemiazygos veins from all of the intercostal spaces on the left except for the
upper three spaces. The first intercostal space on the right drains to the right brachiocephalic vein. Valves
in the intercostal veins direct blood toward the azygos vein. The anterior intercostal spaces drain
anteriorly to the internal thoracic veins. The difference in termination of the intercostal veins of the left
and right sides is explained by the embryonic origin of the azygos system from the (originally
symmetrical) supracardinal veins.
FIGURE 4.12 Exposure of the posterior part of the intercostal space. Note that the intercostal vein (v), artery (a), and nerve
(n) lie between the internal and innermost intercostal muscle layers. From the intervertebral foramen to the angle of the rib, the
intercostal vessels and nerves are covered by the internal intercostal membrane.
FIGURE 4.13 Axial section of an intercostal space, showing arteries on the left side and nerves on the right side.
INTERCOSTAL NERVES
The intercostal nerves are the thoracic spinal nerves T3 through T12. For points of reference, the 7th
intercostal nerve terminates at the lower end of the sternum (xiphoid process) (Fig. 4.13). The 10th
intercostal nerve terminates at the belly button.
The anterior divisions of the thoracic nerves are 12 in number on either side. Eleven of them are
situated between the ribs, and are therefore termed intercostal; the 12th lies below the last rib. The
intercostal nerves are distributed chiefly to the parietes of the thorax and abdomen. They differ from the
anterior divisions of the other spinal nerves, in that each pursues an independent course. The first two
nerves supply fibers to the upper limb in addition to their thoracic branches. The next four are limited in
their distribution to the parietes of the thorax and the lower five supply the parietes of the thorax and
abdomen. The 12th thoracic is distributed to the abdominal wall and the skin of the buttock.
Because of its importance and special mixed origin, the 1st thoracic nerve has a distinct anatomy. The
anterior division of the 1st thoracic nerve divides into two branches: one, the larger, leaves the thorax in
front of the neck of the first rib, and enters the brachial plexus; the other and smaller branch, the 1st
intercostal nerve, runs along the 1st intercostal space, and ends on the front of the chest as the 1st anterior
cutaneous branch of the thorax. Occasionally, this anterior cutaneous branch is wanting. The 1st
intercostal nerve as a rule gives off no lateral cutaneous branch, but sometimes it sends a small branch to
communicate with the intercostobrachial. From the 2nd thoracic nerve it frequently receives a connecting
twig, which ascends over the neck of the 2nd rib.
The upper thoracic nerves (2nd to 6th) also vary from the other intersegmental nerves. The anterior
divisions of the 2nd, 3rd, 4th, 5th, and 6th thoracic nerves, and the small branch from the 1st thoracic, are
confined to the wall of the thorax, and are named thoracic intercostal nerves. They pass forward in the
intercostal spaces below the intercostal vessels. At the back of the chest they lie between the pleura and
the posterior intercostal membranes, but soon pierce the latter and run between the two planes of
intercostal muscles as far as the middle of the rib. They then enter the substance of the internal
intercostals, and, running amidst their fibers as far as the costal cartilages, they gain the inner surfaces of
the muscles and lie between them and the pleura. Near the sternum, they cross in front of the internal
mammary artery and transversus thoracis muscle, pierce the internal intercostals, the anterior intercostal
membranes, and pectoralis major, and supply the integument of the front of the thorax and over the
mamma, forming the anterior cutaneous branches of the thorax. The branch from the 2nd nerve unites with
the anterior supraclavicular nerves of the cervical plexus.
Numerous slender nerve filaments supply the intercostals, the subcostals, the levatores costarum, the
serratus posterior superior, and the transversus thoracis. At the front of the thorax some of these branches
cross the costal cartilages from one intercostal space to another. Lateral cutaneous branches are derived
from the intercostal nerves, about midway between the vertebrae and sternum. These pierce the external
intercostals and serratus anterior, and divide into anterior and posterior branches. The anterior branches
run forward to the side and the forepart of the chest, supplying the skin and the mamma. Those of the 5th
and 6th nerves supply the upper digitations of the external obliquus abdominis. The posterior branches run
backward, and supply the skin over the scapula and latissimus dorsi.
The lateral cutaneous branch of the 2nd intercostal nerve, the intercostobrachial nerve, does not
divide, like the others, into an anterior and a posterior branch. It pierces the external intercostals and the
serratus anterior, crosses the axilla to the medial side of the arm, and joins with a filament from the
medial brachial cutaneous nerve. It then pierces the fascia, and supplies the skin of the upper half of the
medial and posterior part of the arm, communicating with the posterior brachial cutaneous branch of the
radial nerve. A 2nd intercostobrachial nerve is frequently given off from the lateral cutaneous branch of
the 3rd intercostal and supplies filaments to the axilla and medial side of the arm.
The lower thoracic nerves (7th to 11th) do not differ greatly from the abdominal intersegmental nerves.
The anterior divisions of the 7th, 8th, 9th, 10th, and 11th thoracic nerves continue anteriorly from the
intercostal spaces into the abdominal wall and are named the thoracicoabdominal intercostal nerves.
They have the same arrangement as the upper ones as far as the anterior ends of the intercostal spaces,
where they pass behind the costal cartilages, and between the internal obliquus and transversus
abdominis, to the sheath of the rectus abdominis, which they perforate.
The lower intercostal nerves supply the intercostal and abdominal muscles with the last three sending
branches to the serratus posterior inferior. About the middle of their course they give off lateral cutaneous
branches. These pierce the external intercostals and the external obliquus abdominis, in the same line as
the lateral cutaneous branches of the upper thoracic nerves, and divide into anterior and posterior
branches, which are distributed to the skin of the abdomen and back. The anterior branches supply the
digitations of the obliquus externus abdominis, and extend downward and forward nearly as far as the
margin of the rectus abdominis. The posterior branches pass backward to supply the skin over the
latissimus dorsi.
The lower thoracic nerve (12th) varies in function from its upper cousins. The anterior division of the
12th thoracic nerve is larger than the others where it runs along the lower border of the 12th rib. It often
gives a communicating branch to the 1st lumbar nerve, and passes under the lateral lumbocostal arch. It
then perforates the transversus and passes forward between it and the internal obliquus to be distributed
in the same manner as the lower intercostal nerves.
The lateral cutaneous branch of the last thoracic nerve is large, and does not divide into an anterior
and a posterior branch.
INTERCOSTAL LYMPHATIC VESSELS

At the anterior ends of the intercostal spaces are placed the sternal glands, by the side of the internal
mammary artery. The posterior parts of the intercostal spaces are occupied by the intercostal glands, in
relation to the intercostal vessels. They receive the deep lymphatics from the posterolateral aspect of the
chest. The efferents of the glands in the lower four or five spaces unite to form a trunk, which descends
and opens either into the cisterna chyli or into the commencement of the thoracic duct. The efferents of the
glands in the upper spaces of the left side end in the thoracic duct and those of the corresponding right
spaces, in the right lymphatic duct. The intercostal lymphatic vessels are deep lymphatic vessels of the
thoracic wall, which drain the intercostal muscles and parietal pleura. Those draining the external
intercostals run backward and, after receiving the vessels which accompany the posterior branches of the
intercostal arteries, end in the intercostal glands. Those of the internal intercostals and parietal pleura
consist of a single trunk in each space. These trunks run forward in the subpleural tissue and the upper six
open separately into the sternal glands or into the vessels which unite them. Those of the lower spaces
unite to form a single trunk which terminates in the lowest of the sternal glands.
INTERACTIONS BETWEEN THE COMPONENTS OF THE CHEST WALL

DURING RESPIRATION
Other than providing protection for the internal thoracic viscera, the most important function of the chest
wall is its contribution to respiration. The physiologic respiration is the result of both active and passive
movements. The active and coordinated muscle contraction during inspiration causes enlargement of the
rib cage. As a result of increased thoracic diameters, the intrathoracic, intrapleural, and intrapulmonic
pressures are reduced to levels below atmospheric pressure. This causes the aspiration of air into the
lungs. Expiration is the passive return of thoracic diameters to resting levels. It causes an increase of
intrathoracic, intrapleural, and intrapulmonic pressures to levels higher than the atmosphere, causing the
air outflow. Accessory muscle activity may facilitate the expiratory event, but they are not essentials.
Inspiratory movements enlarge the thoracic cavity in anteroposterior, lateral, and superoinferior
dimensions. The increasing of anteroposterior diameter is the result of the elevation of the sternal body
outward and foreword, lifted by the ribs. The greatest excursion occurs at the level of the longest ribs,
from 5th to 7th. During normal quiet respiration, the ribs are elevated by synchronous contraction of the
intercostal muscles.4 The accessory muscles cooperate in forced inspiration.4–6
The increase in lateral dimension of the thorax is the result of upward and lateral movement of ribs at
the level of midaxillary line. The greatest degree of movement is noted in ribs 7 to 10, the costal cartilage
of which descend and then ascend before articulation with the sternum. Because the middle of each rib
cartilage unit is lower than either the costovertebral or costosternal articulations, elevation swings each
unit upward and laterally (bucket handle) (Fig. 4.14). This action is accomplished by contraction of
intercostal muscles and facilitated by muscle fibers of the diaphragm.7 The craniocaudal thoracic
dimension is the greatest in increasing during inspiration, as a consequence of the diaphragm contraction.
During quiet respiration, the diaphragm undergoes an excursion of about 1 to 2 cm, but it may move as
much as 6 to 7 cm during deep breathing. The lower ribs are believed to be helpful in resisting upward
and medial pull of the diaphragm. The diaphragm and intercostal muscles are therefore the primary
muscles of inspiration. Movements of the diaphragm account for 75% to 80% of pulmonary ventilation
during quiet respiration, compared with 20% to 25% contributed by the intercostal muscles. However,
during forced and deep breathing other skeletal muscles may participate. The configuration of the thoracic
skeleton and musculature thus acts to create the most effective movements for respiration with the least
requirement of energy.
FIGURE 4.14 The bucket-handle movement of the ribs during breathing increases the lateral dimension of the thoracic cavity.
The distance of the rib from the central axis of the thorax is significantly shorter at the beginning of inspiration (A) than it is at the
end of inspiration (B).
REFERENCES
1. Brock RC. The Anatomy of the Bronchial Tree: With Special Reference to the Surgery of Lung Abscess. 2nd ed. London: Oxford
University Press; 1954.
2. Rendina EA, Venuta F, Ricci P, et al. Protection and revascularization of bronchial anastomoses by the intercostal pedicle flap. J Thorac
Cardiovasc Surg 1994;107(5):1251–1254.
3. Rendina EA, Ciccone AM. The intercostal space. Thoracic Surg Clin 2007;17(4):491–501.
4. Taylor A. The contribution of the intercostal muscles to the effort of respiration in man. J Physiol (London) 1960;151:390–402.
5. Campbell ETM. The role of the scalene and sternomastoid muscles in breathing in normal subjects. An electromyographic study. J Anat
1955;89:378–386.
6. Jones DS, Beargie RT, Pauly TE. Electromyographic study of some muscles of costal respiration in man. Anat Rec 1953;117:17–24.
7. Cherniack RM, Cherniack L. Respiration in Health and Disease. Philadelphia, PA: Saunders; 1961.
SUGGESTED READINGS
Ciccone AM, Vanni C, Venuta F, et al. Chest Wall Masses and Chest Wall Resection. Operative Thoracic Surgery. 6th ed. 2017.
Ferguson Mark K. Thoracic Surgery Atlas. Saunders (W.B.) Co. Ltd; 2007. ISBN 9780721603254.
Gray H. Gray’s Anatomy: The Anatomical Basis of Clinical Practice. 39th American ed. C.V. Mosby; 2004. ISBN 0-443-07168-3.
Netter FH. Atlas of Human Anatomy. 6th ed. Saunders/Elsevier; 2014. ISBN: 9781455704187.
5
Embryology of the Lungs
Alejandro C. Bribriesco ■ Mala R. Chinoy ■ Daniel Kreisel
Traditionally, the study of embryology has been a core subject for those interested in pursuing careers in
the biologic sciences or health professions. A firm understanding of this complex symphony of cell
interaction and movement is important as it provides the means to understand the root cause of disease,
and potentially hold the key to future discovery and innovation.
The history of lung embryology dates back as early as 1661 where Malpighi of Bologna is credited
with examining the microscopic structure of the frog lung. More recently, insights from animal models
from the early 20th century to the present have tremendously advanced our current understanding of human
embryogenesis. Over this period of time, centers such as the Carnegie Institute contributed significantly to
elucidating the events of gross pulmonary organogenesis. Subsequent investigators expanded on this
relative macroscopic perspective of lung development to define increasingly granular details to the level
of DNA regulation of differential morphogenesis of airway, vascular, and parenchymal structures. Deeper
insight into the mechanisms driving lung development uncovers new opportunities for clinical innovation
and translational therapies in patients suffering from pulmonary disease.
The main focus of this chapter is the description of the embryologic events which culminate in the
creation of the adult lung. Street’s crown–rump length and Carnegie stages1–4 with dates (timed from
ovulation) are utilized unless specified. Given the overlapping nature of pulmonary substructure
development, bronchial or airway formation is discussed concurrently with the development of the
adjacent lung parenchymal tissue that creates the blood–air barrier. Finally, advances in genetic and
molecular biology have begun to define roles for the genes, transcription factors, growth factors, and
other small molecules that act at the DNA level. These elements have been shown to play critical roles in
the programmed events of lung development as evidenced by in utero exposure to mutating or damaging
agents resulting in severe consequences. Conversely, targeted gene and molecular therapies are being
developed based on these same principles which offer a promising translational application of pulmonary
embryology.
LUNG FORMATION
Lung development begins with the early interaction (embryonic week 3 to 4) of the mesoderm and
endoderm germ layers resulting in the formation of the primitive lung buds derived from foregut endoderm
(Fig. 5.1). What follows is a complex, three-dimensional process where adjacent portions of the
developing embryo exist in different stages of maturation concurrently. As such, the cellular events and
lung morphology are what truly define the embryologic period rather than firm calendar dates which are
not necessarily absolute. Our current understanding of lung formation is based upon decades of elegant
work by notable embryologists such as Dubreuil, Loosli, Potter, Boyden, and Thurlbeck. Table 5.1
summarizes how each of these groups defined what they considered to be the various stages of pulmonary
development. Currently Thurlbeck’s classification is most widely used and will be utilized in this chapter.
Figure 5.2 is a schematic overview of the five embryologic periods of lung formation which include
(1) embryonic period: defined by development of primordial trachea and lung buds; (2) pseudoglandular
period: bronchial tree arborization and development; (3) canalicular period: formation and
vascularization of air-conducting elements; (4) terminal saccular period: increased respiratory units with
differentiation of type I and II pneumocytes; and (5) alveolar period: increase in alveoli formation with
associated increased respiratory surface area. Table 5.2 highlights important embryologic milestones that
occur during formation of the lung with respect to the concomitant maturation of the airway, interstitial
lung parenchyma, and major pulmonary vasculature.
DEVELOPMENTAL STAGES AND STRUCTURE OF THE LUNG

Embryonic Period: Weeks 0 to 12
The embryonic phase spans gestational days 26 to 52 and involves the morphogenesis of the proximal
airways and early differentiation of surrounding splanchnic mesoderm-derived mesenchymal tissue. The
onset of this period is marked by division of the respiratory diverticulum to form primary bronchial buds
at the end of the fourth gestational week (Figs. 5.1 and 5.2). These endodermal buds continue to grow into
the surrounding splanchnic mesoderm known as the pericardioperitoneal canal which is the precursor of
the pleural cavities. By week 5, the main bronchi have formed with the right main bronchus
asymmetrically larger and more vertically oriented than the left main stem. This position is necessary
given the physical relationship of the airway to the heart and the arch of the aorta. Interestingly, this
asymmetry appears to be independent of purely mechanical forces caused by the developing heart which
does not assume its final position in the chest until the sixth week of gestation. Multiple rounds of
dichotomous divisions result in generation of secondary bronchi at approximately gestational day 52 and
marks the transition from the embryonic to the pseudoglandular period.
FIGURE 5.1 Early development of lung. At the beginning of the 4th embryonic week (day 26), the primitive lung bud begins to
form from the foregut endoderm to form the laryngotracheal diverticulum or tube. By day 41 the trachea is separated from the
esophagus first as an esophagotracheal ridge which then becomes a longitudinal septum. Secondary bronchial buds mark the
beginning of the pseudoglandular phase with 17 subdivisions occurring by 6 months. (Figure downloaded for free at
http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482e3e22@8.24 and modified.)
One clinically relevant event that occurs during the embryonic period is the separation of the
primordial trachea from esophagus. As noted in Table 5.2, the laryngotracheal diverticulum forms at day
26 followed by the development of longitudinal invaginating ridges of endodermal tissue called
tracheoesophageal folds. These folds ultimately fuse in a caudal to cephalad manner to form the
tracheoesophageal septum which demarcates the laryngotrachea from the esophagus. At the boundary of
the developing trachea and esophagus, programmed cellular degeneration of shared tissue results in
complete separation of the two structures at gestational day 41. Incomplete fusion of the
tracheoesophageal folds resulting in a defect in the tracheoesophageal septum is thought to be the cause of
congenital tracheoesophageal fistulas which occur once in 3,000 to 4,500 live births.8
Pseudoglandular Period: Weeks 5 to 16

This stage of development derives its name from the glycogen-rich cuboidal bronchial epithelium that
histologically resembles an exocrine gland. Secondary bronchi established during the transition from
embryonic period to pseudoglandular period continue to divide with proliferation of endothelial and
mesenchymal structures to form primordial terminal bronchi (Fig. 5.3). While the majority of respiratory
components are present at the end of this period, the fetal lung at this time is unable to produce a
pulmonary surfactant (discussed in detail later), and thus a fetus born at this stage is not viable.
The developing endoderm-derived bronchial tree is enveloped in splanchnic mesoderm. Crosstalk
between these two layers regulates key processes such as bronchial arborization and pulmonary
endothelial formation.9,10 In parallel to these airway changes, the surrounding mesenchyme differentiates
into supporting vascular and stromal tissue. For example, early in this period mesenchymal-derived
vascular networks form around the developing lung bud which ultimately establish the connections
between the lung and the developing heart necessary for gas exchange.
As outlined in Figure 5.3, bronchi at this stage are both elongating and dividing. The right mainstem
bronchus bifurcates twice forming three secondary or lobar bronchi (upper, middle, and lower lobes).
The left mainstem bronchus undergoes a single division producing the upper and lower lobar bronchi.
Continued division results in a total of 18 tertiary branches called bronchopulmonary segments. There are
10 segments on the right and 8 on the left.
The tertiary bronchi continue dichotomous branching throughout gestational weeks 10 through 16 with
subsegmental branching continuing into the beginning of week 17 such that all nonrespiratory airway
elements have formed distally to the level of terminal bronchioles which lack alveoli. The end of the
pseudoglandular and beginning of the canalicular period is defined by the development of air-conducting
respiratory bronchioles with alveolar structures present.
TABLE 5.1 Human Pulmonary Developmental Stages as Defined by Different

Embryologists
Dubreuil et al. (1936)5 Loosli and Potter (1951) Boyden (1972)6 Thurlbeck (1988)7
Glandular: up to 6 months’ Glandular: 5 weeks’ to 4 months’ Pseudoglandular: 5–17 weeks’ Embryonic: 26–52 days’ gestation
gestation gestation gestation
Canalicular: 7 months’ Canalicular: 4 months’ to 6 Canalicular: 13–25 weeks’ Pseudoglandular: 52 days’–16
gestation to birth months’ gestation gestation weeks’ gestation
Alveolar: postnatal Alveolar: 6 months’ gestation to Terminal sac period: 24 weeks’ Canalicular: 17–28 weeks’
birth gestation to birth gestation
Saccular: 29–36 weeks’ gestation
Alveolar: 36 weeks’ gestation to
term
FIGURE 5.2 Lung development during the embryonic (A–F) and pseudoglandular (G,H) stages of organogenesis. The overall
branching pattern of the primitive lung (left panels) results in the development of the bronchial tree. The histologic organization of
the fetal lung becomes more complex as branching morphogenesis progresses through these stages (right panels).
TABLE 5.2 Major Events of Lung Embryogenesis

Period Weeks Airway Parenchyma Vasculature Other
(Endoderm) (Mesoderm) Cells/Structures
Embryonic Connective tissue, muscle
0–12 from splanchnic
mesoderm
Cartilage from neural crest
cells
day 22 Double aortas
Primordial pulm. veins
exit heart tube
day 26 Laryngotracheal Nerves
diverticulum forms wk 4: Neural crest
from foregut tube cells migrate to
Primitive lung buds mesenchyme
develop at distal end wk 7: Extrachondral
of forming trachea nerve bundles
form
day 33 6th arch = pulmonary
artery circulation –
primordial Rt and Lt
PA’s
Pulm. veins begin
connection to lung
buds
day 41 Separation of trachea
from esophagus
day 50 Ventral left 6th = main
PA
Dorsal left 6th arch
remains as ductus
arteriosus
Right and left mainstem Left atrium formed
bronchi form with pulm. veins
day 52 Bronchial divisions until Intrapulmonary system
secondary bronchi follows branching of
formation bronchi
Pseudoglandular day 52 Secondary bronchi form Glandular appearance Begins differentiation Nerves
5–16 from mesenchymal wk 10:
cells Extrapulmonary
PA and pulm.
veins innervated
Tertiary branches = Vascular plexus forms
bronchopulmonary around lung bud
segments
Tall columnar epithelial Pulm veins: Diaphragm:
cells Wk 9: Left atrium wk 8–10: Complex
Unable to produce formed with 4 pulm fusions of chest
surfactant vein orifices wall layers
wk 15: Diaphragm
formed
wk 16 Subsegmental branching Connections to Bronchial support
developing heart structures:
formed wk 10–16
cartilaginous
exoskeleton
wk 17 All nonrespiratory
airway have formed
Canalicular Lumen of bronchi and Increased vascularity and
17–28 bronchioles become thinning of mesenchyme
larger
Respiratory bronchioles,
alveolar ducts, and
some terminal sacs
develop
All axial, nonrespiratory Interstitial tissue thins
bronchi present
(conducting zone)
Acinus becomes defined Elastic tissue forms,
(single layer of tall demarcates each saccular
columnar cells) unit
Airway cells differentiate
(ciliated, goblet,
baseal)
Tall to short epithelial Capillaries move to
cells airspaces beginning at
distal bronchial tree and
at branch points
Acinar endoderm
become type I and II
pneumocytes
wk 20 Type II pneumocytes Wks 20–32: Bronchial
produce surfactant arteries and veins
mature
wk 24– Surfactant production
26 now sufficient for
sustained respiration
Few terminal saccules
form
16 bronchial subdivisions
present
Terminal More terminal sacs Capillaries bulge into alveoli
Saccular Epithelium thins Capillary network
28–Birth
Saccules continue to
septate forming thin-
walled subsaccular
structures
Short to cuboidal
epithelial cells
wk 40 20–50 million alveoli
present (8% of adult
alveoli)
Alveolar Formation of squamous
Birth–Age 8 epithelium necessary
for border of airway
lumen
Growth in number, not
size of alveoli
FIGURE 5.3 Branching and maturation of respiratory tree through stages of pulmonary development. The morphology and
substructure of the developing airway serves to mark the various stages in lung development from the Embryonic period to the
postnatal Alveolar period. (Reprinted from Kajekar R. Environmental factors and developmental outcomes in the lung.
Pharmacol Ther 2007;114(2):129–145. Copyright © 2007 Elsevier. With permission.)
The formation of the diaphragm is another notable event that affects lung formation during the
pseudoglandular period. As the developing lung grows dorsally then inferiorly, the pleural space
descends accordingly. At this time, mesenchymal layers of the chest wall begin to fuse. First is the septum
transversum that occupies the majority of the ventral aspect of diaphragm and will then ultimately become
the central tendon of the diaphragm. The residual gap between the chest and abdomen present at this time
is called the pericardioperitoneal canal and is closed by the ingrowth and fusion of the septum
transversum with the mesentery of the primordial esophagus and the pleuroperitoneal folds. Finally,
muscular ingrowth from the posterolateral body wall bilaterally completes the formation of the
diaphragm. This process must occur before the intestines return to the peritoneal cavity from the umbilical
coelom at embryonic day 60. Failure of diaphragm formation at this point results in a congenital
diaphragmatic hernia (CDH) which occurs most commonly through the foramen of Bochdalek with an
incidence of 1 in 2,500. The major morbidity and mortality associated with CDH is the associated
pulmonary hypoplasia (discussed later in this chapter) which often requires aggressive respiratory
strategies and sometimes extracorporeal membrane oxygenation.
Canalicular Period: Weeks 17 to 28

The focus of the canalicular period is the development of the air-conducting unit of the lung: the acinus.
The acinus (or saccular unit) is composed of one terminal bronchiole which gives rise to two to four
respiratory bronchioles, each with four to seven saccules (primordial alveoli) per respiratory bronchiole
(Figs. 5.3 and 5.4). During this phase, the parenchyma surrounding the acinar units become increasingly
thin and vascularized as a suitable blood–air barrier form. In fact, small numbers of terminal sacs with a
thin blood–air barrier are present at this stage. In addition, elastic fibers form around the distal airspaces
allowing for generation of passive expiratory force. Taken together, these developments result in a
nascent respiratory system capable of gas exchange.
As noted earlier and demonstrated in Figure 5.2, there is overlap between the pseudoglandular phase
and canalicular phase because proximal segments of the respiratory tree mature faster than distal
segments. Figure 5.5 exemplifies this histologic transition where the lung loses its “pseudoglandular”
appearance as primordial air spaces grow, the interstitium shrinks, and mesenchymal-derived vasculature
become more abundant. These developing capillaries move toward adjacent saccules (primordia of future
alveoli) in a distal to proximal fashion at branch points along the airway as the overall respiratory air
space enlarges in concert with thinning of the interstitium.11 Electron microscopic studies demonstrated
that the capillaries assume a position between cuboidal respiratory epithelium without penetration of the
airway itself as illustrated in Figure 5.6.12
Respiratory epithelial cells differentiate at this time into a variety of tall cuboidal cells such as goblet
cells, ciliated cells, and basal epithelial cells. As further airway branching proceeds, the distal regions
become lined with a single layer of tall columnar cells with these distal tubular structures destined to
become future acini. As these primordial acini develop, the surrounding mesenchyme thins and a
transition in the respiratory epithelium is observed. The columnar epithelial cells initially present become
short columnar cells during the canalicular phase and will eventually transform into cuboidal epithelial
cells in the terminal saccular phase (Fig. 5.5).
FIGURE 5.4 Structural division of distal airways. The acinus is the functional unit of the airway as it is the first portion that
contains alveoli capable of gas exchange. It is composed of one terminal bronchiole which gives rise to multiple respiratory
bronchioles. Each respiratory bronchiole then divides into between 2 and 11 alveolar ducts which in turn are in continuity with
common air spaces called alveolar sacs. These alveolar sacs open into two or more alveoli. In summary, the division of the
intrapulmonary airway from proximal to distal is terminal bronchiole, respiratory bronchiole, alveolar duct, alveolar sac, and
alveolus.
Another essential event occurs concomitantly with saccular capillarization and that is the development
of type I and type II pneumocytes derived from acinar epithelium. Type I pneumocytes are formed by
disposing the majority of cellular contents from the precursor cuboidal cells to become ultrathin (4 μm),
specialized squamous cells optimized for gas exchange. These cells account for 80% to 90% of the
alveolar surface area at birth.
Type II pneumocytes measure approximately 6 μm and characteristically retain the intracellular
glycogen seen in their precursor cuboidal cells. Key functions of type II pneumocytes are the production
and storage of pulmonary surfactant which is a major factor in the ability of a fetus to survive postnatally.
Surfactant consists of phospholipid, cholesterol, and surfactant proteins of both hydrophilic (surfactant
proteins (SP)-A, -B, -C, and -D) and hydrophobic (SP-B and SP-C) varieties. When produced, surfactant
creates a protective monolayer lining that reduces surface tension in the alveolus. This effect prevents
complete collapse of the alveoli during expiration by reducing the overall elastic property of the lung.
Clinically, increased production of surfactant at this stage in the immature human fetus can be induced by
administration of corticosteroids resulting in stimulation of the cytidine diphosphocholine (CDP-choline)
pathway.13 Gestational age 24 to 26 has been traditionally defined as the period where sufficient
quantities of surfactant are produced or inducible in the setting of adequate numbers of alveolar
capillaries to sustain acceptable gas exchange.14 Premature infants born at this stage are potentially viable
from a pulmonary perspective because the small number of terminal saccules capable of gas exchange can
be optimized by induction of endogenous surfactant production with steroids or by administration of
exogenous surfactant material. However, most fetuses still do not survive given the summative immaturity
of all organ systems.
Terminal Saccular Period: Week 28 to Birth

The process of terminal sac formation that began in the canalicular period continues and accelerates in the
terminal saccular period as the name suggests. At the onset of the third trimester, individual terminal
bronchi subdivide three times into respiratory bronchi. Respiratory buds present in the canalicular period
continue to develop and become increasingly septated leading to increasing smaller subsaccular
structures that will ultimately form true alveoli. Respiratory epithelium continues to thin while capillary
networks, which rapidly increase in size and bulge into alveoli in preparation for extrauterine gas
exchange. This alveolar morphogenesis begins in this period and continues postnatally until an
approximate age of 8 years. In fact, it is estimated that only 8% of the final number of adult alveoli are
present by 40 weeks of gestation.15
Intermittent respiratory movements are observed during this gestational period. The primordial
diaphragm has been shown to contract and through studies based in an ovine model have demonstrated
that these movements are coordinated at the level of the brain stem.16,17 Fetal lung movement allows for
the expulsion of fluid from the lung into the amnion. Based upon work by DeBlasio and colleagues18
which showed that there is no aspiration of amniotic fluid while in utero, fetal lung maturity can be
assessed clinically by analyzing the ratio of surfactant proteins lecithin and sphingomyelin in the amniotic
fluid.
FIGURE 5.5 Histologic photomicrographs of four different stages of human lung development. A: Pseudoglandular period
(week 8) where the lung resembles an exocrine gland. B: Canalicular period (week 16) showing enlarging lumen of the bronchial
tree. C: Canalicular period (week 18) demonstrating the increasing vascularity of the interstitial mesenchyme. D: Terminal sac
period (week 24) in which primordial alveoli and components of the blood–air barrier have formed distal to the respiratory
bronchioles. (Reprinted from Moore KL, Persaud TVN, Shiota K. In Color Atlas of Clinical Embryology. 2nd ed. Philadelphia,
PA: WB Saunders; 2000. Copyright © 2000 Elsevier. With permission.)
Alveolar Period: Late Fetal Period to Childhood

This final stage completes the transition from terminal sacs to alveolar ducts as the alveolar squamous
epithelium becomes widespread. Two types of alveolar development occur during the first several
months of life. First, saccule walls continue to septate and become thinner, transforming a greater number
of alveolar primordia into mature alveoli. Second, alveolar ducts are created as transitional ducts linking
distal respiratory bronchioles to the saccules being alveolarized. Alveolar development then progresses
centripetally from the alveolar ducts toward the terminal bronchioles. The individual alveoli marginally
grow in size but this effect is overshadowed by the rapid increase in the number of alveoli. Over time,
their number increases with 127 million alveoli by the age of 3 years, 280 million by age 9, and finally
roughly 300 million alveoli in the adult. This translates to a total surface area of 32 m2 at age 3, which
doubles to 75 m2 by adulthood.
One clinical manifestation of perinatal disruption of alveolar genesis is bronchopulmonary dysplasia
(BPD). At the core of the disease process is damage to developing alveoli by oxygen or ventilator trauma
resulting in the need for supplemental oxygen support in neonates often with concomitant severe
pulmonary hypertension. Due to improved treatment of premature infants with pulmonary surfactant-
enhancing therapy and lung protective ventilator strategies, the histopathology of BPD shifted from that of
airway injury and fibrosis to a different pattern of alveolar hyposeptation and microvascular
abnormalities. A full review of this entity is beyond the scope of this chapter but the pathogenesis of BPD
underscores the importance of the alveolar period of development as well as the interdependence of
alveolar and microvascular embryonic development.19,20
FIGURE 5.6 Electron microscope studies of the human lung. A: Pseudoglandular phase showing tall columnar cell rich in
glycogen. B: A cell becoming cuboidal. The capillary is now closer. C: Canalicular phase showing types 1 and 2 alveolar cells.
The blood–air barrier has formed.
At birth, the alveoli are filled with fluid which is rapidly expelled prior to the baby’s first breath of
air. The pulmonary fluid burden is removed through not just the nose and mouth but also via blood vessels
and lymphatics. Rapid expulsion of liquid from submerged airspaces is a key step in establishing the
critical transition from placental to pulmonary gas exchange at birth.4 While significant progress has been
made to elucidate how liquid is produced in the fetal lung and removed during and after birth, relatively
little investigation has been conducted on how this information relates to the human lung during
development. The opportunity remains to explore the potential translational capability to augment lung
growth in utero to prevent or ameliorate postnatal respiratory distress. For example, the mechanism
underlying epithelial chloride secretion might be enhanced pharmacologically to promote the expansion
and growth of the fetal lung in situations known to be associated with pulmonary hypoplasia such as CDH
and prolonged oligohydramnios.21
STRUCTURAL/FUNCTIONAL DISTINCTIONS OF THE LUNG

The lung is a multifaceted organ whose function goes far beyond gas exchange as evidenced by more than
40 different pulmonary cell types which execute a host of metabolic, endocrine, and immunologic actions.
Structurally the lung consists of cells and stroma that create a conduit to allow efficient conduction of air
to the blood stream at the single cell layer thick blood–air barrier of the alveolus. Given this direct and
constant communication with the ambient environment and its associated pathogens, a robust pulmonary
defense system is paramount. Complex and complementary processes have evolved from sites of entry in
the nasopharyngeal orifice to the cellular alveolar level. Airway epithelium is central to this defense
system and is composed of a heterogeneous population of cells that perform a variety of specific functions
including mechanical barriers to exogenous agents, inflammatory responses, metabolic activities,
immunologic defense, and repair after injury. There is spatial variation in cellular components in the
airway with the trachea having approximately 8 different cell types, whereas there are about 49 different
cell types in the airways (including 12 distinct epithelial cell types). The most common airway cell types
are basal cells, ciliated cells, goblet cells, Clara cells, and alveolar type I and II pneumocytes. In the
distal lung, fibroblasts, adipocytes, neuroendocrine cells, macrophages, smooth muscle cells, and
endothelial cells are a few of the 40 different cell types which underscore the complexity of the lung (Fig.
5.7).
FIGURE 5.7 Wide variety of unique, specialized cells seen in different regions of the lung. EP, Epithelium; BM, Basement
membrane; SM, Smooth muscle; FC, fibrocartilagenous layer.
REGULATION AND DISRUPTION OF PULMONARY MORPHOGENESIS

As noted above, histologic changes in airway branching and pulmonary vascular development define the
different stages of embryonic and postnatal development. Various regulatory genes, growth factors,
hormones, associated cellular receptors, and other protean factors regulate different aspects of lung
growth and development. These normal pathways can be disrupted by exposure to environmental toxins,
pharmacologic agents, excess hormones or vitamins, and other teratogens leading to compromised
formation and therefore function. An understanding of pre- and postnatal lung growth and development
provides insights into lung function under normal conditions as well as the mechanisms involved in
disease resulting from developmental anomalies or response to injury.
HOX GENES
The Homeobox or Hox genes were among the first families of transcription factors to be described. They
are a group of regulatory proteins with a helix-turn-helix DNA binding motif and are considered master
regulators of developmental processes. They are expressed in overlapping domains and are responsible
for the creation and positioning of major body structures including the lung. Initiation of lung
morphogenesis from the embryologic foregut is associated with differentially high expression of Hoxb3,
Hoxb4, and Hoxb5 of primordial lung endothelial cells.22,23 Furthermore, respiratory specification of the
anterior foregut tube is based upon the expression gradient of Hox gene Nkx2.1 in ventral endothelial
cells.24 Finally, the lung buds are guided to the asymmetric development of right and left lungs by several
regulatory genes including the Hox gene Pitx2.25,26 These examples demonstrate the importance of the
expression pattern of these essential transcription factors in directing temporal and spatial development of
the lung and parallels the role of Hox genes in formation of other organs and structures such as the
extremities, vertebrae, and brain.
Hox genes are organized in four highly conserved clusters—Hoxa, Hoxb, Hoxc, and Hoxd. These
clusters are located on different chromosomes in mice—chromosome 6, 11, 15, and 2, respectively.27
Expression of Hox genes can be influenced by the exposure and concentration of many factors including
those mentioned above: glucocorticoids, growth factors, and retinoic acid (RA). Specifically, Hoxb5
protein levels are influenced by dexamethasone and growth factors (TGF-β and epidermal growth factor)
which results in a correlative effect of Hoxb5 downregulation with advanced development of the lung.28
The effect of RA gradients also plays a role in activation of early Hox genes with early Hox genes
requiring higher gradients of RA than that of the late developmental Hox genes.29
GROWTH FACTORS
Transforming growth factor-beta (TGF-β) and bone morphogenetic proteins (BMPs, member of TGF-β
superfamily) are groups of cytokines that play essential roles in regulating all aspects of the cell cycle
(proliferation, differentiation, migration, and apoptosis). Mouse models of lung development have
demonstrated the key role of TGF-β. Experiments utilizing murine lung explant cultures showed that the
early embryonic pulmonary development was inhibited by TGF-β and stimulated by BMP.30 Furthermore,
abrogation of BMP signaling during mouse embryogenesis in vivo results in neonatal respiratory failure.
However, blockade of Smad3/TGF-β signaling causes abnormal postnatal lung growth and maturation
further contributing to the susceptibility of adult mice to emphysema. In humans, deficient BMP signaling
has been shown to be associated with primary pulmonary hypertension through the study of explanted
lungs obtained from recipients during heart–lung transplantation.31 Therefore, TGFβ-R and BMP
regulation play a critical role in proper lung development and lung injury repair. Overexpression or
deficiencies of these pathways may contribute to several respiratory diseases such as emphysema and
idiopathic pulmonary fibrosis (Fig. 5.8).32,33
FIGURE 5.8 Growth factors in development and disease.
STEROID–THYROID–RETINOID FAMILY OF RECEPTORS

Developmental “master” genes such as Hox genes are themselves under the influence of regulatory genes
in the form of proteins called transcription factors or nuclear receptor proteins. One set of nuclear
receptor proteins that has gained attention with respect to lung development is the steroid–thyroid–
retinoid family which consists of the glucocorticoid receptor (GR), thyroid hormone receptor (TR), and
retinoic acid receptor (RAR). Engagement of one type of receptor can crosstalk with the other members
resulting in a cascade affecting multiple downstream pathways.34
GR is a widely expressed nuclear receptor transcription factor which regulates a number of
physiologic processes. During lung development, surfactant proteins are observed to be upregulated in
concert with GR which suggests a role for GR in surfactant regulation.35 This notion is reinforced by the
salutary effect of administering the steroid betamethasone to pregnant mothers at risk of premature birth,
thereby promoting lung maturity in the fetus. Low levels of GR have also been observed in humans with
pulmonary hypoplasia, which further underscores the importance of GR in lung development and
function.36
Thyroid hormone (T3)—is an essential hormone required for normal human growth, differentiation,
and development. T3 enters cells via transmembrane transporters, then binds to its receptors within the
nucleus to modulate gene expression. T3 receptors include TR-α and TR-β which also have multiple
subisoforms. These function as transcription factors that can act in a ligand-dependent or ligand-
independent fashion. The current prevailing mechanistic theory is that TRs exert their biologic effects by
forming heterodimers with retinoid-x-receptors (RXRs). This explains the observed transactivation and
overlap among the members of the steroid–thyroid–retinoid family of nuclear receptors. The
compensatory function of this family of receptors is demonstrated in mice with double TR knockout
having normal survival.37 Specific to the lung, T3 has been shown to affect lipid synthesis and creation of
lamellar bodies in type II cells which are essential for cellular function including production of surfactant.
RA is an oxidative metabolite of vitamin A that is widely involved in embryonic development.
Differential gradients of RA are known to guide cell migration and specific differentiation during
embryogenesis and so it follows that excess or deficiency of RA is known to be teratogenic. RA exists in
two forms: All-trans-RA and 9-cis-RA. This allows RA to activate two types of nuclear receptors: RARs
and RXRs. Specifically, All-trans-RA binds RARs, whereas 9-cis-RA engages via both RARs and RXRs.
These receptors exhibit temporal and spatial expression during development. As with other members of
this receptor family, there are three major RAR isoforms, -α, -β, and -γ, each in turn with multiple
subisoforms with extensive redundancy. As noted above, there is crosstalk among RA and the other
steroid–thyroid–retinoid receptors facilitated by RARs sharing a common domain with TR allowing
interactions with both TR and GR during embryogenesis. Evidence suggests that RAR-α and -β, are
involved in morphogenic events including septation and alveolarization. Multiple elegant studies in
rodent models have shown that RAR-β functions as an inhibitor of alveolar septation and so disruption of
the normal downregulation of RAR-β leads to development of immature distal lung structures.38–40
ANGIOGENESIS AND PULMONARY VASCULAR MORPHOGENESIS

Blood flow is critical for the execution of gas exchange and is essential for the developing lung in the
delivery of nutritional and metabolic needs. In general, there are two distinct processes involved in the
development of blood vessels: (1) vasculogenesis, in which blood vessels are created de novo from
precursor angioblasts, and (2) angiogenesis, with new vessels sprouting from existing ones. Both of these
processes are involved with lung development where mesenchymal cells serve as the substrate for the
vasculogenesis of endothelial cells that form small parenchymal vessels, whereas the macrovascular
endothelium is derived from existing pulmonary vascular tissue through the process of angiogenesis.
Circulating angioblasts or endothelial precursor cells (EPCs) from different sites can incorporate into
developing vessels, which may lead to endothelial cell heterogeneity observed in the distal aspects of
vascular beds. After proximal (angiogenic) and distal (vasculogenic) portions of the circulation have
joined, circulating precursor cells contribute another source of vascular cells and further enhance the
phenotypic cellular heterogeneity of the lung. The potential importance of these EPCs in lung development
was demonstrated in a murine model where neonatal mice exposed to high levels of oxygen had a
decrease in circulating EPCs and underdeveloped lung structure reminiscent of BPD.41
VASCULAR DEVELOPMENT
The vasculature of the heart and lung are contiguous and so an understanding of pulmonary vasculature is
predicated on knowledge of the embryonic aortas and developing heart (Fig. 5.9, Table 5.2). At
embryonic day 2, there is a ventral aortic sac and paired dorsal aortas. The ventral aortic sac is
contiguous with the cranial aspect of the heart tube known as the truncus arteriosus. Paired aortic arches
connect the ventral aortic sac to the two dorsal aortas. Pharyngeal pouches are endodermal structures
located in this area which give rise to structures such as the inner ear, parathyroid glands, and thymus.
Each aortic arch is associated with a pharyngeal pouch such they are referred to as “pharyngeal arch
arteries.”
The aortic arches form in a cranial to caudal fashion. Initially, only the first arch is present and
provides the only connection between the dorsal aortas and the ventral aortic sac. Over the next several
days, the regression, formation, and transformation of the ventral aortic sac, dorsal aortas and pharyngeal
arch arteries culminate in shaping the normal aortic arch and pulmonary artery structure. At embryonic
day 30, the first two pharyngeal arch arteries have regressed and the 3rd through 6th arches are now
present. Ultimately, the 3rd arch becomes the common carotid arteries while the aortic arch proper is
derived from the 4th arch. The 5th arch is vestigial and regresses by embryonic week 6. Specific to
vascular development of the lung, the 6th arch forms the proximal pulmonary artery by the eighth
embryonic week.
Focusing on pulmonary artery development, at approximately day 32 of fetal development the 6th
pharyngeal arch arteries give off primordial left and right pulmonary arteries. A complex set of
transformations occurs over 2 weeks in the 6th arch region with respect to ventral or dorsal aspects of
each 6th arch (right and left). First, the dorsal portion of the right arch thins and will later regress. The
ventral portion of the left 6th arch absorbs the ventral portion of the right 6th arch to become the
primordial main pulmonary artery. Simultaneously, the aorticopulmonary septum divides the truncus
arteriosus which isolates the right ventricle as the source of blood to the pulmonary artery. By embryonic
day 50, the dorsal right 6th arch has disappeared while the ventral left 6th arch is now firmly established
as the main pulmonary artery. The dorsal aspect of left 6th arch is maintained as the ductus arteriosus
which connects the main pulmonary artery at its bifurcation to the left dorsal aorta. The intrapulmonary
development of the pulmonary arterial system follows the bronchial branching pattern as mentioned
previously. At the conclusion of gestation, the pulmonary artery vasculature feeds all of the alveolar units
and majority of the visceral pleura.
FIGURE 5.9 Embryologic development of the aorta, arch vessels, and main pulmonary artery. The pharyngeal arches are
designated by color and number as indicated. A: Configuration of pharyngeal arch arteries and aortic sac at 6 weeks with
involution of 1st and 2nd pharyngeal arches. B: Arches at 7 weeks. Dotted line indicates normal pattern of disappearance of
arches. C: Configuration at 8 weeks. D: Vascular structure of a 6-month old.
Pulmonary vein development begins around embryonic day 22 with primordial common pulmonary
veins noted to exit the sinoatrial region of the heart tube bilaterally. The veins begin as an outgrowth of
the left atrial wall and over time as the atrium expands, the veins are gradually incorporated into the left
atrium. By day 32, the pulmonary venous system begins to connect to the vascular plexuses of the
developing lung buds. Both left and right main pulmonary veins then undergo a series of divisions which
mirrors intrapulmonary bronchial arborization. By week 9 of development, the left atrium has formed
including paired left and right pulmonary venous orifices.
The bronchial circulation is rooted in the early period of lung development when both nonrespiratory
and air-conducting aspects of the primordial lung are supplied by the systemic connections to the dorsal
aortas. These join to vascular plexuses derived from mesenchyme surrounding each lung bud. As
nonrespiratory parts of the bronchial tree form, they are vascularized by this foregut-derived plexus
arising directly from the aorta with systemic drainage to the subcardinal veins and venae cavae. Later,
these systemic connections are lost as formal connections are created to the systemic circulation in the
form of bronchial arteries and veins which mature between weeks 20 and 32. Ultimately, bronchial
arteries vascularize the airway, hilum, hilar pleura, and walls of large blood vessels. The bronchial
venous system drains the hilar area, while the remainder of the lung and visceral pleura flow into the
pulmonary circulation.
ENDOTHELIAL–EPITHELIAL INTERACTIONS DURING LUNG

DEVELOPMENT
As described above, lung development is a highly coordinated process that includes: airway and acinar
development; cellular differentiation; biochemical maturation; interstitial development (including
vasculature and extracellular matrix); and physical growth and enlargement. The characteristic
appearance and relationships among these parallel events serve to define the various stages of lung
development.
The intimate interface of alveolar epithelium and associated capillary endothelium is established by
the interconnected and parallel development of vessels and airways down to the alveolar substructure of
the lung.42 These developmental processes result in a structurally and biochemically mature lung, which is
well suited for respiration. Abnormalities in these developmentally coordinated processes may result in
dysfunctional lung formation and function which is apparent at birth by immediate respiratory compromise
and distress.
Normal pulmonary vascular development and pulmonary blood flow are interrelated and important for
proper lung development. The process where alterations in blood flow through a vessel signals feedback
within the said vessel is called vascular remodeling.43 This dynamic process underlies many biologic
processes such as organogenesis, growth, and response to injury. Blood vessels are composed of three
layers: the adventitia, media, and intima. The intima is the inner layer directly in contact with blood. It is
comprised of a single cell layer of endothelial cells which are the main effector cells of vascular
remodeling and act as both sensing and effector cells which respond to changes in blood flow. In response
to changes in blood flow (known as shear stress), endothelial cells release molecules such as platelet-
derived growth factors (PDGF), nitric oxide synthase (NOS), TGF-beta, and VEGF in paracrine and
autocrine fashions that stimulate cell growth, movement, and death, thereby resulting in structural changes
to the vessel wall and the surrounding interstitial matrix.
Normal systemic blood flow in prenatal development is essential for proper lung formation. As a
corollary, the intrapulmonary blood flow is similarly critical to local development of the pulmonary
vasculature and airways. In abnormal lungs, both the vasculature and airway development are defective.
This is demonstrated clinically by pulmonary hypoplasia associated with CDH. The physical
displacement of lungs by the abdominal viscera leading to aberrant flow and shear stress is associated
with significantly fewer airways, reduced blood vessel density, and abnormally muscular arteries.44 The
interrelationship between the airway and pulmonary vasculature has been demonstrated in animal
experiments in which tracheal ligation reverses the maladaptive vascular changes seen with lung
hypoplasia.45
INNERVATION OF THE LUNG AND NEUROENDOCRINE CELLS

The lung is a significantly innervated organ with cholinergic, noradrenergic, and sensory components and
its maladaptive function can contribute to the pathophysiology of diseases such as asthma and COPD.46 At
embryonic week 4, ectodermally derived neural crest cells migrate into the undifferentiated mesenchyme
and development of the pulmonary nerve supply parallels that of the airways and pulmonary blood
vessels. Nerve development then continues centrifugally from hilum to periphery as target tissues develop
with contributions from the vagus nerve and the thoracic sympathetic plexus. By week 7, extrachondral
nerve bundles are seen in proximal airway walls. Later, subchondral plexuses are visualized in parallel
to the extrachondral plexuses. These two plexuses merge in the noncartilaginous distal airways before
terminating at the level of the terminal sacs.
By week 10, the extrapulmonary pulmonary arterial and venous trees are innervated. As
intrapulmonary vascular connections mature, more peripheral arteries and veins are innervated. The
nerves themselves receive a rich blood supply from the bronchial arteries. At the eighth postnatal month,
the entire nervous system is complete. At maturity, the pulmonary nervous system innervation includes
airways from the trachea to the alveolus; airway appendages and epithelium including mucus glands; and
peripulmonary tissues including blood vessels, lymphatics, and the visceral pleura.
Pulmonary neuroendocrine (PNE) cells occur both as single cells and as organized clusters of cells
called neuroepithelial bodies (NEBs).47 The earliest PNE cells in humans can be identified at 8 weeks of
gestation when airway development begins which is long before the actual airway gas exchanges begin.48
PNE cells synthesize and secrete a number of peptides that exhibit growth factor activity, such as gastrin-
releasing peptide (GRP) in humans, which is a homolog of bombesin, found in amphibians.49 In adult
humans, PNE cells are homologously distributed in the epithelium. The physiologic role of innervation is
not well understood although a recent study in a mouse model suggests that PNE cells cluster into NEBs
or “organoids” that sample the air and elicit immune responses via secretion of neuropeptides.50 Studies
in rabbits also suggest a neurohormonal regulatory role for PNE cells and NEBs in the sensing of
intraluminal stimuli such as hypoxia which leads to adaptive changes in the airway.51
FUTURE DIRECTIONS: EMERGING ROLE OF LUNG STEM CELLS AND

ORGAN ENGINEERING
As detailed above, lung formation is a dynamic process in which multiple cell types interact and engage
with each other in a milieu of exogenous factors both in utero and years after birth. However, the mature
lung has generally been considered a relatively quiescent organ with limited ability to repair itself after
serious injury. This notion is being increasingly challenged by our evolving understanding of the presence
and activity of stem cell populations in the adult lung.52,53 Different organs have distinct capabilities to
repair or regenerate damaged cells. In the small bowel for example, there is a “production line” of
continuous turnover of epithelial cells arising from well-described stem cell populations located in the
intestinal crypts of Lieberkühn.54 In contradistinction, the brain has essentially no ability for repair after
injury as exemplified by the devastating effects of cerebrovascular accidents. Figure 5.10 demonstrates
how the lung compares with other organs with respect to cellular regeneration after injury. While the lung
has not been shown to possess the baseline regenerative properties of bowel or blood, it is evident that
the lung has the inducible ability for self-repair through stem cell populations. The reader is referred to an
excellent review of this topic by Kotton and Morrisey.52 Briefly, certain mature/differentiated cells in the
lung have been shown to possess the ability to re-enter the cell cycle to generate the necessary cell types
required for repair after injury. These “adult stem cells” can be also be referred to as facultative
progenitor cells. Mirroring the branching process of embryogenesis, there are different candidate stem
cells in the proximal, distal, and terminal airway/alveolus. In the proximal or conducting airway, basal
cells are currently thought to be the main progenitor cells via a Notch signaling-dependent process.
Further along the tracheobronchial tree located adjacent to neuroendocrine bodies and at the
bronchoalveolar duct junctions (BADJs), variant Club cells (previously called Clara cells) function in the
role of adult stem cells. In the alveolus, evidence supports type II alveolar cells as the strongest candidate
for facultative progenitor cells.
FIGURE 5.10 Inducible regeneration of the lung compared to other organs. This figure from Kotton and Morrisey depicts the
relationship between cellular regeneration and engagement of adult stem cells in different tissues. While the blood, gut, and hair
follicles have a high capacity for regeneration from constitutive stem cell populations, organs such as the lung, liver, and pancreas
respond to injury by upregulating activity of relatively quiescent stem cells known as facultative progenitor cells. (From Kotton
DN, Morrisey EE. Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med 2014;20(8):822–
832.)
In 2012, a seminal article by Longmire and colleagues36 reported the in vitro generation of primordial
lung progenitor cells through directed differentiation or “reprogramming” of murine pluripotent stem cells
(PSCs) (Fig. 5.11). By applying knowledge of the Hox gene Nkx 2.1 and its response to signaling factors
such as BMP and FGF (Fig. 5.8), Longmire’s group55 and others have been able to direct the
differentiation of PSCs into lung epithelium, thereby creating a powerful tool for both research and
translational medicine.52 To date, this technique has been applied to humans with genetic diseases such
that inducible pluripotent stem cell (iPSC) lines have been created specifically from patients with
diseases such as cystic fibrosis, alpha-1 antitrypsin deficiency, and pulmonary alveolar proteinosis.56–58
A landmark report by Vacanti’s group in Boston further demonstrated the potential translational
capability of basic science research in pulmonary organogenesis. This group created a bioartificial rodent
lung by first decellularizing a cadaveric lung to serve as a biologic scaffold and then seeded this construct
with viable pulmonary cells.59 These bioartificial lungs were capable of physiologic gas exchange in
vitro. To demonstrate proof-of-principle, engineered lungs were orthotopically transplanted and shown to
function in vivo for 6 hours after extubation of the animal. Taken with expanding stem cell science, these
exciting developments pave the way for the ultimate treatment for end-stage lung diseases: allowing
physician-scientists to create new, fully immunologically matched organs suitable for transplantation into
patients with lung failure.
These examples of cutting edge research highlight the exciting translational capability of basic science
research rooted in pulmonary embryology. From the early beginnings of Malpighi’s frog lungs to the
possibility of engineering de novo a functional human lung, the field of lung biology continues to be rich
and full of possibilities.
FIGURE 5.11 Creation of lung progenitor cells from pluripotent embryonic stem cells. This schematic from Longmire et al.
demonstrates the process of preferentially driving the differentiation of an embryonic stem cell (ESC) to create cultures of lung
primordial progenitor cells. This technology provides the opportunity for precise modeling of human lung disease as well as being
a step toward the in vitro engineering of a functional human lung. (From Longmire TA, Ikonomou L, Hawkins F, et al. Efficient
derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 2012;10(4):398–411.)
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6
Ultrastructure and Morphometry of the
Human Lung
Matthias Ochs ■ Peter H. Burri ■ Ewald R. Weibel
ORGANIZATION OF THE LUNG

The application of electron microscopy and quantitative methods in morphology (morphometry) has
widened the general understanding of lung structure and set the course for a more functional approach to
the study of pulmonary architecture. It cannot be the aim of this chapter, however, to cover all aspects of
lung microanatomy. In this respect, the reader is referred to the specialized literature. The authors would
rather present the morphologic and quantitative background needed to understand the functioning of the
gas-exchange apparatus.
The lung is composed of three phases: air, tissue, and blood. The tissue forms a complete barrier
between air and blood; it is a stable structural framework, whereas air and blood are continuously
exchanged. In describing the ultrastructure of the lung, the authors emphasize the specializations of the
tissue in forming boundary spaces for air and blood. Morphometry reveals the quantitative relations
among these three phases.
FIGURE 6.1 Schematic representation of lung zones.
From the functional point of view, the organization of the lung may be defined in relation to the
hierarchy of airways and blood vessels, from the trachea down to alveoli, or from the main stem of the
pulmonary artery through the capillary network to the pulmonary veins entering the left atrium. All of this
is jointly considered in the scheme of Figure 6.1. Besides showing the three phases, the diagram
introduces the three major functional zones of the lung: first, the conductive zone, consisting of air
channels and blood vessels, the function of which is to guide and distribute air and blood into the
peripheral lung units; second, the respiratory zone, composed of alveoli and capillaries; and third, the
intermediate or transitory zone, containing elements of both. The structural framework of the lung ensures
that a very large surface area of air–blood contact can be maintained with a minimum of tissue.116
COMPARTMENTAL DISTRIBUTION OF LUNG VOLUME

Any morphologic analysis of the functional capacity of the gas-exchange apparatus requires exact
knowledge of the total lung volume and of its compartmental distribution. To illustrate the distribution of
the lung volume among the various zones and constituents, consider the lung of a medium-sized adult
inflated to about three-fourths of total lung capacity; the total lung volume then amounts to about 5.7 L.
Table 6.1 gives the approximate distribution of this volume among the lung compartments as derived from
morphometric analysis of fixed lungs. The greatest compartment is the airspace, of which about two-thirds
is in alveoli and only a small fraction in conductive airways, representing the anatomic dead space.
FINE STRUCTURE OF THE LUNG

FINE STRUCTURE OF CONDUCTING AIRWAYS
The conducting airways are a system of tubes that multiply toward the periphery by division according to
the principle of irregular dichotomy. From the trachea to bronchi to bronchioles, the structure of the
airway gradually changes. Common to all is the general scheme of a three-layered wall made of a
mucosa, a muscle layer, and a connective tissue sheath (Fig. 6.2). The mucosa of conducting airways is
characterized by the presence of a typical ciliated epithelium, which is described here first.
TABLE 6.1 Approximate Distribution of Total Lung Volume in Milliliters for Adult
Human Lung at Three-Fourths Total Lung Capacitya
Zones Compartments
Air Channels Tissue Blood
Conducting Bronchi: Walls Arteries: Veins:
170 Septa 150 150
Fibers
Transition Respiratory bronchioles Arterioles: Venules:
Lymph:
Alveolar ducts:
200
1,500 60 60
Respiratory Alveoli: Barrier: Capillaries:
3,150 150 140
a Total lung volume is 5.7 L.
Reprinted by permission of Edizioni Minerva Medica from Weibel ER. Morphometry of the human lung. In Arcangeli P, et al., eds. Normal
Values for Respiratory Function in Man. Milan: Panminerva Medica, 1970:242.
Lining Epithelium of Conductive Airways

The inspired air must be humidified and warmed before it reaches the delicate gas-exchange area;
furthermore, air pollutants and dust, as well as airborne microorganisms, must be removed. Although the
upper respiratory tract, in particular the nasal portion, is especially designed for these functions, the
respiratory epithelium (Fig. 6.3), of all conducting airways, shows special features for the handling of
airborne particles. Cytologic, kinetic, and histochemical studies10,47,48,95,96 have provided insights into the
cell types of the airway epithelium of various species, including humans. The respiratory epithelium is a
ciliated pseudostratified columnar epithelium with numerous scattered goblet cells. Ciliated cells occur
from the trachea down to the last respiratory bronchiole, but their height decreases with the reduction of
the airway diameter. Ciliated cells of the trachea are columnar (Fig. 6.4), whereas those of the respiratory
bronchioles are cuboidal (Fig. 6.5). The frequency of goblet cells also decreases toward the periphery,
and, in bronchioles, they are replaced by club cells (formerly called Clara cells) (Fig. 6.5).68,86,87 Club
cells account for about 11% of the total epithelial cell number in terminal bronchioles and about 22% in
respiratory bronchioles.8 A characteristic feature of club cells is the presence of membrane-bound
electron-dense granules. Among their secretory products is the so-called club cell secretory protein
(CCSP). Although the detailed functions of CCSP in the human lung remain to be elucidated, experimental
studies suggest immunomodulatory functions for CCSP. The club cell is also the main site of cytochrome
P450 activity in the lung, illustrating their role in detoxification of foreign substances. Club cells also
contribute to bronchiolar epithelial cell renewal and regeneration. In investigations, great emphasis also
has been put on the neuroendocrine cells interspersed in the epithelium, often called Feyrter, or more
often called, Kulchitsky cells. These are amine precursor uptake and decarboxylation (APUD), or small
granule cells. These neuroendocrine cells are present in the respiratory tract of all vertebrate species
investigated so far. Occasionally, they are arranged in groups termed neuroepithelial bodies.
Neuroepithelial bodies are extensively innervated and are assumed to function as chemoreceptors and
they may act on pulmonary vascular or airway smooth muscle by secreting vasoactive
substances.2,22,36,42,59,60,91,94 Basal cells are frequently found in larger conductive airways. They represent
a proliferative pool of undifferentiated cells that are able to replace the overlying cells by differentiation
and maturation.55,88 Less common are the brush cells and migratory cells. Finally, the occurrence of nerve
endings between individual cells, more frequent in the trachea and large bronchi, should be mentioned.
They are thought to be irritant receptors.129
FIGURE 6.2 Structure of bronchi and bronchioles. (1) Mucosa with epithelium and elastic fibers; (2) smooth muscle layer; (3)
fibrous layer containing cartilage (C) in the bronchi; (4) peribronchial sheath of loose connective tissue.
FIGURE 6.3 Pseudostratified epithelium of bronchus with brush, ciliated, basal, and goblet cells. The cilia beat in a serous fluid
(yellow) that is topped by a mucous layer (orange) secreted partly by goblet cells. A strong basement membrane (BM green)
and a layer of longitudinal elastic fibers (purple) form the basis of the epithelium.
FIGURE 6.4 Pseudostratified epithelium from human bronchus. Note goblet cells (arrows) (×600).
Figure 6.3 is a schematic representation of a portion of the respiratory epithelium of a bronchus. The
function of this epithelium is to capture airborne particles in a sticky mucous layer and to remove them
efficiently from the lung. For this purpose, cilia show a synchronized rhythmic beat within a thin layer of
low-viscosity fluid. On top, a blanket of mucus is moved in the direction of the pharynx, carrying
intercepted particles. This cleaning mechanism can be compared with a conveyor belt and is often called
the mucociliary escalator. The mechanism of mucus propulsion has been described in detail.89,102,132 The
mucous layer is secreted onto the epithelial surface by goblet cells and by seromucous glands located in
the walls of trachea and bronchi (Fig. 6.2). The small bronchioles are most likely devoid of mucus
because their wall contains neither goblet cells nor glands. Their surface is formed by a fluid layer of low
viscosity that is topped by a thin osmiophilic film representing airway surfactant.33 Finally, the presence
in the bronchial secretion of several humoral agents, which would protect the airways against infections,
has been reported.
FIGURE 6.5 Electron micrograph of bronchiolar wall with simple cuboidal epithelium made up of ciliated cells (Ci) and club
cells (Ca). In place of the mucous layer is a fine osmiophilic film (arrows) at the air–liquid interface. A smooth muscle cell (M)
and collagenous (C) and elastic (E) fibers are seen in the subepithelial tissue. Rat lung fixed by vascular perfusion (×9,200).
Trachea and Bronchi

Trachea and bronchi are characterized by the presence of cartilage within the fibrous sheath of their walls
(Fig. 6.2). In the trachea and stem bronchi, the cartilage is in the form of incomplete rings. These rings in
the trachea cover the ventral and lateral aspects, whereas the dorsal wall contains a strong layer of
transverse smooth muscle. After about the second or third generation, these rings are gradually replaced
by irregular cartilage plates, and a layer of smooth muscle appears between mucosa and cartilage.
All conducting airways are surrounded by an external, loose connective tissue sheath (Fig. 6.2), which
is continuous with the other connective elements of the lung. It is a structure of considerable physiologic
significance because it contains both bronchial vessels to supply the bronchial wall with blood from the
systemic circulation as well as nerves and lymphatic vessels. Only a small part of the arterial bronchial
flow, in some species as little as 25%, is drained by the bronchial veins. Most of it goes into the
peribronchial venous plexus and from there into the pulmonary veins, forming a small right-to-left
shunt.70,82 The bronchus is accompanied usually by a branch of the pulmonary artery, which is enveloped
by connective tissue continuous with the peribronchial sheath, thus forming the so-called
peribronchovascular space, a preferential site of leukocyte infiltration or edema formation under
pathologic conditions.83 Lymphatic vessels contained in these peribronchial and perivascular sheaths, as
well as in the subpleural and septal connective tissue, constitute the main drainage path for the interstitial
fluid.
Bronchioles
A bronchiole is an airway devoid of cartilage and seromucous glands; goblet cells are rare. Because
airway structure does not change abruptly, either seromucous glands or goblet cells may still be present in
transitional zones. Bronchioles are rather small conducting airways, measuring about 1 mm or less in
diameter. Their added cross-sectional area is such, however, that they are not supposed to contribute
substantially to the flow resistance of the airways in the normally breathing healthy individual. Their
walls are generally thin and molded into the surrounding parenchyma. They are supplied with blood from
the pulmonary circulation rather than from bronchial arteries. The bronchiolar mucosa is lined by a
simple cuboidal epithelium (Fig. 6.5) composed of ciliated cells and club cells, which, as mentioned in
the section discussing epithelial properties, have a dual detoxifying and secretory function. They are the
object of intense study, and their exocrine secretory activity is being linked with a modulation of the
inflammatory and immunologic response to injury. Their position as defensive cells is crucial, because in
the normal respiratory tidal range, bronchioles are the last conducting airways to receive bulk air in
conjunction with inspiration. In bronchioles, club cells take the place of goblet cells found in larger
airways. In bronchioles, the smooth muscle cells form a well-developed, relatively thick layer arranged
in a geodesic network, capable of narrowing the airway.
Resistance to Airflow in Conducting Airways

The partition of airflow resistance between large and small airways both in health and disease has been
controversial. It is universally accepted that, in the healthy lung, the major site of resistance is the large,
central airways, whereas the bronchioles contribute less than 20%, but it is important to know that
pathologic increases of resistance always occur in the bronchiolar region. Airflow in the trachea is
turbulent; in the bronchioles, it is laminar. In between, it is often referred to as transitional, implying an
admixture of both, although experimental studies are difficult to perform. One of the major contributions
to the understanding of the pathophysiology of emphysema was the clarification of the mechanisms of
early airway closure.
A priori examination of the bronchiolar anatomy immediately reveals the factors that account for their
active and passive narrowing: smooth muscle, compression by neighboring parenchyma during inflation,
and internal surface tension. The elements that counteract the narrowing and act to cause bronchiolar
dilation are less evident, however, made possible only by the radial insertion of alveolar walls in their
periphery and by the principle of mechanical interdependence. The integrity of alveolar walls is therefore
essential in keeping bronchioles open during deflation. In conditions such as emphysema, in which
alveolar walls are lost, the loss of bronchiolar support causes a calamitous early collapse of small
bronchioles at the onset of expiration, with trapping of air in all areas of the parenchyma located behind
the obstruction.
FIGURE 6.6 Schematic representation of the sequence of airway branches as a function of generation Z from trachea
(generation 0) to alveolar ducts and sacs (generations 20–23). The first 14 generations are purely conducting; transitional airways
(generation 15) lead into the acinar airways with alveoli that branch over 8 generations (Z′). (Modified from Weibel ER.
Morphometry of the Human Lung. Geometry and Dimensions of Airways of Conductive and Transitory Zones. Heidelberg:
Springer, 1963:110–135. Copyright © Springer-Verlag Berlin Heidelberg 1963. With permission of Springer Nature.)
FINE STRUCTURE OF TRANSITORY AIRWAYS

Respiratory Bronchioles
The last generation of exclusively conducting bronchioles is the terminal bronchioles. These branch to
form about three generations of respiratory bronchioles (Fig. 6.6), which have essentially the same
structure as other bronchioles except that, here and there and increasingly toward the periphery, the
continuity of their wall is interrupted by areas of typical gas-exchanging tissue. The cuboidal epithelial
cells of respiratory bronchioles are in most cases ciliated. Short cilia can even be demonstrated in close
proximity to alveoli.
Alveolar Ducts and Sacs

The mammalian airways form a blind-ending system. Dichotomy as a branching pattern can be
demonstrated up to the last ranks of the airway system, the alveolar ducts and alveolar sacs (Fig. 6.6).
These structures differ from the bronchioles described previously in that they lack a proper wall; instead,
their “wall” is formed by the openings of alveoli (Fig. 6.7), and their epithelial lining is nothing more than
extensions of squamous alveolar epithelial cells. It is generally admitted that three generations of alveolar
ducts immediately follow the last respiratory bronchioles. Finally, the last ducts give rise to two alveolar
sacs. An alveolar sac represents the blind end of the airway branching system.
FIGURE 6.7 A: Schematic representation of arrangement of alveoli around the alveolar duct. (From Weibel ER. Morphometry
of the Human Lung. Heidelberg: Springer, 1963. Copyright © Springer-Verlag Berlin Heidelberg 1963. With permission of
Springer.) B: Scanning electron micrograph of human lung (×150). A, alveoli; AD, alveolar duct; arrows point to pores of Kohn.
FINE STRUCTURE OF THE GAS-EXCHANGE REGION

In the respiratory zone of the lung, the blood is spread in capillaries in the walls of the alveoli. The air–
blood contact becomes intimate, and gas exchange can take place.
Alveoli
Alveoli are small pouches placed in groups around respiratory bronchioles, alveolar ducts, and alveolar
sacs. They are polyhedral structures lacking one side (the mouth, which opens into the airways), and they
have been compared with the cells of a honeycomb (Fig. 6.7) or with the air bubbles in foam. A polygonal
shape in general is economical because it allows a close packing of the alveoli. Studies on human
pulmonary acini revealed that the shape of alveoli is not simple and that often an alveolus appears like a
cluster of several connected pouches, as in Figure 6.7B.37 Furthermore, alveolar shape also depends on
the degree of lung inflation.30 In fully inflated lungs the alveolar configuration shows some similarity to
the cells of a honeycomb. At lower inflation degrees, alveoli are often cup-like.
The alveolar wall is always common to two adjacent alveoli and is called the alveolar or
interalveolar septum (Fig. 6.7B). The most conspicuous feature of the septum is a single but dense
network of capillaries, which is shown in Figure 6.8 in face view. Sometimes, the septa are interrupted by
interalveolar pores of Kohn, which are covered by surfactant. The septa also contain a skeleton of
connective tissue fibers that is especially well developed around the mouth of the alveoli, where it forms
a polygonal ring, the alveolar entrance ring (Fig. 6.7), and may contain smooth muscle cells. The
collagenous and elastic fibrous elements form a three-dimensional continuum that extends from the pleura
to the hilum. This continuum ensures transmission of chest and diaphragmatic movements into the deeper
regions of the lung, but it contributes only a smaller part to the retracting force of the lung, the major part
being caused by surface forces.111,119
FIGURE 6.8 Capillaries in the alveolar wall of the human lung are shown in a scanning electron micrograph (A); note the thin
tissue barrier separating air and blood (arrow). A model of such a septum (B) shows how fibers (F) are interwoven with the
capillary network (C) as well as the lining by type I alveolar epithelial cells (Ep1) that lines an interalveolar pore of Kohn (PK)
(scale marker = 10 μm). (Modified from Weibel ER. The Pathway for Oxygen: Structure and Function in the Mammalian
Respiratory System. Cambridge, MA: Harvard University Press, 1984:1–425. Copyright © 1984 by the President and Fellows of
Harvard College. With permission.)
In the adult, the number of alveoli averages 300 to 500 million.80,109 This number is related to body
length and lung volume and may vary largely between 200 and 800 million.4,80 For a lung of an adult
inflated to three-fourths of its maximal volume, the average alveolar diameter lies between 200 and 290
μm.80,109 It has been shown in dog lungs that alveolar size is not identical in all parts of the lung, but that
in an erect lung, the upper parts contain larger alveoli than the dependent parts because of the weight of
the lung tissue.34
Alveolocapillary Tissue Barrier

Figure 6.9 shows a section of a small portion of an interalveolar septum with a capillary. The septum is
lined on both sides by alveolar epithelial cells, which, in this instance, are thin. The capillary is lined
also by a single squamous cell layer, the endothelium. Together with the intercalated connective tissue,
these two cell layers constitute the alveolo-capillary tissue barrier, which is the structure separating air
and blood in the pulmonary gas-exchange region. It is supplemented by an extremely thin extracellular
lining layer that contains macrophages (Figs. 6.10 and 6.11). The morphometric characteristics of the cell
population that constitutes this tissue barrier in the human lung are shown in Table 6.2.
FIGURE 6.9 Electron micrograph of alveolar capillary (C) from monkey lung with erythrocyte (EC). Note endothelial cell lining
of capillary (EN), processes of pericytes (P), and the thin extensions of squamous type I alveolar epithelial cells (EP) covering
the alveolar surface. The interstitial space (IN) is bounded by two basement membranes (BM) and contains some fibroblast
processes (FB) as well as a few connective tissue fibrils. This lung was fixed by instillation of fixative into airways, resulting in a
loss of the surface lining layer; hence, only parts 2 (tissue barrier), 3 (blood plasma), and 4 (erythrocyte) of the gas-exchange
pathway are preserved, whereas the first layer, the surface-lining layer (Fig. 6.10), is missing (×8,600). (Reprinted from Weibel
ER. Morphometric estimation of pulmonary diffusion capacity. I. Model and method. Respir Physiol 1971;11:54. Copyright ©
1970 Elsevier. With permission.)
FIGURE 6.10 Air–blood barrier of rat lung fixed by vascular perfusion to preserve surface lining layer (S) made up of
hypophase and osmiophilic surface film (arrows) (×38,700). EN, endothelial cell lining of capillary; EP, squamous type I alveolar
epithelial cells; IN, interstitial space. (Reprinted from Weibel ER. Morphometric estimation of pulmonary diffusion capacity. I.
Model and method. Respir Physiol 1970;11(1):54–75. Copyright © 1970 Elsevier. With permission.)
Epithelium
The epithelium of the alveoli is continuous, although its thickness in places reaches only 0.1 to 0.3 μm,
which is at the limit of resolution of conventional light microscopy. Early electron microscopic studies
brought the first conclusive evidence for an uninterrupted epithelial lining of alveoli.61 It consists of the
following cell types (Table 6.2):
FIGURE 6.11 Alveolar macrophage (M) with pseudopods and a group of lysosomal vesicles (L) in cytoplasm submerged
beneath surface lining layer (S) and closely stuck to the alveolar epithelium (arrows). The hypophase of the surface lining layer
contains so-called tubular myelin figures. The capillary (C) is empty because of fixation by vascular perfusion (×10,500).
(Reproduced with permission from Gil J. Ultrastructure of lung fixed under physiologically defined conditions. Arch Intern Med
1971;127:896. Copyright © 1971 American Medical Association. All rights reserved.)
TABLE 6.2 Morphometric Characteristics of Cell Population in the Human Alveolar
Septal Tissue
Cell Number Average Cell
Absolute (n × 109) Relative (%) Volume (μm3) Apical Surface (μm2)

Pneumocytes I 19 8.3 1,763 5,098
Pneumocytes II 37 15.9 889 183
Endothelial cells 68 30.2 632 1,353
Interstitial cells 84 36.1 637 —
Macrophages 23 9.4 2,491 —
From Crapo JD, et al. Cell numbers and cell characteristics of the normal human lung. Am Rev Respir Dis 1982;126:332.
Alveolar Epithelial Type I Cells

Type I cells (Fig. 6.12), also called squamous cells or type I pneumocytes, send out broad, thin
cytoplasmic extensions. Although they are some 30% to 40% less numerous than the type II cells, they
cover 92% to 95% of the total alveolar surface. The nuclei lie in depressions between two capillaries.
These cells are poor in organelles, such as mitochondria or endoplasmic reticulum, which are confined to
the perinuclear cytoplasm, whereas the cytoplasmic extensions essentially contain only fibrils of the
cytoskeleton and pinocytotic vesicles. In humans, a single type I cell covers some 5,000 μm2 of the
alveolar surface, on the average.20 To achieve this extraordinarily large extent, type I cells are complex
structures by forming branches that cross over to the other surface of the alveolar septum.117 As a
consequence of this complex structure, type I cells cannot divide by mitosis. The generation of new type I
cells during lung growth as well as alveolar epithelial cell turnover and epithelial regeneration after
injury is accomplished by proliferating and differentiating type II cells.1,25,49,53
Alveolar Epithelial Type II Cells

Type II cells are cuboidal (Fig. 6.13). These cells have also been called granular pneumocytes, type II
pneumocytes, or great alveolar cells, although they are smaller than type I cells. They have no
cytoplasmic extensions and typically are in niches between capillaries of the alveolar septum. Their free
surface is covered by somewhat irregular microvilli, mostly around their periphery. The cells occupy 5%
to 8% of the alveolar surface and form tight junctional complexes with neighboring alveolar type I cells.
Compared with alveolar type I cells, the type II cell is rich in mitochondria, endoplasmic reticulum, Golgi
apparatus, and multivesicular bodies. Their most distinctive morphologic feature, however, is the
presence of lamellar osmiophilic inclusions, the lamellar bodies, which are unique organelles known as
the sites of storage of pulmonary surfactant.5,24,31,39,79,85,108 The synthesis, storage, secretion and at least
partial recycling of surfactant components is one of the two main functions of type II cells. The other is the
contribution to alveolar epithelial regeneration under physiologic and pathologic conditions. Thus, the
alveolar epithelial type II cell is regarded as the “defender of the alveolus.”26,66
FIGURE 6.12 Type I alveolar epithelial cell with thin cytoplasmic extensions (arrows) (×8,600). C, alveolar capillary; EN,
endothelial cell lining of capillary; EP, squamous type I alveolar epithelial cells; FB, fibroblast process with an intracytoplasmic
bundle of contractile filaments.
FIGURE 6.13 A: In a type II alveolar epithelial cell, the abundant cytoplasm surrounding the nucleus (N) contains the
characteristic osmiophilic lamellar bodies (LB), which store surfactant, and a rich complement of organelles such as endoplasmic
reticulum (ER) and mitochondria (MI). The surface membrane carries microvilli (arrow) and junctions (J) with neighboring type
I epithelial cells (scale marker = 1 μm). B: Schematic diagram of pathways for synthesis and secretion of surfactant lipids and
apoproteins by a type II cell, for their recycling by type II cells, and for their removal by alveolar macrophages. Note the
arrangement of phospholipids and apoproteins in the lamellar bodies, in tubular myelin, and in the surface film. (From Ochs M,
Weibel ER. Functional design of the human lung for gas exchange. In Fishman AP, Elias JA, Fishman JA, et al., eds. Fishman’s
Pulmonary Diseases and Disorders, 4th ed. New York, McGraw Hill, 2008:23–69. Copyright © 2008 by McGraw-Hill
Education. All rights reserved.)
Brush Cells
A third pneumocyte, the brush cell, was first described in the rat lung.73 In the rat, this cell can be found in
terminal bronchioles; it is, however, rare in the gas-exchange zone. The brush cell is characterized by a
spray of rather thick and regular cylindrical microvilli at the surface and by thick bundles of microfibrils
in the cytoplasm. Brush cells are large, but only a small part of their membrane reaches the epithelial
surface. Similar cells occur in larger airway epithelia and in other organs also. Recent evidence suggests
a function for brush cells as receptors for “tasting” the chemical composition of the airway lining
fluid.56,57
Interstitium
The interstitium is the space between the basal laminae of alveolar epithelium and capillary endothelium
(Fig. 6.9). It contains connective tissue and interstitial fluid. The connective tissue comprises cells,
fibers, and an amorphous substance containing proteoglycans, allegedly in a gel matrix. The distribution
of connective tissue can vary considerably. In places where the air–blood barrier is thin, connective
tissue may be reduced to a few isolated fine fibrils or may even be absent, in which case the adjoining
basement membranes fuse. These last regions are particularly important for gas exchange. In lung edema,
they are usually not widened by interstitial fluid and can therefore be called restricted, as opposed to
those unrestricted, thicker portions of interstitium between capillaries, where interstitial fluid can
accumulate under pathologic conditions. The interstitial fibroblasts have been demonstrated to contain
contractile filaments (Fig. 6.12), and, it has therefore been suggested that they could regulate blood flow
through the alveolar septum.50,51 In view of the interstitial structure described, an alternative function for
these cells has been proposed118: they could control the compliance of the unrestricted interstitial regions
by regulating the width of the septum. In rodents, particularly during postnatal development, the interstitial
cells form two distinct populations of cells: a lipid-containing and a nonlipid-containing type. The lipid
droplets of the lipid-containing type, often referred to as lipofibroblast,3 mostly disappear before
weaning.50,59 In a recent study, lipid droplet-containing interstitial cells were not found in the postnatal
and adult human lung.98 Lymphatic vessels are never found in alveolar septa. Nevertheless, a continuous
path of the interstitial fluid toward the lymphatics of the subpleural space and of the peribronchial and
perivascular connective sheaths has been postulated. The fluid probably follows connective fibers.
Endothelium
The endothelial cells form a capillary wall that is similar in structure to the endothelium in some other
organs (Figs. 6.9, 6.10, and 6.14). The cells form thin cytoplasmic extensions that resemble those of
alveolar type I epithelial cells, but they are smaller. A single cell covers between 1,000 and 1,500 μm2 of
the capillary lumen (Table 6.2). Lung capillaries have no fenestrations. Further details are discussed
below.
Extracellular Lining Layer and Pulmonary Surfactant

On the basis of theoretical considerations, as early as 1929, von Neergaard105 predicted that the alveolar
surface must be lined by a surface-active substance, now commonly called pulmonary surfactant.19 It is an
essential element, ensuring the stability of the air-filled lung. Its basic biophysical characteristics are
twofold: first, it lowers the surface tension at the air–liquid interface of the alveoli; and second, its
surface tension is variable with the degree of inflation of alveoli. In addition, certain surfactant
components have important immunomodulatory functions in the lung.130,131
Morphologic demonstration of pulmonary surfactant is possible only with the electron microscope. In
routine preparations, usually no traces of this material are found (Fig. 6.9). In lungs fixed by vascular
perfusion, an extracellular duplex lining layer on the alveolar surface, consisting of a surface film and a
hypophase, can be preserved (Fig. 6.10).32 Much of this material forms pools in pits and irregularities of
the alveolar wall, which smoothes it out. These pools in the hypophase are polymorphous, consisting of
several surfactant subtypes representing different stages in intra-alveolar surfactant metabolism. Freshly
secreted surfactant is present as lamellar body-like forms that rapidly transform into tubular myelin
figures with a characteristic lattice-like structure. Although the precise function of tubular myelin is still
unknown, it is thought to be the immediate precursor of the surface film. In addition, tubular myelin may
act as a reservoir for host-defense molecules. Inactive surfactant components can be found in the
hypophase as small unilamellar vesicles.
FIGURE 6.14 A: Air–blood barrier showing thin cytoplasmic extensions of type I alveolar epithelium (EP) and endothelial cells
(EN) with intercellular junction. Note abundance of pinocytotic vesicles (V) (×37,000). B: High-power view of the junction
between two capillary endothelial cells. The triple-layered structure of the cell membranes is apparent. In the junction, the
membranes are closely apposed over a short stretch (arrows). Note pinocytotic vesicles (V) (×184,800). A, alveolus; C,
capillary.
The cellular source of pulmonary surfactant are the type II alveolar epithelial cells. Figure 6.13B
shows how the organelles of this cell are involved in synthesizing, storing, and secreting the surfactant
lipids and the specific apoproteins. The single most abundant component of surfactant is the phospholipid
dipalmitoyl phosphatidylcholine. Four major proteins have been identified in alveolar surfactant, termed
SP-A, SP-B, SP-C, and SP-D. The surfactant proteins, as the “smart molecules in the surfactant system,”38
are important for surfactant subtype assembly, biophysics, homeostasis, and immunity. Two of these, SP-A
and SP-D, are hydrophilic and members of the collectin family of proteins; they are mainly involved in
the immunomodulatory functions of surfactant, whereas the two hydrophobic proteins SP-B and SP-C are
mainly involved in the biophysical surfactant functions (for further details and references, see
Hawgood,39 Mason and Shannon,65 Notter,77 Ochs and Weibel,81 and Weibel112).
Alveolar Macrophages
Alveolar macrophages (dust cells) are the sentinel phagocytic cells of the alveolar lining layer (Fig.
6.11). They are large cells exhibiting many vacuolar inclusions and lysosomes. Most of their phagosomes
are filled with dark, lipid-rich inclusions. In their functional location, they are closely apposed to the
alveolar epithelial surface and are submersed under the surfactant film of the lining layer (Fig. 6.11).
Their bodies are in depressions of the alveolar wall, and they send out large extensions. In conventional
histologic preparations after fixation via the airways, they have been removed from their original position
on the alveolar wall. These cells appear to float in the alveolar space, and their surface is generally
rounded off so that they acquire the appearance of large, spherical cells. Alveolar macrophages have been
shown to derive from blood monocytes.
Gas-Exchange Surface and the Air–Blood Barrier

The alveolocapillary air–blood barrier is composed of the surface-lining layer, the epithelium, the
interstitium, and the endothelium that have to be crossed by the oxygen molecules on their way from air to
blood (Fig. 6.9). The chief characteristic of this barrier is that it is extremely thin but extends over a very
large surface.
The alveolar surface area of the adult human lung has been found to vary between 97 and 194 m2
(mean, 143 m2)28 and is larger than older data that had been obtained by light microscopy that does not
fully resolve the complex surface.109,120 In studying different mammalian species it is found that the
alveolar surface area is linearly proportional to body mass.122
In most species investigated, the total capillary surface area did not differ from the alveolar surface
area by more than 10% to 15%. In the rat lung, the capillary-to-alveolar surface ratio is 1.05 to 1.1, which
means that the capillary surface area of the rat lung is 5% to 10% higher than the alveolar surface. In the
human lung and in the dog lung, where the capillaries are less dense, the quotient is about 0.88.
From Figure 6.9, it is evident that the width of the alveolocapillary barrier can vary from about 0.3 μm
to several microns. The thickness of this tissue barrier is important because it determines, together with
other parameters, the diffusion resistance of the barrier that oxygen molecules moving from the alveolus to
the capillary must overcome. This resistance is low in thin parts and higher in thick parts, so that the flux
of gas at each point is inversely proportional to local barrier thickness. Hence, the thin parts of the
barrier, which constitute about half of the total alveolar surface area, contribute most to gas exchange. In
estimating an effective average thickness of the barrier, this is best taken into account by determining the
harmonic mean thickness of the air–blood barrier—that is, the average of the reciprocal value of local
thickness, rather than the arithmetic mean, which estimates the tissue mass building the barrier. The
arithmetic and harmonic mean thicknesses vary relatively little in various mammalian species. On
average, the harmonic mean thickness is about one-third of the arithmetic mean thickness. Estimates on
human lungs give values of about 0.6 μm for the harmonic mean thickness of the tissue barrier, whereas
the arithmetic mean thickness is about 2 μm.
FIGURE 6.15 The pulmonary arteries (red) branch in parallel with the airways (yellow) to which they are closely apposed all
the way out to the periphery. The pulmonary veins (blue) are positioned in between the bronchoarterial bundles.
PULMONARY BLOOD VESSELS

The pulmonary vascular system is tightly associated with the airway tree following all its ramifications.
Beginning in the hilus the pulmonary arteries branch in parallel to the conducting airway tree being tightly
associated with these airways with a common connective tissue sleeve. Figure 6.15 shows that even in
more peripheral branches the arteries are tightly associated with the branching airways, whereas the
pulmonary veins branch independently. And, even though they show a similar branching pattern, their
position is intermediate with respect to the bronchoarterial bundle. Figure 6.16 shows a more peripheral
aspect of such a cast where alveolated airways that constitute the core of an acinus are seen to form dense
bundles into which the pulmonary artery branches penetrate along the air ducts. The peripheral branches
of the pulmonary veins penetrate into these acinar units from interlobular regions. With this arrangement
blood flow occurs from the center of the acinar gas exchange units through the capillary network (Fig.
6.17) to the interlobular veins. Accordingly, pulmonary veins receive arterialized blood from several
acinar units.
FIGURE 6.16 In this cast the airways (yellow) are filled out to the acinus including part of the alveoli. The pulmonary artery
branches (red) are seen to penetrate into the acini whereas the pulmonary veins (blue) are at the periphery of the acinar units
and branch into them from the periphery.
FIGURE 6.17 A peripheral branch of the pulmonary artery forms multiple arterioles that feed into the dense alveolar capillary
network. Inset: high power view of the network showing erythrocytes in the plasma (black) and other cells in red. Rabbit lung:
the blood plasma was labeled with colloidal gold demonstrated as black marker. (From König MF, Lucocq JM, Weibel ER.
Demonstration of pulmonary vascular perfusion by electron and light microscopy. J Appl Physiol 1993;75:1877–1883. Copyright
© 1993 The American Physiological Society (APS). All rights reserved.)
Alveolar Capillaries
A dense capillary network (Fig. 6.8) is intercalated between adjoining alveoli and occupies a little more
than half of the alveolar septum. It differs from the capillary arrangements in the systemic circulation in
that it forms an extensive, dense hexagonal network109 that is supplied by multiple short arterioles (Fig.
6.17) and is drained into similar venules. In the systemic circulation, the capillaries form looser networks
that are connected to systemic arterioles and veins. The alveolar capillary network forms a three-
dimensional continuum over the region of several acini (Fig. 6.17), extending from one alveolar wall
facet to the next so that the erythrocytes course through this network along variable paths. This is
important because surface forces caused by surface tension can reduce the size of capillaries in the
alveolar septa if blood pressure is lower than the forces exerted by surface tension, as is often the case in
upper lung regions. Capillaries that do not lie in the flat parts of the septum but rather in the “corners” of
alveoli will, however, always remain open because they are exposed to three negative surface forces due
to high surface curvature at these triple lines formed by the junction of alveolar facets (Fig. 6.18).6 The
three-dimensional network of these corner vessels ensures that a minimal tract is always perfused.
In all capillary segments, regardless of their shape or degree of filling, the lumen is lined by
nonfenestrated endothelial cells consisting of a perinuclear region of cytoplasm containing cellular
organelles—such as mitochondria, endoplasmic reticulum, Golgi complex, and various granules—and
thin, virtually organelle-free cytoplasmic extensions. These abruptly turn into the thinnest cytoplasmic
areas (less than 0.1 μm), composed of two cell membranes separated by a minimal volume of interposed
cytoplasm (Fig. 6.9). The endothelial portions of average thickness contain numerous pinocytotic vesicles
that are, in part, attached to either of the two cell membranes (Figs. 6.9 and 6.14). Despite the
morphologic similarity of epithelial and endothelial cells, there are differences in permeability for solutes
and macromolecules between endothelium and epithelium. The epithelium represents the chief
permeability barrier of the lung. Endothelium can be permeated under a variety of circumstances. The
explanation for this difference was provided by comparative freeze-fracture studies of endothelial versus
epithelial junctions. The epithelial tight junctions consist of a continuous network of three to five
interconnected ridges and grooves and the endothelial junctions have only one to three rows of particles,
with few interconnections and even some discontinuities.93 The strands are made up of claudins,
transmembrane proteins associated with cytoplasmic contractile filaments. Because it is believed that an
inverse correlation exists between the number of strands constituting a tight junction and its permeability
to solutes, it follows that epithelial junctions are tight, whereas endothelial junctions are relatively leaky
to small solutes. Both cell types are equally permeable to water when the hydrodynamic pressure is
elevated. Starling’s law applies to the balances.
FIGURE 6.18 Scanning electron micrograph of three alveolar septa in rabbit lung perfusion-fixed under zone 2 conditions
showing the corner capillary to be wider than those in the septa due to the pull by three surface tension vectors at the triple line.
(From Bachofen H, Wangensteen D, Weibel ER. Surfaces and volumes of alveolar tissue under zone II and zone III conditions.
J Appl Physiol 1982;53:879–885. Copyright © 1982 The American Physiological Society (APS). All rights reserved.)
Alveolar capillaries are associated with pericytes. These seem to be less frequent and less densely
branched in the alveolar than in the systemic capillaries. As in the systemic circulation, pericytes are
supposed to be contractile cells. In normal lungs, they are positive for actin and muscle-specific antigen
but negative for smooth muscle myosin (heavy chain) and desmin.75
Structure of Larger Pulmonary Vessels

The endothelial cells of larger pulmonary vessels are more homogeneous in thickness and contain
characteristic rod-shaped granules (Fig. 6.19) known to occur in all vascular endothelia of all vertebrate
species.121 In the mammalian vascular system, these Weibel–Palade bodies are particularly numerous in
medium- and large-sized branches of pulmonary arteries and veins, but they are absent in capillaries. The
occurrence of these bodies is similar in systemic vessels of the same size. Based on indirect evidence, it
had been proposed that these organelles contain a procoagulative substance that can be secreted into the
vascular lumen.16 Using immunocytochemical techniques, it was demonstrated and now well-established
that the Weibel–Palade bodies contain as their main component factor VIII–related antigen, also called
von Willebrand factor,106,107 and that their content is secreted into the vascular lumen.21,77,115 The granule
membrane also contains the endothelial leukocyte-binding protein P-selectin, also found in the granules of
platelets, which is responsible for the initial inflammatory endothelial reaction and the rolling stage of
early neutrophilic adhesion, a key early development in acute inflammation.9,71
FIGURE 6.19 Bronchial arteriole (BA) in a semicontracted state with thick endothelium (EN) and a simple layer of smooth
muscle cells (M). Note numerous contacts between endothelial and muscle cells (arrows). At top, note the section of wall of a
small pulmonary vein (PV) with loose smooth muscle layer (M) and endothelium (×485). Inset shows sample of specific
endothelial organelles (also called Weibel–Palade bodies) at higher power. Note membrane and internal tubules (×83,200).
The electron microscopic study of intima and media of pulmonary vessels does not reveal many
features that are not manifest by light microscopy. The circular smooth muscle cells of peripheral vessels
of the muscular type are long, slender, and rather densely arranged (Fig. 6.20). It is important to note that
the thickness of the muscular layer varies with species and is thicker in mice than in humans, which raises
doubts about a straightforward relationship between pulmonary arterial pressure and medial thickness. In
elastic vessels (larger pulmonary arteries), the connective tissue elements prevail (Fig. 6.21). The space
between the prominent elastic laminae contains much collagenous tissue and relatively short smooth
muscle cells, which extend from one elastic lamina to the next in an oblique course and appear to insert
on the elastic laminae with ramified ends (Fig. 6.21). In Figure 6.19, a portion of a longitudinal section of
a medium-sized pulmonary vein is shown with its thin wall made up of an endothelium, a few irregularly
arranged smooth muscle fibers, and collagenous as well as elastic fibers. One interesting feature is that
smooth muscle cells of these vessel walls not only form close intercellular contacts in the form of patches
or nexus (Figs. 6.20 and 6.21) but also have close cell-to-cell contact with endothelial cells by means of
short extensions across the internal elastic membrane (Fig. 6.19). It is assumed that cell-to-cell contacts
between endothelial or epithelial cells and smooth muscle or interstitial cells are important in inducing
and regulating various cell functions.
FIGURE 6.20 Electron micrograph of longitudinal section of medium-sized pulmonary artery of muscle type. The endothelium
(EN) lies over a strong elastic membrane (E). The smooth muscle cells (M) are obliquely sectioned; their cytoplasm shows a fine
filamentous structure. Some muscle cells (labeled N) show intercellular contacts (nexus), serving to spread excitation among the
cells (×5,850).
DEVELOPMENT AND GROWTH OF THE LUNG

Despite its ability to supply the organism with enough oxygen, the lung of the newborn is still structurally
immature. Besides primitive air sacs, which have often been misinterpreted as alveoli, only a fraction of
the final number of alveoli is present at birth. Also, the capillary network is not yet mature, because the
parenchymal septa contain two layers of capillaries, as opposed to a single one in the mature adult lung. It
is evident that the last two stages of lung development—the stage of alveolarization and the stage of
microvascular maturation—occur after birth, to a large part in the first couple of years.
FIGURE 6.21 Electron micrograph of pulmonary artery of elastic type. Note three strong elastic membranes (EM) paralleling
the endothelium (EN), and ramified smooth muscle cells (M), which take an oblique course, reaching from one elastic membrane
to the next (arrows). The direction of the muscle fibers alternates from one layer to the next. Collagen fibrils (CF) are abundant
and mixed with elastic fibers (×4,850).
For technical and ethical reasons, the morphologic alterations and mechanisms of lung restructuring
were first extensively studied using the rat lung as a model.11,13 However, it has been well established by
comparative studies that the developmental processes in human and rat lung are morphologically highly
congruent.133,134 In both species, the postnatal lung must undergo alveolarization and reshaping of the
parenchymal capillary networks before normal growth takes over.
In the human, the exact timing of these stages is still a matter of debate, because the processes are
slow, do not occur simultaneously all over the lung, and do hence largely overlap (Fig. 6.22).
FIGURE 6.22 Stages and timing of human lung development. Open-ended bars indicate that the exact start and end of the
stages are still unknown. (Reprinted from Zeltner TB, Burri PH. The postnatal development and growth of the human lung. II.
Morphology. Respir Physiol 1987;67:269. Copyright © 1987 Elsevier. With permission.)
FIGURE 6.23 Illustration of alveolarization in the rat lung by scanning electron microscopy. A: Day 1: At birth, lung
parenchyma contains smooth-walled channels and saccules (s). B: Day 21: The secondary septa (arrows) have produced alveoli
(a) and subdivided the saccules into alveolar sacs and the channels into alveolar ducts (ad) (×450).
ALVEOLARIZATION OF THE LUNG

At birth, the human lung contains only about one-fifth to one-tenth of the final alveolar number of 200 to
800 million. The lung is still largely in the saccular stage and the pulmonary parenchyma contains mainly
smooth-walled channels and terminal saccules. The channels are later transformed into alveolar ducts and
the saccules into alveolar sacs (Fig. 6.23). This happens through the outgrowth of new so-called
secondary septa from the saccular walls termed primary septa, because they are already present at birth.
The secondary septa appear first as low ridges, which increase in height and subdivide the airspaces into
smaller units, the alveoli (Fig. 6.23). Morphological studies show that the primary septa contain a double
capillary network and that the secondary septa are formed by lifting off of one of the two layers.
There is strong evidence today that three components of the interairspace walls are involved in this
process: the septal myofibroblasts, the elastic fibers, and the collagen fibrils. Myofibroblasts are assumed
to proliferate and to move to the sites of the future ridges, where they produce elastin strands and collagen
fibrils. The elastin assembles to a network of ropes, which stays at the tip of the ridges while these are
lifted off. The elastic network will finally represent the main component of the alveolar entrance rings.
In the rat, this form of classic alveolarization occurs as long as the interairspace walls show a double
capillary network and it proceeds at a high rate within a few days, mainly in the second postnatal week.
Because of its suddenness and eruptive character, it has also been termed “bulk alveolarization.” In
humans, this phase starts just before term and extends over the first 6 months of life. At about 1 month of
age, the human lung closely resembles a 1-week-old rat lung. This phase of alveolarization is terminated
at 2 weeks in the rat and at about 12 months to 2 years in the human.58 More recent investigations in rats
and in humans have shown that further alveoli are formed after this age, but at a much slower pace.40,92,104
This “continued alveolarization” adds a substantial number of alveoli to the lung.
MICROVASCULAR MATURATION
As mentioned before, the saccular walls contain a double capillary layer. This immature structure allows
for the upfolding of one layer within the secondary septum (Fig. 6.24). As a result of this process, the
secondary septa will also contain a double capillary network (i.e., the intersaccular and new
interalveolar walls are both of the immature type). As described earlier in this chapter, the adult lung
contains a single capillary layer interwoven with an axial sheet of supporting connective tissue (Fig. 6.8).
This makes it clear that the alveolar stage cannot be the last stage in lung development. It has to be
followed by the stage of microvascular maturation during which the septal capillary bilayer is
restructured into a single layer.
Septal restructuring is a complex mechanism closely related to growth. Early in alveolarization, the
capillary layers are separated by a thick sheet of connective tissue. With ongoing lung development and
growth, this sheet thins out and the capillary layers come to lie close to each other, to contact each other,
and finally to merge their lumina. Multiple focal fusions and subsequent preferential growth of fusion sites
soon transform large parts of the parenchyma into its mature structure. As a side effect, the septal thinning
also leads to transseptal epithelioepithelial contacts, which end up in the formation of the interalveolar
pores of Kohn.127 Their appearance is timed with the stage of microvascular maturation in all species
investigated so far.
FIGURE 6.24 Schematical illustration of alveolar formation. The saccular lung is made of primitive septa containing a capillary
bilayer (A). The future alveolar walls appear first as low ridges (arrows in B), which increase in height and form the new
interalveolar walls (arrows in C). Notice the importance of strands of elastin (black dots). (From Burri PH. Pulmonary
development and lung regeneration. In: Fishman AP, ed. Fishman’s Pulmonary Diseases and Disorders. New York, McGraw
Hill, 1988:61–78. Copyright © 1988 by McGraw-Hill Education. All rights reserved.)
In humans, microvascular maturation starts early after birth and goes partly along with alveolarization,
so that, already at the age of 1 year, large parts of the lung show slender, mature interalveolar walls. The
process, however, goes on until the age of 2 to 3 years, so that from the point of view of septal
morphology (but not regarding alveolar number), we may consider a child’s lung at the age of 3 years as a
miniature version of the adult lung.
WHEN DOES ALVEOLAR FORMATION STOP?

This pertinent question is sitting around for decades because of the pathophysiologic concept that if the
lung were able to form new alveoli during childhood, structural damage could be more readily and
adequately repaired. It is interesting that early studies postulated alveolar formation to go on up to the age
of 18 years. Later, this limit was successively brought down to 8 and then even to 2 years. Today, because
of new findings,40,74 there is a reverse trend, and one readily hypothesizes that continued alveolarization
could exist in the human lung.
Counting alveoli is no easy task, and most approaches in the past were using biased counting
techniques. Only recently unbiased methods have become available.78,80 However, even with perfect
counting techniques, the results may be inconclusive because of genetic and environmental influences
combined with statistical constraints. Burri12 published a more detailed review of how continued
alveolarization could be achieved in a mature lung.
THE GROWING LUNG

First, it is important to notice that normal lung growth does not imply a proportionate increase of all the
pulmonary compartments. Major volume shifts occur in the first 1½ to 2 years, a period marked by a
massive decrease in the proportion of interstitial tissue paralleled by an increase in airspace and
capillary blood volumes. These changes greatly contribute to an improvement in the gas-exchange
function of the lung. While parts of these alterations have to be attributed to ongoing developmental
processes in early childhood, similar trends can be observed after the age of 2 years. Between birth and
adulthood, lung volume increases by a factor of 23, the amount of pulmonary interstitium increases only
sixfold, but capillary volume 35-fold, making up 45% of the volume of the mature interalveolar walls.
Further relevant parameters for gas exchange, the alveolar and capillary surface areas, augment about 20
times between birth and young adulthood, reaching, on average, values of about 140 and 125 m2,
respectively.
FIGURE 6.25 Mechanism of intussusceptive microvascular growth. A: Very small meshes appear in the capillary network; they
correspond to slender tissue pillars across the capillaries (arrowheads). B: The labeled meshes of (A) have increased in size
(arrowheads), while further tiny meshes appear (arrows). The capillary network increases both in area and in number of
capillaries. (From Djonov V, Burri PH. Basic concepts of intussusceptive angiogenesis. In: Shepro D, ed. Microvascular
Research: Biology and Pathology. Philadelphia PA: Elsevier, 2006:91–96. With permission.)
Overall, these results mean that during growth, a steady state in the proportions of the lung
compartments does not exist. This holds even for the adult lung. As an example, we can mention here the
increase in the volume of the parenchymal airspace with aging.
GROWTH OF THE PULMONARY CAPILLARY BED

The overproportionate increase in capillary blood volume and capillary surface area implies that new
capillaries must continuously be added to the existing network. It has been demonstrated, by scanning
electron microscopy and ultrastructural analysis of serial sections, that the pulmonary capillary network
grows by formation of new intercapillary meshes rather than by sprouting of new capillaries.15,18 This
new mode of angiogenesis has been termed intussusceptive microvascular growth (i.e., growth within
itself), analogous to the growth of cartilage. It consists in the formation of transcapillary tissue pillars that
form new capillary loops (Fig. 6.25). The newly formed, extremely thin individual tissue pillars (with a
diameter of <1.5 μm) subsequently increase in diameter and thus give rise to full-sized intercapillary
meshes.23,84 As depicted in Figure 6.25, this mechanism allows the interalveolar capillary networks to
expand in surface area without the need of sprouting.
In the meantime, it could be shown that there are various modes of pillar formation and also that
intussusceptive microvascular growth is present not only in the lung but represents a widespread and
fundamental angiogenic process in vascularized organisms (for review, see Burri and Djonov14).
FUNCTIONAL DESIGN OF THE LUNG AS A GAS EXCHANGER
MORPHOMETRIC ESTIMATION OF DIFFUSING CAPACITY

The term diffusing capacity of the lung (DL) has been introduced by physiologists, as noted by Forster,27
to estimate the conductance of the pulmonary gas-exchange apparatus for gaseous diffusion between
alveolar air and capillary blood. The physiologic definition uses Ohm’s law and states that, for oxygen,
DLO2 = O2/ΔPO2
in which O2 is the O2 uptake and ΔPO2 is the mean difference of O2 partial pressure between alveoli
and capillaries.
It is implicit in the definition that a major part of DL is determined by structural properties of the lung,
mainly by the available gas-exchange surfaces, by the thickness of the air–blood barrier, and by the
capillary blood volume. The evolution of morphometric methods has made it possible to estimate DL
from measurements of lung structure performed on electron micrographs.110,125 To this end, the air–
hemoglobin barrier must be subdivided into two partial conductances for diffusion of O2 molecules: the
conductance of the membrane (DM) (tissue barrier and plasma layer combined) and the conductance of
the erythrocytes (De), as shown in Figures 6.9 and 6.26. We then find DL from the sum of the partial
resistances—that is, the reciprocals of the conductances:
In the model,97 DM is obtained as the product of the gas-exchange surface area with a diffusion
coefficient divided by the total diffusion barrier thickness (τhb) estimated as extending from the alveolar
to the erythrocyte surface (Fig. 6.26). The erythrocyte diffusing capacity (De) is obtained as the product of
the capillary blood volume with the coefficient θO2, which estimates the rate of O2 binding by the blood.
DL can thus be calculated if we measure the alveolar and capillary surface areas (Sa and Sc), the
capillary volume (Vc), and the harmonic mean thickness of the total barrier (its harmonic mean thickness
τhb). In addition, we need to know appropriate values for the physical coefficients of permeability and of
the rate of O2 binding by the blood (θO2). Table 6.3 presents the results from a morphometric study of
adult human lungs.28,125 Using the most reasonable estimates of the physical coefficients, one calculates
DLO2 to amount to about 160 mL O2/min per mm Hg.
FIGURE 6.26 Model for estimating pulmonary diffusing capacity from physiologic (left) and morphometric information (right).
The membrane barrier includes the tissue (green) and plasma (yellow) layers as well as the thin surfactant lining (grey).
For comparison, the physiologic values of DL at rest amount to about 30 mL O2/min per mm Hg. This
value is far below the morphometric estimates. It should be noted that two different things are being
measured: morphometry estimates the size of the gas-exchange apparatus that is maximally available for
gas exchange. Its values refer to a fully expanded lung. This leads to an overestimation of DL by as much
as 25% to 50%, because in lungs inflated with air and fixed by vascular perfusion, parts of the diffusion
barrier are folded away from the surface even at highest inflation and thus do not contribute to gas
exchange.30 Furthermore, an assumption is made that a gradient from air to blood exists at every point
along the alveolar capillary. Under resting conditions, this is most certainly not the case. In fact, it is
probable that the capillary blood is saturated before it leaves the capillary, as Karas and colleagues52
showed for the lungs of animals performing heavy exercise. Thus, the physiologic estimates of DL at rest
should amount to only 20% to 40% of the maximal or true diffusing capacity. In the findings of Bitterli and
colleagues7 in exercising humans, physiologic estimates may yield DL values between 70 and 100 mL
O2/min per mm Hg, but the morphometric estimate of pulmonary diffusing capacity in humans is therefore
about two times larger than the physiologic estimate. This has been confirmed by direct measurement of
the physiologic and morphometric values of DLO2 in animals.123 So, it may be concluded that the lung
provides a gas-exchange apparatus that is large enough to allow O2 to diffuse to the blood in sufficient
quantity when O2 consumption is elevated because of work. Destruction of lung tissue, as occurs in
emphysema, would tend to reduce the true diffusing capacity by reduction of the gas-exchange surfaces
and possibly by thickening of the barrier.
TABLE 6.3 Basic Morphometric Parameters and Diffusing Capacity in Human Lung
Weight 74 kg
Alveolar surface 130 m2
Capillary surface 115 m2
Capillary volume 194 mL
Tissue barrier 0.62 μm
Total barrier 1.10 μm
DLO2 170 mL O2
min/mm Hg
In recent studies it was shown that partial pneumonectomy in dogs reduces the pulmonary diffusing
capacity in proportion to the tissue loss.43 Yet when 40% of lung tissue is removed by left
pneumonectomy, the lung can achieve 85% of its maximal O2 uptake, making use of some of its reserve
capacity, since in this case no growth of tissue occurs in the residual lung. But when right pneumonectomy
removes 60% of lung tissue, adequate function can be achieved only after a compensatory growth of gas-
exchange tissue, including capillaries, has occurred and can thus restore diffusing capacity. Thus the lung
has a limited reserve diffusing capacity.44,99
Figure 6.27 shows the results of a comparative study of DL in mammalian species ranging from the
smallest mammal, the Etruscan shrew, weighing only 2 g, to the horse. It is apparent that DL is related
directly to body mass and, in contrast, maximal O2 consumption ( O2max) varies with the 0.8 power of
body mass. Consequently, the lung’s capacity for O2 uptake is not matched to the body’s need for O2 when
one compares animals of different body size.
On the other hand, the lung can respond to increased O2 demands or to reduced environmental O2 at
high altitude by enlarging the pulmonary diffusing capacity.17,29,46 It is also found that athletic animals,
such as dogs and horses, have a larger diffusing capacity than animals of the same size but lower O2
needs. The question of how the lung’s morphometric properties are related to the body’s O2 needs is still
a matter of scientific debate.100 Furthermore, numerous reports indicate that the perinatal and postnatal
period of alveolarization is a highly sensitive phase susceptible to disturbances induced by
environmental, chemical, and hormonal factors. In particular, it was shown, first by Massaro and
colleagues67 and then by others, that alveolarization of the rat lung is seriously impaired by minute
repeated postnatal doses of dexamethasone. Tschanz and colleagues103 demonstrated that glucocorticoids
induced a precocious maturation of the lung microvasculature and thus prevented adequate septation of the
peripheral airspaces, resulting in a lower number of alveoli.
FIGURE 6.27 The pulmonary diffusing capacity (full dots) and maximal O2 consumption (open circles) scale with body mass
at a different slope on a double-logarithmic plot. (From Weibel ER. The Pathway for Oxygen: Structure and Function in the
Mammalian Respiratory System. Cambridge, MA: Harvard University Press, 1984:1–425. Copyright © 1984 by the President
and Fellows of Harvard College. With permission.)
MORPHOMETRY OF CONDUCTING AND TRANSITORY AIRWAYS AND

BLOOD VESSELS
Figure 6.28 shows a plastic cast of a human lung. In the right lung, only the airways have been modeled,
whereas in the left lung, pulmonary arteries and veins have been demonstrated also. It is apparent that the
airways branch toward the periphery by systematically dividing in two—that is, by dichotomy. This
dichotomy, however, is not regular with the two branches arising from a parent branch differing
considerably in both length and diameter. This is called irregular dichotomy. Figure 6.29 shows a similar
cast of an acinus from a human lung in which the casting material, silicon rubber, has filled the airways to
the most peripheral alveoli. On such preparations, Haefeli-Bleuer and Weibel37 showed that the most
peripheral airways, the respiratory bronchioles, and the alveolar ducts also branch by irregular
dichotomy.
The pattern of dichotomous branching provides a scheme with respect to which the systematic
progression of the increase in the number of branches and of the reduction in dimensions can be
described. If we first disregard the irregularities, we can estimate the average number of generations
necessary to provide a sufficient number of terminal airway channels to carry alveoli for gas exchange—
namely, alveolar ducts and sacs. This average number of generations was estimated at 23.120 Figure 6.6
shows that the first 14 generations are purely conducting airways, leading from the trachea to the terminal
bronchioles. From generation 15 on, alveoli are progressively incorporated into the airway wall until, in
the 19th generation, the entire wall is occupied by them.37 It must be stressed that these are average values
and that, because of the irregularity, airways terminate in alveolar sacs anywhere from about generations
15 to 30.
FIGURE 6.28 Cast of human lung showing airways (yellow) in right lung and pulmonary arteries (red) and veins (blue)
together with airways in left lung. Note irregular dichotomy of all branches.
FIGURE 6.29 Scanning electron micrograph of a silicon rubber cast of a human pulmonary acinus. Parts of the alveolar ducts
have been trimmed off to show the transitional bronchiole (arrow) and the first few orders of the respiratory bronchioles. Note
that alveolar ducts and sacs are densely covered by alveoli (scale marker = 1 mm). (From Haefeli-Bleuer B, Weibel ER.
Morphometry of the human pulmonary acinus. Anat Rec 1988;220:401. Copyright © 1988 by John Wiley Sons, Inc. Reprinted by
permission of John Wiley & Sons, Inc.)
This irregularity becomes apparent if length and diameter of the bronchial branches are measured on
casts. Nevertheless, average dimensions can be calculated from these size distributions. If the average
diameters (d) are plotted semilogarithmically against generations (z) (Fig. 6.30), we find them to follow
an exponential function, namely,
d(z) = do 2-z/3
Therefore, with each generation, the average airway diameter is reduced by a factor of cube root of
one-half, which, as pointed out by D’Arcy Thompson,101 is known in hydrodynamics to be a function of
optimal size relationship between parent and daughter branches. A refined analysis of this data set has,
however, shown that the diameter reduction factor is slightly larger than the physical optimum, thus
providing the airways with a certain safety factor for the regulation of airway caliber and avoiding
asthma, as shown by Mauroy and colleagues.69 But Figure 6.30 also reveals that the diameters of
peripheral or acinar airways that are provided with alveoli do not fit on this function. They are
considerably larger than one would expect from their position in the bronchial tree. This difference can be
explained by their different roles in conveying oxygen from ambient air to alveoli. In conducting airways,
air is transported en masse—that is, a solution of O2 in nitrogen is flowing through the tubes, and
hydrodynamic principles prevail. Toward the periphery, however, O2 molecules have to advance toward
the alveolar surface by diffusion in the gas phase, and this, as emphasized by Gomez,35 requires a greater
cross-sectional area of the peripheral airways.
FIGURE 6.30 Progressive reduction by cube root of 1/2 of the average diameter of conducting airways in regularized
dichotomy model contrasts with the slow decrease of diameter of acinar airways with progressive generations of branching.
Compare text. (From Haefeli-Bleuer B, Weibel ER. Morphometry of the human pulmonary acinus. Anat Rec 1988;220:401.
Copyright © 1988 by John Wiley Sons, Inc. Reprinted by permission of John Wiley & Sons, Inc.)
FIGURE 6.31 Arrangement of alveoli and capillary perfusion units along the acinar airways shown (A) in a scanning electron
micrograph of the first few generations of alveolar ducts in a rabbit lung, and (B) in a model diagram that depicts the serial
ventilation and parallel perfusion of the gas exchange units. (Part B from Sapoval B, Filoche M, Weibel ER. Smaller is better, but
not too small: a physical scale for the design of the mammalian pulmonary acinus. Proc Natl Acad Sci USA 2002;99:10411–
10416. Copyright © 2002 National Academy of Sciences, U.S.A.)
It is now important to note that the alveoli are arranged along the terminal generations of the airway
tree forming the pulmonary acinus (Fig. 6.31). Note that this arrangement differs from the common
representation of the alveolar–capillary unit as a terminal “bubble.” This has functional consequences,
because ventilation of alveoli occurs in two steps: (1) upon inspiration, oxygen-rich air flows through the
airways into the acinus carrying along O2, and (2) in the peripheral airways, flow velocity slows down
because the airway cross-section increases, and O2 now moves toward the periphery by diffusion in the
air phase, driven by the PO2 gradient that becomes established as O2 is absorbed at the alveolar surface
(Fig. 6.31B). Thus, in the peripheral airways, diffusion along the airways is combined with diffusive
permeation of O2 into the alveoli and across the tissue barrier to the blood, the actual process of gas
exchange. Whereas all capillary network units are individually perfused with venous blood, the alveoli
are not independent in terms of their O2 supply, which tends to be higher in the central parts of the acinus
than in the most peripheral units. The design of the acinus therefore has significant effects on the gas-
exchange conditions, as has been elaborated by Sapoval and colleagues,90 Weibel and colleagues,126 and
Swan and Tawhai.97
From this detailed information, we can construct a first model of the lung that may be useful for some
general considerations on the structure–function relationship in the airway system. The model assumes
regular dichotomy over 23 generations. Its most pertinent dimensional properties are given in Table 6.4. It
may be noted that the anatomic dead space of 150 mL, as estimated by physiologic methods, is reached at
about generation 14, which corresponds to terminal bronchioles.
Irregular dichotomous models also can be constructed. Figure 6.32 reveals the numbers of generations
necessary to arrive at airways 2 mm in diameter as well as the distribution of distances from these
branches to the trachea; these branches were located between generations 4 and 13 and were 18 to 31 cm
from the root of the trachea. Each of these approximately 400 branches 2 mm in diameter leads through an
average of 14 subsequent branchings until alveolar sacs are reached. The units of lung tissue that they
supply have a volume of some 12 mL and contain about 740,000 alveoli each. This consideration of
irregularity can be carried further, but one should refer to the original publications of Weibel109 and
Haefeli-Bleuer and Weibel37 for additional information.
Different models of the airway tree have been proposed. Horsfield41 considers the airway tree as a
system of confluent tubes originating in parenchymal airways and ending in the trachea. This model
minimizes the effects of branching irregularities but otherwise leads to the same conclusions on the
physiologic effects of airway design.
TABLE 6.4 Dimensions of Human Airway Model (Average Adult Lung With Volume of
4,800 mL at About Three-Fourths Maximal Inflation)
Generation No. per Diameter Length Total Cross Total Wall Total Volume Accumulated
z Generation d(z) cm l(z) cm Section A(z) cm2 Surface S(z) V(z) cm3 Volume
n(z) cm2
cm3
0 1 1.8 12.0 2.54 68 30.50 30.5
1 2 1.22 4.76 2.33 36 11.25 41.8
2 4 0.83 1.90 2.13 20 3.97 45.8
3 8 0.56 0.76 2.00 11 1.52 47.2
4 16 0.45 1.27 2.48 29 3.46 50.7
5 32 0.35 1.07 3.11 38 3.30 54.0
6 64 0.28 0.90 3.96 51 3.53 57.5
7 128 0.23 0.76 5.10 70 3.85 61.4
8 256 0.186 0.64 6.95 96 4.45 65.8
9 512 0.154 0.54 9.56 134 5.17 71.0
10 1,024 0.130 0.46 13.4 192 6.21 77.2
11 2,048 0.109 0.39 19.6 273 7.56 84.8
12 4,096 0.095 0.33 28.8 403 9.82 94.6
13 8,192 0.082 0.27 44.5 570 12.45 106.0
14 16,384 0.074 0.23 69.4 876 16.40 123.4
15 32,768 0.066 0.20 113.0 359 21.70 145.1
16 65,536 0.060 0.165 180.0 038 29.70 174.8
17 131,072 0.054 0.141 300.0 — 41.80 216.6
18 262,144 0.050 0.117 534.0 — 61.10 277.7
19 524,288 0.047 0.099 944.0 — 93.20 370.9
20 1,048,576 0.045 0.083 1,600.0 — 139.50 510.4
21 2,097,152 0.043 0.070 3,220.0 — 224.30 734.7
22 4,194,304 0.041 0.059 5,880.0 — 350.00 1,084.7
23a 8,388,608 0.041 0.050 11,800.0 — 591.00 1,675.0
a Adjusted for complete generation.
Another way of looking at airway design starts with the observation that the branching pattern of
airways is similar at all levels from the mainstem bronchi out to the peripheral bronchioles. This is an
example of what is called scale-invariant self-similarity, and it results from lung development that
progresses systematically by branching of the terminal tube combined with proportional growth of the
airways, as demonstrated by Kitaoka and colleagues.54 Self-similarity is the basic feature underlying a
geometry of nature called fractal geometry, as introduced by Mandelbrot.63,64 Then the following question
obviously comes up: are the airways designed like a fractal tree?
The test for the fractal nature of the airway tree is to see whether the dimensions of the branches,
diameter and length, follow a power-law function of the generation. This is indeed observed if the
diameter data shown in Figure 6.30 are replotted on a double logarithmic scale.113 From this type of
analysis, performed on several species including humans, West and colleagues128 concluded that the
airways have the basic properties of a fractal tree. This has interesting consequences in our interpretation
of the relation between form and function in the lung.113,114 The most interesting virtue of a fractal tree is
that it fills, with its tips, the space homogeneously and densely, as shown by Kitaoka and colleagues.54
Furthermore, in an ideal fractal tree,64 the distance from each end tip to the origin is equal for all tips,
irrespective of whether they are in the center of the lung or at its outermost corner. If the lung can be
conceived of as a fractal tree, we predict that the pathway length for ventilation from the trachea to all the
end tips of the airway tree should be about equal by basic design. Figure 6.32 shows that the distribution
of these distances is quite narrow.
The blood vessels undergo, in principle, the same sequence of branching as the airways, with some
differences in detail. Pulmonary arteries are topographically closely associated with the airways (Fig.
6.28); down to the respiratory bronchioles, their branching would therefore seem to parallel that of the
airways, but this is only partially true. It is well known that relatively large pulmonary arteries may send
smaller branches to the capillary network of adjacent groups of alveoli (Fig. 6.33). These accessory
branches are called supernumerary arteries and cause, on the one hand, a more rapid progression of
arterial branching and, on the other, greater irregularity in the arterial dimensions per generation.
The larger branches of the pulmonary artery have dimensions closely approximating those of the
accompanying bronchi (Fig. 6.33). In a first approximation, we may therefore use the measurements
obtained of the bronchial tree to describe the major branches of the pulmonary arterial tree to find that
they reduce their dimension with each generation according to the “cube-root-of-one-half” law (Fig.
6.30). Next, we may determine the total number of arterioles—that is, of the terminal arterial branches
that lead into the capillary network—and calculate from that the average generation number of
dichotomous branching needed to reach this number; Weibel and Gomez120 found this to be on the order of
28 generations—hence about five generations more than the airways. The diameter of these precapillaries
is between 20 and 30 μm; if this range is plotted in Figure 6.30, it falls on the function for dimensional
reduction fitted to the major branches, which suggests that the pulmonary arterial tree reduces the
dimension of its branches progressively, following a hydrodynamic law for optimal reduction of
diameters in a dichotomous branching system all the way out to the terminal branches.
FIGURE 6.32 Distribution of airways of 2-mm-diameter with respect to generation Z and distance from larynx. (Modified from
Weibel ER. Morphometry of the Human Lung. Geometry and Dimensions of Airways of Conductive and Transitory Zones.
Heidelberg: Springer 1963;110–135. Copyright © Springer-Verlag Berlin Heidelberg 1963. With permission of Springer Nature.)
FIGURE 6.33 Cast of human lung showing airways in yellow and pulmonary arteries in red. Note parallel course of arteries and
airways as well as their similar dimensions. Arrows point to supernumerary small arteries that branch off the main tract of the
artery to perfuse adjacent gas-exchange regions.
Because of the highly irregular branching pattern, the dichotomous tree model is, however, not a
realistic analytical approach for pulmonary arteries or for the veins. A better strategy has been used by
Huang and colleagues45 who used a so-called Strahler ordering system that groups vessels in “orders”
comprising a narrow size range, beginning with the smallest vessels (arterioles of about 20 μm in
diameter) in order 1. Figure 6.34 shows that in this ordering system the diameters increase in a regular
fashion up to order 15, which comprises the main left pulmonary artery as the largest size class. The
pulmonary veins show the same regression pattern. From this analysis one finds that, from one order to the
next, the diameters increase regularly by a factor of 1.5, called the diameter ratio while the number of
branches in each order increases by 3.36 times (the branching ratio) in reverse order from 1 in order 15
to about 260 · 106 in order 1. Note that in the dichotomous tree model (Fig. 6.30), there are about the
same number of end branches in generation 28, but the diameter ratio was 1.25 because of dichotomy. The
two models thus yield similar results, but the data set of Huang and colleagues45 is much more thorough,
as is their analysis. Both models agree, however, with a basic fractal nature of the branching vascular
trees, and they allow the conclusion that the vascular tree is designed for optimal blood flow conditions.
FIGURE 6.34 Relation between order, number, and diameter of pulmonary arteries and veins (mean and standard deviation) of
human left lung. (From Huang W, Yen RT, McLaurine M, et al. G. Morphometry of the human pulmonary vasculature. J Appl
Physiol 1996;81:2123–2133. Copyright © 1996 The American Physiological Society (APS). All rights reserved.)
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Medicine. Basel: Birkhäuser Verlag, 1994:68.
Weibel ER. Symmorphosis: On Form and Function in Shaping Life. Cambridge MA: Harvard University Press, 2000.
7
Cellular and Molecular Biology of the Lung
Steven J. Mentzer
The primary function of the lung is the gas exchange necessary to maintain aerobic metabolism. To sustain
an active human adult, oxygen must be adsorbed and carbon dioxide removed. This process requires a
mechanism for the ventilation of large volumes of respiratory gases. The upper airways function to
conduct gas into and out of the lung. When the respiratory gases reach the alveoli, a large alveolar surface
area facilitates the efficient exchange of oxygen and carbon dioxide.
The ventilation of respiratory gases results in the exposure of the lung to a variety of airborne
pathogens. A complex defense system uses mechanical and immunologic mechanisms to protect the host
from biological pathogens. The importance of mechanical mechanisms of mucociliary clearance is
illustrated by the heritable disease cystic fibrosis. The abnormal mucus in cystic fibrosis leads to lung
hyperinflation and recurrent infections. In addition to biological threats, the ventilation of gases means
that the lung is also exposed to a variety of environmental toxins. Cigarette smoke is a toxin that has
effects on both gas exchange (emphysema) and the cells that line the airways (bronchial carcinoma).
Similar environmental exposures are responsible for other acquired diseases of the lung.
LARGE CONDUCTING AIRWAYS

A variety of cells and their products ensure optimal gas exchange and limit the impact of airborne
pathogens on lung function. The tracheobronchial tree is characterized by airway epithelium specialized
for conductance and mucociliary clearance. A mixed population of epithelial cells lines the trachea and
bronchi (Table 7.1). These epithelial cells include basal cells, goblet cells, and ciliated columnar
epithelium. Characteristic of the proximal airways is the presence of ciliated columnar epithelial cells
and goblet cells. Basal cells and so-called intermediate cells are also present. The function of basal cells
is unclear, but these cells may function as multipotent stem cells—giving rise to both goblet cells and
ciliated epithelial cells. Specialized lymphoid tissues, often referred to as bronchus-associated lymphoid
tissues (BALT), are located along the main airways and especially at the bifurcation of airways where
particles and pathogen deposition is concentrated.
TABLE 7.1 Epithelial Cells
Cells Location Function
Basal Tracheobronchial airways Barrier, progenitor
Columnar secretory Tracheobronchial airways Mucus production
Ciliated Tracheobronchial airways Mucociliary clearance
Club Bronchioles Secretory progenitor
Alveolar type I Alveoli Air–blood barrier
Alveolar type II Alveoli Surfactant, progenitor
MUCOUS AND SEROUS GLANDS

Mucous and serous glands are present in the large airways down to the bronchiolar level. These glands
are located between the muscle and the cartilage layers of the large airways. The glands are composed of
both serous and mucous tubules. Although there may be some mixture, separate areas of the gland are
composed of either serous or mucous tubules.
The mucous cells are primarily restricted to mucous tubules. The myoepithelial cells that line part of
the mucous glands are responsible for expelling mucous contents into the airway lumen. The mucous
glands are supplied by the sympathetic nervous system. Serous cells can be found in serous tubules and
have been identified to the level of the bronchioles. The main function of serous cells is to produce
lysozyme and possibly aid in the transport of immunoglobulin A (IgA) across the glandular epithelium.
IgA is produced by plasma cells, which are found in the region of bronchial glands.
GOBLET CELLS
The goblet cell is a surface mucus-secreting cell present throughout the bronchial airways. Goblet cells
produce mucus. Respiratory airway mucus is composed of glycoproteins with unique viscoelastic
properties. These glycoproteins are collectively called mucins. Mucins are heterogeneous
macromolecules that have domains for the passive clearance of both proteins and lipids. Mucins may also
actively bind microorganisms. The mucin glycoproteins may function as ligands for lectin-like surface
receptors expressed by microorganisms. The role of the goblet cell in mucin production is particularly
apparent after airway injury. Exposure to cigarette smoke, for example, leads to goblet cell metaplasia as
well as glandular hypertrophy. Goblet cell metaplasia may also be observed in a variety of other
inhalational injuries. Mucins are overexpressed in lung diseases such as asthma, bronchitis, chronic
obstructive pulmonary disease, and cystic fibrosis.
CILIATED COLUMNAR CELLS

The percentage of ciliated columnar epithelial cells is generally higher in the large airways than in the
peripheral airways. About 50% of the cells in the trachea are ciliated epithelium, whereas only 15% of
cells in the fifth-generation airways are ciliated. In humans, the ratio of ciliated cells to goblet cells is
about 5:1. Ciliated cells propel mucus through the airways.
About 250 cilia are located on the luminal surface of each ciliated cell. The cilia are composed of an
array of longitudinal microtubules called an axoneme. The axoneme is arranged with a central doublet
surrounded by nine outer doublets. A sliding movement of the microtubules past each other generates the
movement of the cilia. The 9 + 2 arrangement of microtubules in human cilia is similar to the structure of
axonemes in other plants and animals. The clinical importance of cilia is illustrated by the syndrome
primary ciliary dyskinesia (PCD). PCD can involve bronchiectasis, chronic rhinosinusitis, and poorly
motile spermatozoa. Kartagener syndrome, which includes the diagnosis of situs inversus in addition to
cilia dysfunction, is a subset of PCD.
The normal airway cilia function to propel both water and mucus. When the cilia propel mucus, the tip
of the cilium penetrates the mucus and claws the mucus forward. At the end of the propulsive stroke, the
cilium’s tip leaves the mucus and moves backward beneath the mucus in a recovery stroke. The average
beat frequency of cilia ranges from 12 to 15 beats per minute but is sensitive to both clinical and
pharmacologic factors. Neurohormonal control of ciliary beat frequency appears to be regulated by an
adrenergic mechanism. Ciliated epithelial cells also appear to be sensitive to environmental injury.
Cigarette smoke is associated with a loss of ciliated epithelium and replacement with squamous
metaplasia. Ischemic injury of the airway, as seen after lung transplantation, is also associated with the
loss of ciliated epithelium and an increase in squamous metaplasia.
Effective mucociliary clearance is critical for lung defense (Table 7.2). When ciliary activity is
inadequate to remove all secretions from the airway, the physical presence of the mucus initiates a neural
reflexive cough. The cough generates a high shear force that dislodges the mucus and expels it from the
airway. In healthy people, mucus transport in the airways does not require a cough. In contrast, when
excess mucus resides in the airway, the high expiratory air velocity associated with a cough can play an
important role in the clearance of secretions.
Effective mucociliary clearance also depends on the viscoelastic properties of the mucus. In general,
the viscosity and elasticity of the mucus varies inversely with the water content. When the water content
of the mucus is high, the mucus is effectively cleared without a cough. When the water content of the
mucus is low, the mucus is thick and tenacious. Mucus with high viscosity and elasticity can be effectively
cleared by a cough. The clinical problem of high viscosity and elasticity occurs in the patient with a poor
cough or impaired airflow. For example, the patient with a paretic vocal cord or chronic obstructive lung
disease may not be able to generate sufficient airflow to expel mucus with high viscoelasticity. The
inability to clear the airway mucus may result in decreasing airflow and subsequent mucous impaction.
TABLE 7.2 Factors Influencing Mucociliary Clearance

Factor Effect on Mucus Effect on Cilia
Smoke Increase quantity Decrease
Lidocaine No effect No effect
β-Adrenergic agonists No effect Increase
Expectorants Mucolytic effect No effect
Gravity No effect No effect
Hydration Decrease viscoelasticity No effect
SMALL CONDUCTING AIRWAYS

The terminal bronchiole represents the most distal purely conducting portion of the tracheobronchial tree.
Although there is some anatomic variation, bronchioles are generally distinguished from bronchi by the
absence of cartilage in their walls. Terminal bronchioles, like the proximal airways, have an epithelial
lining that is specialized for conductance and mucociliary clearance.
The transitional zone between gas exchange areas and the conducting airways is characterized by a
change in the epithelium—from columnar to squamoid epithelium. This transitional zone is termed the
bronchoalveolar duct junction. Because of the role of this transitional epithelium in re-epithelializing the
airways after injury, the bronchoalveolar duct junction is suspected to be a source for multipotent stem
cells. Bronchioles are the most distal conducting airways proximal to the pulmonary acinus. The
epithelial lining of bronchioles is largely composed of club cells. These nonciliated and nonsquamous
epithelial cells constitute 70% to 90% of the cells throughout the transitional bronchiolar zone.
CLUB CELLS
Club cells, formerly termed Clara cells, appear to have multiple metabolic functions. The ultrastructure of
the club cell is characterized by extensive apical projections into the airway lumen and prominent
endoplasmic reticulum. A variety of functional studies have established club cells as a primary site of
xenobiotic metabolism. The club cell may also function as a secretory cell for the terminal airways. Club
cell secretory granules may be a source of surfactant apoproteins in the human lung. Club cells may also
serve as a source of arachidonic acid metabolites and antileukoproteases.
The turnover of epithelial cell populations in the bronchiolar region of the lung is very low. With
injury, however, there is a dramatic increase in epithelial proliferative activity. Club cells appear to
function as a progenitor of themselves as well as ciliated cells in the bronchioles. The bronchiolar
ciliated cell appears to be a principal target of oxidant gases. As bronchiolar ciliated cells are injured,
there is proliferation of bronchiolar club cells. The hyperplasia of club cells may effectively increase the
number of respiratory bronchioles by several airway generations. The relationship of club cell
hyperplasia to bronchiolitis and obliterative small airway processes is unknown.
ALVEOLAR DUCTS
The terminal bronchioles give rise to respiratory bronchioles. The respiratory bronchioles are not only
conducting airways but also give rise to alveolar ducts. Alveolar ducts are terminal air passages that are
partitioned by septa that form the walls of alveoli. In lung development, the outer walls of the alveolar
ducts form the “primary septa” of the lung. Partitions arising within the primary septa—so-called
“secondary septa”—form the walls of peripheral alveoli. Alveoli are the true gas-exchange surfaces of
the lung. The alveoli are composed of specialized epithelial and endothelial cells separated by an
interstitial matrix. Associated with these cells are alveolar macrophages. These are pivotal regulatory
cells in the host defense of the distal airway.
ALVEOLAR TYPE I CELLS

The alveolar type I cells are the dominant component of a continuous layer of alveolar epithelium. These
cells form a thin membrane over 90% of the alveolar surface. The alveolar type I cell is broad and flat,
with highly branched cytoplasmic processes. Ultrastructural studies have shown that alveolar type I cells
have small nuclei and very few mitochondria. This simplified cellular machinery is believed to be
associated with terminal differentiation. Because of their inability to divide, alveolar type I cells are
dependent on alveolar type II cells for their replacement.
Alveolar type I cells provide an important barrier to the leakage of water and solutes out of the blood
and into the airspaces. This function is the result of tight junctions between alveolar cells. The alveolar
tight junctions form a continuous seal between the luminal and abluminal compartments. In addition to
serving a barrier function, tight junctions may regulate the polarity of the cell membrane.
Because the alveolar type I cell is incapable of mitosis and repair, it is very sensitive to injury. In most
models of acute lung injury, alveolar type I cells are the first cells to be damaged. Damaged alveolar type
I cells detach from the epithelium, leaving behind a denuded basement membrane. The basement
membrane alone provides a poor mechanical barrier. The consequence of a loss of alveolar type I cells is
edema and hemorrhage into the alveolar spaces. Subsequent impairment in gas exchange persists until the
proliferation of the alveolar type II cells can replace the lost alveolar type I cell population.
ALVEOLAR TYPE II CELLS

Alveolar type II cells constitute about 15% of the cells in the distal lung. The cells have a distinctive
appearance by light microscopy. In contrast to the squamous alveolar type I cells, alveolar type II cells
are cuboidal in shape. The intracellular stores of surface-active material give the alveolar type II cells a
distinctive granular appearance. This distinctive appearance has led to the description of alveolar type II
cells as granular pneumocytes.
The primary function of alveolar type II cells is the synthesis and secretion of surface-active material.
Alveolar type II cells contain unique organelles called lamellar bodies, which contain layers of surfactant
phospholipids surrounded by a limiting membrane. Lamellar bodies also contain lysosomal enzymes and
surfactant proteins. The lipid contained in the lamellar bodies is secreted at the cellular apex. The
lamellar body fuses with the apical cell membrane, and the surfactant is released into alveolar space.
After the release of surfactant lipids, the spheroid lamellar bodies appear to reorganize into a structure
called tubular myelin, which may function to aid in adsorption and facilitate the distribution of surfactant
along the alveolar surface.
Alveolar type II cells may also play an important role in the maintenance of the alveolar epithelium by
their ability to differentiate into alveolar type I cells. The repair of injured alveolar epithelium occurs by
the proliferation of alveolar type II cells. The proliferating type II cells appear to be capable of
differentiating into either new alveolar type II cells or squamous alveolar type I cells. The differentiation
of the proliferating alveolar type II cells appears to be regulated by the extracellular matrix. The
connective tissue that supports the alveolar epithelium likely provides the signals that control alveolar
type II cell differentiation.
Alveolar type II cells also appear to be important in disease. Alveolar type II cells are
morphologically hyperplastic after lung injury. The appearance of alveolar type II cells by light
microscopy has led to the term reactive pneumocytes. Reactive pneumocytes also expressed more class I
and II major histocompatibility complex (MHC) images. The expression of increased levels of MHC
suggests that alveolar type II cells may have an immunologic function or play a role in local autoimmune
processes.
SURFACTANT
Surfactant plays an important role in modulating the surface forces in the alveolus. It forms a film at the
surface of the alveolar lining fluid. The effect of surfactant on surface tension is particularly important at
low lung volumes. In early inspiration, surfactant promotes lung expansion by reducing alveolar surface
tension. At end expiration, the reduction in surface tension at low transpulmonary pressures prevents
atelectasis and lung collapse.
Surfactant is composed of several heterogeneous phospholipid-rich lipoproteins. In the alveolus,
surfactant includes the surface phospholipid monolayer, tubular myelin, as well as an apoprotein
component. The dominant component of surfactant is phospholipids (Table 7.3). Phospholipids are
amphipathic molecules with a polar head attached to a glyceryl backbone. Acyl chains of variable length
are attached to this backbone. In an aqueous environment, such as the alveolus, the phospholipids
generally exist as a closed bilayer. Although the behavior of phospholipids can vary with composition,
the general characteristic of phospholipid mixtures is that they spontaneously form a surface film at an
air–fluid interface. The formation of this surface film significantly lowers surface tension. When the
surface area decreases, as in expiration, the phospholipid molecules are packed more tightly, further
lowering surface tension.
The protein composition of surfactant appears to play an important role in surfactant function. The most
abundant surfactant protein is SP-A. SP-A is a large collagen-like glycoprotein that makes up about 4% of
the total mass of isolated surfactant. Surfactant is produced in the alveolar type II cells and perhaps is
also synthesized in club cells. The chemical interaction between SP-A and surfactant lipids is complex.
SP-A may play a role in regulating the secretion and turnover of surfactant. Two additional surfactant
apoproteins, SP-B and SP-C, are remarkably hydrophobic. Because of their hydrophobicity, these two
apoproteins are often referred to as surfactant proteolipids. Both of these proteins are thought to play a
role in the formation of the surfactant film.
The functional role of surfactant system is illustrated in several pathologic conditions. The acute
respiratory distress syndrome linked to premature birth is associated with a deficiency of the surfactant
system. When these infants are treated with exogenous surfactant, there can be a dramatic improvement in
the mechanical properties of their lungs. The reduction in surface tension associated with the exogenous
surfactant therapy results in pulmonary inflation and an improvement in alveolar ventilation.
TABLE 7.3 Components of Surfactant

Component Percentage Function
Lipids 95
Phospholipids 78 Modify surface tension
Neutral lipids 10 Modify surface tension
Proteins 5–10
Serum proteins 0–5 Variety of functions
Apoproteins 5 Regulate turnover
ENDOTHELIAL CELLS
Endothelial cells in the lung form a continuous and nonfenestrated vascular lining extending from the
pulmonary arteries, through an intervening capillary network, to the pulmonary veins. The blood vessels
in the lung are unique vessels in the body because they are low-resistance vessels that carry deoxygenated
blood on the arterial side and oxygenated blood on the venous side of the circulation. Endothelial cells
compose 40% of all lung cells. The endothelial cells of the lung form a continuous sheet with an area of
130 m2 in an average adult (a tennis court is 195 m2). In the alveolar capillaries, endothelial cells have
specialized organelle-free cytoplasm, only 35 to 55 nm thick, to facilitate gas exchange.
Endothelial cells generally orient in the long axis of the vessel, suggesting a morphologic response to
existing shear forces. Like epithelial cells, endothelial cells have both luminal and abluminal domains to
the cell membrane. These cell membrane domains are separated by intercellular tight junctions. Luminal
domains have distinct functional characteristics. Proteins that regulate a variety of metabolic functions are
expressed on the luminal surface (Table 7.4) and frequently associated as “rafts” in the lipid membranes.
In addition, luminal domains appear to direct the secretion of cellular products, including von Willebrand
factor. The abluminal cell membranes interact with extracellular matrix and direct transport of plasma
molecules toward the interstitium.
The luminal membrane of endothelial cells is covered by a “fuzzy coat,” or glycocalyx, composed of
glycosaminoglycans, oligosaccharide moieties of glycoproteins, glycolipids, and sialoconjugates. The
cell membrane and its glycocalyx regulate a variety of cell functions. The luminal cell membrane
mediates all cellular interactions and regulates recruitment of leukocytes into the lung. Enzymes such as
angiotensin-converting enzyme, lipoprotein lipase, and receptors for insulin and low-density lipoproteins
are expressed at the blood interface. Plasma proteins such as immunoglobulin, fibrinogen, fibrin, alpha2
macroglobulin, and albumin can be transiently associated with the cell surface.
ALVEOLAR MACROPHAGES
The most common immune cell in the lung is the alveolar macrophage. The alveolar macrophage is 5 to
10 times more common in the lung than are T lymphocytes. Alveolar macrophages appear to have multiple
functions in the lung. A primary function is their ability to scavenge particles and remove debris from the
lung parenchyma. The ability of alveolar macrophages to phagocytize microorganisms provides an
important defense against airborne pathogens. The alveolar macrophage also appears to play an important
role in the repair and maintenance of lung parenchymal tissue.
Macrophages are far more common in the lower respiratory tract than in the proximal airways.
Resident alveolar macrophages were originally thought to have a limited potential to divide and
proliferate; however, recent evidence suggests that alveolar macrophages can proliferate in response to
growth and pathologic signals. The significant increase in alveolar macrophage concentration in diseases
such as granulomatous lung disease, suggests that some conditions involve both active recruitment of
blood monocytes and the local proliferation of alveolar macrophages.
TABLE 7.4 Endothelial Cell Surface Proteins and Enzymes

Angiotensin-converting enzyme
Nucleotidases
Lipoprotein lipase
Thrombin
Fibrinolytic factors
Antifibrinolytic factors
Although alveolar macrophages can have several different phenotypes, subpopulations of alveolar
macrophages have not been clearly defined. The reason for this discrepancy is that alveolar macrophages
can exist at a variety of different activation states. The activation states of alveolar macrophages appear
to regulate the capacity to phagocytize, kill target cells, migrate, and release a broad range of secretory
products. The activation signals for alveolar macrophages can include such diverse signals as the
phagocytosis of inert particles, receptor binding of immunoglobulin, or exposure to chemokines and
cytokines.
Alveolar macrophages play an important role in maintaining the sterility of the airway. Airborne
bacterial pathogens can be phagocytized as inert particles or by specific surface receptors on the alveolar
macrophage membrane. Surface receptors may include membrane-bound immunoglobulin or receptors for
terminal mannose sugars. Once the pathogen is phagocytized, the phagosome fuses with lysosome, and the
organism is killed by an oxidative burst. Alveolar macrophages also use nonoxidative mechanisms,
including proteases, lysozymes and a variety of other bactericidal proteins. An understanding of
macrophage-dependent mechanisms of bactericidal activity holds the promise of novel antibacterial
therapies.
The effectiveness of alveolar macrophages to eliminate microorganisms is varied with some
microorganisms susceptible to alveolar macrophages, whereas others are resistant. Some common
bacterial pathogens, such as Staphylococcus aureus, are readily eliminated by alveolar macrophages. In
contrast, Pseudomonas aeruginosa and Klebsiella pneumoniae are relatively resistant to alveolar
macrophages and require the presence of neutrophils for elimination. The antimicrobial selectivity of
alveolar macrophages can be of clinical importance. For example, patients who have neutropenia from
chemotherapy have an enhanced susceptibility to macrophage-resistant bacteria. Other resistant infectious
agents include organisms such as Mycobacterium tuberculosis and Toxoplasma gondii. These organisms
can continue to grow within alveolar macrophages. Activation of alveolar macrophages, with cytokines
such as interferon-gamma, can be effective in suppressing the growth of these pathogens.
Alveolar macrophages also play an important role in eliminating damaged lung tissue and airway
debris. The role of the alveolar macrophage in maintaining the normal structure of the lung is illustrated
by several clinical examples. Alveolar proteinosis is a disease characterized by hypoxemia from large
amounts of proteinaceous material found within the alveolar air spaces. The alveolar macrophages in
these patients are filled with surfactant-like material—a situation likely reflecting impairment in
surfactant turnover. Another example is the anthracosis observed in long-term smokers. The anthracotic
material found in bronchoalveolar lavage specimens, as well as in the histologic examination of the
peripheral lung, is commonly found within alveolar macrophages. The macrophage appears to be the
primary mode of elimination of airway debris.
Alveolar macrophages may also play an important role in directly modulating lung function. Alveolar
macrophages have been found to secrete a variety of products that have a direct effect on pulmonary
blood flow and vascular permeability. An example of this activity is the ability of alveolar macrophages
to secrete nitric oxide. They may also secrete a variety of substances that effect airway resistance and
hyperreactivity. Examples of these mediators include thromboxane A2, platelet-derived growth factor, and
platelet activating factor.
LUNG LYMPHATICS
Individual lymphocytes can be located in the alveolar walls and on the epithelial surfaces of the airways.
These airway-associated lymphocytes are recovered in the bronchoalveolar lavage specimens along with
alveolar macrophages. In the normal bronchoalveolar lavage specimen, the mononuclear cells include
lymphocytes, alveolar macrophages, and epithelial cells. The normal lavage lymphocyte composition is
about 60% T cells, 10% B cells, and 30% “null” cells. Clinical conditions in which large numbers of T
lymphocytes are obtained from bronchoalveolar lavage specimens include sarcoidosis and acute lung
transplant rejection. The study of these T lymphocytes holds the promise of a minimally invasive
diagnostic test for a variety of inflammatory lung diseases.
More organized lymphoid tissue, composed of lymphoid aggregates and nodules, can be found along
the bronchial tree. These so-called BALT are located beneath the airway epithelium and are most
common at the bifurcation of airways. The lymphocytes found in BALTs are the B lymphocytes associated
with humoral immunity. Although BALT tissues are common in experimental animals, the normal human
lung has only rudimentary BALT tissues.
The anatomic distribution of lymphoid cells in the lung can be illustrated by lymphomatous
involvement of the lung. Lymphoma tissue in the lung generally predominates along the airways and
subpleural surfaces of the lung. Recent work in lymphocyte trafficking suggests that lymphocytes “home”
to these tissues. The predominance of lymphocytes along the airways appears to be a pathologic reflection
of the normal trafficking of lymphocytes to mucosa-associated lymphoid tissue (MALT).
Lymph nodes play a more important role in the response to inhaled antigens in humans than in
experimental animals. Most of the lymph node tissue is located in the hilum of the lung and in the
mediastinum. Inhaled antigens are delivered to these lymph nodes through peribronchial afferent
lymphatics. The course of these lymphatic channels is illustrated by the embolic spread of lung
malignancies. Tumor emboli sequentially appear in hilar and mediastinal lymph nodes. Interruption of
these hilar lymphatic channels can be of clinical importance, for example, in lung transplantation and
sleeve resections of the lung. Submucosal lymphatics do not recanalize for >3 weeks after interruption
and can be associated with increased lung water and impaired immunity.
The lymph node provides the scaffolding that facilitates the interaction of the B and T lymphocytes as
well as the antigen-presenting cells of the immune system. T lymphocytes are cells that constantly
recirculate throughout the body. Recirculation provides a mechanism for distributing immune cells
throughout the body as well as ensuring antigen-reactive diversity. B lymphocytes can be found leaving
the antigen-stimulated lymph node but generally are not found in the unstimulated efferent lymph. When the
lymph node is stimulated by antigen, the cell output in the lymph transiently decreases and the size of the
lymph node increases dramatically. This type of antigen-induced lymph node enlargement is commonly
observed in a variety of infectious conditions. The increase in lymph node size is due to the rapid
recruitment of lymphocytes from the blood. The lymphocytes recirculating in the blood bind to specialized
lymph node endothelium called high endothelial venules (HEVs). These are plump endothelial cells found
only in specialized lymphatic tissue such as the lymph node. The recruited lymphocytes migrate to
specific compartments within the lymph node. T cells are found in the paracortical regions, whereas B
cells and associated germinal centers are found in the cortex of the lymph node. The enlarged lymph node
provides the ideal cellular and chemical microenvironment for the generation of antigen-specific immune
responses. Ultimately, these activated lymphocytes are released into the efferent lymph and eventually into
the bloodstream.
GENETIC REGULATION IN THE LUNG

Genetic control of lung cells has important implications for the normal growth and development of the
lung. Some diseases of the lung, such as cystic fibrosis and alpha1-antitrypsin deficiency, have a clear
hereditary association. In these diseases, genetic changes or mutations occur in the germline. Because the
genetic changes are inherited, the genetic abnormalities exist in every cell of the body.
More commonly, the genetic associations in lung diseases are sporadic. For example, most of the
genetic changes leading to cancer in lung cells occur in cells that would otherwise be considered
genetically normal. Environmental toxic or infectious exposures can lead to acquired or somatic
mutations. These genetic changes exist only in the affected cells.
MULTIPLE GENETIC “HITS” OF CARCINOGENESIS

The potential interaction of inherited and acquired genetic mutations was initially described by studying
the epidemiology of retinoblastoma. Patients with retinoblastoma were found to have either a positive
family history of the disease (inherited retinoblastoma) or no apparent family history (sporadic
retinoblastoma). Statistical analysis by Knudson1 suggested that more than one genetic mutation (or “hit”)
is required for either inherited or sporadic retinoblastoma. People born with a germline retinoblastoma
(Rb) gene mutation already have one hit. Any retinal cell that acquires a second hit in the Rb gene can
develop into a retinoblastoma tumor. People with this germline mutation are therefore more likely to
develop cancer than those without this mutation. In the setting of this genetic predisposition,
retinoblastoma tends to occur earlier in life and is commonly associated with other malignancies.
In contrast, retinal cells in people born without the Rb germline mutation must acquire two mutations to
develop into the retinoblastoma tumor. Consistent with these enhanced requirements for tumorigenesis
(Fig. 7.1), patients with a sporadic form of retinoblastoma manifest the disease later in life, and the
disease is less likely to be associated with other cancers. These observations suggest that the hits
necessary to transform a cell toward malignancy can be both acquired and inherited.
The basic concept of multiple mutational hits has been supported with studies of the Rb tumor
suppressor gene. Cloning of the Rb gene has shown that in Rb tumors, both alleles of the Rb gene are
inactivated—a finding consistent with the two hits necessary for tumorigenesis. The mutational hits
described in tumorigenesis generally mean a change in the normal sequence of nucleotide base pairs. This
change can be as small as the deletion of one nucleotide base pair or as large as the elimination of the
entire gene or group of genes. In non–small-cell carcinoma of the lung, absent or abnormal Rb proteins
have been observed in ≤30% of tumors. There may also be a correlation between the level of abnormal
Rb protein expression and the stage of the non–small-cell lung cancer. In one study, Xu and colleagues2
found that abnormal Rb expression was present in 20% of stage I and II patients and in 60% of stage III
and IV patients.
FIGURE 7.1 Schematic of the Rb gene and the two-hit hypothesis. A: An individual who inherits a mutation of the Rb gene
requires only one additional hit for the development of retinoblastoma. B: In contrast, an individual without a germline mutation of
the Rb gene requires mutational events affecting both genes to develop retinoblastoma.
There are several potential mechanisms for the development of genetic mutations. In the normal cells,
the DNA of the 46 chromosomes is stably replicated during each mitotic cycle. When damage occurs in
the DNA of the somatic cells, there are several DNA repair mechanisms to ensure the fidelity of DNA
replication. Disruptions in the DNA repair mechanisms are observed naturally in aging. This genetic
instability is also associated with prolonged exposure to occupational and environmental carcinogens.
Cigarette smoke, for example, may play a role in disrupting DNA repair mechanisms.
A common feature of lung cancer is an abnormal number or arrangement of chromosomes in the tumor
cells. Chromosomal aneuploidy is a gross manifestation of genetic instability. Aneuploidy is often
detected by cytogenetic analysis or flow cytometry. Large segments of genetic information can be
inverted, duplicated, deleted, or translocated onto another chromosome. These arrangements frequently
result in the disruption of genes that can be associated with malignancy. The most common chromosomal
abnormality identified in lung cancer is the loss of chromosome 3p. The loss of 3p has been observed in
more than 90% of small-cell lung cancers and in about 50% of non–small-cell lung cancers. Angeloni3
has noted that the loss of 3p may contribute to the development of lung cancers because of the many tightly
clustered tumor suppressor genes that reside on the 3p chromosome.
Another mechanism for the mutation of somatic genes is the insertion of viral DNA. DNA viruses
incorporate themselves into genomic DNA. The presence of viral DNA frequently leads to cell death. On
occasion, however, viral DNA can convert normal cells into cancer cells. Examples of viral induction
include Epstein–Barr virus–associated lymphomas and SV-40–associated malignant mesothelioma.
ONCOGENES
Oncogenes are a class of genes expressed in normal cells. The overexpression or mutation of these genes,
however, can be associated with uncontrolled growth and tumorigenesis (Table 7.5). In general,
oncogenes are phenotypically dominant; a single mutation in one of the paired alleles is sufficient to
promote carcinogenesis. An operational definition of an oncogene is a gene whose introduction into a cell
results in the transformation of the cell. That is, the cell takes on some of the phenotypic and growth
characteristics of a cancer cell.
TABLE 7.5 Common Oncogenes
Name Tumor Associations
Erbb2, neu Breast, ovary, gastric
Myc Lymphomas, carcinomas
Ret Thyroid carcinoma
K-ras Lung, colon
H-ras Bladder
N-Myc Neuroblastoma
The description of oncogenes originated in the study of cancer-associated viruses. These viruses were
associated with cellular transformation in animals such as monkeys, chickens, rodents, and cats. The
classic definition of an oncogene is a cancer-causing gene carried by an acute transforming retrovirus that
has a normal counterpart (homolog) referred to as a protooncogene. Work by Cordell and colleagues4–6
and Bishop5 showed that the oncogene in the Rous sarcoma virus was not a genuine viral gene but a
preexisting cellular gene that was copied and modified by an ancestor of the Rous sarcoma virus.2 The
copied and modified gene was used by the virus to transform animal cells. Oncogenes were identified,
and are generally named, based on the virus in which they were originally carried. For example, ras is an
oncogene from the rat sarcoma virus, and src is an oncogene from the Rous sarcoma virus. Although the
research into RNA tumor viruses has found no causal link to human cancer, research on animal
retroviruses has provided pivotal insights into the identity of cancer-causing genes.
Oncogenes have been found to encode proteins typically involved in signal transduction. Signal
transduction proteins are responsible for the transmission of signals from the cell membrane to the
replication machinery within the cell nucleus. The involvement of oncogenes in the transduction of these
signals provides clues to the understanding of normal growth and control as well as tumorigenesis. When
they are functioning normally, protooncogenes promote cell growth and division. The mutations that
transform these protooncogenes into oncogenes lead to a loss in normal cellular regulation and
uncontrolled cell growth. The growth-promoting function of oncogenes in signal transduction explains the
genetic dominance of the mutation. A mutated oncogene will have a growth-promoting effect on the cell
irrespective of the function of the other allele.
Of the approximately 23,000 genes in the human genome, only about 50 have been found to transform
cells in vitro. Even fewer genes have been found in mutant form in human cancers (Table 7.6). Only 20 of
the protooncogenes capable of cellular transformation have actually been found in human tumors, and
even fewer have been associated with thoracic malignancies. An example of a clinically relevant
oncogene is K-ras, homologous to Kirsten murine sarcoma virus oncogene. K-ras mutations are found in
up to 30% of adenocarcinomas. Rosell and colleagues7 have shown that ras mutations and increased ras
expression have been correlated with decreased survival in patients with non–small-cell lung cancer.
TABLE 7.6 Oncogenes Associated With Human Lung Cancer
Name Frequency (%)
Egfr 30–40
K-ras 30
Myc 10–40a
Erb2 25
Bcl2 25
Alk 5
a Expression of myc varies from 10% in non–small-cell lung cancers to up to 40% in some series of small-cell lung carcinomas.
Mutations of the epidermal growth factor receptor (EGFR) can lead to overexpression of the receptor.
Overexpression of EGFR has been associated with a number of epithelial malignancies including lung
cancer, anal cancers, and glioblastoma. EGF is a cell surface receptor and member of the ErbB family of
receptors; ErbB receptors include EGFR (ErbB1), HER2/c-neu (ErbB2), HER3 (ErbB3), and HER4
(ErbB4). EGFR is expressed on many cells in the lung. In 2004, the use of tyrosine kinase inhibitors
directed against EGFR were shown to be effective in the treatment of lung cancers. Although the
development of resistance to tyrosine kinase inhibitors has emerged, new inhibitors to tyrosine kinase
receptors is an area of active research.
In 2007, an unexpected gene rearrangement was discovered in approximately 5% of lung cancer
patients.8 The genetic abnormality was the fusion of the anaplastic lymphoma kinase (ALK) with the
echinoderm microtubule-associated protein-like 4 (EML4). The EML4-ALK fusions were identified in
never smokers with adenocarcinoma. The presence of ALK tyrosine activity is necessary for its
transforming activity and oncogenicity. As a result, a variety of ALK kinase inhibitors have been
introduced with reports of dramatic responses in as many as 60% of patients with the EML4-ALK
translocation.
TUMOR SUPPRESSOR GENES

A commonsense approach to cellular regulation would suggest that there are growth-suppressing as well
as growth-promoting signals within the cell. The finding that only about 20% of human tumors are
associated with oncogenes suggests that the mutation or loss of growth-suppressing genes might also be
important in tumorigenesis. The discovery of the retinoblastoma (RB) gene has provided a model for this
type of dysregulation. The normal RB gene product (Rb) serves to constrain cell growth and division.
When both alleles are mutated or lost, the normal cellular control mechanism is lost. The genes with these
features have been collectively referred to as antioncogenes or tumor suppressor genes (Table 7.7).
Tumor suppressor genes are present in all normal cells. When these genes are missing or inactivated
by mutation, the cells exhibit uncontrolled growth. This observation has led to the conclusion that tumor
suppressor genes normally function to restrain cell growth. In general, one normal allele of a tumor
suppressor gene pair is sufficient to prevent malignant transformation. The loss of all or part of the
chromosome containing the tumor suppressor gene is commonly referred to as the loss of heterozygosity
(LOH). If both copies of the gene are mutated or deleted, the function of the tumor suppressor gene is lost.
TABLE 7.7 Common Tumor Suppressor Genes
Name Tumor Association
Dcc Colon
Apc Colon, familial polyposis
Brca1, Brca2 Hereditary breast, ovarian
p53 Leukemia, multiple carcinomas
Rb Retinoblastoma
WT1 Wilms tumor
TABLE 7.8 Tumor Supressor Genes in Human Lung Cancer

Name Frequency (%)a
3p Chromosome deletion 50–90
RB 15–90
p53 50–80
p16 60
a In almost all series, the lower frequency reflects findings in non–small-cell lung cancer and the higher frequencies reflect small-cell lung
cancer.
In cancers with an inherited component, one copy of the tumor suppressor gene is mutated at birth.
With the acquired mutation of the remaining allele, cellular growth is no longer suppressed and
tumorigenesis can occur (Fig. 7.1). As heritable forms of retinoblastoma have demonstrated, people who
inherit a mutated allele have a much higher risk for developing cancer because they have only one
functioning gene in reserve. The molecular data from a variety of malignancies suggests that tumor
suppressor gene mutations contribute to the development of many cancers.
The most common tumor suppressor gene mutations have been observed in the p53 gene. Mutant
versions of p53 have been found in DNA samples from more than half of human tumors examined. The
reason that p53 is so common in human tumors is partly related to its mode of action. When the p53 gene
is mutated, the mutated gene loses its ability to suppress cell growth. It also acquires the ability to
actively disrupt the function of the remaining intact gene. The consequence of this ability is that only one
mutated gene copy is required to interfere with growth suppression, an effect described as a dominant-
negative mode of action. Levine and colleagues9 have shown that the p53 gene also appears to have
several other unique functions that promote cellular proliferation and inhibit cell death (apoptosis).
In lung cancer, p53 is associated with a point mutation. This point mutation appears to be related to
chemicals from cigarette smoking. The overall frequency of p53 mutations in non–small-cell lung cancer
is about 50%; it is 80% in small-cell lung cancer. The expression of p53 mutations has not yet been
correlated with prognosis in lung cancer (Table 7.8).
As more is learned about the function of these genes, tumor suppressor genes will probably be found to
encode proteins involved in transducing negative signals. Tumor suppressor gene products will be
involved in the receiving and processing signals from the cell membrane—that is, proteins that normally
function to inhibit the replication machinery within the cell nucleus. An example of this processing is the
growth-suppressing signal provided by transforming growth factor-beta (TGF-β). When TGF-β binds to
the cell membrane, most cells stop growing. In contrast, when cells lose the Rb gene function, they lose
the ability to respond to TGF-β. These cells grow unrestrained even when exposed to high doses of TGF-
β.
The clinical relevance of any given tumor suppressor gene most likely will depend on the condition of
the entire tumor cell genome. The multiple-step model of carcinogenesis argues that a mutation or
alteration in any given gene only serves to push a cell down the pathway to malignancy. The evolution of a
clinically relevant cancer requires the presence of multiple successive changes in distinct genes (Fig.
7.2). The collective effect of these changes is required to push the cell from abnormal to malignant.
FIGURE 7.2 Schematic of the multiple-hit hypothesis of carcinogenesis. The specific mutations that lead to human lung cancer
are unknown at this time. Based on observed abnormalities in lung cancer tumors, a schematized sequence of events is the
following: Step 1: The deletion of the 3p chromosome results in the loss of several tumor suppressor genes, leading to
dysregulated bronchial epithelial growth and possibly to adenoma. Step 2: The loss of the tumor suppressor gene p53 results in
cytologic changes consistent with carcinoma in situ. Step 3: The overexpression of the ras oncogene results in the development
of invasive bronchogenic carcinoma.
CYSTIC FIBROSIS
Cystic fibrosis is a common genetic disease, with 5% of white Americans carrying the mutant version of
the gene. About 1 in 2,500 children of European descent carries two defective copies of the gene. These
children have the disease of cystic fibrosis, which causes functional impairment of the pancreas,
intestines, and liver. Frequently, the most devastating consequence of the disease is persistent infection in
the lung and subsequent damage to the airways.
For many years, clinicians recognized that children with cystic fibrosis have excessive salt in their
sweat. This clinical observation reflects both the pathogenesis and genetic basis for cystic fibrosis. Even
the test for cystic fibrosis, the measurement of chloride content in the child’s perspiration, remains the
cornerstone of the clinical diagnosis. The observation of the excessive salt secretion of children with the
disease also provides an important clue to its genetic origin.
In 1989, a large group of collaborators announced the identification of the gene responsible for cystic
fibrosis. The product of this gene was called the cystic fibrosis transmembrane conductance regulator
(CFTR) because of its probable regulation of chloride secretion. Sequencing of the gene revealed a
mutation that was present in 70% of all cystic fibrosis patients (although more than 900 mutations are
known for the CFTR gene). This gene is frequently referred to as the F508 mutation, which involves the
deletion of three nucleotides from the gene, with the resultant loss of a single amino acid (phenylalanine)
at position 508 in the CFTR protein.
The CFTR protein appears to form a chloride-permeable channel in the outer membrane of many cells.
The movement of chloride through the pore is regulated by the protein, depending on the metabolic
condition of the cell. When the gene is mutated, the protein product is retained within the endoplasmic
reticulum of the cell and is never expressed at the cell surface. If a normal gene exists, sufficient
quantities of the CFTR reach the cell membrane to facilitate relatively normal chloride movement.
Consistent with the recessive inheritance pattern of cystic fibrosis, the clinical disease is apparent only
when both genes are abnormal.
Although the genetic defect of cystic fibrosis is clear, the pathogenesis of the clinical syndrome
remains unclear. The submucosal glands in the conducting airways appear to express a large amount of the
CFTR protein. How the absence of normal CFTR leads to the hyperinflated lungs and recurrent P.
aeruginosa infections is unknown. Further studies of the function of this protein may provide important
clues regarding normal ventilation and host defense of the lung.
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8
Surgical Anatomy of the Lungs
Nirmal K. Veeramachaneni
Over the last 100 years, surgery of the lung has been transformed from mass ligation of the structures of
the hilum and drainage of the pleural space, to a detailed, and often minimally invasive strategy to remove
an anatomic portion of the lung.
The essential anatomic unit of the lung, the bronchopulmonary segment, was established as that portion
of the lung substance that represents the total branching of a major, segmental subdivision of a lobar
bronchus. These units are named for their topographic position in the lung, and the nomenclature of the
segments will be discussed. The author is indebted to the comprehensive review of the anatomy of the
lung written by TW Shields in the previous edition of this textbook. In this version, the material will be
presented in a slightly different manner, to highlight the variations in anatomy encountered by the surgeon
in the conduct of a lobectomy or segmentectomy. The reader will be urged to refer to the relevant chapters
in this textbook for a more comprehensive description of the actual surgical procedure. It is the purpose of
this chapter to highlight the major anatomic considerations necessary for safe anatomic lung resection.
LOBES AND FISSURES

The right lung is composed of three lobes (the upper, middle, and lower) and is the larger of the two
lungs. The left is made up of only two lobes, the upper and lower. Two fissures are usually present on the
right. The oblique (major) fissure separates the lower lobe from the upper and middle lobes, and the
horizontal (minor) fissure separates the other upper and middle lobes. In life, the oblique fissure on the
right begins posteriorly at the level of the 5th rib or intercostal space, runs downward and forward
approximating the course of the 6th rib, and ends at the diaphragm in the vicinity of the 6th costochondral
junction. The horizontal fissure begins in the oblique fissure in the region of the midaxillary line at the
level of the 6th rib and runs anteriorly to the costochondral junction of the fourth rib. The oblique (major)
fissure is found on the left. This begins at a somewhat higher level posteriorly, between the 3rd and 5th
ribs and runs downward and forward to end in the region of the 6th or 7th costochondral junction. The
knowledge of the location of these fissures is especially important for surgeons performing minimally
invasive operations. The main working port, or port in which to pass a stapling device, is typically
oriented in the direction of the fissure.
Variations in the fissures do occur, and often part or all of a fissure fails to develop. This is seen
commonly as a complete fusion of the middle lobe and the anterior portion of the upper lobe in more than
50% of lungs examined. Accessory fissures also occur, and certain portions of the lung may be
demarcated into the so-called accessory lobes. On occasion, such fissures are visible as linear shadows
on the radiograph of the chest, and the accessory lobe may appear less radiolucent than the surrounding
portions of the lung. The usual accessory lobes are the posterior accessory, inferior accessory, middle
lobe of the left lung, and azygos lobe. In contrast to the first three, which are true accessory lobes made up
of specific bronchopulmonary segments, the azygos lobe is not a true accessory lobe because it is formed
of varying portions of one or two segments (apical and posterior) of the right upper lobe. The fissure is
formed by an aberrant loop of the azygos vein and its mesentery of two layers of the parietal pleura and
two of the visceral pleura. On the radiograph, this fissure may appear as an inverted comma to the right of
the mediastinum. This anomaly is seen in 0.5% to 1.0% of the anatomic dissections and routine
radiographs of the chest.
BRONCHOPULMONARY SEGMENTS
Each lobe of the right and left lung is subdivided into several individual anatomic units, the
bronchopulmonary segments. The general pattern is that of 18 segments: 10 in the right lung and 8 in the
left. Initially, there were many differences in the nomenclature for the various segments as the result of the
publications of the individual investigators working in North America and Europe. In 1989, the Nomina
Anatomica nomenclature for the lung segments was published. Sealy and colleagues1 presented an
excellent review of this topic in 1993. The numerical designations, especially those for the segments and
structures of the right and left upper lobes, are dissimilar between the Nomina Anatomica, and the
proposal adopted by the Ad Hoc International Committee on Nomenclature by Brock2 in 1950. Therefore,
one should be aware of the discrepancies in the literature relative to the numerical designations for the
various segments and the structure contained therein (bronchi, veins, and arteries). Table 8.1 provides a
comparison of the nomenclature systems widely used today. The system as proposed by Huber is perhaps
most germane to those performing bronchoscopy. The topographic positions of the segments are shown in
Figure 8.1. Knowledge of the detailed anatomic features of the bronchial distribution and the vascular
supply of each segment is essential for the surgeon. Although a general pattern exists in the anatomic
features in each segment, variation is the rule. We approach each lobe separately, and describe the
variations of the bronchial and vascular supply for each lobe. This approach may be helpful to the reader
preparing for an anatomic lung resection. The described anatomic patterns and variations of the bronchi
and pulmonary arteries and veins have been selected by TW Shields in the previous version of this
chapter primarily from the studies of Birnbaum13; Bloomer, Liebow, and Hales14; and Boyden15 and have
been updated to reflect the data presented by Nesbitt and Wind in their book Thoracic Surgical Oncology,
Exposures and Techniques.
TABLE 8.1 Nomenclature Adopted by the Ad Hoc International Committee Meeting at
the Time of the International Congress of Otorhinolaryngology in 1949
International Nomenclature Brock Jackson & Huber
Right upper-lobe bronchus
Apical3 Pectoral Anterior
Posterior4 Subapical Posterior
Anterior5 Apical Apical
Middle-lobe bronchus
Lateral6 Lateral Lateral
Medial7 Medial Medial
Right lower-lobe bronchus
Apical8 Apical Superior
Medial basal (cardiac)7 Cardiac Medial basal
Anterior basal10 Anterior basal Anterior basal
Lateral basal11 Middle basal Lateral basal
Posterior basal12 Posterior basal Posterior basal
Left upper-lobe bronchus

Upper division Apicopectoral Upper division
Apical1 Apical Apical
Apicoposterior 1 and 2 Apical–posterior
Posterior4 Subapical Posterior
Anterior5 Pectoral Anterior
Lingula Lingula Lower (lingular) division
Superior6 Upper Superior
Inferior7 Lower Inferior
Left lower-lobe bronchus
Apical8 Apical Superior
Anterior basal10 Anterior basal Anterior medial basal
Lateral basal11 Middle basal Lateral basal
Posterior basal12 Posterior basal Posterior basal
Two of the five systems, those of Brock and of Jackson and Huber, are included. The problem of the presence of a medial basal segment on
the left was not resolved and was omitted entirely. Brock’s apical instead of Jackson and Huber’s superior was adopted for the first branch of
the lower lobe.
Reprinted from Sealy WC, Connally SR, Dalton ML. Naming the bronchopulmonary segments and the development of pulmonary surgery.
Ann Thorac Surg 1993;55:184–188. Copyright © 1993 The Society of Thoracic Surgeons. With permission.
ORIENTATION OF KEY STRUCTURES

The trachea bifurcates at about the level of the seventh thoracic vertebra into the right and left mainstem
bronchi. Compared with the left bronchus, which arises at a sharper angle, the right bronchus arises in a
more direct line with the trachea, an important factor in the localization of aspirated material.
At the level of the hilum of the lung, the bronchus becomes the most posterior structure, and the
pulmonary veins are the most anterior structure. The main pulmonary artery will be between these two
structures; however, knowledge of the location of the pulmonary arteries branches feeding each lobe is of
utmost importance in the conduct of lobectomy or other anatomic lung resection.
The main pulmonary artery arises to the left of the aorta and passes superiorly and to the left (Fig. 8.2).
It occupies a position anterior to the left main bronchus and divides into the right and left main pulmonary
arteries. These two vessels lie in an oblique line that is parallel and slightly superior to the pulmonary
veins. The right main pulmonary artery is longer than the left, but its extrapericardial length up to its first
branch is less than that of the left. The branching pattern of the pulmonary arteries is more variable than
that of the bronchi, although the arteries tend to lie closely adjacent to the segmental bronchi and to follow
their branching. No one pattern for either the right or the left pulmonary artery may be described as
standard. However, a relatively typical distribution of the segmental arteries is often encountered, and
from this the multitude of variations may be readily understood.
The venous drainage pattern of the lung reveals a greater number of variations than does the arterial
pattern. The usual two major venous trunks from both lungs are the superior and inferior pulmonary veins.
The tributaries of these veins are intersegmental and form various combinations to create the major trunks.
FIGURE 8.1 Bronchi and bronchopulmonary segments. A–D: The bronchopulmonary segments are demonstrated after
injection of different color latex into each tertiary segmental bronchus as shown in (E). (From Moore KL, Agur AMR, Dalley
AF. Essential Clinical Anatomy. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014.)
RIGHT BRONCHIAL TREE

The length of the right main bronchus from the trachea to the point where the right upper-lobe bronchus
branches from its lateral wall is about 1.2 cm. The upper-lobe bronchus, about 1 cm in length, in turn
gives off three segmental bronchi—one to the apical, one to the posterior, and one to the anterior segment.
The branching may be a simple trifurcation or include varying combinations of the three major branches.
The segmental bronchi further subdivide to supply the various portions of the segments.
Proceeding distally from the takeoff of the upper-lobe bronchus, the primary bronchus is known as the
bronchus intermedius, over which the mainstem pulmonary artery crosses, thus giving rise to the term
eparterial bronchus to designate the right upper-lobe bronchus. After a distance of about 1.7 to 2.0 cm, the
middle-lobe bronchus arises from the anterior surface of the bronchus intermedius. It varies in length
between 1.2 and 2.2 cm before it bifurcates into lateral and medial branches. The superior segmental
bronchus of the lower lobe arises from the posterior wall of the bronchus intermedius, slightly distal to
the middle-lobe bronchus. The superior segment is called the posterior accessory lobe when a fissure is
present. This bronchus most often arises as a single branch and divides into three rami, usually by
bifurcation or rarely by trifurcation. Distal to the superior bronchus, the basal stem bronchus sends off
segmental bronchi to the medial (the inferior accessory lobe when a fissure is present), anterior, lateral,
and posterior basal segments. The medial basal bronchus arises anteromedially and is distributed to the
anterior and paravertebral surfaces of the lower lobe. The anterior basal branch arises on the
anterolateral aspect of the basal trunk about 2 cm distal to the superior segmental bronchus and divides
into two major rami. The lateral basal bronchus and the posterior basal bronchus most often arise as a
common stem. Each of these bronchi, in turn, divides typically into two major subdivisions (Fig. 8.3).
FIGURE 8.2 The main pulmonary artery arises to the left of the aorta and passes superiorly and to the left.
Numerous variations occur, but the basic pattern encountered is as described. Infrequently, the upper-
lobe bronchus on the right undergoes two separate bifurcations to form the three bronchopulmonary
segments. Of more interest is the rare occurrence of a tracheal bronchus that arises most commonly 2 cm
above or at the level of the tracheal carina. A tracheal bronchus is estimated to be present in 0.1% to
2.0% of human tracheobronchial trees, depending on the manner of diagnosis and the population group
studied, as noted by Barat and Konrad6 in 1987. The tracheal bronchus occurs for all practical purposes
exclusively on the right. In the division of the lower-lobe bronchus, the presence of a subsuperior or an
accessory subsuperior bronchus is a frequent finding. One to three such bronchi may be identified.
LEFT BRONCHIAL TREE

The left main bronchus is longer than the right, and its first branch arises anterolaterally as the left upper-
lobe bronchus about 4 to 6 cm distal to the tracheal carina. This bronchus is about 1.0 to 1.5 cm long and
divides into superior and inferior (lingular) branches. The superior division ascends and the inferior one
descends. The superior branch most often bifurcates into an apical posterior segmental bronchus and an
anterior segmental bronchus. Occasionally, the anterior segment migrates inferiorly to create a trifurcate
pattern. The inferior or lingular bronchus, the analog of the middle lobe, is variable in length (1 to 2 cm)
and subsequently divides into superior and inferior divisions, the former of which, in turn, subdivides into
posterior and inferior rami.
About 0.5 cm distal to the left upper-lobe orifice, the lower-lobe stem bronchus gives off its first
branch, the superior segmental bronchus. This bronchus arises posteriorly and bifurcates in most
instances, but trifurcation does occur. After giving off the superior branch, the basal trunk continues for an
average distance of 1.5 cm as a single trunk. The bronchus then usually bifurcates into an anteromedial
basal segmental bronchus and a common stem bronchus for the lateral basal and posterior basal bronchi.
These branches further subdivide into numerous rami for their respective segments.
FIGURE 8.3 Right bronchial tree (anterior and lateral views). Boyden modification of numerical nomenclature used. (Redrawn
and modified from Brock RC. In The Anatomy of the Bronchial Tree. 2nd ed. London: Oxford University Press; 1954:190–
191.)
On the left side, the common variations are in the distribution of the segmental bronchi from the
superior and inferior divisions of the left upper-lobe bronchus and the presence of a subsuperior or
accessory subsuperior bronchus arising from the lower-lobe bronchus. Many of these deviations from
normal have little clinical importance but are significant at the time of surgical resection of the various
portions of the lungs.
RIGHT UPPER LOBE
As it leaves the pericardial sac, the right pulmonary artery is anterior and inferior to the right main
bronchus and posterior and superior to the superior pulmonary vein (Fig. 8.4). The first branch is the
truncus anterior, the major vessel carrying blood to the right upper lobe. It arises superolaterally,
posterior to the superior vena cava and divides into two branches. The more superior branch of the
truncus anterior again divides to form an apical branch, which loops posteriorly over the upper-lobe
bronchus to supply a variable portion of the posterior segment. The latter vessel is known as the posterior
recurrent artery. The more inferior branch of the truncus anterior goes to the anterior segment but may also
give off a branch to the apical segment. The truncus anterior carries the entire blood supply to the right
upper lobe in 1 of 10 individuals. In most people, one or more ascending vessels from the interlobar
portion of the pulmonary artery are also present. The interlobar portion crosses over the bronchus
intermedius. Generally only one ascending vessel to the upper lobe is present. This branch, frequently
small in caliber, supplies almost exclusively the posterior segment and is referred to as the posterior
ascending artery (Fig. 8.4).
The major variations in the right arterial system occur with almost each of the aforementioned
branchings. In as much as 20% of the population, two arteries arise from the anterior trunk. These vessels
are designated as the truncus anterosuperior and the truncus anteroinferior. When they are present, the
recurrent posterior branch is almost always a branch of the truncus anterosuperior. Infrequently, more than
one ascending branch to the upper lobe arises from the interlobar portion of the artery; the more proximal
branch supplies a portion of the anterior segment. On occasion, the posterior ascending artery arises from
the superior segmental artery or, even more rarely, from the middle-lobe artery. The middle-lobe artery as
well as the superior segmental artery, although usually single vessels, may be represented by two or at
times even three vessels. Finally, in addition to the variable branchings of the common basal trunk, a
subsuperior or accessory subsuperior artery may arise from either the common stem or the posterior basal
branch.
The superior pulmonary vein lies anterior and somewhat inferior to the pulmonary artery. It is usually
made up of four major branches, which drain the upper and middle lobes. The first three branches from
above downward drain the upper lobe and are identified as the apical anterior, anteroinferior, and
posterior branches. The posterior branch is composed of central and interlobar divisions.
Spaggiari and colleagues16 in 2002 described the anomalous course of venous drainage from the
posterior segment of the right upper lobe to the left atrium. The draining vein passes posteriorly rather
than anteriorly to the bronchus intermedius, as is normally the case. This variant was considered to be
quite uncommon. However, in 2005, Asai and colleagues3 recorded that the various upper-lobe veins may
take this abnormal route in a greater number of individuals than had previously been believed. One of
three variants was discovered by CT examination in 5.7% of 725 subjects and in 3.9% of 230 patients
undergoing a right thoracotomy. The three patterns were (a) the superior pulmonary vein group (55%), (b)
the inferior pulmonary vein group (41%), and (c) the superior segmental inferior pulmonary vein group
(4%). Ideally, the identification of such anomalous routes preoperatively or before division of any
vascular structures would be helpful in avoiding inadvertent injury to these veins during an operative
procedure.
Another example of an anomalous course of a pulmonary vein is the drainage of the right upper-lobe
vein(s) into the azygos vein and into the site of the confluence of the superior vena cava and the azygos
vein. This anomaly was described by Galetta and colleagues.17 In their report, they noted that anomalous
venous drainage of the lungs is quite uncommon—seen in 0.4% to 0.7% of the general population. Kirks
and Griscom18 have divided the various anomalous routes of venous drainage into four groups designated
as (a) supracardiac, (b) cardiac, (c) infradiafragmatic, and (d) mixed. Fraser and colleagues19 presented a
helpful discussion of the developmental anomalies affecting the pulmonary veins and the role of various
roentgenographic studies in the identification of many of these abnormalities in Volume 1, Part IV of their
text.
FIGURE 8.4 Demonstration of variations in the pulmonary artery anatomy of the right upper lobe.
RIGHT MIDDLE LOBE

At the same level or even either slightly proximal or distal to the posterior ascending artery, the middle-
lobe artery arises anteromedially from the interlobar portion of the pulmonary artery. The site of origin is
usually at the level of the junction of the horizontal and oblique fissures. The artery is usually single, and
bifurcation of the vessel is the rule, but the subdivisions are variable.
The fourth and most inferior trunk of the superior pulmonary vein drains the middle lobe and is
generally made up of two branches (Fig. 8.5).
Although the middle-lobe vein most often joins the superior pulmonary vein, on occasion, it may enter
the pericardium and drain into the atrium as a separate vessel. Rarely, it becomes a tributary of the
inferior pulmonary vein. This variant on the right side has been described in two patients by Sujimoto and
colleagues.20 Yamashita21 has reported the incidence of this anomaly at 4.8% in 120 specimens of the
right lung and only 2.5% in the left lung.
RIGHT LOWER LOBE

The inferior pulmonary vein is inferior and posterior to the superior vein. It drains the lower lobe and as
a rule is made up of two major trunks. The first is the superior segmental vein, which drains the superior
segment. The other branch, known as the common basal vein, is made up of superior basal and inferior
basal tributaries, and these vessels drain the various basal segments of the lower lobe (Fig. 8.6).
LEFT UPPER LOBE

The left pulmonary artery ascends to a higher level, passes more posteriorly, and has a greater
extrapericardial length before giving off its first segmental branch to the lung than does the right
pulmonary artery. The branches to the left upper lobe arise from the anterior, posterosuperior, and
interlobar portions of the vessel. The number of branches may vary from two to seven, but four branches
to the lobe form the most common pattern. Generally, the first branch arises from the anterior portion of
the artery to supply the anterior segment, a part of the apical segment, and occasionally the lingular
division of the lobe. The first branch of this anterior segmental artery supplies the anterior segment and
may also give off a lingular branch. Usually, it also branches to provide a vessel carrying blood to the
apical segment. The second—and, infrequently, a third branch from this first anterior trunk—gives rise to
a vessel or vessels going to the anterior segment, to the apical segment, and uncommonly to the posterior
segment. This anterior trunk is generally short, and often the branches may appear as separate vessels
arising from a common opening from the main artery. A second branch from the main artery as it passes
distally and posterosuperiorly over the left upper-lobe bronchus and into the interlobar fissure is present
in almost 80% of cases. This second arterial branch and, occasionally, a third is given off
anterosuperiorly to the apical posterior segment (Figs. 8.7 and 8.8).
FIGURE 8.5 Variations in the pulmonary artery anatomy of the right middle lobe.
FIGURE 8.6 Variations in the pulmonary artery anatomy of the right lower lobe. Note that in a minority of patients, the posterior
ascending branch to the RUL originates from the right lower lobe superior segment PA branch.
FIGURE 8.7 Orientation of the left main pulmonary artery in relation to the bronchus.
Likewise, major variations may occur in all the segmental branches of the left pulmonary artery. As
mentioned, the first anterior branch may supply the lingular division as well as other portions of the upper
lobe, and although it occurs in less than 1 in 10 individuals, this branch may carry all the blood supplying
the lingular division. Another variation is that the first anterior branch may carry only the blood supplying
the apical segment; the anterior segment in this situation receives its arterial supply from the interlobar
portion of the artery. As noted, the superior segmental artery usually arises proximal to the branch or
branches going to the lingula, but in as many as one of three persons the superior segmental branch may be
distal to the lingular artery takeoff. Both these vessels may be multiple. Again, in one of three persons, a
branch of one of the lingular vessels or even a direct branch from the interlobar portion of the artery may
supply some blood to the anterior segment of the left upper lobe. Rarely, this vascular branch carries the
entire arterial supply to this segment. As on the right, branches to the subsuperior segmental region are
often found arising as single or multiple vessels from the common basal stem or, more frequently, from the
posterior basal branch. Finally, a vessel may arise from the common basal stem or one of its branches to
contribute to the lingular blood supply.
On the left, the superior pulmonary vein is applied closely to the anteroinferior aspect of the
pulmonary artery; as a result, it obscures the anterior branches of the artery. This vein is made up of three
to four tributaries that drain the entire upper lobe. The first division, the apical posterior vein, is made up
of apical and posterior rami. The second division represents the anterior vein, which may have three
rami: superior, inferior, and posterior. The third and fourth divisions represent the superior and inferior
lingular veins. A single trunk may represent these veins in about 50% of persons. This trunk, as seen with
the middle-lobe vein on the right, may drain into the inferior pulmonary vein; this variant occurs more
commonly on the left than the right, although, as noted previously, the data of Yamashita21 do not support
this statement.
FIGURE 8.8 The pulmonary artery anatomy to the left upper lobe may be highly variable. Recognizing this remarkable
variability is essential to the safe conduct of a lobectomy.
LEFT UPPER LOBE

Posteriorly, as the artery passes into the interlobar fissure, it branches to form a vessel going to the
superior segment of the lower lobe. This vessel usually is a single one that bifurcates or, infrequently,
trifurcates at a variable distance from its takeoff from the mainstem arterial trunk. Most often, the lingular
artery originates from the interlobar portion of the pulmonary artery distal to the superior segmental artery
and constitutes the lingular arterial supply in toto in 80% of persons. At a variable distance from the
origin of the lingular vessel, the pulmonary stem artery, now the common basal trunk, most commonly
divides into two major branches. The more anterior branch supplies the anteromedial basal segment, and
the posterior one supplies the lateral basal and posterior basal segments. The patterns of branching of the
common basal trunk and its major divisions are variable (Figs. 8.9 and 8.10).
FIGURE 8.9 The lingular artery most often arises distal to the origin or the superior segmental PA to the left lower lobe.
The inferior pulmonary vein, as on the right, is located inferior and posterior to the superior vein and
has two similar tributaries: the superior segmental and the common basal veins. The latter is made up of
superior and inferior basal divisions, which drain the basal segments of the lobe.
ANOMALOUS SINGLE PULMONARY VEIN

On rare occasions, either in the right or left lung, the superior and inferior pulmonary veins may join
within the lung substance or in the fissure to form a single trunk draining the entire lung before entering the
pericardial sac. This occurrence is known as an anomalous unilateral single pulmonary vein (AUSPV).
There is normal venous drainage into the left atrium; although, infrequently, a small secondary vein may
drain into a systemic vein in the chest that flows into the right atrium. In some cases, the single vein from
the right lung follows a circuitous route before entering the left atrium, resulting in a “pseudo” scimitar
radiographic finding.
The anomalous unilateral single pulmonary vein has been identified infrequently. Twenty patients have
been recorded in the literature. This anomaly may occur equally in either gender and is most commonly
recognized in adults. An AUSPV has been observed more often in the right lung (65%) than in the left lung
(35%). An AUSPV has been identified slightly more often as a single inferior pulmonary vein.
As a general rule, the presence of an AUSPV is asymptomatic but may have serious surgical
implications when unrecognized, as noted by Meguro and colleagues,22 who reported the necessity of a
completion pneumonectomy following a left upper lobectomy when the entire venous drainage was
through a single superior pulmonary vein.
A roentgenographic abnormality is present in most patients with an AUSPV. The roentgenographic
abnormality may appear (a) as a varix, as reported by Ben-menachem10 and Hasuo23 and their colleagues;
(b) as a possible pulmonary mass lesion, as noted by Benfield7 and Gilkeson24 and their colleagues; or
(c) as an abnormal shadow along the right border simulating a scimitar syndrome, as described by
Goodman,25 Valdez-Davila,26 and Cukier27 and their colleagues. Additional cases of AUSPV have been
recorded.8,28–36
FIGURE 8.10 The arterial anatomy to the left lower lobe is highly variable.
FIGURE 8.11 Intrapericardial anatomy on the right. (Reprinted from Healey JE Jr, Gibbon JH Jr. Intrapericardial anatomy in
relation to pneumonectomy for pulmonary carcinoma. J Thorac Surg 1950;19:864. Copyright © 1950 The American Association
for Thoracic Surgery. With permission.)
INTRAPERICARDIAL ANATOMY
The right pulmonary artery passes from the left to the right behind the ascending aorta and constitutes the
superior border of the transverse sinus. It then lies behind the superior vena cava and forms the superior
border of the postcaval recess of Allison (Fig. 8.11); the medial and inferior borders of this recess are the
superior vena cava and right superior pulmonary vein. Although the right pulmonary artery is longer than
the left pulmonary artery, it is not as accessible as the left.13 The left pulmonary artery passes inferior to
the aortic arch and forms the superior border of the left pulmonary recess. The medial border of this
recess is formed by the fold of Marshall (Fig. 8.12).
FIGURE 8.12 Intrapericardial anatomy on the left. (Reprinted from Healey JE Jr, Gibbon JH Jr. Intrapericardial anatomy in
relation to pneumonectomy for pulmonary carcinoma. J Thorac Surg 1950;19:864. Copyright © 1950 The American Association
for Thoracic Surgery. With permission.)
The superior and inferior pulmonary veins bulge into the pericardium and are invested to a greater or
lesser extent by the pericardium’s serous layer. On the right, these two vessels most often enter into the
left atrium separately, although rarely they form one vessel. In contrast, on the left, the two veins form a
common trunk in one of four persons.
The serous (parietal) pericardial investments of the vessels are important because these fibrous tissue
layers must be divided to obtain free access to the entire circumference of the individual vessel. On the
right, the serous layer leaves the lateral and posterior surfaces of the superior vena cava and comes to lie
on the artery in the postcaval recess. At this point, only about one-fifth of the circumference of the vessel
is free. In contrast, three-fourths of the circumference is free in the transverse sinus medial to the superior
vena cava. From the artery, the serous layer passes inferiorly and reflects on the superior, anterior, and
inferior surfaces of the superior vein; about one-third of this vessel is not free posteriorly. The layer then
descends to cover most of the inferior pulmonary vein and then passes down to envelop the inferior vena
cava. On the left, the reflection of the serous pericardium passes over the anterior and inferior surfaces of
the left pulmonary artery, and about half of the vessel is free in the pericardial sac. The layer then
descends inferiorly to the superior vein, so that only the posterior surface is not free in the sac. It then
passes downward to envelop the inferior vein, which is subsequently almost totally free within the sac
except for a small surface located posteriorly.
BRONCHIAL ARTERIES AND VEINS

The bronchial arterial system arises from the systemic circulation and accounts for about 1% of the
cardiac output. It empties mainly into the pulmonary veins and a lesser bronchial venous system that
enters the azygos venous system on the right and the hemiazygos system on the left. The origins of the
arteries are variable from the aorta, intercostal arteries, and, occasionally, subclavian or innominate
arteries. Rare origin from other systemic vessels of the chest (internal mammary artery) or even from a
coronary artery has been recorded.
The most extensive anatomic study was reported by Caudwell and colleagues.37 These investigators
recorded nine patterns of origin. In 90% of the 150 cadaver specimens studied, the pattern was one of
four types (Fig. 8.13); Liebow38 performed corrosion casts of the bronchial arterial system in 50
cadavers, and his findings were in essential agreement with those of the aforementioned authors.
Caudwell and colleagues37 reported that the level of origin of the bronchial arteries was from the 3rd
to 8th vertebral bodies, most commonly between the levels of the 5th and 6th thoracic vertebrae, and that
they arose from the descending thoracic aorta and rarely from the arch. Most of the bronchial vessels
arose separately (74% of specimens), and the two vessels had a common origin in only 26%. The right
bronchial arteries arose from the anterolateral or lateral surface of the aorta and rarely from its posterior
aspect. In 88.7% of specimens, the right bronchial artery arose in common with an aortic intercostal
vessel: 78% from the first, 7.3% from the second, and 1.3% from the third. Nathan and colleagues39
described the anatomy of this major right bronchial artery. They found that it arose anywhere from 0.5 to
5.0 cm from the origin of the intercostal artery from its origin from the aorta and coursed upward and
forward toward the right mainstem bronchus. In its course on the right anterolateral aspect of the vertebral
column, it passes to the right of the thoracic duct and crosses the esophagus to terminate at the lower level
of the trachea near the origin of the right mainstem bronchus. At the level of the trachea, it crosses lateral
to the vagus nerve. In its mediastinal course, the right bronchial artery generally runs parallel to the arch
of the azygos vein, by which it is overlapped.
FIGURE 8.13 The four most common sites of origin and numbers of bronchial arteries to the right and left lung. (From
Cauldwell EW, Siekert RG, Lininger RE, Anson BJ. The bronchial arteries: an anatomic study of 150 human cadavers. Surg
Gynecol Obstet 1948;86(4):395–412. Reprinted with permission from the Journal of the American College of Surgeons, formerly
Surgery Gynecology & Obstetrics.)
On the left, the bronchial arteries are more variable in their courses to the bronchus and, according to
Caudwell and colleagues,37 94% arise directly from the aorta. Only 4% are associated with an intercostal
vessel, which invariably is a right intercostal artery. In most instances, the bronchial vessels that arise
from the aorta pass in back of the trachea; in only a few cases, one passes in front of the trachea. Rarely,
such a branch to the right may be in close proximity to the tracheal carina. It is possible that a branch of
such an anatomically situated vessel could be injured during a mediastinoscopy, as suggested by Miller
and Nelems40 in 1989.
These anatomic studies by the aforementioned investigators have been confirmed by the angiographic
observations of Olson and Athanasoulis41 and other interventional radiologists. Deffebach and
colleagues42 in 1987 reviewed the distribution of the bronchial arteries once they entered the hilum of the
lung and course within the bronchial tree. Essentially, the arteries to either side form a communicating arc
around the main bronchus. From here, the main arterial divisions radiate along the major bronchi. These
vessels are closely applied to the bronchial wall, with generally two divisions, an anterior and posterior
branch, along each bronchus. The vessels follow the course of the bronchus and divide, as do the bronchi.
Networks of intercommunicating vessels are often present on the bronchial walls. It has been assumed that
two-thirds of this blood supply empties into the pulmonary veins and that the rest empties into the
bronchial veins. The bronchial veins are present in the mucosa and also external to the bronchial
cartilage. The direction of flow is to the venous plexus of the perihilar regions and then subsequently into
either the azygos or hemiazygos systems.
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2002;74:267.
17. Galetta D, Veronesi G, Leo F, et al. Anomalous right upper lobe venous drainage. Ann Thorac Surg 2006;82:2272–2274.
18. Kirks DR, Griscom NT. Diagnostic Imaging in Infancy and Childhood. Philadelphia, PA: Lippincott-Raven; 1999.
19. Fraser RS, Muller, NL, Colman N, et al. Developmental anomalies affecting the airways and lung parenchyma. In Fraser RS, Muller
NL, Colman N, et al, eds. Diagnosis of Diseases of the Chest. 4th ed. Philadelphia, PA: Saunders; 1999;597–635.
20. Sujimoto S, Izumiyama O, Yamashita A, et al. Anatomy of inferior pulmonary vein should be clarified in lower lobectomy. Ann Thorac
Surg 1998;66:1799–1800.
21. Yamashita H. Variations in the pulmonary segments and the bronchovascular tree. In Yamashita H, ed. Roentgenographic Anatomy
of the Lung. Tokyo: Igakushoin; 1978:70.
22. Meguro H, Kohiyama R, Abe N, et al. A case of single left pulmonary vein with deficiency of left inferior pulmonary vein. J Jpn Assoc
Chest Surg 1998;12:529–534.
23. Hasuo K, Numaguchi Y, Kishikawa T, et al. Anomalous unilateral single pulmonary vein mimicking pulmonary varices. Chest
1981;79:602–604.
24. Gilkeson RC, Haaga JR, Ciancibello LM. Anomalous unilateral single pulmonary vein: multidetector CT findings. AJR Am J Roentgenol
2000;175:1464–1465.
25. Goodman LR, Jamshidi A, Hipona FA. Meandering right pulmonary vein simulating the scimitar syndrome. Chest 1972;62:510–512.
26. Valdez-Davila O, Avila-Varguez J, Castaneda-Zunega WR, et al. A variation of scimitar syndrome. ROFO 1978;128:271–274.
27. Cukier A, Kavakama J, Teixeira LR, et al. Scimitar sign with normal pulmonary venous drainage and systemic arterial supply. Scimitar
syndrome or bronchopulmonary sequestration? Chest 1994;105:294–295.
28. Kozuka T, Nosaki T. A pulmonary vein anomaly: unusual connection and tortuosity of the right lower lobe vein. Br J Radiol
1968;41:232–234.
29. Lutman M, Galofaro G, Cassin M, et al. Anomala unica vena polmonare unilateral (AUVPU). Importanza diagnostica della tomografia
computerizzata. Radiol Med (Torino) 1986;72:239–242.
30. Morgan JR, Forker AD. Syndrome of hypoplasia of the right lung and dextroposition of the heart: “scimitar sign” with normal pulmonary
venous drainage. Circulation 1971;43:27–30.
31. Moro C, Marin E, Sanchez A, et al. Pulmonary varix: report of a case with additional anomalies of the vascular pulmonary tree. Am
Heart J 1978;95:243–246.
32. Papamichael E, Ikkos D, Alkalais K, et al. Pulmonary varicosity associated with other congenital abnormalities. Chest 1972;62:107–109.
33. Remy-Jardin M, Remy J. Spiral CT angiography of the pulmonary circulation. Radiology 1999;212:615–636.
34. Rey C, Vaksmann G, Francart C. Anomalous unilateral single pulmonary vein mimicking partial anomalous pulmonary venous return.
Cathet Cardiovasc Diagn 1986;12:330–333.
35. Tretheway DG, Francis GS, MacNeil DJ, et al. Single left pulmonary vein with normal pulmonary venous drainage: a roentgenographic
curiosity. Am J Cardiol 1974;34:237–239.
36. Twersky J, Levin DC, Twersky N, et al. Further observation on pulmonary venous varix. AJR Am J Roentgenol 1976;127:435–440.
37. Caudwell EW, Siekert RG, Lininger RE, et al. The bronchial arteries. An anatomic study of 150 human cadavers. Surg Gynecol Obstet
1948;86:395–412.
38. Liebow AA. Patterns of origin and distribution of the major bronchial arteries in man. Am J Anat 1965;117:19–32.
39. Nathan H, Orda R, Barkay M. The right bronchial artery. Anatomical considerations and surgical approach. Thorax 1970;25:328–333.
40. Miller RR, Nelems B. Mediastinal lymph node necrosis: a newly recognized complication of mediastinoscopy. Ann Thorac Surg
1989;48:247–250.
41. Olson PR, Athanasoulis CA. Hemoptysis: treatment with transcatheter embolizations of the bronchial arteries. In Athanasoulis CA, et
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42. Deffebach ME, Charan NB, Lakshminarayan S, et al. The bronchial circulation. Small but a vital attribute of the lung. Am Rev Respir
Dis 1987;135:463–481.
9
Lymphatics of the Lungs
Marc Riquet ■ Ciprian Pricopi
The lymphatic system of the lungs is of paramount importance and is vital in both homeostasis and
protection against disease. The lymphatic vessels remove the constant filtration of liquid from the
microcirculation and return it into the blood circulation preventing pulmonary edema to occur. The
lymphatic (lymphoid) tissue plays an important role in pulmonary defenses and pathology.1 In the
cancerous process, the lymphatic system behaves ambiguously, being at the same time the first protection
against the cancer spread and the major way of its systemic dispersion. A thorough knowledge of the
lymphatic drainage of the lungs is mandatory when treating patients with lung cancer.
The lung has an extensive network of lymphatic vessels that are situated in the loose connective tissue
beneath the visceral pleura, in the connective tissue in the interlobular septa, and in the peribronchial
vascular sheaths.
In the pulmonary parenchyma, the lymphatic capillaries form extensive plexuses within the connective
tissue sheaths that surround the airways and the blood vessels. The origin of these channels is believed to
be at the level of the terminal and respiratory bronchioles, and not to extend into the interalveolar
septa.2–4 However, Kambouchner and Bernaudin5 using D2-40 immunostaining demonstrated some small
lymphatic channels within the lobules of normal human lung in the interstitial space around small blood
vessels and emerging from the interalveolar interstitium.
The channels begin as blind-end tubes and saccules. As these channels extend proximally toward the
hilar area associated with the enlarging airways and blood vessels, they have been designated as juxta-
alveolar lymphatics by Lauweryns6,7 and Leak.8 These networks drain into larger collecting vessels
(collectors) with thicker walls. The lymphatic collectors contain smooth muscles and monocuspid, one-
way conical valves each 2 to 10 mm along their length. The flow of lymph is directed toward the hilar
area in a centripetal direction.9 The phenomenon is induced by a spontaneous and adjustable mechanism.2
The segment within two valves is called a “lymphangion” and acts as a small pump. Smooth muscle
contraction in one lymphangion forces fluid into the next lymphangion in a pulsatile manner. Retrograde
flow is prevented by the valves.
Lymphatic channels that also drain the periphery of the lung lobules run in the lobular septa along with
the pulmonary veins. With the occurrence of extra-alveolar interstitial edema, some of these may be
recognized as Kerley B lines radiographically, as noted by Steiner.10 The channels in the lobular septa
have multiple connections with the channels in the bronchovascular sheaths. These connecting channels
are frequently ≤4 cm in length and lie midway between the hilus and the periphery of the lung. When
distended, they are recognized as Kerley A lines.
Collections of lymphoid tissue are present in an intimate relationship with the mucous membrane of
bronchi and bronchioles1 and with the lymphatic collectors.11 Bronchi and bronchioles lymphoid tissue is
sparse at birth and progressively increases in number throughout infancy and early childhood.12 Lymphatic
vessels may be observed in the human lung and mediastinum at the end of 7 weeks’ gestation (21 mm
crown-rump length).11 Lymphoid clusters within the mediastinal lymphatics are visible between 8 and 9
weeks’ gestation (42 mm crown-rump length), and lymph nodes, the more elaborate lymphoid structures,
between 11 and 13 weeks, at the end of embryonic life and beginning of fetal life.11 Lymph nodes are
currently present during the fetal life and at birth, not only in the mediastinum but also at the level of the
main and lobar bronchi.13 Distal lymph nodes located within the lobes along the segmental bronchi
lymphatics probably appear during the years following birth like bronchi and bronchioles lymphoid tissue
does with their development environmentally and antigenically stimulated.12,14
LYMPH NODES DISTRIBUTION
PULMONARY LYMPH NODES

The pulmonary lymph nodes are divided into the intrapulmonary and bronchopulmonary nodes. The latter
are subdivided into the lobar and hilar lymph nodes.
Intrapulmonary Lymph Nodes

The intrapulmonary lymph nodes, when present, are located most often just beneath the visceral pleura. A
peripheral lymph node may present as a solitary peripheral nodule, as reported by Greenberg,15 Houk and
Osborne,16 and Ehrenstein.17 Trapnell18 reported the identification of other intrapulmonary lymph nodes in
the substance of the lung by a combined technique of injection of the subpleural lymphatics and
subsequent radiologic evaluation of autopsy lung specimens. Intrapulmonary nodes were observed in 5 of
28 injected specimens, an incidence of 18%. Trapnell19 was also able to identify peripheral lymph nodes
radiologically in 1 of 92 inflated lungs obtained at autopsy, an incidence of just over 1%. Despite this
early study, Dail20 reported that intraparenchymal lymph nodes could be identified in about 10% of
resected lobes when they were sought. Kradin and colleagues21 had previously recorded that all such
nodes were anthracotic and were not encapsulated. In Kradin and colleagues21 report, the identified
lymph nodes were solitary in 65% of the cases and multiple in the remainder; in 22%, two lymph nodes
were found, and in 12% three or more were identified. The multiple nodes were in the same lobe in 40%
of the cases in which they are found, but were located bilaterally in 60%. Most were in the size range of
0.5 to 1.0 cm and only rarely was a larger one present. All these intraparenchymal lymph nodes were
within 1 cm of the pleura, adjacent to it, or in an interlobular septum. With rare exception, these lymph
nodes are found only in adults and are identified more commonly in individuals >50 years of age, their
development appearing to be environmentally stimulated.
With high-resolution computed tomography (HRCT), some of the small lesions identified in patients
with multiple metastases to the lung are proved subsequently to be small peripheral lymph nodes.
Tsunezuka and colleagues22 performed exploratory video-assisted thoracic surgery (VATS) in 48 patients
suspected of malignant lesions and reported intrapulmonary lymph nodes in 8: their diameter varied from
4 to 10 mm; 6 were located in the lower lobes and 2 in the lingula. Anthracosis was observed in five
subpleural nodes. It was not possible to distinguish an intrapulmonary node from a malignant lesion using
CT findings in their short series. Over a 2-year period in nine patients, Nagahiro and colleagues23
resected 13 intrapulmonary lymph nodes that had been identified on chest radiographs in three patients
and on HRCT in the other six. The characteristics of these nodes on HRCT were that the borders were
sharp, the shapes were ovoid, all were located in the lower portion of the lungs in a subpleural location,
and the interval density was high and homogeneous. No borders were irregular, although short spicules
could be present, and none contained cavities or calcifications. Nagahiro23 and Yokomise24 and their
colleagues, have pointed out that these lesions must be differentiated from small malignant nodules. The
aforementioned features of thin-slice HRCT could be helpful to avoid performing an unnecessary
operation and also to prevent the improper staging of lung cancer.25,26
Bronchopulmonary Lymph Nodes

Nagaishi27 noted that segmental lymph nodes are related to the bifurcation of the segmental bronchi. They
may also lie in the bifurcation of the branches of the associated pulmonary arteries and extend out to the
fifth- or sixth-order segmental bronchi.
The lobar bronchopulmonary lymph nodes are found at the angles formed by the origins of the various
lobar bronchi and lie in close association with the bronchus or the adjacent pulmonary vessels. The hilar
lymph nodes are situated alongside the lower portions of the main bronchi or the respective pulmonary
artery and the pulmonary veins lying within the visceral pleural reflections.
In a study of 200 operative specimens of lungs containing lung cancer, Borrie28 identified lymph nodes
in 13 locations in the right lung and 15 in the left that are now considered bronchopulmonary lymph nodes.
The number of bronchopulmonary lymph nodes is variable in each lung and within each location in the
lungs.28 These lymph nodes are more frequently present in greater numbers in children than in adults.
Borrie28 suggests that the maximal development of these nodes is reached by the end of the first decade of
life, and, then these lymph nodes gradually atrophy and disappear during adulthood. The presence of
pulmonary infection or malignancy greatly affects the number of bronchopulmonary lymph nodes that may
be identified.
Lobar Lymph Nodes

The two most common locations in which lobar lymph nodes are found in the right lung are between the
upper-lobe bronchus and middle-lobe bronchus: the area that Borrie29 termed the right bronchial sump
(the superior interlobar lymph node of Rouvière13) and the region just below the middle-lobe bronchus
adjacent to the lower lobe bronchus (the inferior interlobar lymph node of Rouvière13). In the left lung, the
most common location is at the angle of the left-upper-lobe bronchus and the lower-lobe bronchus.
Borrie7 designated this area as the left lymphatic sump, and the nodes found here correspond to the left
interlobar node of Rouvière.13 The number of lobar lymph nodes is variable from one individual to
another.30 They are present at birth as well as the hilar and mediastinal lymph nodes.13
LOBAR LYMPH NODES OF THE RIGHT LUNG

The lymph nodes in the lymphatic sump of the right lung lie in relation to the bronchus intermedius (Fig.
9.1). According to Nohl-Oser,31 a constant lymph node is found at the upper posterior end of the major
fissure in the angle between the right-upper-lobe bronchus and the bronchus intermedius. A branch of the
bronchial artery coursing over the posterior aspect of the right main bronchus leads to it (Fig. 9.2).
Another lymph node is found on the interlobar portion of the pulmonary artery where this vessel gives off
the posterior ascending segmental branch to the posterior segment of the upper lobe and the superior
segmental artery to the superior segment of the lower lobe. Inferiorly, this lymph node is contiguous with
a constant node lying above the superior segmental bronchus of the lower lobe. Other lymph nodes of the
sump are found at the base of the major fissure lying closely alongside the interlobar portion of the
pulmonary artery or in the bifurcations of its branches. Frequently, lymph nodes are identified more
anteriorly, lying among the upper lobe branches of the superior pulmonary vein.
In addition to the sump nodes, the other interlobar lymph nodes can be grouped, according to Borrie,28
into those of the upper, middle, and lower lobes. The lymph nodes of the right upper lobe are located
above the upper-lobe bronchus, medial to it, and just behind it. Those lying above the bronchus merge
with the hilar nodes of the distal portion of the right mainstem bronchus. The lymph nodes of the middle
lobe, in addition to the subjacent node below the middle-lobe bronchus (the inferior interlobar node of
Rouvière13) are located lateral to the middle-lobe bronchus near its confluence with the lower-lobe
bronchus as well as medial to it. The right–lower-lobe lymph nodes, in addition to the aforementioned
superior and inferior sump nodes, are found medial to the superior segmental bronchus or between it and
the basal bronchi. Lymph nodes are present also in relationship to the basal stem of the lower-lobe
bronchus and lie on its medial aspect, lateral to it, and between the anterior and medial basal bronchi.
FIGURE 9.1 Diagram showing the collection of lymph nodes lying within the right lymphatic sump (see text). The line drawn
through the axis of the superior segmental bronchus of the lower lobe and the middle lobe bronchus represents the level below
which nodes are not involved by malignant disease in the upper lobe. Arrows indicate the tendency of lymphatic drainage.
FIGURE 9.2 Diagram showing the posterior aspect of the right main bronchus as seen when the lung is pulled forward during
dissection. The subcarinal lymph nodes and the node below the right upper lobe bronchus are seen. A constant bronchial artery
leading to the latter node is shown.
LOBAR LYMPH NODES OF THE LEFT LUNG

The collection of lymph nodes described by Nohl32,33 and Nohl-Oser31 as composing the left lymphatic
sump lies between the upper and lower lobes in the main fissure (Fig. 9.3). A constant node is present in
the bifurcation between the upper- and lower-lobe bronchi in close relation to the origin of the lingular
(inferior division) branch of the upper lobe (Fig. 9.4). A small bronchial arterial branch passing across
the membranous portion of the left main bronchus leads to it. Other lymph nodes are found lying on the
interlobar portion of the left pulmonary artery in the fissure and in the angles formed by its branches.
Another frequent node is described, which is found above and posterior to the left interlobar bronchus.
This node is contiguous with a node lying in the angle formed by the interlobar bronchus and the takeoff of
the bronchus to the superior segment of the lower lobe.
In addition to the left lymphatic sump nodes, Borrie28 noted that lymph nodes of the left upper lobe are
present medial, posterior, and lateral to the upper-lobe bronchus. Lymph nodes are present also between
the segmental divisions of this bronchus. The lymph nodes of the left lower lobe are located more
commonly in the vicinity of the superior segmental bronchus of the lobe. They are found medial, above,
and inferior to it, between it and the basal bronchi. The other lobar nodes of the lower lobe are found
medial or lateral to the basilar stem of the lower lobe bronchus.
FIGURE 9.3 Diagram showing the left lymphatic sump found by opening the main fissure. The straight line, drawn through the
superior (apical) segmental bronchus of the left lower lobe, represents the level below which lymphatic drainage from the upper
lobe does not occur. Arrows indicate tendency of lymphatic drainage.
FIGURE 9.4 Diagram showing the lymph nodes most frequently seen on opening the main fissure of the left lung. A constant
node (A) lies in the angle between the upper and lower lobe bronchi, with a bronchial artery leading to it. Other lymph nodes (B)
are found on the main pulmonary artery and in the angles of the branches. The constant node (C) behind and above the
pulmonary artery, before it enters the fissure, is shown. Another node (D) above the inferior pulmonary vein is seen with its
connections to the inferior tracheobronchial nodes higher up.
Hilar Lymph Nodes

The hilar lymph nodes are contiguous with the lobar lymph nodes distally as well as with the mediastinal
lymph nodes proximally. The hilar lymph nodes lying superior to the right main stem bronchus classically
have been considered to extend up to the inferior border of the azygos vein, but the boundary between
hilar and mediastinal location may be fuzzy. The lymph nodes medial to the right mainstem bronchus might
be considered as hilar nodes when located away from the tracheal carina and within the visceral pleural
sheath, but as they become subjacent to this structure, they are best termed subcarinal lymph nodes and
thus belong to the lymph nodes of the mediastinal compartment.
On the left side, the anatomic separation between the hilar and the mediastinal lymph nodes proximally
is at an imaginary plane connecting the lateral surfaces of the ascending and descending portions of the
thoracic aorta. The left hilar nodes are located medial, anterior, posterior, and lateral to the left mainstem
bronchus in order of decreasing frequency in number. The hilar nodes located anteriorly are found in
relation to the left mainstem pulmonary artery. Proximally, these latter nodes are contiguous with the
subaortic lymph nodes of the mediastinum, including the lymph node located at the site of the ligament
arteriosum, the so-called Bartello’s node. The nodes on the medial surface of the main-stem bronchus, as
their position advances upward, become subcarinal in location.
In fact, determining whether the hilar nodes are bronchopulmonary or mediastinal nodes is only
oncological questioning and does not matter on a purely anatomical basis. When such lymph nodes are
present, their exact location and their size are variable from one individual to another and their
anatomical significance is the same wherever they seem to be in that area.34,35
MEDIASTINAL LYMPH NODES

The mediastinal lymph nodes are located in the mediastinal compartments: the anterior (prevascular)
lymph nodes in the anterior mediastinal compartment, the tracheobronchial lymph nodes, the paratracheal
lymph nodes, and the posterior lymph nodes in the posterior area of the visceral compartment of the
mediastinum.
Anterior Mediastinal Lymph Nodes

The anterior mediastinal lymph nodes are in the prevascular compartment of the mediastinum and
override the upper portions of the pericardium and great vessels as these extend upward. On the right
side, the nodes lie parallel and anterior to the right phrenic nerve, upward to and along the superior vena
cava to the area beneath the right innominate vein. On the left, they are in close proximity to the origin of
the pulmonary artery and the ligamentum arteriosum (Fig. 9.5). These lie anterior to and along the left
phrenic nerve (Fig. 9.5). The others, the para-aortic nodes, lie anterior and lateral to the ascending aorta
and the arch in the triangle delineated by the left phrenic and vagal nerves.34,35 They include the lymph
nodes lying along the inferior border of the left innominate vein in the region where it is joined by the left
superior intercostal vein (Fig. 9.5).
Tracheobronchial Lymph Nodes

The tracheobronchial lymph nodes lie in three groups around the bifurcation of the trachea. The right and
left superior tracheobronchial nodes are located in the obtuse angles between the trachea and the
corresponding mainstem bronchus. These nodes lie outside of the pretracheal fascia. The lymph nodes of
the right superior tracheobronchial group are medial to (beneath) the arch of the azygos vein and above
the right pulmonary artery. These nodes are contiguous with the right superior hilar nodes distally and the
right paratracheal nodes proximally. On the left side, the superior tracheobronchial nodes lie deep within
the concavity of the aortic arch. Some are closely related to the left recurrent laryngeal nerve. Others are
situated slightly more anteriorly and are contiguous with the node at the ligamentum arteriosum and the
root of the left pulmonary artery. Their association with these nodes constitutes the link between the nodes
in the visceral compartment and those in the anterior mediastinal lymph node group.
FIGURE 9.5 Diagram showing the mediastinal nodes on the left side. The superior tracheobronchial nodes, in relation to the
recurrent laryngeal nerve, have connections with the anterior mediastinal group, which ascends upward to the left innominate
vein; small nodes anterior to the phrenic nerve are shown; *phrenic nerve; **vagal nerve.
The inferior tracheobronchial nodes, more commonly referred to as the subcarinal nodes, lie in the
angle of the bifurcation of the trachea. Some of them, in contrast to the superior tracheobronchial groups,
lie within the pretracheal fascial envelope, outside the relatively dense bronchopericardial membrane.
These nodes are contiguous with the hilar nodes on the medial aspect of both the right and left mainstem
bronchi. Some of the subcarinal lymph nodes lie more posteriorly in relationship to the tracheal
bifurcation and are on the anterior surface of the esophagus and are thus connected with the posterior
group of lymph nodes. In addition, Brock and Whytehead36 described a low anterior tracheal group lying
in front of the lower end of the trachea, which constitutes a bridge between the right superior
tracheobronchial lymph nodes and the subcarinal, inferior tracheobronchial lymph nodes. This node is
frequently present.34
The paratracheal lymph nodes are situated on the right and left sides of the trachea above the
respective superior tracheobronchial nodes and extend upward along the trachea. The right paratracheal
lymph nodes lie anterolaterally to the trachea and to the right of the innominate artery. Inferiorly, these
nodes are overlapped by the superior vena cava. More superiorly, these nodes lie behind and above the
innominate artery to the right of the midline of the trachea and extend to the inlet of the chest. Inferiorly,
the left paratracheal nodes lie above the tracheobronchial angle to the left of the trachea behind the aortic
arch, mainly located in the groove formed by the esophagus and the trachea, along the left recurrent
nerve.34,35 More superiorly, they are situated above the arch but behind the great vessels and extend to the
inlet of the chest.
Posterior Mediastinal Lymph Nodes
The posterior mediastinal lymph nodes may be separated into two groups: the paraesophageal nodes and
those located in either pulmonary ligament. These posterior nodes are identified less commonly in the
superior portion than in the inferior portion of the mediastinum. A paraesophageal node occasionally is
found retrotracheally at the level of the arch of the azygos vein. There may be nodes lying along the
groove formed by the trachea and the esophagus, the most constant being located in the inlet of the
chest.34,35 The paraesophageal nodes as a group are more numerous in the inferior portion of the
mediastinum and are found more frequently on the left than on the right side. In the pulmonary ligament on
either side, usually two or more small lymph nodes may be present. A relatively constant node, and
usually the largest, lies in close proximity to the inferior border of the inferior pulmonary vein and is
often termed the sentinel node of the pulmonary ligament.
Number and Size of Lymph Nodes in the Various Mediastinal Locations

The first major report of the number of lymph nodes in the mediastinum was published by Beck and
Beattie.37 In cleared specimens of the mediastinum from five autopsies, they reported an average of three
nodes in the anterior mediastinum and an average of 50 in the tracheobronchial area of the mediastinum.
Of the latter, an average of 16 nodes was located in the peribronchial region, 11 in the subcarinal, and 23
in the paratracheal regions. These data were essentially nonspecific anatomically, as were the data
recorded by Genereux and Howie.38 These authors, however, were among the first investigators—
including Baron,39 Osborne,40 Ekholm,41 and Moak42 and their colleagues—to record the size of normal
mediastinal lymph nodes as identified by CT scanning. Some 85% to 95% of normal lymph nodes
identified in these studies were <11 mm. The data of Genereux and Howie38 were essentially similar to
those of the other early investigators. Glazer and colleagues43 not only reported the size of normal nodes
but also correlated the number of lymph nodes usually identified by CT and their size in each of the
superior mediastinal and subcarinal regions. The data were generated by a retrospective review of 56 CT
scans of patients without primary inflammatory pulmonary disease or primary lung neoplasm. The largest
normal mediastinal nodes were found in the subcarinal and right tracheobronchial regions and, as a rule,
the nodes were larger on the right side than on the left side. From these data, it was suggested that 10 mm
be considered the upper limit for the short axis of normal mediastinal lymph nodes. An anatomic study by
Kiyono and colleagues,44 in which the mediastinal lymph nodes were dissected in 40 cadavers, produced
similar results. These authors suggested the normal size for the diameter of the short axis of the lymph
nodes may vary from 8 mm to 10 mm in the right tracheobronchial and 12 mm in the subcarinal regions.
Relative to the number of lymph nodes, it may be noted that CT examination may fail to identify all the
nodes present, particularly in the subaortic and subcarinal regions, and does not demonstrate nodes
present in either of the pulmonary ligaments or those in the inferior paraesophageal area. The use of
esophageal endoscopic ultrasound examination, which is particularly sensitive for the detection of
mediastinal nodes in these latter areas, was reported by Kondo and colleagues.45 These investigators,
although the patients studied had carcinoma of the lung, were able to identify lymph nodes in these latter
areas, but the data are incomplete as to the actual number of normal nodes identified in the various
regions. Again, however, most lymph nodes considered normal were <10 mm (97%) in their short axis.
The number of lymph nodes also varies from one region to another. Darling and colleagues46 reported
a median of at least six lymph nodes from at least three regions in 99% of patients. The largest numbers of
lymph nodes were resected from the subcarinal regions and right tracheobronchial, with a median of three
and four lymph nodes, respectively. Occasionally, a few or even no lymph nodes were found in some
regions, results reflecting a high intra-individual variability.34,35 Thus, carrying things to extremes, it
could be possible to encounter an individual without any mediastinal lymph nodes (Fig. 9.6).
The number of lymph nodes to be removed during surgery for lung cancer has long been a matter of
debate. Some authors observed that examining a greater number of lymph nodes in patients with non–
small cell lung cancer treated by surgical resection increased the likelihood of proper staging and affected
outcome.47–49 Those reports demonstrated a large variability in the number of lymph nodes in accordance
with the study design, tumor stage, and nodal station considered. This variability was apparently
associated with prognostic value. In fact, variability and prognostic value are characteristic of anatomical
variants, a fact only demonstrable by complete lymphadenectomy. In a recent study, 1,095 patients
underwent lung cancer resection in association with systematic lymphadenectomy where pulmonary and
mediastinal lymph node counts were reviewed.30 The variability and prognostic impact of the number of
lymph nodes on overall survival were analyzed: the mean number of harvested pulmonary and mediastinal
lymph nodes was found to be 17.4 ± 7.3 (range, 1 to 65), the lower ranges supporting what is suggested in
Figure 9.6. The mean number was higher in male patients, right lung surgical procedures, pneumonectomy,
and in case of lymph node involvement. The mean number of harvested mediastinal lymph nodes was
10.7+/−5.6 (range, 0 to 49; median, 10) and was normally distributed, following a Gaussian curve (Fig.
9.7). Overall survival was influenced by the number of involved stations (single-station vs. multistation
disease: 5-year survival rates 31.5% vs. 16.9%, respectively; p = 0.041), but not by the number of
harvested lymph nodes, the number of harvested mediastinal lymph nodes, or the number of positive
mediastinal lymph nodes. The mean number of harvested pulmonary and mediastinal lymph nodes was
curiously higher in case of lymph node involvement.30
Saji and colleagues50 also reported that the mean number of resected LNs was significantly increased
in N1 and N2/N3 compared with N0 cases. Similarly, Darling and colleagues46 reported higher N stage to
be associated with increased lymph nodes removal. There is no clear explanation for these findings, but
some hypotheses can be stated. The lymphatic system is an active participant in metastatic tumor
dissemination, regulated by a complex array of lymphangiogenic factors, chemokines, and immune cell
subsets.51 The development of most secondary lymphoid organs (mainly lymph nodes) is restricted to
embryogenesis, but the development of isolated lymphoid follicles can occur in adults.52 Tertiary
lymphoid organs may appear in lymphatic malformations53 and chronic inflammatory diseases,54 and they
might also be induced by tumoral disease.
FIGURE 9.6 Upper mediastinum right paratracheal collectors and left paratracheal collectors and their termination into the
venous angles. Note the absence of lymph nodes. The bulges correspond to the lymphangion valves insertion. (Reprinted from
Riquet M. Bronchial arteries and lymphatics of the lung. Thorac Surg Clin 2007;17:619–638. Copyright © 2007 Elsevier. With
permission.)
FIGURE 9.7 Distribution of the number of harvested mediastinal lymph nodes (med-LN) by complete lymphadenectomy.
(Reprinted from Riquet M, Legras A, Mordant P, et al. Number of lymph nodes in non-small cell lung cancer: a Gaussian curve,
not a prognostic factor. Ann Thorac Surg 2014;98:224–231. Copyright © 2014 The Society of Thoracic Surgeons. With
permission.)
FIGURE 9.8 Lymph node map of Naruke (see Table 9.1 for definitions). (Reprinted from Naruke T, Suemasu K, Ishikawa S.
Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg
1978;76:832. Copyright © 1978 The American Association for Thoracic Surgery. With permission.)
Mediastinal Lymph Node Maps

Naruke and colleagues55 suggested the use of an anatomic map with the aforementioned conventional
lymph node regions numbered as stations so that the various lymph node stations involved by tumor could
be uniformly recorded in patients with lung cancer (Fig. 9.8). This mapping scheme was used by most
Japanese surgeons. The American Joint Committee for Cancer Staging and End Results Reporting (AJC)
published a similar map,56,57 whose lymph node stations are defined in Table 9.1. The American Thoracic
Society (ATS) in a report by Tisi and colleagues,58 however, noted deficiencies in the commonly
accepted specific anatomic definition of each nodal station when determined by mediastinoscopy,
mediastinotomy, and computed tomography (CT) examinations of the chest. They recommended that the
hilar stations, the right and left stations, 10 of the Naruke and AJC maps be deleted because of the
ambiguity of the radiologic definition of these areas. It is suggested that these areas be redesignated as
peribronchial on the left and tracheobronchial on the right and be assigned to the mediastinal
compartments, both stations being outside of the pleural reflection. The ATS suggested the anatomic
stations as listed in Table 9.2 and located as represented in Figure 9.9.
TABLE 9.1 American Joint Committee for Cancer Staging and End Results Reporting
Classification of Regional Lymph Nodes
Mediastinal (N2) Nodes Bronchopulmonary (N1) Nodes
Superior mediastinal nodes 10. Hilar

1. Highest mediastinal 11. Interlobar
2. Upper paratracheal 12. Lobar
3. Pretracheal and retrotracheal 13. Segmental
4. Lower paratracheal (including azygos nodes)
Aortic nodes
5. Subaortic (aortic window)
6. Para-aortic (ascending aorta or phrenic)
Inferior mediastinal nodes
7. Subcarinal
8. Paraesophageal (below carina)
9. Pulmonary ligament
In an attempt to resolve the confusion created by the aforementioned classifications and maps of the
lymph node stations, a committee representing both the American Committee on Cancer and the Union
International Contre le Cancer decided to adopt a modified version of both the AJC and ATS
classifications and lymph node maps. The adapted classification and map were published by Mountain
and Dresler.59 Graphic representations are shown in Figure 9.10. The anatomic definition of each station
is given in Table 9.3. The application of the classification to helical computed tomographic evaluation
was illustrated by Cymbalista and colleagues.60
The map caused a lot of controversies. Some topics were periodically highly debated. The station 3
lymph nodes (anterior midline paratracheal nodes superior to the tracheal bifurcation and extending
upward to the inferior border of station 1) was believed by Naruke61 and Naruke and colleagues62 as well
as Asamura63 and Watanabe64 and their colleagues, among others, to be an important individual
mediastinal nodal station and had been placed in the broad category of station 4 nodes. However, station
3 nodes remained in the classification used by most Japanese surgeons. The station 3a consists of lymph
nodes in the anterior mediastinal compartment located on the anterior surface of the superior vena cava at
the level of the anterior wall of the ascending aorta. Station 3p nodes are the central retrotracheal lymph
nodes located behind the trachea extending from the caudal border of station 1 inferior to the apex of the
tracheal bifurcation.
The anatomic landmarks that identified all lymph node stations within the mediastinal pleural
reflection as N2 nodes and all lymph node stations distal to the pleural reflections and within the visceral
pleural envelope as N1 nodes were questioned. Asamura and colleagues65 believed that the pleural
reflection was an inappropriate boundary to separate N1 from N2 lymph nodes because some lymph
nodes around the main bronchus could be considered to be N2 lymph nodes. Okada and colleagues66 also
argued against the validity of the use of the pleural reflection as the boundary between N1 and N2 lymph
node groups. Both authors believed that the relationship of the lymph node to the mainstem bronchus was
more likely the main feature in the decision as to whether or not a given lymph node is a N1 or a N2
lymph node. No clear borders really have been determined. Several reports65–68 have shown that survival
in patients with a solitary metastasis in the hilar areas (stations 7, 10, and 11) may behave more like
single lower mediastinal lymph node disease than that of more distally located bronchial N1 involvement.
In fact, these results reflect in an indirect way that using motionless anatomical landmarks to distinguish
between N1 and N2 is not always suitable. Such landmarks cannot reflect the instability of the lymphatic
anatomy in that area. The proximal hilar nodes are equivalent to the distal mediastinal ones, and vice
versa, their location depending on individual variability as above mentioned. Reconsidering more
utilitarian anatomical landmarks might improve the classification.67
TABLE 9.2 Proposed Definitions of Regional Nodal Stations for Prethoracotomy
Staging
X Supraclavicular nodes
2R Right upper paratracheal (suprainnominate) nodes: nodes to the right of the midline of the trachea between the intersection of the
caudal margin of the innominate artery with the trachea and the apex of the lung. (Includes highest R mediastinal node.)
(Radiologists may use the same caudal margin as in 2L.)
2L Left upper paratracheal (supra-aortic) nodes: nodes to the left of the midline of the trachea between the top of the aortic arch and the
apex of the lung. (Includes highest L1 mediastinal node.)
4R Right lower paratracheal nodes: nodes to the right of the midline of the trachea between the cephalic border of the azygos vein and
the intersection of the caudal margin of the brachiocephalic artery with the right side of the trachea. (Includes some pretracheal
and paracaval nodes.) (Radiologists may use the same cephalic margin as in 4L.)
4L Left lower paratracheal nodes: nodes to the left of the midline of the trachea between the top of the aortic arch and the level of the
carina, medial to the ligamentum arteriosum. (Includes some pretracheal nodes.)
5 Aortopulmonary nodes: subaortic and para-aortic nodes, lateral to the ligamentum arteriosum or the aorta or left pulmonary artery,
proximal to the first branch of the left pulmonary artery.
6 Anterior mediastinal nodes: nodes anterior to the ascending aorta or the innominate artery. (Includes some pretracheal and preaortic
nodes.)
7 Subcarinal nodes: nodes arising caudal to the carina of the trachea but not associated with the lower lobe bronchi or arteries within
the lung.
8 Paraesophageal nodes: nodes dorsal to the posterior wall of the trachea and to the right or left of the midline of the esophagus.
(Includes retrotracheal but not subcarinal nodes.)
9 Right or left pulmonary ligament nodes: nodes within the right or left pulmonary ligament.
10R Right tracheobronchial nodes: nodes to the right of the midline of the trachea from the level of the cephalic border of the azygos vein
to the origin of the right upper lobe bronchus.
10L Left peribronchial nodes: nodes to the left of the midline of the trachea between the carina and the left upper lobe bronchus, medial to
the ligamentum arteriosum.
11 Intrapulmonary nodes: nodes removed in the right or left lung specimen plus those distal to the main-stem bronchi or secondary
carina. (Includes interlobar, lobar, and segmental nodes.)
From Tisi GM, Friedman PH, Peters RM, et al. American Thoracic Society: Clinical staging of primary lung cancer. Am Rev Respir Dis
1983;127:659. With permission.
FIGURE 9.9 A: American Thoracic Society map of regional pulmonary nodes (see Table 9.2 for definitions). B: American
Thoracic Society map of regional nodes in stations 5 and 6. (From Tisi GM, Friedman PH, Peters RM, et al. American Thoracic
Society: Clinical staging of primary lung cancer. Am Rev Respir Dis 1983;127:659–694. With permission.)
A new lymph node map which attempted to reconcile differences among the Naruke and MD-ATS
maps was proposed by the International Association for the Study of Lung Cancer (IASLC).69 New
descriptions were provided for all lymph node stations and are shown in Table 9.3. Numerous and major
proposals were adopted69 and were summarized as follows. Concerning the upper and lower borders of
lymph node stations 1 through 10, the pleural reflection no longer serves as the border between nodal
stations 4 and 10. The supraclavicular and sternal notch lymph nodes are now described as level 1. The
discrepancies between levels 2 and 4 lymph nodes in the Naruke and MD-ATS lymph node maps have
been revisited. The arbitrary division along the midline of the trachea created by the ATS has been
eliminated. Recognizing that lymphatic drainage in the superior mediastinum predominantly occurs to the
right paratracheal area and extends past the midline of the trachea, the boundary between the right- and
left-sided levels 2 and 4 lymph nodes has been reset to the left lateral wall of the trachea (Fig. 9.11). The
arbitrary designation of level 3 lymph nodes as nodes overlying the midline of the trachea in the Naruke
map has been eliminated because these nodes are not reliably distinguishable from levels 2 and 4 and are
generally removed en-bloc with level 4 during a mediastinal component of systematic nodal dissection
from the right. The designation of prevascular (anterior mediastinal) nodes 3a has been extended to the
posterior aspect of the sternum. The entire subcarinal group of lymph nodes, previously labeled as level 7
in the MD-ATS map but divided into levels 7 and 10 in the Naruke map is now defined as level 7, again
with precise anatomic borders. Specific boundaries are also provided for the frequently problematic
separation between levels 4 and 10 on the right, levels 5 and 10 on the left, and levels 10 and 11
bilaterally.
Rusch and colleagues69 also illustrated how the anatomic definitions of the lymph node stations may
apply to clinical staging on CT scans in the axial (Fig. 9.12A–C), coronal (Fig. 9.12D), and sagittal (Fig.
9.12E,F) views. The division between right- and left-sided nodes at levels 2 and 4 is shown in Figure
9.12 (A, B).
Exploratory analyses of overall survival in relationship to various levels of lymph node involvement
seemed to make it possible to group together certain lymph node stations into “zones.”70 That zone-
concept was proposed for future survival analyses, but not for current standard nomenclature, in the hope
that this concept will prove of value to oncologists and radiologists when dealing with large nodal
masses that transgress individual nodal stations.
FIGURE 9.10 Regional lymph node stations: Superior mediastinal nodes are stations 1, 2, 3, and 4; aortic nodes are stations 5
and 6; and inferior mediastinal nodes are stations 7, 8, and 9. Intrapleural nodes are stations 10, 11, 12, 13, and 14. (See Table 9.3
for definitions.) Ao, aorta; PA, pulmonary artery. (Adapted from Mountain CF, Dresler CM. Regional lymph node classification
for lung cancer staging. Chest 1997;111:1718. Copyright © 1997 The American College of Chest Physicians. With permission.)
Finally, it is worth to mention that the anatomic interpretation of any given map will also vary among
two or more surgeons. This was pointed out by Watanabe and colleagues64 at the Royal Brompton
Hospital in London as well as at two or more institutions. This problem is inevitable and difficult to
solve even if a single map becomes standard throughout the surgical community. Thus, in the New Lymph
Node Map, caudal border definition of level 2R might change station 2R into 4R,71 and critiques of
stations 1 to 11 were addressed by radiologists.72 For all those different reasons, suggestions
recommending specific alternative definitions to anatomical boundaries will still be necessary and are
expected.73 However, the main problem remains that lymphatic anatomy cannot be perfectly represented
by a lymph node map nor by the station zones that are proposed.56 The thoracic anatomy is slightly
different from one individual to another and the anatomy of the lymphatic system is still more varying.
TABLE 9.3 Comparison of the Naruke, MD-ATS and IASLC Lymph Node Maps With Respect to the Anatomical
Definitions for Each Lymph Node Station
Japan Lung MD-ATS Map IASLC Map

Cancer Society
Map
#1 Low Cervical, Supraclavicular, and Sternal Notch Nodes
Located in the area Nodes lying above a horizontal line at the upper rim of the Upper border:
of the upper 1/3 brachiocephalic (left innominate) vein where it ascends to lower margin
of the the left, crossing in front of the trachea at its midline of cricoid
intrathoracic cartilage.
trachea. Lower border:
Boundary level from clavicles
the upper margin bilaterally
of the subclavian and, in the
artery or the apex midline, the
to the crossing upper border
point of the upper of the
margin of the left manubrium,
brachiocephalic 1R
vein and the designates
midline of the right-sided
trachea nodes, 1L,
left-sided
nodes in this
region.
For lymph node
station 1, the
midline of
the trachea
serves as the
border
between 1R
and 1L
#2 Paratracheal #2 Upper Paratracheal Nodes
Lymph Nodes
Located in the area Nodes lying above a horizontal line drawn tangential to the 2R: Upper
between the upper margin of the aortic arch and below the inferior border: apex
superior boundary of No. 1 nodes of the right
mediastinal lymph lung and
nodes (#1) and pleural
the space, and in
tracheobronchial the midline,
lymph nodes (#4). the upper
Paratracheal border of the
lymph nodes with manubrium.
primary tumor can Lower border:
be defined as intersection
ipsilateral lymph of caudal
nodes; margin of
paratracheal innominate
lymph nodes vein with the
without primary trachea.
tumor can be As for lymph
defined as node station
contralateral 4R, 2R
lymph nodes includes
nodes
extending to
the left
lateral
border of the
trachea.
2L: Upper
border: apex
of the left
lung and
pleural
space, and in
the midline,
the upper
border of the
manubrium.
Lower border:
superior
border of the
aortic arch
#3 Pretracheal #3 Prevascular and Retrotracheal Nodes
Lymph Nodes
Located in the area Prevascular and retrotracheal nodes may be designated 3A 3a: Prevascular
anterior to the and 3P; midline nodes are considered to be ipsilateral On the right
trachea and Upper border:
inferior to the apex of chest
superior Lower border:
mediastinal lymph level of
nodes (#1). On carina
the right side, the Anterior
boundary is border:
limited to the posterior
posterior wall of aspect of
the superior vena sternum
cava. On the left Posterior
side, the boundary border:
is limited to the anterior
posterior wall of border of
the superior
brachiocephalic vena cava
vein. On the left:
#3a Anterior Upper border:
mediastinal lymph apex of chest
nodes. Lower border:
On the right side, level of
located in the area carina
anterior to the Anterior
superior vena border:
cava. On the left posterior
side, the boundary aspect of
is limited to the sternum
line connecting Posterior
the left border: left
bracheocephalic carotid artery
vein and the 3p:
ascending aorta. Retrotracheal
#3p Retrotracheal Upper border:
mediastinal lymph apex of chest
nodes/Posterior Lower border:
mediastinal lymph carina
nodes
Located in the
retrotracheal or
posterior area of
the trachea
#4 #4 Lower Paratracheal Nodes
Tracheobronchial
Lymph Nodes
Located in the area The lower paratracheal nodes on the right lie to the right of 4R: includes
superior to the the midline of the trachea between a horizontal line drawn right
carina. tangential to the upper margin of the aortic arch and a line paratracheal
On the right side, extending across the right main bronchus at the upper nodes, and
located medial to margin of the upper lobe bronchus, and contained within pretracheal
the azygos vein. the mediastinal pleural envelope; the lower paratracheal nodes
On the left side, nodes on the left lie to the left of the midline of the trachea extending to
located in the area between a horizontal line drawn tangential to the upper the left
surrounded by the margin of the aortic arch and a line extending across the lateral
medial wall of the left main bronchus at the level of the upper margin of the border of
aortic arch. left upper lobe bronchus, medial to the ligamentum trachea.
arteriosum and contained within the mediastinal pleural Upper border:
envelope. Researchers may wish to designate the lower intersection
paratracheal nodes as No. 4s (superior) and No. 4i of caudal
(inferior) subsets for study purposes; the No. 4s nodes margin of
may be defined by a horizontal line extending across the innominate
trachea and drawn tangential to the cephalic border of the vein with the
azygos vein; the No. 4i nodes may be defined by the lower trachea.
boundary of No. 4s and the lower boundary of no.4, as Lower border:
described above lower border
of azygos
vein.
4L: includes
nodes to the
left of the left
lateral
border of the
trachea,
medial to the
ligamentum
arteriosum.
Upper border:
upper margin
of the aortic
arch.
Lower border:
upper rim of
the left main
pulmonary
artery.
#5 Subaortic #5 Subaortic (Aortopulmonary Window)
Lymph
Nodes/Botallo’s
Lymph Nodes
Located in the area Subaortic nodes are lateral to the ligamentum arteriosum or Subaortic
adjacent to the the aorta or left pulmonary artery and proximal to the first lymph nodes
ligamentum branch of the left pulmonary artery and lie within the lateral to the
arteriosum mediastinal pleural envelope. ligamentum
(Botallo arteriosum.
ligament). The Upper border:
boundary extends the lower
from the aortic border of the
arch to the left aortic arch.
main pulmonary Lower border:
artery. upper rim of
the left main
pulmonary
artery.
#6 Paraaortic Nodes (Ascending Aorta or Phrenic)
Located along the Nodes lying anterior and lateral to the ascending aorta and Lymph nodes
ascending aorta, the aortic arch or the innominate artery, beneath a line anterior and
and in the area of tangential the upper margin of the aortic arch. lateral to the
the lateral wall of ascending
the aortic arch. aorta and
Posterior aortic arch.
boundary limited Upper border: a
to the site of the line
vagal nerve. tangential to
the upper
border of the
aortic arch.
Lower border:
the lower
border of the
aortic arch.
#7 Subcarinal Nodes
Located in the area Nodes lying caudal to the carina of the trachea, but not Upper border:
below the carina, associated with the lower lobe bronchi or arteries within the carina of
where the trachea the lung the trachea
bifurcates to the Lower border:
two main bronchi the upper
border of the
lower lobe
bronchus on
the left; the
lower border
of the
bronchus
intermedius
on the right
#8 Paraesophageal Nodes (Below Carina)
Located below the Nodes lying adjacent to the wall of the esophagus and to the Nodes lying
subcarinal lymph right or left of the midline, excluding subcarinal nodes adjacent to
nodes, and along the wall of
the esophagus the
esophagus
and to the
right or left
of the
midline,
excluding
subcarinal
nodes.
Upper border:
the upper
border of the
lower lobe
bronchus on
the left; the
lower border
of the
bronchus
intermedius
on the right.
Lower border:
the
diaphragm
#9 Pulmonary Ligament Nodes
Located in the area Nodes lying within the pulmonary ligament, including those Nodes lying
of the posterior in the posterior wall, and lower part of the inferior within the
and the lower pulmonary vein pulmonary
edge of the ligament.
inferior Upper border:
pulmonary vein the inferior
pulmonary
vein.
Lower border:
the
diaphragm
#10 Hilar Nodes
Located around the The proximal lobar nodes, distal to the mediastinal pleural Includes nodes
right and left main reflection and the nodes adjacent to the bronchus immediately
bronchi intermedius on the right; radiographically, the hilar adjacent to
shadow may be created by enlargement of both hilar and the mainstem
interlobar nodes. bronchus and
hilar vessels
including the
proximal
portions of
the
pulmonary
veins and
main
pulmonary
artery.
Upper border:
the lower rim
of the azygos
vein on the
right; upper
rim of the
pulmonary
artery on the
left.
Lower border:
interlobar
region
bilaterally
#11 Interlobar Nodes
Located between the Nodes lying between the lobar bronchi Between the
lobar bronchi. On origin of the
the right side, lobar bronchi
subclassified into a#11s: between
2 groups: the upper
#11s: Superior lobe
interlobar nodes: bronchus and
located at the bronchus
bifurcation of the intermedius
upper and middle on the right
lobar bronchi. a#11i: between
#11i: Inferior the middle
interlobar nodes: and lower
located at the lobe bronchi
bifurcation of the on the right
middle and lower
lobar bronchi.
#12 Lobar Nodes
Located in the area Nodes adjacent to the distal lobar bronchi Adjacent to the
around the lobar lobar bronchi
branches, which
are subclassified
into three groups:
#12u: Upper lobar
lymph nodes
#12m: Middle lobar
lymph nodes
#12l: Lower lobar
lymph nodes
#13 Segmental Nodes
Located along the Nodes adjacent to the segmental bronchi Adjacent to the
segmental segmental
branches bronchi
#14 Subsegmental Nodes
Located along the Nodes around the subsegmental bronchi Adjacent to the
subsegmental subsegmental
branches bronchi
aOptional notations for subcategories of station.
M D-ATS, M ountain-Dresler modification of the ATS map; IASLC, International association for the study of lung cancer; ATS, American Thoracic Society.
Reprinted from Rusch VW, Asamura H, Watanabe H et al. The IASLC lung cancer staging project: a proposal for a New International Lymph Node M ap in the forthcoming
seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009; 4:568–577. Copyright © 2009 International Association for the Study of Lung Cancer. With
permission.
FIGURE 9.11 The International Association for the Study of Lung Cancer (IASLC) lymph node map, including the proposed
grouping of lymph node stations into “zones” for the purposes of prognostic analyses. (Reprinted from Rusch VW, Asamura H,
Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a New International Lymph Node Map in the
forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4:568–577. Copyright © 2009
International Association for the Study of Lung Cancer. With permission.)
LYMPHATIC DRAINAGE OF THE LOBES OF THE LUNG
LYMPHATIC DRAINAGE TO THE BRONCHOPULMONARY LYMPH NODES

The lymphatic drainage of the lobes of the lungs is primarily to the bronchopulmonary nodes, although
direct lymphatic drainage to the mediastinal lymph nodes was described by Rouvière,13 Borrie,29
Cordier,74 and Riquet75 and their colleagues, as well as by the last author in 1993. This direct drainage is
discussed subsequently.
The right-upper-lobe lymphatic drainage, as deduced from the study of Borrie,28 is commonly to one of
the superior interlobar lymph nodes (the sump nodes) on the lateral aspect of the bronchus intermedius, to
the nodes above the right-upper-lobe bronchus and to those medial to it. Subsequent drainage is proximal
to the azygos or subcarinal lymph nodes. Distal drainage has not been described as occurring to any
lymph nodes below the lower level of the right lymphatic sump, which means to the nodes of the lower
lobe.
The middle lobe lymphatics drain to lymph nodes of the superior sump region, although drainage to the
inferior sump node also occurs. Okada and colleagues4 also recorded drainage directly to the subcarinal
nodes. Later studies by Watanabe76 and Asamura63 and their colleagues as well as by Naruke61 have
confirmed this direct drainage to the subcarinal area and also to the midline pretracheal mediastinal nodal
area.
FIGURE 9.12 A–F: Illustrations of how the International Association for the Study of Lung Cancer (IASLC) lymph node map
can be applied to clinical staging by computed tomography scan in axial (A–C), coronal (D), and sagittal (E, F) views. The
border between the right and left paratracheal region is shown in A and B. Ao, aorta; AV, azygos vein; Br, bronchus; IA,
innominate artery; IV, innominate vein; LA, ligamentum arteriosum; LIV, left innominate vein; LSA, left subclavian artery; PA,
pulmonary artery; PV, pulmonary vein; RIV, right innominate vein; SVC, superior vena cava. (Reprinted from Rusch VW,
Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a New International Lymph Node Map in
the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4:568–577. Copyright © 2009
Drainage from the right lower lobe is to the inferior interlobar node and to the superior sump nodes,
primarily those lying on the medial surface of the bronchus intermedius. However, drainage may be direct
to the superior sump nodes, and removing the latter in case of lower lobectomy for lung cancer is
mandatory. Proximal drainage may also occur directly as well to the subcarinal nodes, as recorded by
Okada and colleagues4 and subsequently by the authors noted previously in the discussion of the drainage
of the middle lobe.
Drainage of the left upper lobe from all segments may occur to the left sump nodes. Nodes around the
upper lobe bronchus and the left mainstem bronchus also receive drainage from this lobe. Direct drainage
to subaortic mediastinal nodes may occur from the superior division of the left upper lobe, whereas direct
drainage to the mediastinum from the inferior division (lingula), when it occurs, is commonly to the
subcarinal mediastinal nodes, as recorded by Asamura and colleagues.63,77
Lymphatic drainage of the lower lobe is to the subjacent peribronchial nodes and to the interlobar
sump nodes. From here, drainage is proximal to the hilar or mediastinal lymph node groups or both.
Interlobar sump nodes may receive left lower lobe lymph directly and, as on the right, removing them is
mandatory during lower lobectomy for lung cancer, even when the lower lobe peribronchial nodes are not
involved.34,35
Lymphatic drainage from the middle and right lower lobes and the left lower lobe also is directed to
the nodes in the respective pulmonary ligament. These lymph nodes are considered to be mediastinal
lymph nodes. The incidence of nodes identified in Borrie’s work28 was 12% in the right pulmonary
ligament and 47% in the left.
LYMPHATIC DRAINAGE TO THE MEDIASTINAL LYMPH NODES

The lymphatic drainage of the lungs to the mediastinal lymph nodes has been studied by various
techniques of injection of dyes into the lymphatic channels of lungs from autopsy specimens of stillborn
infants and adults without pulmonary disease.13,34,74,75,78,79 One study correlated such a technique of
injection performed in adults’ cadavers with the drainage patterns observed by dissecting the operative
specimens from lungs of cancer patients.80 However, the most numerous studies are above all based on
the lymphatic spread of lung cancer to the mediastinum,28,29,33 and subsequently use a lymph node
classification map since the 70s.55,61,63,76,81–86 Also, in living patients without known pulmonary disease,
the lymphatic drainage of the lungs was studied by the technique of lymphoscintigraphy using antimony
sulfide colloid or rhenium colloid labeled with technetium-99m (99mTc) injected into the various
bronchopulmonary segments through the fiberoptic bronchoscope by Hata and colleagues.87
Although the terminology for the lung segments and the mediastinal lymph nodes, as well as their
locations, varied considerably in these multiple studies, relatively consistent drainage patterns for each
lung and its respective lobes and segments can be identified. The patterns of normal lymphatic drainage
from the lungs to the mediastinal lymph nodes are relatively consistent despite minor variations suggested
by different workers, which may be the result of the methods of investigation used and the selection of the
subjects studied.
Lymphatic Drainage and Lymphoscintigraphy From the Lungs

The dynamic study by lymphoscintigraphy in normal healthy subjects as reported by Hata and colleagues87
estimated general patterns of drainage from the right and left lung segments (Fig. 9.13).
Lymphatic Drainage From the Right Lung

The lymphatic drainage from the apical and posterior segments of the right upper lobe flows through the
hilar nodes into the right superior tracheobronchial nodes, further into the paratracheal nodes, and up into
the neck in the right scalene nodes through ipsilateral upper paratracheal nodes. About half of the lymph
from the anterior segment of the upper lobe flows through the same route. The other half flows into the
subcarinal nodes or into the right anterior mediastinal nodes. Lymph that passes through the subcarinal
nodes may flow further into the right scalene nodes through the pretracheal and ipsilateral paratracheal
nodes, and a small amount of lymph is observed to flow into the left paratracheal nodes. Lymph that goes
to the right anterior mediastinal nodes flows along the left brachiocephalic vein into the left anterior
mediastinal nodes and into the left scalene nodes.
The routes of lymphatic drainage from the bronchi of the middle lobe and the superior segment of the
right lower lobe are similar. Most of the lymph from these segmental bronchi flows into the subcarinal or
right superior tracheobronchial nodes and then to the right upper paratracheal nodes. Some of the lymph
from the bronchi of the middle lobe also flows into the subcarinal, anterior paratracheal, and left
paratracheal nodes or into the right anterior mediastinal nodes, as mentioned for lymphatic drainage from
the anterior segment of the right upper lobe.
A dominant flow of the lymphatic drainage occurs from the basal segments of the right lower lobe into
the subcarinal nodes through the bronchopulmonary nodes. The lymph then flows into the ipsilateral lower
and upper paratracheal nodes and further into the right scalene nodes.
Lymphatic Drainage From the Left Lung

The lymphatic drainage from the segmental bronchi of the left lung follows four major routes. The first
passes through the subaortic nodes. This route divides into two pathways. One runs along the left vagus
nerve to the left scalene nodes, and the other runs along the left recurrent laryngeal nerve to the highest left
mediastinal nodes. The second route runs through the para-aortic nodes upward along the left phrenic
nerve through the anterior mediastinal nodes to the left scalene nodes. The third route runs along the left
main bronchus to the left superior tracheobronchial nodes and the paratracheal nodes. From the left
tracheobronchial nodes, this route divides into two branches. One extends to the right side of the
mediastinum through the right upper pretracheal node, and the other runs upward along the left side of the
trachea to the highest left mediastinal nodes. The fourth route runs under the left main bronchus to the
subcarinal nodes. After passing the subcarinal nodes, this route extends to the right superior
tracheobronchial nodes or through the lower pretracheal node to the right upper paratracheal nodes. Some
branches extend upward along the left side of the trachea to the highest left mediastinal nodes.
FIGURE 9.13 Standard patterns of lymphatic drainage of the lungs. A: From segments of the right upper lobe. B: From
segments of the middle lobe and superior segment of the right lower lobe. C: From basal segments of the right lower lobe. D:
Route 1 from the left lung. E: Route 2 from the left lung. F: Route 3 from the left lung. G: Route 4 from the left lung. See text
for explanation. (From Hata E, Troidl H, Hasegawa T, et al. Lymphatics of the lungs. In: Shields TW, Locicero III J, Reed CE,
Feins RH, eds: General thoracic surgery. 7th ed. Philadelphia, PA: Wolters Kluwer–Lippincott–Williams & Wilkins; 2009:87–
101.)
The major routes of lymphatic drainage from each segment are as follows. The most important route of
lymphatic drainage from the apicoposterior segmental bronchus of the upper lobe is the first route.
Although the second route is the most common for lymphatic drainage from the anterior and lingular
segments of the upper lobe, the other routes are used as well for lymphatic drainage from these segments.
Lymph from the superior segmental bronchus of the lower lobe drains commonly along the first, third, and
fourth routes. The most important route of drainage from the basal segmental bronchi of the lower lobe is
the fourth route.
Lymphatic Drainage Through the Lymphatic Chains of the Mediastinum

Postmortem injection studies of the subpleural lymphatics of a total of 343 pulmonary segments of the
right lung and 344 segments of the left lung34 demonstrated that the lymphatic drainage is carried out by
lymphatic vessels, some of them crossing the bronchopulmonary and/or mediastinal nodes. These
anatomical entities are known as lymphatic chains. Eight drainage lymphatic chains were identified in the
superior mediastinum: two major and two minor on the right side and two major and two minor on the left
side. In the inferior mediastinum, one major group of nodes was identified, as well as two minor chains
(the right and left pulmonary ligament chains) and a very infrequently identified group of juxtaesophageal
(JE) lymph nodes.
The first of the major chains on the right side of the superior mediastinum is the right pretracheal or
paratracheal chain (RPT) from the anterior aspect of the tracheal carina to the right supraclavicular fossa.
Three groups of nodes were identified, those of station 3, R4, and L4. The second major chain is the
tracheoesophageal chain (TE) situated behind the trachea. The minor chains are the right phrenic chain
(RP) and the chain of the arch of the azygos vein (AZM). This latter chain empties directly into the
thoracic duct, and only infrequently are lymph nodes identified along this chain. In the left superior
mediastinum, the preaortic carotid chain (AO) most often begins as a large node situated at the level of
the ligamentum arteriosus (station 5) and passes from below upward behind the phrenic nerve anteriorly
and in front of the vagus nerve posteriorly to its apex in the neck. The second major chain, the left
superior bronchial and left recurrent chain (LSB), corresponds to the TE on the right. Two minor chains
are the left phrenic chain (LP) and chain of the aortic arch (Azao). The distribution of the main major
chains is asymmetric, with the tracheoesophageal and RPT being close together and the LSB and AO
being distant from one another because the aortic arch separates them. According to Caplan,78 the AO is
the left-side equivalent of the RPT. This chain, together with the vagal nerve, is displaced from the
trachea to the anterior mediastinal plane of the superior mediastinum during the embryologic development
of the aortic arterial system.
TABLE 9.4 Percentage of Drainage From the Segments of the Right and Left Lungs to
the Mediastinal Chains
Right Superior Mediastinal Chains Right Lung Segment Left Lung Segment
RPT 76.7% 25.9%
TE 26.5% 10.8%
RP 7.8% <1%
AZM 7.5% <1%
Left Superior Mediastinal Chains
AO <1% 48.8%
LSB 24% 57.6%
LP <1% 8.4%
AZao <1% 5.2%
Inferior Mediastinal Chains
ITB 65% 41.3%
Lt. PL <1% 7.8%
Rt. PL 9% 0%
JE <1% <1%
AO, preaortic carotid; AZao, chain of the aortic arch; AZM, chain of the arch of the azygos vein; ITB, the group of intertracheobronchial
lymph nodes; JE, juxtaesophageal lymph nodes; LSB, left superior bronchial and left recurrent chain; LP, left phrenic; PL, chains of the
pulmonary ligaments; RP, right phrenic; RPT, right pretracheal or paratracheal; TE, tracheoesophageal.
Adapted from the data of Riquet M. Anatomic basis of lymphatic spread from carcinoma of the lung to the mediastinum: surgical and
prognostic implications. Surg Radiol Anat 1993;15:271. Copyright © Springer-Verlag 1993. With permission.
In the inferior mediastinum, a major group of intertracheobronchial lymph nodes (ITB) is arranged in
three clusters: one midline subcarinal group (station 7) flanked bilaterally by right and left clusters of
nodes located below the respective bronchus. On either side, the chains of the pulmonary ligaments (PL)
derive most of their drainage from the ipsilateral basilar segments; subsequent drainage is primarily to the
ITB nodes, but in 40% of the specimens, some of the flow is either directly to the thoracic duct or
indirectly to the duct through an intra-abdominal lymph node (20%). The percentages of crossover from
an ipsilateral lung to a contralateral mediastinal chain are shown in Table 9.4. The final chain, the JE,
drains very little of the lungs. Direct flow from the lungs initially to the mediastinum rather than by a
bronchopulmonary route was observed in just over 28% of the injections from each lung. This
phenomenon is discussed subsequently in this chapter.
This study was continued by further investigations of the lymphatic drainage from the various lymph
node groups and organs in the thorax.88 In a portion of this report, the direct tributaries between various
nodal groups of the lung and the thoracic ducts were described. These tributaries and lymphatic
connections may well be one of the routes of egress of cancer cells directly into the bloodstream.
Lymphatic vessels from the lung connected directly with the thoracic duct in 115 of 390 adult cadavers of
a total of 530 subjects in whom dye injections were attempted. These connections originated from
mediastinal lymph node groups in all (112 specimens) but those specimens (3) in which the connections
occurred from the right (inferior) pulmonary ligament. The sites of the direct connections between the
tributaries and the thoracic duct were (a) in the mediastinum in 73 specimens, (b) at the level of the arch
of the thoracic duct in 40 specimens, and (c) at the origin of the duct in 2 specimens. From the right
paratracheal nodes (station 4R), the tributaries traveled along the arch of the azygos vein on the right of
the trachea and esophagus. On the left from station 4L, the lymphatic tributaries drained directly into the
thoracic duct within the superior mediastinum in 34 specimens and to the arch of the duct in 28. From
station 5, again the tributaries drained either directly into the duct traveling along the arch of the aorta (4
specimens) or into the arch of the duct by the anterior mediastinal lymph node chain in 11. From station 7,
a tributary in 18 specimens joined the duct either on the right or the left of the esophagus. This new
information (Table 9.5) is supplemental to the normally described drainage patterns of the various lobes
of the lungs. The main lymphatic connections between the lymph node chains and the thoracic duct are
shown in the form of a drawing, in Figure 9.14. It must be mentioned that chylothorax may occur
following injury of these connections. In effect, when an injured tributary has valve competence, which
remains a rare eventuality, chyle can reflux from the thoracic duct into the pleural space.
TABLE 9.5 Lymphatic Vessels From the Lungs

Thoracic In the Mediastinum Arch Origin Total
Duct CE
RPT LSB Ao RPL BIF LSB LRC Ao+ LAM LPL
(4R) (4L) (5) (9) (7) (2L) (6) (9)
Right lung 14 6 0 6 11 7 0 0 2 46
Left lung 0 25 4 0 7 21 11 1 0 69
Total 14 31 4 6 18 28 11 1 2 115
Lymph node groups at the “origin” of the tributaries connecting with the thoracic duct. All lymphatic vessels connecting with the thoracic duct
originated from lymph node groups, except three located within the right inferior pulmonary ligaments and directly connecting from the lung
with the thoracic duct without nodal mediation. Numbers in parentheses refer to the regional lymph node classification for lung cancer staging
by Mountain and Dresler.59
Ao, aortic arch nodes (5) (aortic subclavian and carotid node chains); BIF, nodes of tracheal bifurcation (intertracheobronchial nodes) (7); CE,
celiac or cardiac lymph nodes; LAM, left anterior mediastinal (6); LPL, left inferior pulmonary ligament nodes (9); LRC, left recurrent chain;
LSB, left superior bronchial nodes (4L); RPL, right inferior pulmonary ligament nodes (9); RPT, right paratracheal nodes (4R). Note that BIF
(nodes of tracheal bifurcation) in Table 6.10 is the same as ITB (group of intertracheobronchial lymph nodes) as described in Table 6.10
originally from Riquet’s publication in 1993.
Reprinted from Riquet M, Le Pimpec Barthes F, Souilamas R, et al. Thoracic duct tributaries from intrathoracic organs. Ann Thorac Surg
2002;73:892–898. Copyright © 2002 The Society of Thoracic Surgeons. With permission.
ROUTES OF THE LYMPHATIC DRAINAGE

The routes of the lymphatic drainage described by Hata and colleagues87 mainly agree with the patterns
described by Rouvière,13 Nohl,32 and Riquet34 but some of the aforementioned observations must be
pointed out.
MEDIASTINAL CONTRALATERAL LYMPHATIC DRAINAGE

The drainage from the right lung is preponderantly unilateral, and crossover to lymph nodes in the
contralateral mediastinum seems infrequent. However, Hata and colleagues87 noted drainage from the
right upper lobe into the left paratracheal nodes and sequentially from the right prevascular nodes into the
left prevascular (anterior) nodes. Similar pathways were observed infrequently from the middle lobe and
superior segment of the lower lobe. Drainage from the basilar segments of the right lower lobe rarely
progressed to the left side of the mediastinum. In the lymph node chain study,34 drainage from one chain
into another was common. Lymph from the ITB lymph nodes reached the LSB chain in 37.8% of cases
(85.2% coming from the right lung). Lymph of the right pretracheal or paratracheal chain (RPT) might
reach the LSB chain in 14%, always arising from right-sided injections.
In patients with known carcinoma of the lung studied by prethoracotomy mediastinoscopy, contralateral
drainage from the right lung to the mediastinum was likewise observed with minimal frequency. Nohl-
Oser89 and Greschuchna and Maassen90 reported that from tumors of the right lower lobe with associated
metastatic mediastinal node disease, the incidences of contralateral disease were 7% and 5%,
respectively. The incidence of contralateral metastases from tumors of the right upper lobe with metastatic
mediastinal node disease were 5% and 9%, respectively. However, in 37 patients who underwent a
cervical and bilateral mediastinal nodal dissection during right upper lobectomy for lung cancer, 10 out of
19 patients with cervical and/or mediastinal involvement had contralateral associated disease (52.6%).91
In contrast, contralateral mediastinal drainage from the left lung was considered relatively common,
occurring most frequently through the subcarinal nodes, as initially pointed out by Rouvière.13 In the
mediastinoscopy data of Nohl-Oser89 and Greschuchna and Maassen,90 contralateral involvement from
tumors of the left upper lobe to the right side of the mediastinum in patients with mediastinal node
involvement was 22% and 21%, respectively. From the left lower lobe, the figures were 40% and 33%,
respectively. Again, to put these data into perspective, 28% of the patients in Nohl-Oser’s89 study had
metastatic mediastinal nodal involvement from tumors of the left lung, so that the 22% and 40%
incidences represent actual 6% and 11% incidences of crossover from the left upper and lower lobes to
the right side of the mediastinum. These percentages are in agreement with the findings of Hata and
colleagues,87 who found 7% and 11% incidences, respectively, in patients who had undergone bilateral
mediastinal node dissection for left lung tumors.
UNFAMILIAR IPSILATERAL MEDIASTINAL DRAINAGE

Drainage from the lower lobes on either side to the ipsilateral superior mediastinal lymph nodes is
common.
Drainage to the inferior mediastinum, to the subcarinal lymph nodes, from the right upper lobe does
occur. This finding was first observed by Rouvière,13 and although discounted by Nohl33 and Nohl-
Oser,89 it has been amply reconfirmed by the studies of Borrie28 and Hata,87 Riquet,75 Watanabe,85 and
Asamura63 and their colleagues. Watanabe and colleagues85 reported a 13% incidence of subcarinal
lymph node involvement in 45 patients with right upper lobe tumors. Libshitz and coinvestigators82
reported a similar 14% incidence of such involvement.
Drainage of the superior division of the left upper lobe to the subcarinal area is unusual but, as noted
by Hata87 and Asamura63 and their colleagues, commonly occurs from the inferior (lingular) division of
that lobe. A study by Watanabe and colleagues86 of 139 patients with non–small-cell lung cancer, ≤5 cm in
size, located in either the right or left lower lobes and associated with mediastinal lymph node
metastases, identified that there was a significant difference in the routes of metastatic spread between the
superior segment and the basal segments of these lobes. From the basal segments the mediastinal spread
was most often to the subcarinal nodal station with or without involvement of any of the superiorly
located nodal groups. Metastatic disease from the superior segment most often bypassed the subcarinal
station and involved one or more of the superior nodal stations. The synchronous subcarinal and superior
nodal involvement associated with the basal segmental tumors was 81% versus an incidence of only 39%
in the tumors located in the superior segment of the lower lobes. The authors’ conclusion was that the
basal segmental tumors metastasize primarily to the subcarinal station whereas the superior segment
tumors most often metastasize directly to one of the superior mediastinal nodal stations.
FIGURE 9.14 Connections of lung lymphatic collectors with the thoracic duct within the mediastinum and lymph nodes
«stations» from which connecting collectors are issuing. (Reprinted from Riquet M. Bronchial arteries and lymphatics of the lung.
Thorac Surg Clin 2007;17:619–638. Copyright © 2007 Elsevier. With permission.)
NODELESS DIRECT LYMPHATIC DRAINAGE
Direct lymphatic channels from either lung drain to the mediastinal lymph nodes, bypassing the
bronchopulmonary nodes in a significant number of lungs. This phenomenon was observed previously and
has been described as skip metastases in lung cancer patients by Martini and Flehinger92 as well as by
Libshitz82 and Ishida81 and their associates, among others, including Riquet34 and Asamura and
colleagues.77 Skip metastases from the right upper lobe were seen in the superior tracheobronchial nodes
most frequently with a few occurring in the paratracheal node group and infrequently to the subcarinal
lymph nodes. Right–lower-lobe tumors exhibited skip metastases to the subcarinal nodes and to the
pulmonary ligament nodes. On the left side, upper lobe lesions tended to show skip metastasis to the
aortic window and subcarinal areas. The lower lobe lesion showed a similar pattern as seen on the right;
that is, the skip to the subcarinal and pulmonary ligament nodes. Riquet34 and Riquet and colleagues75
used injection studies of the subpleural lymphatics of adult lungs obtained at autopsy to identify direct
lymphatic channels running from the subpleural plexus of the lobar segments to the various mediastinal
lymph nodes without passing through the bronchopulmonary nodes. Most of these channels were
superficial, but a few penetrated the lung substance. On occasion, these direct but separate channels
coexisted with other channels draining into the bronchopulmonary lymph nodes. These direct channels
were observed in 28.5% of the segments injected in the right lung and 28.8% of the segments in the left
lung in Riquet’s 1993 report.34 In all other specimens, the dye followed the classic patterns and filled the
respective bronchopulmonary lymph nodes. A summary of the study by Riquet and colleagues75 is found in
Table 9.6.
TABLE 9.6 Direct Pathways to Mediastinal Lymph Nodes From the Lungs
Site Percent Total Percentage for Each Lung
Right upper lobe 36.3
Middle lobe 18.6 22.2
Right lower lobe 22.3
Left upper lobe 38.6 25.0
Left lower lobe 21.1
Adapted from Riquet M, Hidden G, Debesse B. Abdominal nodal connexions of the lymphatics of the lung. Surg Radiol Anat 1988;10:251.
Copyright © Springer-Verlag 1988. With permission of Springer.
Thus, direct drainage to the ipsilateral mediastinal nodes may be frequent but it is worth to notice that
direct lymphatic channels to contralateral mediastinal lymph nodes are extremely rare. However, they
may exist: one direct draining channel from the right basal segments to the left pulmonary ligament nodes
and one from the left to a right paratracheal node have been documented.75
ULTIMATE ISSUE OF LYMPHATIC DRAINAGE

The lymph drainage from both lungs ultimately joins the blood circulation.34,93 The drainage from the
inferior mediastinum progresses cephalad to the superior mediastinum, but lymphatics issuing from the
subcarinal nodes and pulmonary ligament also drain into the thoracic duct. From the superior
mediastinum, the drainage continues to progress cephalad to the scalene lymph nodes in the neck. At that
level, the chains of the superior mediastinum, right paratracheal, right trachea-esophageal, right phrenic
nerve, left preaortocarotid and left recurrent lymph node chains drain by many lymphatic arches into the
ipsilateral jugulo-subclavian confluences. Some lymphatic chains may drain contralaterally in 10% to
15% of cases, and the left mediastinal lymph node chains also drain into the arch of the thoracic duct in
40% of cases.93 The following is important: at their beginning, the right paratracheal, left preaortocarotid,
and left recurrent chains also drain into the thoracic duct within the mediastinum as aforementioned (Fig.
9.14).
Occasionally, lymphatic drainage from the lower regions of the mediastinum may progress caudad to
the para-aortic lymph nodes below the diaphragm. Riquet34 and Riquet and colleagues94,95 described a
direct channel from the basal segments of both lungs to juxtaceliac nodes. This drainage pathway also had
been noted previously by Meyer.96 At that level, the lymph joins the roots of the thoracic duct.
SIGNIFICANCE OF THE LYMPHATIC DRAINAGE

In an anatomo-clinical study,80 the lymph node chains draining the lungs were correlated with the N2
pattern of patients who underwent surgery. The prognosis was better when only one mediastinal lymph
node chain was involved (5-year survival rates 27.4%) than when two or more chains were (5-year
survival rates 9.31%, P-0.0001). The anatomy could provide an explanation: as above mentioned the
lymph from one chain may drain into the venous circulation in the neck, join the thoracic duct in the
mediastinum, and also connect with the ipsi- and contralateral lymph node chains (Fig. 9.15). Thus, a
single involved lymph node chain may behave as a still local disease that was eradicated by surgery in
the surviving patients. When a second chain is involved, tumor cells having acquired a seeding capability
due to numerous and complex lymphangiogenic factors51 may have already disseminated into the blood
circulation and generated occult systemic metastases. Systemic metastases as the major cause of cancer-
related deaths (90% of patients, 117/130) supported this finding.80 This is a questionable hypothesis, but
when a single chain is involved, the number of involved lymph nodes in the chain and their size are no
longer so important prognostic factors,80,97 which may reinforce the potential role of the chain. In several
reports,98–101 one-station N2 disease was also reported as the most important factor of survival. As most
lymph node chains contain only one N2 station, this could support the same explanation. In the TNM
classification, ipsilateral cervical and contralateral mediastinal lymph node involvements are both termed
N3. However, ipsilateral cervical lymph nodes are located in ipsilateral mediastinal chains, whereas
contralateral mediastinal lymph nodes are located in contralateral mediastinal chains.35 Their regrouping
does not correspond to anatomy and biases the significance and interpretation of N3 tumor spread,
ipsilateral cervical involvement still potentially being a N2 disease.
FIGURE 9.15 Diagram showing how the lymph flowing within one lymphatic chain may drain into the cervical venous
circulation and the thoracic duct in the mediastinum, but also connect with another lymph node chain at the same time.
All of the aforementioned points must be remembered and thought about in the overall consideration of
the lymphatic drainage from the lungs. The clinical relevance of the lymphatic drainage and the various
lymph node groups are discussed in the respective chapters relating to infections and tumors of the lungs.
However, resorting to anatomy and taking into account the drainage of each lymphatic chain by
considering it as a “functional unit” instead of a lifeless station might be of great interest in the early stage
of lung cancer.
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10
Mechanics of Breathing and Pulmonary
Gas Exchange
Giuseppe Miserocchi ■ Egidio Beretta ■ Francesca Lanfranconi
This chapter covers the basic physiologic function of the lung necessary to sustain life. All cells require a
constant supply of oxygen to fuel the production of energy and the removal of carbon dioxide, the
byproduct of that process. In order to perform this vital function, the lungs must take in atmospheric gases
and extract the oxygen and eliminate the excess carbon dioxide. Since the supply of oxygen is limited in
each aliquot of gas inhaled, this process must be repeated multiple times each minute with repeatable
efficiency. The process is best discussed in two parts. The first part is the mechanics of breathing, which
moves the atmospheric gases in and out of the alveolus where the second part, gas exchange, takes place.
MECHANICS OF BREATHING
The term mechanics of breathing refers to the elastic properties of the lung and chest wall and to airflow
resistance. These properties are described by and related to lung volume and airflow measurements.
MECHANICAL LUNG–CHEST WALL COUPLING

The lung is a volume-elastic organ that tends to deflate itself. The deflation force exerted by the lung is
termed elastic recoil pressure. This pressure increases with lung volume, and the pressure required to
maintain inflation equals the elastic recoil. Lung expansion is maintained either by negative pleural
pressure at the outer surface of the lung or by positive pressure applied via the airway opening to the
inner surface of the lung. Irrespective of the manner in which inflation pressure is applied, lung recoil
pressure is considered positive and is always expiratory.
Figure 10.1 shows the lungs expanded within the thorax that comprises the chest wall and the
diaphragm. Close apposition between lung and thorax is guaranteed by the subatmospheric pressure of a
thin layer of fluid contained in the pleural space. The existence of a subatmospheric pleural pressure is
necessary because of the opposite recoil of lung and chest: the lung develops a retractive elastic force that
is balanced by an opposite elastic recoil of the chest. To simplify, if a wound is opened in the chest
allowing air to enter the pleural cavity (pneumothorax), the lung will collapse and the chest wall will
expand. During inhalation, inspiratory muscles have to challenge the elastic forces in order to generate an
increase in chest size and, consequently, in lung volume.
The elastic properties of the lung reside both in the elastic continuum that bounds and mechanically
couples alveolar walls and in the liquid lining of individual alveoli. The lung parenchyma contains a
continuous elastic network of collagen, elastic, and reticular fibers in addition to alveolar capillary
endothelium and the alveolar epithelial lining. In addition, a thin liquid film on the luminal surface of the
alveolar epithelium creates a surface tension that accounts for a substantial portion of lung recoil. Surface
tension tends to minimize surface area. In the bubble-like alveolus, surface tension increases as the size of
the alveolus decreases, and, if unopposed, leads to alveolar instability because smaller units, with greater
recoil, tend to empty into larger units. A lipid substance normally present in the alveolar lining fluid
reduces surface tension at the gas–liquid interface, thereby protecting the lungs against alveolar collapse.
This substance, called surfactant, can be extracted from normal lung tissue and is absent or reduced in
acute lung injury, prolonged pulmonary atelectasis, and hyaline membrane disease. Surfactant maintains
relatively constant surface-tension forces despite varying degrees of lung inflation and alveolar size.
Given the mechanical arrangement of lung and chest that exert opposite elastic forces, it is of interest
to analyze the energy transfer between these two structures during the respiratory cycle. Figure 10.2
shows a simplified mechanical drawing to describe the mechanical coupling between lung and chest wall.
Lungs and chest wall are represented as two springs with similar elastic properties exerting an opposite
recoil force: the lung pulling inward and the chest wall outward. Springs are mechanically linked (as
indicated by the red dot) thanks to the subatmospheric pleural liquid pressure. The model refers to lung
volume changes starting from the end of a normal expiration (functional residual capacity [FRC]) up to
end-inspiratory volume. As suggested by the drawing, the action of the inspiratory muscles causing an
increase in lung volume generates stretching of the lung with corresponding increase in its elastic energy;
the opposite holds true for the chest due to destretching. Thus, at peak inspiratory volume there is an
increase in elastic energy of the lung and a decrease in the elastic energy of the chest wall. When
inspiratory muscles relax (deactivated), the energy stored by the lung is being released allowing
expiration and return of the respiratory system down to the FRC without active intervention of the
expiratory muscles. Thus, in a wide range of pulmonary ventilation (up to about three-fold the control rest
condition), inspiration requires muscular work while expiration is purely passive. On mechanical
grounds, FRC represents the equilibrium condition between elastic forces developed by lung and chest
wall.
FIGURE 10.1 Schematic drawing to show lung expansion within the chest that is delimited by the rib cage and the diaphragm.
FIGURE 10.2 Mechanical coupling between lung and chest wall that are represented as two springs exerting opposite elastic
recoil force. The drawing highlights how the elastic forces developed by the two structures change when the inspiratory muscles
generate an increase in lung volume.
The simplest model to describe the mechanical properties of the respiratory system is an anesthetized,
paralyzed, intubated individual being mechanically ventilated (Fig. 10.3). The question is: which
pressures are appropriate to ventilate the patient?
With the apparatus presented in the figure, it measures the alveolar pressure (Palv) necessary to
increase the volume of the respiratory system (V), with no intervention of the respiratory muscles since
the subject is paralyzed. By inflating the lungs at low flow rate, flow resistances are minimized and
therefore the pressure to be exerted only has to match the elastic recoil of the lung and chest wall,
indicated as Pl and Pcw, respectively. Thus:
Palv = Pl + Pcw
To partition between Pcw and Pl one can define Pl = Palv − Ppl, where Ppl represents the average
pleural pressure surrounding the lung and can be estimated from a catheter placed in the esophagus. Thus,
substituting in equation 1,
Palv = Pcw + Palv − Ppl
and therefore
Pcw = Ppl
Thus, in anesthetized individuals, Pcw can be derived from Ppl values at any alveolar inflation
pressure. One can derive Pl as:
Pl = Palv − Pcw
FIGURE 10.3 Definition of pressure required to mechanically ventilate a curarized subject. Total alveolar pressure (Palv)
exerted by the ventilator pump accounts for the pressure needed to move the lungs (Pl) as well as the chest wall (Pcw). Thus,
Palv = Pl + Pcw.
Although an esophageal catheter is considered invasive and rarely used today, it remains a very useful
method to assess the elastic properties of the lung and chest wall allowing one to relate Pl and Pcw to the
corresponding changes in lung volume.
COMPLIANCE
Elastic properties of the lung and chest wall are usually defined as compliance (the inverse of resistance).
This variable represents the slope of the dynamic changes in lung volume versus either the Pl or Pcw
relationships. Lung compliance (Cl) is the ratio between lung volume changes to the corresponding
pressure changes:
Compliance is an important parameter defining the pathologic-dependent changes in lung elasticity. It

is characteristically increased in emphysema and decreased in fibrosis. Compliance greatly affects the
work of breathing. Figure 10.4 presents examples of volume–pressure relationships for the lung in healthy
condition, after emphysema, or in conditions producing pulmonary fibrosis.
Compliance of the chest wall is similar to that of the lung within the respiratory volume changes during
quiet breathing. Chest wall compliance also varies with pathologic conditions, it decreases in emphysema
and as a consequence of rib fractures.
In diseases of the lungs in which the elastic properties are not uniformly the same, regional ventilation
becomes nonuniform. Adjacent lung regions, even neighboring alveoli, have different P–V characteristics.
Thus, the same pressure change, even when beginning at the same absolute level of intrapleural pressure,
produces different volume changes in neighboring areas. The P–V characteristics as measured with an
esophageal balloon are those of the whole lung and are averages that may obscure regional differences.
Diffuse infiltrative disease, such as diffuse pulmonary fibrosis, produces inequalities not only in inspired
gas distribution but also in the distribution of blood flow, resulting in ventilation/perfusion mismatch and
abnormal gas exchange. The overall adverse effects of these diseases are assessed best by measurements
of gas exchange and arterial blood gas content.
Aside from processes that alter lung elastic recoil, there are others that restrict movement of the chest
wall, reducing its compliance. An increase in the longitudinal dimension of the thorax is primarily
determined by movement of the diaphragm. Diaphragmatic movement may be restricted by conditions that
increase intra-abdominal pressure, such as obesity, ascites, intra-abdominal tumors, and inflammation of
abdominal structures. Changing from the erect to the supine position may also restrict the diaphragm by
shifting the weight of the abdominal contents toward it. These conditions generally increase the
inspiratory work of breathing and reduce FRC. In the extreme, vital capacity (VC) and TLC are also
reduced.
FIGURE 10.4 Volume–pressure curves of the lung in control condition, emphysema, and fibrosis. The slope of the relationships
represents the lung compliance. Emphysema leads to increase in lung compliance, while the opposite is true for fibrosis.
Changes in the anteroposterior and transverse dimensions of the chest wall are primarily affected by
the intercostal muscles and accessory muscles of respiration and depend on the mobility of the rib cage.
Thus, conditions that result in deformation or fixation of the thorax, such as kyphoscoliosis or ankylosing
spondylitis, also may restrict expansion.
Obesity may also reduce chest wall compliance by increasing the soft tissue mass of the thorax.
Moreover, because respiratory movement ultimately depends on the action of the respiratory muscles,
conditions that result in paralysis or weakness of the respiratory muscles severely limit ventilation and
often cause respiratory failure. Because of the difficulties of measuring chest wall compliance, muscle
strength, and leverage as well as intra-abdominal pressure and gravitational forces, it is customary to rely
on measurements of their consequences, such as changes in lung volumes, gas exchange, ventilation, and
perfusion. The results of these tests plus knowledge of the clinical status of the patient are often sufficient
to differentiate altered compliance of the chest wall or lungs from neuromuscular insufficiency.
AIRWAY FLOW RESISTANCE

The tracheobronchial tree is modeled as 23 generations with dichotomous symmetric bifurcations from
the trachea, which is considered generation 0. With increasing generation, the airway caliber is reduced,
but the number of daughter branches increases so that the overall section of the tracheobronchial tree
increases exponentially (Fig. 10.5A); based on this geometrical feature, it follows that air flow velocity
decreases toward the terminal airways. Figure 10.5B shows that the highest airflow resistance occurs in
the larger intrapulmonary bronchi where the flow regime is partly turbulent, while there is a large
decrease in flow resistance down to the terminal airways where flow becomes laminar.1 From the
functional point of view, the first 16 generations are referred to as the conducting zone: their main function
being humidification of air and trapping of particulate within the mucopolysaccharide layer covering the
epithelium. The volume of air contained in lungs down to generation 16 is referred to as anatomical dead
space. The generations from 17 to 23 represent the respiratory zone, where the physical process of
diffusion is favored by the thinness of the alveolar–capillary membrane and by the reduction of the
airflow velocity almost to zero in the alveoli.
To generate airflow, ventilatory muscles must not only distend elastic structures of the lungs and chest
wall but also develop the force to overcome frictional resistance to motion. Frictional resistance consists
of pressure losses both from airflow through conducting airways and tissue flow within the lung and chest
wall during breathing movements. Unlike measurements of elastic recoil pressure made under static
conditions, resistance is a dynamic property and must be measured while there is airflow. The
components of total airflow resistance within the lungs and thorax are airway resistance, lung tissue
resistance, and chest wall tissue resistance. Change in tissue resistance tends to be minimal in most
obstructive lung diseases and is therefore overshadowed by the magnitude of change in airway resistance.
The majority of expiratory airflow resistance ordinarily occurs in larger, more central airways, those 2
mm or more in diameter.
FIGURE 10.5 A: Cross-section area of the 23 generations of the airways, from the trachea (generation 0) down to the terminal
airways (generation 23). B: Airflow resistance as a function of airways generation.
Direct measurement of airway resistance is technically difficult and yields variable results. Therefore,
indirect measurements, such as the peak expiratory flow rate (PEF) or the volume exhaled during the first
second of the forced vital capacity (FVC) maneuver (FEV1), are commonly used to assess airway
resistance. These measurements are made during maximally forced expiratory efforts.
These indirect measures of airflow resistance provide average values for the entire system of airways.
In diffuse obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD) and asthma,
some airways have a higher resistance to airflow than others, resulting in nonuniform distribution of
inspired air and a mismatch between ventilation and perfusion with impairment of gas exchange.
Airway Resistance During Exhalation

Maximum expiratory flow is primarily determined by mechanical properties of the lungs and airways and
is usually not limited by effort. At most lung volumes, maximal expiratory flow can be achieved with
submaximal expiratory effort. This concept is illustrated in the isovolume pressure–flow curves in Figure
10.6. These curves are obtained by performing a series of active exhalations with increasing effort at a
particular lung volume and plotting the resulting flow rates against corresponding pleural pressures. In
this instance, pleural pressure represents the driving pressure or force related to muscular effort. These
curves are obtained at three different lung volumes. Between TLC and 75% of TLC, flow increases with
effort and depends not only on pleural pressure but also on the patency of airways and the elastic recoil of
the lung at high volumes. At volumes below approximately 75% of TLC, expiratory flow increases with
effort up to a point beyond which further increases in effort do not lead to a higher flow rate. Flow
limitation occurs as expiratory resistance within the intrathoracic airways decreases gas pressure by an
amount equal to elastic recoil. The point along the airway at which this occurs, the equal pressure point
(EPP), sees gas pressure within the intrathoracic airway equivalent to the pleural pressure on the outer
surface of the airway. With further resistive pressure loss in the downstream (toward the mouth) airway
segment, pressure across the airway wall (transmural pressure [PTM]) becomes negative and the airway
tends to be compressed. Flow reaches a maximal level at this point because further increases in pleural
pressure resulting from effort tend to compress airways and limit flow to the same extent that they tend to
drive flow. This dynamic compression occurs because intrathoracic airways are exposed to pleural
pressures.
This concept is illustrated by the model in Figure 10.7. In this model, the lung or alveolus and airway
are suspended in a box representing the thorax. The lung is separated from the chest wall for descriptive
purposes only, and the space between the lung and chest wall should be considered the airless pleural
space. The numbers represent pressure in centimeters of water. In Figure 10.7A, the pleural pressure is
equal to the pressure surrounding the airways. At this level of lung inflation, the pleural pressure is equal
and opposite in sign to the elastic recoil pressure of the lung (+10; no pressure gradient is present to
produce airflow), and net alveolar pressure is atmospheric, or zero. During active exhalation (Fig.
10.7B), pleural pressure becomes positive, to +10. Because alveolar pressure is equal to the sum of
pleural pressure and lung recoil pressure, it increases by an amount equal to the increase in pleural
pressure. At this point, the difference between alveolar pressure (+20) and airway opening pressure (0)
represents the total pressure producing expiratory flow. It follows that as pressure falls due to flow
resistance, at some point between the alveolus and airway opening, the airway intraluminal pressure is
equal to pleural pressure, and intraluminal pressures downstream from this point are less than pleural
pressure. If this occurs along intrathoracic airway segments, where pressure surrounding airways is
pleural, downstream segments tend to collapse, limiting flow. With any further increase in effort, the
downstream segment tends to collapse even further. In this case, any additional increase in driving
pressure resulting from greater effort is merely dissipated in keeping the collapsed segment open.
FIGURE 10.6 Isovolume pressure flow plot at three different lung volumes. TLC, total lung capacity.
FIGURE 10.7 Model illustrating pleural pressures. Static recoil pressure is +10 cm H2O. A: Static conditions. B: Dynamic
conditions. Airway is compressed downstream from the point marked by asterisk.
Because this dynamic expiratory collapse occurs with submaximal effort over most of the VC,
maximum expiratory flow is not limited by effort during the FVC maneuver. Instead, maximum flow is
determined by intrinsic characteristics of the lung, such as lung recoil pressure and the resistance of
peripheral airways upstream from the EPP. Therefore, diseases such as emphysema that reduce the
elasticity of airways and lung tissue tend to produce flow limitation by reducing the driving pressure and
by making airways more collapsible. Diseases such as chronic bronchitis and asthma produce flow
limitation by increasing the resistance of upstream or peripheral airways. Because maximal expiratory
flow over the effort-independent range of the VC (<75% of TLC) depends on the resistive characteristics
of intrathoracic airways, tests of forced exhalation have become a useful means of detecting, quantifying,
and following obstructive lung disease.
Expiratory flow limitation ordinarily occurs within more central airways at higher lung volumes and
within smaller, more peripheral airways at lower lung volumes. Because chronic airflow obstruction is
thought to progress from smaller, more peripheral airways to larger airways, much attention has been
focused on identification of reduced maximum expiratory flow at lower lung volumes in the early
detection of COPD. It has been proposed that by measuring forced expiratory flow at a low lung volume,
say when 50% or 75% of the VC has been exhaled, and comparing it with established normal standards,
one might detect the presence of minimal airflow limitation. Thus, measurements made from the end-
expiratory portion of the maximal expiratory flow–volume curve could identify patients with early
expiratory airflow limitation before abnormalities occur in their timed VC measurements. In practice,
while such measurements may be more sensitive, they are neither as reproducible nor as specific as
spirometric tests of forced exhalation that relate expired volume to the time of exhalation, such as the
Forced Expiratory Volume at 1 second (FEV1).
Airway Resistance During Inhalation

Airway cross-section varies depending on both PTM and airway compliance. PTM depends on flow
direction and airway location. For intrathoracic airways, PTM is negative (compressing) during
exhalation and positive (distending) during inhalation. The tendency of intrathoracic airways to collapse
during forced exhalation results in flow limitation, as described previously. The PTM across
extrathoracic airways is in the opposite direction—negative during inhalation and positive during
exhalation.
Inspiratory airflow is effort-limited and thus increases in direct proportion to the force or effort
applied. Patients with COPD, in whom impaired expiratory airflow is invariably present, may have
decreased inspiratory flow as well. Inspiratory flow may be reduced in patients with chronic bronchitis
and in those with asthma because the bronchial lumen is narrowed by secretions, exudate, and
bronchospasm. Inspiratory flow is also reduced when airways become stiff and less expansile because of
inflamed bronchial walls or become narrow owing to decreased radial traction demonstrated
schematically in Figure 10.6. However, the magnitude of reduced inspiratory flow does not provide a
reliable index of the presence or severity of chronic airflow obstruction in emphysema, asthma, and most
other airway diseases.
LUNG VOLUME MEASUREMENTS

An isolated modest decrease in lung volume does not limit performance as long as adequate volume
remains to permit normal alveolar ventilation. Although the tidal volume normally increases with
exercise, the ventilation necessary for a given level of exercise can be achieved by increasing either tidal
volume or breathing frequency. Thus, compensation for limited lung volume can be attained by increasing
the breathing frequency. However, in the presence of lung diseases characterized by airway obstruction,
ventilation is maintained by a relatively greater increase in tidal volume than in frequency. This
interrelation between tidal volume and frequency is further considered under “The Work of Breathing,”
later in this chapter.
The reduction of lung volume occurring with diseases of the chest wall, lungs, or pleura provides a
crude guide to the severity of the disease. Thus, volume measurements may be useful for deciding when
therapeutic intervention is appropriate or assessing therapeutic efficacy. Lung volume measurements are
made easily, and their reproducibility renders them useful for serial evaluation of patients. Although no
specific diagnosis is suggested by a lung volume decrease, simple volume measurements, particularly the
VC, are just as sensitive an index of disease as the direct measurement of mechanical factors that
determine static lung volumes, such as lung compliance.
SPIROMETRY
The precise evaluation of respiratory mechanical parameters is important to check the degree of deviation
relative to healthy state and to estimate the progression of a chronic pulmonary disease or, conversely, the
effect of a drug. This consideration also applies to provocative tests to elicit the bronchial
hyperresponsiveness.
FIGURE 10.8 Spirometric tracing to define the subdivision of lung volumes. VT, Tidal volume (the amount of air mobilized
during a normal breath); IRV, Inspiratory Reserve Volume (the maximum volume of air that can be further inspired the end of a
normal breath); ERV, Expiratory Reserve Volume (the volume of air that can be further exhaled at the end of a normal expiratory
act); VC, Vital Capacity (the amount of air that can be mobilized by the lung from maximum inspiration down to maximum
expiration); RV, Residual Volume (the volume remaining in the lungs after a maximal expiration; therefore it cannot be measured
by spirometry. Its measurement requires the use of a tracer gas [methane or helium]); FRC, Functional Residual Capacity (the
volume of air remaining in the lungs at end expiration); TLC, Total Lung Capacity (the sum of VC + RV).
Spirometry is the most widely used method of investigation for the study of lung function, based on two
main physical variables: lung volumes and air flows. Their alteration reflect different respiratory
diseases, namely those implying an expiratory effort due to airways narrowing (obstructive syndromes)
and those implying a reduction of volumes mobilized due to increased stiffness of lung/chest wall
(restrictive syndromes). Figure 10.8 shows a subdivision of lung volumes during a spirometric maneuver
implying slow (quiet) inspiration up to the maximum volume followed by expiration to the minimal
volume.
Several volumes have been defined. Tidal volume (VT) is the amount of air mobilized during a normal
breath. This is usually about 500 mL for quiet breathing. Inspiratory reserve volume (IRV) is the maximum
volume of air that can be further inspired at the end of a normal breath. This corresponds to about 3,500
mL. Expiratory reserve volume (ERV) is the volume of air (about 1,000 to 1,500 mL) that can be further
exhaled at the end of a normal expiratory act. VC is the amount of air that can be mobilized by the lung
from maximum inspiration down to maximum expiration. Most healthy adults have a VC of about 4,500
mL. Residual volume (RV) is the volume remaining in the lungs after a maximal expiration; therefore it
cannot be measured by spirometry. Its measurement requires the use of a tracer gas (methane or helium).
This usually corresponds to about 1,500 to 2,000 mL. FRC is the volume of air remaining in the lungs at
end expiration. It corresponds to the sum of ERV and RV and amounts to about 3,000 mL. Total lung
capacity (TLC) is the sum of VC and RV. These values are compared to expected values normalized for
age, gender, race, and height.
Further information may be obtained from the volume–time and a flow–volume curve shown in Figure
10.9. The values are also normalized for age, gender, race, and height. From a volume–time and a flow–
volume curve, it is possible to obtain the FVC or the total amount of air that is exhaled after maximal
inspiration through a forced maneuver starting from VC down to RV. FVC might be smaller than VC as
forced exhalation increases the tendency to airway collapse causing air trapping. In normal subjects, FVC
is below 2% to 3% if compared to VC, but this difference increases remarkably in subjects with airflow
limitation. One of the most used values obtained is the FEV1 or the Forced Expiratory Volume at 1 second.
This is the volume of air that is exhaled during the first second of the forced maneuver, starting from VC.
Normally its value is greater than 80% of predicted value.
Not shown is probably the most important value of all. This is a dimensionless index known as the
Tiffeneau index. This is calculated by taking the ratio of the FEV1 to the FVC (FEV1/FVC). It may be used
to discriminate an obstructive versus a restrictive defect. In normal and in restrictive subjects this ratio is
of less index known as the Tiffeneau index. This is calculated by taking the ratio of the FEV1 to the FVC
(FEV1/FVC). It may be used to discriminate an obstructive vs a restrictive defect. In normal and in
restrictive subjects this ratio is ≥80%. This ratio is decreased to a various degree depending on the
severity of airway flow limitation in obstructive syndromes.
The so called “flow–volume” loop is depicted on the right side of Figure 10.9. The subject is invited
to make a forced expiration starting from VC. It is characteristic to observe a flow limitation shortly after
the onset of the forced expiration due to early compression of the airways caused by the remarkable
increase in pleural pressure above intra-airway pressure, already in healthy subjects (red line). One can
appreciate, for comparison, that this effect is greatly enhanced in obstructive syndrome (blue line) due to
the loss of elasticity of the airways (e.g., in emphysema).
FIGURE 10.9 Exhalation curves. A: Forced expiratory maneuver. FVC, Forced Vital Capacity (the total amount of air that is
exhaled after maximal inspiration through a forced maneuver starting from VC down to RV); FEV1, Forced Expiratory Volume
in 1 second (the amount of air the subject can exhale in 1 second). B: Expiratory flow–volume curve starting from VC. Note the
large flow limitation in the obstructive syndrome (blue line) relative to that of healthy subject (red line).
FIGURE 10.10 Schematic representation of normal and abnormal flow–volume loops. Flow is on the ordinate and volume on
the abscissa, with residual volume to the right and total lung capacity to the left. A: The solid line represents a normal flow–
volume loop. The dashed line represents a typical loop from a patient with obstructive airway disease, in which the greatest
reduction in airflow occurs in the middle and low ranges of the vital capacity. B: Flow–volume loop shows a truncated expiratory
(Exp) limb with normal inhalation, indicative of a variable intrathoracic obstruction such as an eccentric endotracheal tumor. C:
The truncated inspiratory (Insp) limb with a normal-appearing expiratory limb is consistent with a variable extrathoracic upper
airway obstruction (e.g., laryngeal lesions, vocal cord paralysis). D: Reduced maximal flows during both inhalation and exhalation
are characteristic of a fixed upper airway obstruction, usually seen with circumferential airway lesions.
Because of the pressure, volume, and flow relations of the lung, the presence of airway obstruction can
be determined by measuring maximal expiratory flow. Because maximal flow is relatively independent of
effort and primarily dependent on the recoil pressure of the lung, and because the recoil pressure of the
lung is dependent on lung volume, one need only relate the measured flow to the lung volume at which it
is measured; this relation is called a flow–volume curve shown in Figure 10.10.
Concerning airways resistances, one should remember that spirometry and flow–volume curves act as
surrogate markers of decreased airways caliber and therefore increased airflow resistances. Direct
measurement of airway resistances requires a specific methodology based on the use of a body
plethysmograph or of forced oscillation technique.
The major changes in airflow pathology are demonstrated in the exhalation part of the flow–volume
loop as depicted in Figure 10.10A. Dynamic intrathoracic obstructions such as COPD often produce a
characteristic truncated expiratory phase (Fig. 10.10B). Dynamic extrathoracic obstructions such as
cervical tracheomalacia primarily limit inspiratory flow (Fig. 10.10C). Fixed orifice obstructions such as
strictures or fibrosing mediastinitis limit both inspiratory and expiratory flow (Fig. 10.10D).
Noninvasive Estimate of Respiratory Mechanics: Forced Oscillation Technique

Note that small airways from generation 13 down are mostly involved in lung pathologies leading to air
flow limitation, yet they contribute to only a small share of the overall airways resistance (Fig. 10.5).
Unfortunately, the damage to small airways has to involve over 45% of terminal airways before
spirometry and plethysmography can detect it. Yet, the forced oscillation technique appears more suitable
to detect small alterations due to ongoing or progressing pathologies.
The forced oscillation technique2 helps to evaluate small airway pathology. This technique is based on
the superimposition, during spontaneous breathing, of small pressure waves, with variable frequency (f)
(Fig. 10.11) generated at the mouth by a specific equipment.
The ratio between the amplitude of the pressure signal delivered to the lung (ΔP) and the resulting
pulse flow signals (reflects the total Impedance [Zrs]) of the respiratory system is given by:
Total impedance (Zrs) is the algebraic sum of Resistance of the respiratory system (Rrs) to the airflow
and Reactance (Xrs):
Zrs = Rrs + Xrs
Measurements of Zrs, Rrs, and Xrs are made at different oscillation frequencies. Low oscillation
frequencies (<5 Hz) are transmitted more distally in the lung, therefore reflect the mechanical properties
of the whole bronchial tree plus the elasticity of lung tissue. High oscillation frequencies (>20 Hz) are
damped in airway of greater size, reflecting only mechanical properties of central airway. A distinction of
the mechanical properties of the central airways from that of distal airways + lung parenchyma can be
done by considering the difference in Rrs and Xrs measured at high and low frequencies of oscillation
(ΔR5 − 20). Considering Rrs, this difference reflects the so called frequency dependence of resistance
that essentially depends upon the resistance of small airway as well as the inhomogeneity in mechanical
properties of the lung tissue.3
An example of the usefulness of this observation is shown in Figure 10.12. Two subjects were
subjected to the frequency oscillation test in control conditions and after methacholine challenge, a test
widely used to estimate bronchial hyperreactivity as an index of severity of asthma. In both subjects, no
real difference in both Rrs and Xrs was observed on increasing the frequency of oscillation in control
conditions (black points). Methacholine challenge caused changes of Rrs and Xrs in both subjects on
increasing frequency. However, in subject A there was essentially a parallel shift of Rrs and Xrs while in
subject B a remarkable frequency dependence of both indexes was observed. The difference in the pattern
of response to methacholine allows one to identify the site of action of the challenge: in subject A the
challenge caused a homogeneous constriction along the airways, while in subject B the increase in
frequency dependence reveals a greater bronchoconstriction of the smaller peripheral airways.4
FIGURE 10.11 Schematic representation of the high-frequency oscillation technique to derive airway resistance. The highest
frequency (20 Hz) provides an index of their flow resistance (R20). The lowest frequency (5 Hz) provides an index of total
airways resistance (R5).
FIGURE 10.12 Different response of two subjects to the frequency oscillation test in control conditions and after methacholine
challenge. Rrs, Respiratory Resistance; Xrs, tissue reactance. Control data, closed circles; Methacholine data, open circles.
WORK OF BREATHING
Breathing requires that the respiratory muscles or a mechanical ventilator generate a force (pressure)
sufficient to displace the lung and chest wall and move the volume of air required for ventilation. Force is
required to stretch tissue, counteract gravity, and overcome frictional resistances of tissues and airways.
An optimal combination of breathing frequency and tidal volume exists at which the work of breathing is
minimal. This combination varies between subjects and for specific metabolic requirements. As tidal
volume is increased, elastic recoil pressure accounts for a larger portion of ventilatory work (see the PV
curve in Fig. 10.4). As breathing frequency increases, the airway resistance increases owing to additional
flow turbulence and to increased expiratory airway narrowing because of dynamic airway compression.
At very high frequency or in the setting of airflow obstruction, attempts to drive the respiratory system
faster than it will respond, using pressures greater than those required for maximum expiratory airflow,
represent wasted effort.
In both health and disease, people tend to adopt a combination of tidal volume and breathing frequency
that achieves the required ventilation with minimal work. In normal humans, the work of breathing
requires little energy, approximately 1 mL of oxygen per liter of ventilation, or less than 2% of total
oxygen consumption. In lung and chest wall disease, the oxygen demand of ventilatory muscles may
exceed oxygen delivery capacity, leading to muscle fatigue. In this manner, exercise capacity may be
limited when lung disease causes a substantial increase in the work of breathing.
The elastic work of breathing may be calculated from the pressure–volume curve. Figure 10.13 shows
a schematic representation of the pressure–volume relationship of the respiratory system. The slope of the
relationship is the compliance (Crs) of the respiratory system (including the elastic properties of the lung
and chest wall). The hatched area represents the elastic work (Wel) done during a single inspiration
necessary to increase lung volume by VT from the FRC. We can now estimate the inspiratory work that
requires active energy expenditure by the inspiratory muscles (see paragraph “Mechanical lung chest wall
coupling”).
FIGURE 10.13 Volume–pressure relationship of the respiratory system used to define the elastic (blue area) and resistive (red
area) work during inhalation. FRC, Functional Residual Capacity; VT, Tidal Volume; P RS, Respiratory System Pressure
(measured at the mouth, or through endotracheal tube); Crs, compliance of the respiratory system (including the elastic properties
of the lung and chest wall).
The elastic work for a single breath could be defined in general by:
Wel = VT · ΔP
Considering Crs = VT/ΔP, the blue shaded area in the graph represents the elastic work of breathing
given by:
From the above equation, one can appreciate that the elastic work of breathing is inversely
proportional to the compliance of the respiratory system and directly proportional to the square power of
tidal volume. It is of relevance to note that a decrease in lung/chest compliance markedly affects the
elastic inspiratory work of breathing.
To obtain inspiratory elastic power (PWel), Wel has to be multiplied by the respiratory rate (RR):
Therefore, when the ventilatory demand increases, the increase in WEL depends more on the increase
in VT, being elevated to the squared power, than on the increase in respiratory rate.
Resistive inspiratory work is represented by the red area and obviously increases with increase in
flow rate and airway resistance. In a healthy subject in the range of ventilation increasing from 20 to 80
L/min, inspiratory elastic work accounts from about 60% to 70% of total respiratory work, while
resistive work of breathing remains in the range of 20%.5
Respiratory efficiency may be improved through physical training. Figure 10.14 is an illustration of
this by analyzing several variables during exercise-induced hyperventilation before and after a training
program. On increasing workload without physical training (closed symbols), ventilation (VE on the
ordinate) increases through an increase in both tidal volume (VT on the abscissa) and respiratory rate
(isopleths labeled from 15 to 30).
FIGURE 10.14 Ventilation versus tidal volume relationship for sedentary subject before (closed circles) and after (open
circles) training program. The graph reports iso-Respiratory Rate lines (dashed isopleths, labeled from 15 to 30) and in
inspiratory elastic power (continuous isopleths, labeled 15 to 150). After training, the same ventilation is achieved through a
smaller Vt, a higher RR, and a lower elastic work of breathing. Therefore, training resulted in a greater efficiency of breathing.
Corresponding to an increase in ventilation from about 10 up to about 70 L/min, there is a ten-fold

increase in inspiratory elastic power (isopleths labeled 15 to 150). Interestingly, after training (open
symbols), the whole ventilation versus tidal volume relationship is shifted upward revealing an advantage
to improve the efficiency of breathing. Indeed, the same ventilation is achieved with a lower VT and a
higher RR, and correspondingly with a lower inspiratory power, thus a less costly pattern of breathing.6
Since perceived fatigue during work includes a component of respiratory nature, one can hypothesize
that an increased efficiency of respiratory muscles might contribute to decrease the fatigue sensation
during hyperventilation. In this respect it is important to recall that respiratory fatigue is uniquely related
to respiratory power output. Thus, reducing the latter, implies a decrease in the perception of effort to
breathe.7
After lobectomy and pneumonectomy, respiratory work increases, because lung compliance decreases
in inverse proportion to the resected volume.8 It is therefore expected that this may elicit dyspnea, and
limit exercise capacity.
ALVEOLAR MECHANICS
Of critical importance to the functioning of the lung is the stability of the alveolus. Indeed, the overall
distending pressure (Pd) for an alveolus is the sum of two components, one depending on the elastic
properties of the alveolar wall (Pel) and the other reflecting the surface forces developing at the ABB
tissue–air interphase (P γ):
Pd = Pel + Pγ
Pel was found to vary substantially between alveoli9 and furthermore Pγ relates to the alveolar radius
(R) and the surface tension (γ) according to the Laplace law:
In Figure 10.15, for the same value of γ, Pγ would be greater in the smaller alveolus (A) causing its
emptying into the larger one (B). Therefore, adjacent alveoli that differ in size and mechanical properties
represent an intrinsic unstable system. Stability is partially provided by the existence of surfactant
molecules10 stratified on the ABB surface. As suggested by the figure, a thicker layer of surfactant in the
smaller alveolus decreases γ: as long as the ratio γ/R is kept constant, stability is partially assured,
because Pd would be equal in alveoli of different radius. Another advantage of surfactant is that it
decreases γ considerably and therefore the corresponding value of Pγ. In a healthy lung, γ may be as low
as about 2 to 10 dynes/cm that is well below the value of a tissue–air interface (about 70 dynes/cm). A
low value of Pγ also keeps Pd low, meaning that inspiratory muscles have to exert a smaller pressure to
distend the lungs.
In absence of surfactant, as in preterm lung, alveolar stability is largely compromised and, in fact, the
lung presents overdistended and has atelectatic regions.
PRACTICAL APPLICATION OF PULMONARY MECHANICS

An understanding of pulmonary mechanics is also useful when applied to the management and monitoring
of ventilated patients. Ventilation depends on volume changes driven by pressure gradients, and it does
not matter whether the force is generated by respiratory muscles or by a mechanical ventilator.
FIGURE 10.15 Alveolar stability is guaranteed by a thicker layer of surfactant in alveoli of smaller radius (A), relative to larger
ones (B).
In ventilated patients, for example, it may be useful to evaluate maximal pressure at the airway opening
under both dynamic (peak inspiratory) and static (plateau inspiratory) conditions. Peak pressure is that
required to distend the entire respiratory system at a given inspiratory flow and tidal volume. In ventilated
patients, this system includes the machine circuitry and tubing in addition to the airways, lung, and chest
wall. Increased peak pressure may indicate a variety of conditions associated with either decreased
respiratory system compliance, increased resistance to gas flow, or both. These conditions include
parenchymal lung disease, fluid accumulation in the pleural space, airway secretions, kinked tubing, and
increased intra-abdominal pressure.
Plateau pressure reflects the force required to maintain the respiratory system at an increased volume
in the absence of gas flow. Thus, volume change in relation to the difference between static end-
inspiratory and static end-expiratory pressure, or plateau pressure minus added PEEP (if applied),
reflects respiratory system compliance. Static respiratory system compliance depends on mechanical
characteristics of both the lungs and chest wall. Further distinguishing lung from chest wall compliance
requires measurement of transpulmonary pressure by esophageal balloon. Transpulmonary pressure is
determined by lung elastic recoil, whereas chest wall recoil is the difference between respiratory system
and transpulmonary pressure. Care must be taken to account for pressures associated with spontaneous
ventilatory efforts. For example, active expiratory effort during measurement of the end-inspiratory
plateau can greatly increase pressure and lead to underestimation of compliance.
The measurement of respiratory system compliance and its lung and chest wall components is
worthwhile in diseases such as adult respiratory distress syndrome, in which compliance is severely
reduced. Compliance measurements can be used to monitor progress, modify ventilator strategies to
minimize barotrauma, adjust PEEP to optimize gas exchange, and so forth. For example, compliance and
gas exchange should improve with increase in PEEP as alveoli are recruited, but it may be reduced when
PEEP is increased to the point of overdistention. In addition, the difference between the peak and static
(no-flow) pressures provides an estimate of the pressure required to overcome airflow resistance.
Increases in peak–static pressure difference suggest increasing resistance to airflow. A firm understanding
of the mechanics of breathing can be valuable in optimizing the management of critically ill patients.
PULMONARY GAS EXCHANGE

At the cellular level and in very simple organisms, oxygen is provided by simple diffusion. In more
complex organisms, a more complex delivery system is necessary. The human respiratory system supplies
oxygen through the combined processes of convection (bulk flow) and diffusion. The muscles of the chest
wall and the conducting airways bring large volumes of gas into the alveolar space. The alveolar surface,
on the order of 50 to 100 m2, provides a large area for diffusion of gas into the blood. The cardiovascular
system conveys blood to the tissues, where the large combined capillary surface area facilitates diffusion
of oxygen across the cell membrane and into the mitochondria. The net effect is the passive diffusion of
oxygen down a partial pressure gradient from the atmosphere to mitochondria.
Organisms also require a mechanism to eliminate the end products of metabolism. The renal and
gastrointestinal systems perform this function for liquid and solid wastes, whereas the respiratory system
is the site of elimination for carbon dioxide gas. The term gas exchange thus refers to both the uptake of
oxygen and the elimination of carbon dioxide.
Oxygen consumption and carbon dioxide production occur in the mitochondria and vary with the
metabolic state. At rest, both are on the order of 200 to 250 mL/min, but this can increase to 1 L/min with
brisk walking and 3 L/min with running, although trained athletes commonly achieve consumptions of 5
L/min with transient mean oxygen consumption levels as high as 6.6 L/min.
The relative amount of carbon dioxide and oxygen exchanged is determined by the type of fuel
consumed. Carbohydrate metabolism generates 1 mole of carbon dioxide for every mole of oxygen
consumed. For proteins, the ratio drops to 0.8; for fats, it is 0.7. This ratio of total body carbon dioxide
production to oxygen consumption is termed the metabolic respiratory quotient (RQ). In the lungs, the
ratio of carbon dioxide elimination to oxygen uptake is called the respiratory exchange ratio (R). Because
the lung is the site of all oxygen uptake and carbon dioxide removal in the body, lung gas exchange in the
steady state is equal to tissue gas exchange, and R is equal to RQ.
STRUCTURE OF THE AIR–BLOOD BARRIER

A human lung is composed of a number of alveoli ranging from 200 to 600 million units, with an average
diameter of about 30 to 50 microns. The alveolar walls, alveolar septa, contain an extensive network of
capillaries (Fig. 10.16). The air–blood barrier (ABB) consists of a thick portion, which contains the
fibrous component of the lung parenchyma, and a thin portion, where the thickness is incredibly reduced
( 0.5 μm) due to the thinness of epithelial and endothelial cells as well as of the basal membrane. The
overall surface of the ABB is in the range of 100 m2 corresponding to about 2,000 cm2/g of tissue. The
ABB represents the real functional unit involved in respiratory gas exchanges.
Under physiologic conditions, the blood passing through the alveolar capillaries is enriched with
oxygen that binds to hemoglobin in the blood and releases carbon dioxide in the alveoli through a
combined diffusion—solution of gases across and within the ABB.
FIGURE 10.16 Transmission electron microscopy image of an alveolar–capillary unit (A) and a high-resolution image of the thin
portion of the air–blood barrier (B). Cap, capillary; Alv, alveolus; Ep, epithelium; en, endothelium; bm, basement membrane.
BIOPHYSICS OF GAS DIFFUSION

Gas exchanges occur in generations 17 to 23 where the three functional characteristics that optimize the
diffusion process coexist: (1) huge extension of diffusive surface, (2) the minimum thickness of the
alveolar–capillary membrane, and (3) minimization of convective movements. The latter do not interfere
with gas diffusion as they decrease below the diffusional velocity of respiratory gases even in
hyperventilation that implies an increase in convective flows.
The diffusive flow of a gas across the ABB is defined as:
where SA and τ are the surface and thickness of ABB, P is the pressure gradient for the gas across the
ABB, and D is a diffusion coefficient for the gas given by:
where α is the solubility coefficient and MW is the molecular weight of the gas considered, in this case,
O2 and CO2. Note the morphologic advantage of the morphologic design of the ABB providing a very high
ratio to favor gas exchanges.
In case of oxygen flow (ḊO2) from the alveolar space to the blood, the equation can be written as:
where represents the pressure gradient sustaining O2 diffusion at the entrance into the
alveolar capillary, PAO2 being the partial pressure in the alveolar space ( 100 mm Hg) and the O2
partial pressure in the mixed venous blood ( 40 mm Hg). Obviously, the value of tends to
decrease along the pulmonary capillary due to equilibration of O2 pressure to reach alveolar pressure.
Figure 10.17A is a schematic representation of the alveolar–capillary unit. Figure 10.17B shows that the
kinetics of oxygen pressure along the capillary segment allows equilibration to be reached in physiologic
conditions in about 0.3 second. Figure 10.17C shows the equilibration process for CO2 over the same
time period.
FIGURE 10.17 A: Schema of the alveolar–capillary unit to show the oxygenation process of the blood and the partial pressure
of O2 in the venous blood ( ), in the alveolar air (PAO2), and in the arterial blood (Pa O2). B: Time course of O2
equilibration process as a function of the transit time of the blood in the pulmonary capillary. C: Corresponding equilibration
process for CO2.
Measurement of Alveolar Diffusion Properties

Since, at present, no methods are available to estimate the ratio , gas diffusive properties of the lung are
based simply on the estimate of gas diffusion divided by ∆P. The complication is that in the case of O2, no
precise notion is available for the kinetics of the time-dependent change in along the
pulmonary capillary. To overcome this complication, it was proposed to estimate the diffusion lung
capacity from the alveolar uptake of CO due to the fact that this gas can bind to Hb with high affinity,
essentially without exerting a partial pressure.
The most common method used to estimate the diffusion lung capacity of CO (DLCO) is the so-called
single-breath method. Measurements of DLCO are conventionally performed at TLC. The subject inhales
a given volume of air containing 0.3% CO up to TLC, holds his breath for 10 seconds, and then exhales
down to RV. Based on the washout curve of CO, one can determine its alveolar–capillary diffusion
transfer from its exponential decay as a function of time from the initial alveolar concentration (CO0) as:
COt = CO0 · e−kco−1
where kco is considered a diffusion constant defined as:

COt being the expiratory fraction of CO at a given time t.
The uptake of CO is expressed as DLCO = mL/min/mm Hg, where the reference pressure is
considered, by convention, that of dry gases in the alveolar air (atmospheric – water vapor pressure; at
sea level 760 – 47 mm Hg). This would imply like all the lung were filled with 100% CO, which is
obviously not the case! The use of another tracer (methane of helium) gas that cannot cross the alveolar
barrier is used to estimate the alveolar volume of the subjects (VA) allowing to express DLCO also per
unit of lung volume, thus:
where Kco is the transfer coefficient (Krogh Index).

Normalization of DLCO to lung volume (VA) allows comparing individuals of different sizes as well
estimate within a given subject the dependence of DLCO on lung volume. Figure 10.18 shows data from
several subjects indicating that DLCO decreases when measured at lung volumes lower than TLC,
essentially due to the decrease in alveolar surface area for the diffusion process. The data also reveal
marked interindividual differences11 reflecting essentially peculiar morphofunctional features of the ABB
affecting ABB diffusive properties as well as CO-binding by capillary blood.
Subcomponents of Lung Diffusion

A brilliant method12 is available to partition total lung diffusing capacity (DLCO) into its subcomponents,
that is, the alveolar–capillary membrane diffusing capacity (Dm) and the pulmonary capillary blood
volume (Vc). Figure 10.19 is a schematic functional representation of the subcomponents of diffusion
capacity considering the oxygen pathway, although the estimate of subcomponent relies on the use of CO.
The following relationship holds between total diffusive capacity and its subcomponents:
where (θ) represents the chemical reaction rate of CO (the gas conveniently used for diffusion capacity
measurement) with hemoglobin. The method resides on measuring DLCO for three oxygen gas mixtures
allowing to vary θ so as to obtain a linear regression as shown in Figure 10.20 whose intercept on the Y
axis is 1/Dm and slope is 1/Vc.
FIGURE 10.18 Interindividual differences in total lung diffusion capacity (DLCO) as a function of lung volume (VA). TLC,
Total lung capacity.
Interindividual Differences in Dm
Membrane diffusion capacity is highly individual, with individual responses to exercise as well as
inflammatory insults. Figure 10.21A shows data of Dm measured at various lung volumes for the same
subjects of Figure 10.18.11 The general decrease in Dm on decreasing lung volume reflects the decrease
in the ratio . Indeed, due to destretching of the lung parenchyma, alveolar surface decreases while the
thickness of the septa increases. Yet, the remarkable interindividual differences suggest differences in
morphologic and functional features of the ABB. As shown in Figure 10.21B, a spectrum of slopes can be
obtained on decreasing lung volume by modulating by varying the number of alveoli (Nalv—that
influence SA) and the thickness of the septa (τ).
FIGURE 10.19 Partitioning total diffusing capacity (DLCO) into its subcomponents: membrane diffusive capacity (Dm) and
volume of blood contained in the alveolar capillary network participating to oxygen uptake (Vc). Coefficient θ represents the
amounts of O2 binding to hemoglobin (Hb) in a time unit.
FIGURE 10.20 Method to measure DLCO subcomponent by using three oxygen gas mixtures allowing to vary Θ (the chemical
reaction rate of CO with hemoglobin) so as to obtain a linear regression whose intercept on the Y axis is 1/Dm (membrane
diffusing capacity) and slope is 1/Vc (capillary blood volume). FIO2, Fraction of inspired oxygen.
Interindividual Differences in Vc
Vc can be regarded as the volume of blood contained in the alveolar capillary network contributing to gas
exchange. Figure 10.22 shows data again for the same subjects first demonstrated in Figure 10.18.11 Vc
increases on decreasing lung volume. The drawing demonstrates the mechanical condition of septal and
corner vessels on changing lung volume. Basically, destretching of the lung allows perfusion of the septal
vessels and closure of corner vessels, the opposite being true on increasing lung volume. Note that the
overall value of Vc essentially reflects the patency of septal vessels whose number largely overcomes
that of corner vessels. One can interpret the large interindividual variability as reflecting differences in
alveolar capillary density.
To summarize, measuring diffusion subcomponents represents an important tool to interpret the
interindividual differences in lung diffusion capacity in terms of alveolar geometry as well as extension of
the capillary network of the ABB. This approach may be of potential help to characterize at individual
level the adaptation to particular conditions (such as exercise or exposure to hypoxia),13 as well as the
evolution process of chronic lung disease. Indeed, the reduction of DLCO may reflect the loss of alveolar
surface (emphysema, lung resection), an increase in thickness of ABB (lung edema, fibrosis) leading to a
decrease in Dm; while a decrease in the number of alveolar capillaries (vascular “pruning” as in
pulmonary hypertension) would decrease Vc.
The Oxygen Diffusion-Transport Function

The estimate of oxygen diffusive capacity (DLO2) is obtained simply considering the ratio of O2/CO
diffusion coefficient as given by:
As stated above, one can estimate DLO2 as DLCO × 1.23 and this represents the potential diffusion
capacitance of the lung for oxygen. Actually, the oxygen transfer from ambient air to blood involves two
processes placed in series: diffusion and chemical bond with hemoglobin. This second process depends
on the availability of reduced hemoglobin, continuously supplied by the venous blood flow incoming to
the lungs, namely cardiac output ( ). Considering the lung diffusion-transport of oxygen, the following
mass conservation equation applies:
Mass of O2 diffused = Mass of O2 transported
Based on the above equation, an elegant model was developed14 to describe: (1) the kinetics of the
equilibration process for blood oxygenation to approach the alveolar oxygen partial pressure and (2) the
final level of oxygenation reached when blood exits the alveolar capillary.
The basic equation linking the diffusive and transport, perfusive-dependent mechanisms is:
where PA, Pa are the partial pressures of oxygen in the alveolar compartment, in the mixed venous blood,
and in the blood exiting the alveolar capillary, respectively. DLO2 is the diffusive capacitance and β can
be defined as the perfusive capacitance given by the product of cardiac output and β that represents the
slope of the hemoglobin dissociation curve between arterial and venous point.
FIGURE 10.21 A: Interindividual differences in membrane diffusing capacity (Dm) as a function of alveolar volume (VA). B:
Numerical model to explain the interindividual differences in Dm by varying the number of alveoli (Nalv) and the thickness of the
air–blood barrier (τ). TLC, Total lung capacity.
FIGURE 10.22 Left: Interindividual differences in capillary blood volume (Vc) as a function of alveolar volume (VA). Right:
Effect of lung volume on the patency of corner and septal alveolar vessels. TLC, Total lung capacity.
It is easy to understand that the ratio at the exit of pulmonary capillary may vary between 0 and 1.
A value of 0 indicates a complete equilibration of the venous blood to reach the alveolar oxygen pressure
so that PA = Pa. On the other extreme, if the ratio is equal to 1, the numerator is equal to the denominator,
indicating that no oxygenation occurred as the blood leaving the lung remained venous (the case of a
shunt). This analysis is particularly useful to describe conditions where the oxygen demand by the tissues
is increased and/or limitations to the diffusion or perfusion processes develop affecting the full
equilibration of venous blood with alveolar air. Figure 10.23 shows in healthy subjects the average
values of the ratio (an index of the alveolar–capillary equilibration) as a function of in various
conditions. At rest (complete equilibration of blood with alveolar oxygen pressure) for a
averaging 10 to 12. The latter value reveals an interesting feature of the oxygen diffusion–transport
system, namely a redundant diffusion capacitance relative to perfusion capacitance. With increasing need
for oxygen delivery to the tissues (from normoxia to exercise), the increase in cardiac output leads to a
remarkable decrease of the ratio that, in turn, results in an increase in that reveals an
aggravating lack of equilibration between blood and alveolar gas. A further decrease in β is caused by
hypoxia that decreases DLO2 as a consequence of a decrease in alveolar–capillary O2 pressure gradient.
Thus, heavy exercise in hypoxia is a potent cause of capillary–alveolar disequilibrium for oxygen
diffusion–transport; obviously, the condition of disequilibrium results in the so called alveolar–capillary
gradient, namely a difference between oxygen pressure in the alveoli and in the blood exiting the lung
capillary. Downstream, this condition results in a decrease in arterial blood oxygen saturation.
Functional Considerations Concerning Oxygen Diffusion–Transport

As noted above, is high at rest in healthy subjects (about 10 to 12) revealing a much greater diffusive
relative to perfusive capacity for oxygen. This ratio decreases when there is a need to increase oxygen
delivery to the tissues due to the increase in cardiac output. In physiologic conditions, there is no
limitation to gas diffusion and what limits gas transport in the blood only relates to the possibility to
increase cardiac output (concept of perfusion limitation). In case of pathologic conditions decreasing the
extension of the gas exchange surface area or the extension of the alveolar capillary network and/or
increasing the thickness of ABB, DLO2 is due to decrease implying a condition of diffusion limitation.
Obviously both diffusion and perfusion limitation may coexist in pathologic conditions.
On clinical grounds, the decrease in the ratio below 2 (Fig. 10.23), implies the generation of an
appreciable increase in the alveolar–capillary gradient as well as in the ratio, implying a decrease
in arterial oxygen saturation and therefore in working capacity. It is obvious that when diffusion limitation
in lung disease causes a decrease of already at rest, even a mild exercise may drop this ratio below
the critical value of 2. Although the ratio appears useful to describe pathophysiologic conditions
affecting the oxygen diffusion–transport function, it does not provide indications concerning the matching
of ventilation to perfusion.
FIGURE 10.23 Index of alveolar–capillary equilibration as a function of the ratio of diffusive to perfusive capacity
. P A, Pa are the partial pressures of oxygen in the alveolar compartment, in the mixed venous blood, and in the blood
exiting the alveolar capillary, respectively; DLO2 is the diffusive capacitance and β can be defined as the perfusive
capacitance given by the product of cardiac output and β representing the slope of the hemoglobin dissociation curve between
the arterial and venous points.
FIGURE 10.24 Comparison between a healthy subject (red line) and a pneumopathic patient (blue line) with diffusion
limitation in response to a mild exercise that requires an increase in the metabolic need. A: O2-delivery versus cardiac output
relationship. B: O2 extraction ratio versus cardiac output relationship.
Matching Lung Diffusion–Transport to Metabolic Need

Respiratory function is responsible for keeping constant the partial pressures of alveolar gases, and
consequently, for maintaining unchanged the pressure gradients that support the diffusion of the respiratory
gases through the ABB. This balance is maintained through ventilation, which allows a continuous air
renewal within the lungs to satisfy the oxygen need of the tissues. The numerical relationship, valid for all
mammals, between alveolar ventilation (VA) and oxygen consumption ( O2) is:
Through arterialized blood, oxygen arrives to peripheral tissues, where it passes inside the cells
according to a defined pressure gradient down to mitochondria, where it is used in oxidative
phosphorylation.
The equation relating the peripheral oxygen consumption to oxygen transport in the blood is expressed
by the Fick principle:
where is cardiac output and CaO2 and are oxygen concentration in the arterial and mixed venous
blood, respectively.
Considering that the oxygen delivery to the tissues is defined by, · CaO2 one can define oxygen
extraction ratio as the fraction of oxygen being utilized compared to that potentially available by the
tissues:
The data of Figure 10.24 allow a comparison between a healthy subject (red line) and a compromised
patient (blue line) with diffusion limitation in response to mild exercise that requires an increase in the
metabolic need. In the healthy subject (A), the slope of the O2-delivery versus cardiac output clearly
corresponds to and remains constant on increasing cardiac output; conversely, in the patient the slope of
the same relationship is progressively decreasing revealing a progressive decrease in the O2-delivery due
to a decrease in CaO2. In Figure 10.24B, one can note that the O2 extraction ratio of the healthy subject
remains constant while in the patient this ratio progressively increases reflecting the fact that the decrease
in is greater than the decrease in CaO2. Thus, the diffusion limitation impairs oxygen diffusion–
transport so that the patient has to face the oxygen need by a greater oxygen extraction from the blood
resulting in a lower venous oxygen concentration.
To summarize: the healthy subject extracts the same amount of oxygen from the blood (about 30%) with
increasing cardiac output; whereas the subject with pulmonary disease has to extract up to 70% of the
oxygen delivered to the tissues. The corresponding decrease in the tissue pO2 may reach very low values
(30 to 35 mm Hg) causing significant cellular hypoxia.
REFERENCES
1. Mead J. The lung’s quiet zone. N Engl J Med 1970;282(23):1318–1319.
2. Oostveen E, MacLeod D, Lorino H, et al. The forced oscillation technique in clinical practice: Methodology, recommendations and
future developments. Eur Respir J 2003;22:1026–1041.
3. Goldman MD, Saadeh C, Ross D. Clinical applications of forced oscillation to assess peripheral airway function. Respir Physiol
Neurobiol 2005;148(1–2):179–194.
4. Beretta E, Tana F, Grasso GS, et al. Regional differences in bronchial reactivity assessed by respiratory impedance. Respir Physiol
Neurobiol 2014;192: 23–29.
5. Cross TJ, Sabapathy S, Beck KC, et al. The resistive and elastic work of breathing during exercise in patients with chronic heart failure.
Eur Respir J 2012;39(6):1449–1457.
6. Passoni E, Lania A, Adamo S, et al. Mild training program in metabolic syndrome improves the efficiency of the oxygen pathway.
Respir Physiol Neurobiol 2015;208:8–14.
7. Aliverti A, Kayser B, Lo Mauro A, et al. Respiratory and leg muscles perceived exertion during exercise at altitude. Respir Physiol
Neurobiol 2011;177(2):162–168.
8. Miserocchi G, Beretta E, Rivolta I. Respiratory mechanics and fluid dynamics after lung resection surgery. Thorac Surg Clin
2010;20:345–357.
9. Salito C, Aliverti A, Rivolta I, et al. Alveolar mechanics studied by in vivo microscopy imaging through intact pleural space. Respir
Physiol Neurobiol 2014;202:44–49.
10. Hawgood S, Clements JA. Pulmonary surfactant and its apoproteins. J Clin Invest 1990;86(1):1–6.
11. Miserocchi G, Messinesi G, Tana F, et al. Mechanisms behind inter-individual differences in lung diffusing capacity. Eur J Appl Physiol
2008;102(5):561–568.
12. Roughton F, Foster R. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the
human lung with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl
Physiol 1957;11(2):290–302.
13. Bartesaghi M, Beretta E, Pollastri L, et al. Inter-individual differences in control of alveolar capillary blood volume in exercise and
hypoxia. Respir Physiol Neurobiol 2014;190:96–104.
14. Piiper J, Scheid P. Model for capillary-alveolar equilibration with special reference to O2 uptake in hypoxia. Respir Physiol
1981;46(3):193–208.
Section
III
THORACIC IMAGING
11
Standard Radiographic Evaluation of the
Lungs and Chest
Dong-Seok Daniel Lee ■ Mary Salvatore ■ David Yankelevitz ■ Claudia I.
Henschke ■ Raja M. Flores
INTRODUCTION
It would be difficult to imagine the practice of surgery without radiology. Even from the first publication
on “Roentgen Rays,” scientists understood the potential implications of such a magnificent tool that could
look inside of a person.1 The first case report of the clinical use of x-ray was published in 1896 and
demonstrated images of a dislocated and reduced elbow.2 A current PubMed search of the word radiology
yields 1,173,057 distinct citations. Advances in imaging techniques over the years have made it easier to
diagnose thoracic pathology. The purpose of this chapter is to provide an overview of the thoracic
imaging modalities and some of the most important information provided by the imaging.
IMAGING MODALITIES
Chest x-ray
The initial radiographic evaluation of the chest involves standard x-ray imaging. This provides an
overview of the chest and can yield diagnostic information quickly. It is important to examine all aspects
(bony and soft tissue structures) of the films and not focus solely on the lung fields. The chest is unique in
the ability to identify pathology on a standard radiograph. The air-filled lung allows for excellent contrast
between soft tissue abnormalities. Two views (posteroanterior [PA] and lateral) are performed in order
to construct a three-dimensional representation of the thorax and can confirm whether a lesion is truly
intrathoracic (Fig. 11.1).
Knowledge of the normal thoracic anatomy helps in localization of disease processes within the chest.
A healthy young person should be able to inflate the lungs to the 10th rib posteriorly (Fig. 11.2).
Occasionally, other views may be helpful. Oblique and apical lordotic views operate on the principle
that a change in position separates overlying structures. The lordotic view allows for better examination
of the lung apices with the clavicle and first rib out of the way. Lateral decubitus films are useful in the
evaluation of pleural effusions, especially sub-diaphragmatic pleural effusions which can be missed
because they do not blunt the costophrenic angle.
Computed Tomography
Computed tomography (CT) scan has drastically changed since it was first introduced in the 1970s. The
development of multislice scanners has enabled imaging with better resolution and shorter acquisition
times and has allowed progressively decreasing slice thickness, thus enabling the detection of smaller
nodules. Three-dimensional reconstructions are also possible, aiding in diagnostic accuracy. Computer-
assisted techniques allow for automated nodule detection and for volumetric measurements.
Intravenous (IV) contrast helps delineate mediastinal and hilar lymph nodes from the pulmonary
vasculature. It is of limited utility in the evaluation of parenchymal lesions. The major benefit of IV
contrast is in the investigation of the pulmonary arteries for the diagnosis of pulmonary embolism. Emboli
can be detected within subsegmental arterial branches and the CT angiogram has become the standard
imaging study for the diagnosis of pulmonary emboli (Fig. 11.3).
FIGURE 11.1 Proper positioning for posteroanterior (A) and lateral chest x-ray (B).
Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) utilizes radiofrequency pulses through a strong magnetic field in order
to construct detailed anatomic images. MRI has limited usefulness for evaluation of lung parenchyma and
does not offer much more than a CT scan in the routine evaluation of thoracic pathology. However, its
advantage over CT scan is in its contrast resolution of soft tissue structures. It is adept at differentiating
mediastinal structures and may aid in the diagnosis of mediastinal masses. MRI is particularly superior to
CT scan in the evaluation of neural involvement, such as the brachial plexus in Pancoast tumors and the
spinal cord in malignant schwannomas (Fig. 11.4).
FIGURE 11.2 Posteroanterior (A) and lateral chest x-rays (B) with optimal positioning and inspiratory effort.
FIGURE 11.3 Pulmonary embolism. Contrast CT scan of the chest demonstrates a large occlusive embolus of the right
pulmonary artery.
Positron Emission Tomography

Positron emission tomography (PET) is a nuclear medicine imaging technique that quantifies metabolic
processes in the body. It detects gamma rays emitted by a positron-emitting radionuclide tracer which is
attached to a biologically active molecule. The most common tracer, 18-fluorodeoxyglucose (18FDG), is
an analogue of glucose that is injected into the body and has found utility in the detection of cancer.
Sensitivity and specificity of diagnosing malignant pulmonary nodules are 96.8% and 77.8%,3
respectively, but diagnostic accuracy diminishes with diameter <1 cm.4 18FDG-PET is more accurate than
conventional imaging in the detection of metastatic disease5 and has become the standard imaging study
for the clinical staging of chest malignancies.6,7
ANATOMY OF THE THORAX

Airway, Lung, Pleura
The intrathoracic trachea deviates slightly to the right as a result of the left-sided aortic arch and
terminates at the carina, which is typically located at the level of the T5 vertebra. The left main stem
bronchus arises from the carina at a more acute angle whereas the right main stem bronchus follows a
more vertical course. The bronchi progressively divide into smaller airways and form the basis of the
bronchopulmonary segments. The pulmonary arteries run a similar course and segmental distribution as
that of the segmental bronchi. The pulmonary veins are indistinguishable from the arteries in the periphery
on routine radiograph. Centrally, the inferior veins run a more horizontal course that the vertical lower
lobe arteries.
FIGURE 11.4 Posterior mediastinal mass. A: CT shows malignant peripheral nerve sheath tumor in the posterior mediastinum.
B: MRI shows definite spinal cord involvement.
The interlobar fissures separate the pulmonary lobes and are often incomplete. The major (oblique)
fissure is present bilaterally and separates the upper from the lower lobes. It runs obliquely from
approximately the level of the T5 vertebra posteriorly downward through the hilum to the diaphragm
anteriorly. Although not visible on a PA radiograph, portions of the major fissure are often visible on the
lateral view. The minor (horizontal) fissure is present on the right side and separates the upper from the
middle lobe. Accessory fissures may be present. The most well-known of these, the azygos fissure, is
caused by the course of the azygos vein through the upper lobe. Other common accessory fissures include
the superior accessory fissure which separates the superior segment of the lower lobe from the basilar
segments and the inferior accessory fissure which separates the medial basal segment from the remainder
of the lower lobe.
Mediastinum
The mediastinum is divided into three compartments—anterior, middle, and posterior. The anterior
compartment is bound by the sternum anteriorly and the heart and great vessels posteriorly. The middle
compartment encompasses all the vital organs—the heart, great vessels, trachea and mainstem bronchi,
and esophagus. The posterior compartment is, in reality, considered the paravertebral sulci. These
compartments are easily visible on the lateral chest x-ray. It is important to be familiar with each space
and their contents as surgical approaches differ for each space. For instance, a cervical mediastinoscopy
can only access the middle mediastinum while an anterior mediastinotomy can access the anterior
mediastinum.
FIGURE 11.5 Left diaphragm eventration. Posteroanterior (A) and lateral views (B) show elevated left hemidiaphragm.
Although intraparenchymal lymph nodes can be seen on CT imaging, the vast majority of visible nodes
are distributed throughout the mediastinum and hila. Hilar nodes are difficult to differentiate from
pulmonary vasculature without the presence of IV contrast. Mediastinal nodes can vary in size but
generally should be less than 10 mm in the short axis to be considered normal.8–10
Diaphragm
The diaphragm is a dome-shaped muscle radiating from a central tendon to attach to the ribs and
xiphisternum and separating the chest from the abdominal cavities. The right hemidiaphragm is usually
higher than the left due to the upper displacement of the right from the liver and the downward
displacement of the left from the heart. Unilateral or focal elevation of the diaphragm may occur in
eventration and fluoroscopy or ultrasonography is useful in differentiating between eventration and
phrenic nerve paralysis (Fig. 11.5).
ABNORMALITIES OF THE LUNG

Atelectasis
Atelectasis is volume loss of any portion of the lung. Five causes have been described by Fraser and
Pare.11 Resorption atelectasis occurs due to mechanical bronchial obstruction. Passive atelectasis is the
result of a space-occupying pleural process such as a pneumothorax or a hydrothorax. In contrast,
compression atelectasis occurs due to a space-occupying lesion within the pulmonary parenchyma, such
as a mass or bulla. Cicatrization atelectasis occurs from pulmonary fibrosis and scarring. Adhesive
atelectasis occurs despite patent bronchi and is the result of surfactant abnormalities. A common subtype,
plate atelectasis, is likely caused by a combination of regional differences in gravitational and pleural
pressures, distal airway closure, and surfactant abnormalities.12
Atelectasis is often detected on radiography by localized increasing opacification—from crowding of
pulmonary vessels and air bronchograms—and displacement of interlobar fissures. Other signs occur
with involvement of larger segments and include hilar displacement, mediastinal shift toward the
involved side, ipsilateral hemidiaphragmatic elevation, and ipsilateral crowding of the ribs.13 The
silhouette sign is also useful in diagnosing atelectasis. Normally, there is a difference in contrast between
aerated lung parenchyma and the adjacent soft tissue. However, in atelectasis, this border is obliterated
between the atelectatic lung and the mediastinum or diaphragm (Fig. 11.6).14
Diffuse Pulmonary Disease

Diffuse diseases usually suggest systemic disorders. It is important to recognize the difference between
interstitial and alveolar processes. This distinction helps narrow the differential diagnosis. The
interlobular septa are thickened when there is lung fibrosis or when there is distension of the veins and
lymphatics. Kerley lines represent dilatation of pulmonary veins that travel in the interlobular septa.15
Kerley A lines radiate superiorly from the hila and Kerley C lines result in a reticulation, particularly at
the base. Kerley B lines, the most commonly seen, extend perpendicularly to the pleural surfaces of the
costophrenic angles. Lymphangitic spread of cancer causes an interstitial pattern with thickening of the
interlobular septa due to distended lymphatics. Hilar haze with increased bronchovascular markings and
peribronchial cuffing occur with central connective tissue thickening.16 Discrete nodules up 3 mm in
diameter may be present, producing a reticulonodular pattern. Common interstitial diseases include
idiopathic pulmonary fibrosis and connective tissue disorders such as scleroderma, sarcoidosis, and
chronic hypersensitivity pneumonitis (Fig. 11.7).
FIGURE 11.6 Left lower lobe atelectasis due to mucus plugging. A: Posteroanterior view demonstrates volume loss in the left
lung with obscuration of the left hemidiaphragm and slight shift of the left main-stem bronchus to a more vertical course. B:
Corresponding CT scan revealing atelectasis of the medial basilar segment.
In contrast, alveolar diseases result in increased opacification of the lung. This is due to the absence of
alveolar air, thus obscuring vascular and interstitial markings. Typical findings, as described by
Groskin,16 are lobar or segmental distribution, poor margination of the opacity, tendency to coalesce, air
bronchograms, and butterfly or batwing distribution. Air bronchograms occur when fluid fills the distal
alveolar spaces, allowing intrabronchial air to become visible.17 Common alveolar diseases include
severe pulmonary edema, diffuse alveolar hemorrhage, adult respiratory distress syndrome, and
pneumonia (infectious and aspiration) (Fig. 11.8). Other less common causes include pulmonary alveolar
proteinosis and hemorrhage as is seen in pulmonary–renal syndromes such as Goodpasture and Wegener
granulomatosis.
FIGURE 11.7 Nonspecific interstitial pneumonia (NSIP). A: CXR exhibits hilar haze, increased lung markings, and low lung
volumes. B: CT chest demonstrates lower lobe predominant fibrosis that follows the bronchovascular bundles compatible with
NSIP.
FIGURE 11.8 Lobar pneumonia. A: CXR demonstrates right upper lobe air space opacity with bulging of the minor fissure. B:
CT chest.
Localized Pulmonary Diseases

Localized pulmonary densities can be poorly circumscribed or discrete and may have cavitation. The
term “nodule” is used for spherical lesions under 3 cm in diameter whereas “mass” is used to describe
those larger than 3 cm. Comparison with prior radiographic studies is imperative if available in order to
assess for change.
The likelihood of malignancy in a new pulmonary nodule varies according to patient characteristics
and radiographic appearance of the lesion. Patient age and clinical history are important factors to
consider. Younger patients are less likely to have a malignant diagnosis. Prior history of cancer may
suggest metastatic disease. Smoking history increases the likelihood of lung cancer. Recent acute illness
may suggest an infectious process.
Certain radiographic characteristics of the lesion can provide further elucidation. Bronchogenic
carcinoma typically has a spiculated margin with a corona radiata (Fig. 11.9). In contrast, smooth margins
typically suggest a benign etiology or metastatic malignant disease.
FIGURE 11.9 Non–small cell lung cancer. Left upper lobe cancer with spiculations.
Cavitation can occur with both benign and malignant processes. Malignant nodules tend to have thick,
irregular walls whereas benign lesions tend to have thin, smooth walls (Fig. 11.10). However, there is
significant variability.
Multiple well-circumscribed nodules suggest metastatic malignant disease but can be seen in systemic
processes (Fig. 11.11). Septic embolic often present as multiple pulmonary nodules but these usually
progress to cavitation.
ABNORMALITIES OF THE PLEURA

Pleural Effusion
Fluid within the pleural cavity appears as a homogeneous opacity in the dependent position on the upright
radiograph, often with a meniscus. Small amounts of fluid can be difficult to detect on a chest x-ray but as
little as 50 mL of fluid can be seen with careful examination of the posterior costophrenic sulcus on the
lateral projection. As long as the effusion is free-flowing, the fluid will move to the dependent position on
decubitus radiography (Fig. 11.12).
FIGURE 11.10 Thick-walled cavitary lesion suspicious for lung cancer.
FIGURE 11.11 Metastatic disease. Multiple well-circumscribed, randomly distributed pulmonary nodules of various sizes
compatible with metastatic disease.
Occasionally, free fluid may collect within the interlobar fissures and can mimic a mass. However, this
pleural phantom tumor is usually transient. Effusions large enough to fill the pleural space cause
compressive atelectasis with a contralateral mediastinal shift. Loculated effusions are the result of
adhesions and do not conform to gravitational effects (Fig. 11.13).
CT imaging provides additional clinically useful information. Smaller amounts of fluid are easily
detectable and the presence of loculations can be easily identified. Simple transudative fluid should be
uniform with 0 to 20 Hounsfield units, consistent with water attenuation. However, fluid can be
heterogeneous especially in cases of hemothorax (Fig. 11.14).
FIGURE 11.12 Right pleural effusion. Posteroanterior (A) and lateral (B) views. Note the obscuration of the right
hemidiaphragm and meniscus. In addition to the effusion, CT scan reveals small pericardial effusion (C).
FIGURE 11.13 Left empyema. A: Loculated air-fluid levels are noted on the Posteroanterior view. B: CT scan shows thick
walled loculations with trapped lung medially.
Pneumothorax
Pneumothorax can usually be reliably diagnosed with a chest radiograph. Due to the contrast of air, the
visceral pleura is identified as a thin white line encompassing the partially collapsed lung and surrounded
by air in the pleural space. This is typically seen in the apex with the patient in the upright position and
anteriorly in the supine position. As the pneumothorax enlarges, more air becomes visible laterally down
toward the base. Skin folds can be confused with a pneumothorax on cursory examination but is usually
distinguishable with careful examination (Fig. 11.15).
Tension pneumothorax occurs when the positive pressure causes compression of the vena cavae and
atria resulting in impaired venous return to the heart. This is a clinical diagnosis and typically
characterized by tachycardia and tachypnea. Radiographic findings that are suggestive of tension include
deviation of the mediastinum to the contralateral side and depression of the ipsilateral diaphragm.
Although CT imaging is more accurate in assessing the size of the pneumothorax, one of the main
advantages of CT is the ability to differentiate loculated pneumothoraces from bullous disease (Fig.
11.16).
FIGURE 11.14 Right hemothorax. Fluid is heterogeneous in appearance. Also note the adjacent compressive right lower lobe
atelectasis.
Pleural Thickening
Pleural thickening can be localized or diffuse and is typically due to inflammation, fibrosis, or neoplasm.
It is commonly seen at the apices and the costophrenic sulci. Extrapleural fat and subpleural fibrosis,
particularly in the apex, can be confused for pleural thickening. Diffuse pleural thickening can be
associated with restrictive physiology. Bilateral pleural thickening tends to favor benign disease.
FIGURE 11.15 Right pneumothorax. The visceral pleura is visible extending from the apex down laterally to the base.
FIGURE 11.16 Right pneumothorax in the setting of bullous disease. It is very important to differentiate between bullae and
free air within the pleural space and a CT scan may be helpful.
In pleural thickening, the lung is typically displaced away from the ribs on chest radiography and CT
scan shows soft tissue attenuation, distinguishing it from fluid. Postinflammatory pleural thickening
usually involves the costophrenic sulci. The thick pleural peel seen in empyema usually progressively
decreases in size over 12 weeks.18 The presence of calcifications suggests benign diagnosis such as
chronic benign pleural fibrosis or asbestos-related pleural plaques (Fig. 11.17).
Malignant pleural mesothelioma may be difficult to differentiate from benign pleural thickening.
Benign thickening is usually smooth in contour and rarely involves the mediastinal pleura and fissures.19
In contrast, circumferential thickening, nodularity, parietal pleural thickening >1 cm, and mediastinal
pleural involvement are highly suggestive of malignancy (Fig. 11.18).20 18FDG-PET scan is useful in
determining the optimal site for diagnostic biopsy as well as providing prognostic value.7
FIGURE 11.17 Asbestos-related pleural disease and asbestosis.
FIGURE 11.18 Pleural thymoma. Lobulated drop pleural metastases are seen laterally within the left chest.
ABNORMALITIES OF THE MEDIASTINUM

Mediastinal tumors and their associated radiographic features are discussed in detail in a separate
chapter. However, it is important to emphasize that, in regard to mediastinal disease, it is all about
location. Identification of the involved mediastinal space greatly aids in narrowing the differential
diagnosis (Fig. 11.19). Lymphadenopathy is the one abnormality that commonly occurs in all three
mediastinal spaces and can be caused by a variety of benign and neoplastic etiologies. Lymphadenopathy
can be difficult to adequately diagnose from a chest radiograph, often presenting as a slightly widened
mediastinum. CT scan has become invaluable in the evaluation of mediastinal and hilar adenopathy.
Sarcoidosis is a common cause of mediastinal lymphadenopathy in young adults and has a
characteristic distribution of lymph nodes. Lymph node involvement is symmetrical, involving bilateral
hila. The right paratracheal nodes are also frequently involved and this configuration is called the 1-2-3
sign (Fig. 11.20).21 Conversely, the aortopulmonary window nodes can also be involved. Isolated
mediastinal adenopathy without hilar involvement is unusual in sarcoidosis and should prompt
investigation of a different diagnosis. In addition, the nodes tend to be discrete rather than one amorphous
mass that is more often seen with metastatic tumor or lymphoma.
FIGURE 11.19 Thymoma within the anterior mediastinal space.

FIGURE 11.20 Sarcoidosis. Right paratracheal and bilateral hilar adenopathy are seen (the classic “1-2-3 sign”).
Lymphoma is a common cause of intrathoracic adenopathy. An anterior mediastinal mass may often be
the only site of disease. However, involvement of any or all mediastinal and hilar nodes can occur.
Bilateral involvement is common but, unlike sarcoidosis, is asymmetric. Extrinsic compression of
vascular structures may occur.
Malignant adenopathy is most commonly due to metastatic lung cancer. It is of vital importance to be
familiar with the lymph node stations to accurately stage the patient clinically in order to direct therapy.
Lung cancer has typical lymph node drainage patterns according to the primary site of disease22 with low
incidence of skip metastases.
LUNG CANCER SCREENING

Multidetector CT has drastically revolutionized the detection of lung cancer. Smaller lesions are
discovered, driving treatment at an earlier stage (Fig. 11.21). The results of the International Early Lung
Cancer Action Program (I-ELCAP) highlights this as 85% of patients diagnosed with lung cancer during
screening were clinical stage I disease. The benefit is seen in those patients that underwent surgical
resection within 1 month of diagnosis—their estimated 10-year survival was 92%.23 Due to the
preponderance of evidence, the US Preventive Services Task Force (USPSTF) recommends lung cancer
screening for patients of age 55 to 80 years with a 30-pack-year smoking history. CT scans performed for
lung cancer screening also allow early detection of emphysema, coronary artery disease, osteoporosis,
and breast disease.
FIGURE 11.21 Part-solid nodule which was a 6 mm adenocarcinoma on pathology.
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13. Felton B. Chest Roentgenology. Philadelphia, PA: Saunders; 1973.
14. Groskin SA. Heitzman’s The Lung: Radiographic-Pathologic Correlations. St. Louis, MO: Mosby-Year Book; 1993.
15. Fleischner FG. The visible bronchial tree: a roentgen sign in pneumonic and other pulmonary consolidations. Radiology 1948;50:184–
189.
16. Neff CC, vanSonnenberg E, Lawson DW, et al. CT follow-up of empyemas: pleural peels resolve after percutaneous catheter drainage.
Radiology 1990;176:195–197.
17. Metintas M, Ucgun I, Elbek O, et al. Computed tomography features in malignant pleural mesothelioma and other commonly seen
pleural diseases. Eur J Radiol 2002;41:1–9.
18. Leung AN, Muller NL, Miller RR. CT in differential diagnosis of diffuse pleural disease. Am J Roentgenol 1990;154:487–492.
19. Berkmen YM. Radiologic aspects of intrathoracic sarcoidosis. Semin Roentgenol 1985;20:356–375.
20. Shapiro M, Kadakia S, Lim J, et al. Lobe-specific mediastinal nodal dissection is sufficient during lobectomy by video-assisted thoracic
surgery or thoracotomy for early-stage lung cancer. Chest 2013;144:1615–1621.
21. International Early Lung Cancer Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med
2006;355:1763–1771.
22. Westcott JL, Cole S. Plate atelectasis. Radiology 1985;155:1–9.
23. Shanks SC, Kerley P. A Textbook of X-ray Diagnosis. Philadelphia, PA: Saunders, 1951.
12
Computed Tomography of the Lungs,
Pleura, and Chest Wall
Mary Salvatore ■ Kunwei Li ■ Lea Azour ■ David Yankelevitz ■ Claudia I. Henschke
History, physical examination, and radiologic evaluation are cornerstones in the noninvasive diagnosis of
thoracic disease. Cross-sectional computed tomographic (CT) imaging of the thorax is the highest yield
radiologic modality in the management of chest disease. In order to narrow the differential diagnosis, one
must first decide if the disease process involves the lung parenchyma, pleura, or chest wall. After
compartmentalizing the pathology, the next step is to narrow the differential considerations with a
patterned approach to disease diagnosis, which is the purpose of this chapter.
There are many clinical indications for chest CT, summarized in Table 12.1. In comparison with chest
radiography, which has an effective radiation dose of approximately 0.1 mSv, the effective dose for chest
CT ranges from 1 to 10 mSv depending on patient size and acquisition protocol.1
CT EVALUATION OF THE LUNG PARENCHYMA

The secondary pulmonary lobule is the smallest unit of lung entirely surrounded by connective tissue
septa.2 Understanding the anatomy of the secondary pulmonary lobule allows for the accurate
interpretation of lung parenchymal disease. The secondary pulmonary lobule is irregularly polyhedral in
shape and ranges in size from approximately 13 to 20 mm.3 It is outlined by the interlobular septa, which
represents the scaffolding of the lung (Fig. 12.1). Located within the interlobular septa are the pulmonary
veins and lymphatics. In the center of the secondary pulmonary lobule is the lobular pulmonary artery
(PA) and its adjacent, accompanying lobular bronchus. Surrounding the lobular PA and the bronchus are
the alveoli.
TABLE 12.1 Clinical Indications for a CT of the Chest Including Whether to Use
Contrast. This is not Intended to Suffice as Appropriate Documentation for Insurance
Approval
Clinical Indications for Chest CT IV Contrast Differential Considerations
Abnormality on chest radiograph No Infection, mass, interstitial disease
Acute respiratory illness No Pneumonia, ARDS
Staging of primary thoracic malignancies Yes Non–small cell versus small cell lung carcinoma
Evaluation of metastatic disease No Unknown primary, hemorrhagic metastases, osseous metastases,
lymphangitic spread
Suspected pulmonary emboli Yes; angiography Acute PE, chronic PE
Suspected pulmonary arterial hypertension Yes
Known or suspected congenital Yes
cardiothoracic anomalies
Evaluation and follow-up of parenchymal No
disease
Evaluation and follow-up of airway disease Variable:
Yes—tracheal
masses
No—tracheal
morphology
Blunt and penetrating trauma Yes
Postoperative patients and surgical Variable
complications
Evaluation of the chest wall Variable
Evaluation of the pleura Variable
Radiation therapy planning No
Guidance for percutaneous biopsy or No
drainage
FIGURE 12.1 Evaluation of lung parenchyma involves inspection of the peripheral pulmonary arteries (PA), the interlobular
septa (S), and the alveolar spaces (A).
PULMONARY DISEASES AFFECTING THE ALVEOLI

An average pair of human lungs contains approximately 480 million alveoli, with a range of 274 to 790
million.4 The average diameter of an individual alveolus is 200 µm.4 “High-resolution” CT (HRCT)
provides resolution on the order of 100 to 200 µm. Therefore, alveoli can be seen using newer high-
resolution imaging technology (Fig. 12.2).
Increased Density
Alveoli are most likely to be seen when there is pathology. They become more radiopaque when fluid
such as blood, pus, or edema fills them and more radiolucent when hyperaerated as in emphysema.
a. Pulmonary hemorrhage
Diffuse pulmonary hemorrhage can occur in the setting of pulmonary vasculitis including granulomatosis
with polyangiitis, Goodpasture syndrome, and coagulopathies (Fig. 12.3). Focal hemorrhage may occur
with contusion. The history of hemoptysis or trauma will help narrow the differential for this air space
opacity.
b. Pulmonary vascular congestion
Pulmonary vascular congestion can be mild, moderate, or severe. When severe, it is termed pulmonary
edema, which correlates to a pulmonary capillary wedge pressure of greater than 25 mm Hg, fluid fills the
centrally located alveoli. This gives rise to the classic “bat-wing” appearance on chest radiograph,
perihilar opacity with peripheral sparing. Peripheral sparing is thought to occur as a result of rib motion,
which clears alveolar fluid from the peripheral airways. More commonly than the bat-wing pattern,
alveolar edema presents as poorly marginated consolidation or ground glass opacity.5,6 In Figure 12.4,
unilateral central pulmonary edema is seen following rapid drainage of a large right pleural effusion in a
patient with liver cirrhosis. The central pattern of airspace opacity and the residual pleural fluid can be
appreciated on the image.
FIGURE 12.2 Hypersensitivity pneumonitis caused by exposure to hot tub.
c. Pneumonia
Pneumonia is most commonly an airspace process. Chest CT is more sensitive than radiography in the
diagnosis of pneumonia.7,8 Lobar pneumonia, as its name implies, affects a lobe of the lung and is limited
by the fissures because the infection spreads from one alveoli to the other through the pores of Kohn,
small holes in the alveolar walls. Therefore, there is dense consolidation in the center of the pneumonia
and patchier consolidation in the periphery where fewer alveoli are involved with disease. The airways
are spared in lobar pneumonia giving the classic air bronchogram. Streptococcus is the most common
pathogen to cause this pattern of lobar pneumonia.9 In contrast, bronchopneumonia is patchy and bilateral
because it is spread via the bronchi, as shown in Figure 12.5. The most common pathogen is
staphylococcus, and cavitation may be seen within the consolidation.10,11
FIGURE 12.3 Pulmonary hemorrhage.
FIGURE 12.4 Re-expansion pulmonary edema.
Increased Lucency
The average radiodensity of the normal lung is −900 Hounsfield Units (HU) with distilled water as the
reference measure, with an HU of zero. In contrast, emphysematous lung has an HU measurement of −950
or less, appearing abnormally lower in attenuation, or blacker, on CT scan. The minIP technique may
increase the conspicuity of emphysema.12 There are three main types of emphysema based on their
distribution within the lung parenchyma: centrilobular, panlobular, and paraseptal.13,14 Centrilobular
emphysema involves the central alveoli, is upper lobe predominant, and is associated with smoking.15,16
Centrilobular emphysema can be distinguished from cystic lung diseases by the presence of an artery in
the center of each lucent focus. In the example shown in Figure 12.6, there is an associated saber-sheath
trachea with narrowing of the transverse tracheal diameter, and increase in the AP diameter.
FIGURE 12.5 Bronchopneumonia.
FIGURE 12.6 Centrilobular emphysema.
Paraseptal emphysema (Fig. 12.7) occurs in a peripheral distribution, and is usually one layer thick
along the subpleural lung. It may occur with centrilobular emphysema.14 It is associated with aging of the
lung and is believed to be due to tensile force on the most peripheral secondary pulmonary lobules caused
by rib motion in individuals with relatively rigid lungs. As such, it can be seen in patients with pulmonary
fibrosis and must be distinguished from honeycombing, which is also peripheral. Additional associations
include individuals with a tall and thin body habitus, as is seen in Marfan and Ehlers–Danlos
syndromes.17
Panlobular emphysema affects both peripheral and central alveoli and is associated with alpha-1
antitrypsin deficiency, rendering it less common. The term bullous emphysema is used when there are
large air-filled cysts, typically in the lung apex. They are important to note because of the increased risk
of pneumothorax, and in fact they can be difficult to distinguish from pneumothorax. A helpful sign is the
hugging sign. Lung surrounds a giant bulla hugging it as shown in Figure 12.8, while pneumothorax does
the reverse with air surrounding the lung.
PULMONARY DISEASES AFFECTING THE INTERSTITIUM

The interstitium is the scaffolding of the lung parenchyma and the veins and lymphatics course through the
supporting tissue. Therefore, diseases of the interstitium, pulmonary veins, and lymphatics can have a
similar appearance on CT and must be differentiated. The first thing to do is to note if the bronchi are
dilated. The presence of bronchial dilatation and interlobular septal thickening supports interstitial
fibrosis; in contradistinction, the presence of interstitial thickening without bronchial dilatation is seen
with both pulmonary vascular congestion and lymphangitic spread of cancer.
FIGURE 12.7 Paraseptal emphysema.

FIGURE 12.8 Giant bulla in a patient with bullous emphysema.
Thickened Interlobular Septa With Bronchial Dilatation

There are hundreds of types of interstitial lung disease, which can be most easily separated into
idiopathic fibrosis and those with a known cause. Of the idiopathic diseases, the usual interstitial
pneumonitis (UIP) pattern is most common, and is associated clinically with idiopathic pulmonary
fibrosis (IPF), which has an average life expectancy of 3 years. The American Thoracic Society have
provided criteria for the radiographic diagnosis of UIP which include subpleural basilar predominant
disease with reticulations and honeycombing and absence of features that would suggest an alternative
diagnosis.18 Figure 12.9 is an excellent example of a UIP pattern. There is subpleural, basilar
predominant fibrosis. Note the classic left lower lobe honeycombing with stacked subpleural cysts that
share walls.
FIGURE 12.9 Usual interstitial pneumonitis (UIP) and honeycombing.
FIGURE 12.10 Usual interstitial pneumonitis (UIP) and cancer.
Patients with lung fibrosis are at increased risk for lung cancer due to squamous metaplasia. Figure
12.10 is an example of a right lower lobe peripheral squamous cell lung cancer occurring in an area of
fibrosis.
Not all lung fibrosis is UIP. The second most common type of idiopathic fibrosis, which also is lower
lobe predominant, is nonspecific interstitial pneumonitis (NSIP). Unlike UIP, it is not confined to the
periphery, but rather follows the bronchovascular bundles.19–21 NSIP, as shown in Figure 12.11, is
frequently associated with connective tissue diseases including scleroderma, and is more often seen in
middle-aged nonsmoking females.22
Lymphocytic interstitial pneumonia (LIP) is relatively uncommon, and is associated with Sjogren
disease in adults and HIV in children. As demonstrated in Figure 12.12, the dominant CT finding is
scattered perivascular cysts throughout the lung parenchyma, though ground glass opacities and
centrilobular nodules may also be seen.23–28 The differential diagnosis for lung cysts not found in the
setting of infection (pneumatoceles) includes Birt–Hogg–Dube syndrome, pulmonary Langerhans cell
histiocytosis, and lymphangioleiomyomatosis (LAM). Birt–Hogg–Dube is an autosomal dominant
syndrome associated with cutaneous fibrofolliculomas and renal neoplasms. Pulmonary Langerhans cell
histiocytosis is a smoking-related disease demonstrating bizarre-shaped, upper lobe predominant
cysts.29,30 LAM often has more cysts than LIP, and is characterized by chylous pleural effusions, renal
angiomyolipomas, and lymphangioleiomyomas. LAM is more often seen in women with tuberous
sclerosis.31
FIGURE 12.11 Nonspecific interstitial pneumonitis.

FIGURE 12.12 Lymphocytic interstitial pneumonitis.
Cryptogenic organizing pneumonia (COP) is characterized as an idiopathic interstitial lung disease

(Fig. 12.13). It appears as a subpleural or bronchovascular airspace opacity.32,33 The reverese halo sign
is relatively specific for COP.34 COP can be confused with pneumonia, and should be considered in a
patient who does not respond to antibiotics, as the treatment for this disease is steroids.
FIGURE 12.13 Organizing pneumonia.

FIGURE 12.14 Desquamative interstitial pneumonitis (DIP).
Respiratory bronchiolitis interstitial lung disease (RB-ILD) and desquamative interstitial pneumonitis
(DIP) are characterized as idiopathic, but are known to be associated with smoking and can resolve with
smoking cessation.35–39 There is a male predilection. RB-ILD is a milder form of the disease with
discrete centrilobular nodules. In contrast, DIP is further along the disease continuum, with most cases
involving extensive, basilar predominant ground glass opacity, as seen in Figure 12.14.
Chronic hypersensitivity pneumonitis (CHP) is a fibrosis that is caused by an antigen, as in bird
fancier’s disease, and as such is not included in the classification of idiopathic disease notwithstanding
that an antigen is often not identified. In contrast to UIP and NSIP, CHP is an upper lung predominant
disease following the bronchovascular bundles that is associated with air trapping (Fig. 12.15).40,41
Sarcoidosis is not included within the idiopathic interstitial lung diseases, yet it has no known
etiology. There are four imaging-based stages of pulmonary sarcoidosis: lymphadenopathy,
lymphadenopathy with pulmonary parenchymal disease, only pulmonary parenchymal disease, and
pulmonary fibrosis.42–44 Like hypersensitivity pneumonitis, sarcoidosis is upper lobe predominant and
follows the bronchovascular bundles. It tends to affect the posterior aspect of the upper lobes in its
advanced fibrotic form, which helps to differentiate it from CHP (Fig. 12.16).
FIGURE 12.15 Chronic hypersensitivity pneumonitis (CHP).
FIGURE 12.16 Stage 4 Sarcoidosis.
Radiation pneumonitis causes lung fibrosis with associated bronchiectasis. Pulmonary fibrosis occurs
several months after treatment in areas that receive doses in excess of 20 Gray.45,46 Radiation fibrosis
appears as focal scarring with linear margins and traction bronchiectasis, roughly corresponding the
treatment plane, which helps to differentiate fibrosis from recurrent tumor. Fibrosis typically evolves
over a 2-year period. Notice the characteristic straight border of fibrosis on the coronal image in Figure
12.17. A sign of recurrent disease is occlusion of a dilated, previously patent bronchus, which would
warrant further investigation.45
FIGURE 12.17 A,B: Radiation pneumonitis.
FIGURE 12.18 Pulmonary edema.
Thickened Interlobular Septa Without Bronchial Dilatation

Congestive heart failure (CHF) is common and must be differentiated from pulmonary fibrosis, which is
readily accomplished due to its reversible nature. In CHF, there is increased distension of the pulmonary
veins, causing smooth, relatively uniform thickening of the interlobular septa, as in Figure 12.18. The
ground glass opacity represents fluid spilling into the alveoli. The presence of small bilateral pleural
effusions is also consistent with CHF as the cause of septal thickening, rather than lymphangitic spread of
cancer.
Lymphangitic carcinomatosis is characterized by irregular, nodular thickening of the interlobular
septa.47–49 Typically, the process is bilateral because it is systemic, except when caused by lung cancer,
which can directly invade the lymphatics and cause unilateral thickening, as evident in Figure 12.19.
Adenocarcinomas are typical suspects, with primary tumors often being from the lung, breast, stomach,
and pancreas.
FIGURE 12.19 Lymphangitic spread of lung cancer.
PULMONARY DISEASES AFFECTING THE AIRWAYS

Tracheal Disease
The trachea can be narrowed following prolonged intubation, which may lead to the formation of
granulation tissue. Similarly, tracheal neoplasms such as squamous cell or adenoid cystic carcinoma may
lead to focal areas of tracheal narrowing. More diffuse tracheal narrowing may occur secondary to
granulomatosis with polyangiitis, tracheopathia osteochondroplastica, amyloidosis, sarcoidosis, relapsing
polychondritis, as well as infections.50
In Mounier-Kuhn syndrome, also known as tracheobronchomegaly, the trachea is dilated with a
transverse diameter greater than 27 mm in men and 23 mm in women, with associated central
bronchiectasis of the first to fourth order bronchi. Figure 12.20 is an example of a lemon-shaped trachea
which, in contrast to the saber-sheath trachea of COPD, has an increased transverse diameter and is
commonly associated with tracheomalacia in which the airway collapses on expiration.
FIGURE 12.20 Tracheomalacia.
Bronchial Disease
Bronchiectasis was described by Lynne Reid in the 1950s. The Reid classification describes the types of
bronchiectasis based on CT appearance. While a normal bronchus branches 11 times from trachea to the
periphery, in bronchiectasis there is pruning of the bronchi and decreased branching. Cylindrical
bronchiectasis is the mildest form, followed by varicoid (moderate) bronchiectasis, and cystic/saccular
bronchiectasis, which is the most severe. In cystic bronchiectasis, there is a VQ mismatch where by
pulmonary circulation reaching the area of diseased lung is reduced.
Bronchiectasis can be focal, as in cases of bronchial atresia, bronchial tumor, or broncholith. If the
bronchiectasis is diffuse, we can narrow the differential by noting whether it is peripheral or central.
Central bronchiectasis is most characteristic of allergic bronchopulmonary aspergillosis (ABPA), which
effects the first to fourth level of branching, typically is present in asthmatic patients, and given the classic
“hand in glove” appearance of mucous impaction within a distend bronchus (Fig. 12.21).
Peripheral bronchiectasis can be separated into upper and lower lobe subdivisions. Upper lobe
bronchiectasis is most commonly associated with cystic fibrosis. Figure 12.22 shows a CT image from a
patient with cystic fibrosis with a mycetoma (aspergilloma) located within a dilated airway.
Middle lobe bronchiectasis commonly occurs in elderly women who suppress their cough, and is
associated with Mycobacteria avium intercellulare (MAI) infection. It is a frequent finding on CT
examinations. Bronchiectasis is defined as a bronchus that is larger than its accompanying blood vessel,
as is demonstrated in a patient with MAI in Figure 12.23.
Dysmotile cilia syndrome is suspected in a younger patient with frequent pneumonias and lower lobe
predominant bronchiectasis. If it is associated with situs inversus, the disease is termed Kartagener
syndrome. Notice the thickening of the walls of the airways in the left lower lobe in Figure 12.24.
FIGURE 12.21 Allergic bronchopulmonary aspergillosis (ABPA).
FIGURE 12.22 Cystic fibrosis with mycetoma.
PULMONARY DISEASES AFFECTING THE PULMONARY ARTERY

The PA is best measured on the CT slice shown in Figure 12.25. The transverse dimension of the PA
should be less than 3 cm. In this image, the PA measures 3.7 cm in size compatible with pulmonary
arterial hypertension (PAH). More important for diagnosis is that the PA is larger than the adjacent aorta.
When the ratio of PA/aorta is greater than 1, it lends support for the diagnosis of PAH.
PAH can be precapillary or postcapillary. Precapillary etiologies include chronic PE, left to right
shunts, intrinsic lung disease such as fibrosis, and drugs or toxins. Postcapillary etiologies include left
heart failure, mitral stenosis, or mediastinal fibrosis. The pulmonary veins become distended which can
be used to distinguish it from precapillary disease, where the veins are normal in size. Figure 12.26
shows a filling defect within the opacified PA, representing an acute nonocclusive pulmonary embolus. A
chronic pulmonary embolus would be peripheral rather than central.
FIGURE 12.23 Mycobacteria avium intercellulare.
FIGURE 12.24 Dysmotile cilia syndrome.

FIGURE 12.25 Pulmonary artery hypertension.
FIGURE 12.26 Acute nonocclusive pulmonary embolus.

FIGURE 12.27 Hampton hump seen following a parenchymal infarct.
Some emboli cause infarct of the lung parenchyma. A parenchymal infarct is pleural based and dome
shaped as seen in Figure 12.27. It is called Hampton hump and typically is heterogeneous. An infarct
should be considered when there is a new peripheral opacity in a patient with chest pain. Unlike cancer a
Hampton hump will show a decrease in size over time.
Patients with PAH often have mosaic attenuation or heterogeneity of the parenchyma on CT scan. This
must be differentiated from small airways disease, which can have the same appearance but usually has
bronchial wall thickening as well. In order to distinguish small airways disease from PAH, expiratory CT
images are performed. If the mosaicism worsens on expiration the disease is related to air trapping in
small airways, if not the mosaicism is likely due to PAH. Notice the mosaic pattern in a patient with PAH
in Figure 12.28.
PULMONARY NODULES
There is rarely a CT scan that does not contain at least one pulmonary nodule but not all nodules are the
same, and one must consider the patient’s risk factors when evaluating a new pulmonary nodule. The
likelihood of lung cancer increases if a patient has a smoking history, occupational exposure, prior history
of cancer, family history of lung cancer in first-degree relatives, other lung disease (COPD or pulmonary
fibrosis), or second-hand smoke exposure. In evaluating nodules, one should take into account the
nodules’ characteristics, particularly size, density, number, location, and morphology, as well as the
comparison of the current nodule to prior images.
FIGURE 12.28 Mosaic attenuation.
Solitary
A solitary pulmonary nodule is a focal nonlinear opacity with a generally spherical shape surrounded by
lung parenchyma and is not associated with lymphadenopathy, atelectasis, or pneumonia. Solid, part-
solid, and nonsolid nodules are the three main types of pulmonary nodules.
Solid
If the lung parenchyma within the entire nodule is obscured, it is classified as a solid nodule. This is true
even if there is a small nonsolid rim surrounding the nodule, as this rim may be due to partial volume
averaging at the periphery of a nodule or represent a minimal lepidic component of cell types other than
adenocarcinoma (Fig. 12.29). Solid nodules may have external or internal cystic airspace or internal
cavitation.
Part-solid
If the nodule is composed of both nonsolid as well as solid components which obscured the underlying
lung parenchyma, it is classified as part-solid (Fig. 12.30). Part-solid nodules, if diagnosed as lung
cancer are more likely to be invasive cancers. However, if the diameter of the solid component is greater
than 80% of the diameter of the entire nodule, it should be considered to be a solid nodule.51
FIGURE 12.29 Solid nodule with surrounding nonsolid halo.
FIGURE 12.30 Part-solid nodule.
Nonsolid
If the underlying parenchyma is visible, except for branching blood vessels within the nodule, it is
classified as a nonsolid nodule. In making the distinction between part-solid and nonsolid nodule, blood
vessels within the nodule, despite their appearance as solid components, are not regarded as solid
components. Nonsolid nodules may be indolent adenocarcinomas, such as adenocarcinoma in situ (AIS)
or minimally invasive adenocarcinoma (MIA) (formerly known as bronchioloalveolar carcinomas).
These patients have a 5-year lung cancer–survival rate of 100%. Data also suggest that many nonsolid
nodules can resolve, especially when newly detected on annual CT screening.52–54
THE ROLE OF LUNG CANCER SCREENING

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Five-
year survival rates for lung cancer are typically less than 15%, partly because most patients have
advanced-stage lung cancer at initial diagnosis. Screening tests have been developed for cervical, colon,
and breast cancers. Studies have shown that the estimated cure rate resulting from annual CT screening is
80% or higher, a marked improvement over what is found when screening is not provided,55 and has been
the impetus for the development of a test for early diagnosis of lung cancer. Recent data support using
low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung
cancer.56–58 The goal of screening is to detect disease at a stage before it causes symptoms and when
treatment will be most successful. Screening should benefit the individual by increasing life expectancy
and quality of life.
In CT screening for lung cancer, the regimen of screening is critical in diagnosing lung cancer early
while limiting unnecessary tests and invasive procedures. This has been demonstrated by comparing two
studies, one with a well-defined regimen of screening, and the second, which did not specify a regimen.
The comparison of the two studies showed that the use of a regimen significantly increased the frequency
of diagnosing Stage I lung cancer and thus the resulting estimated cure and decreased the median tumor
size of the cancers.59
Important in the development of the regimen is the recognition of the profound difference between the
first baseline round, which happens only once, while repeat rounds will be performed annually for many
years. This difference needs to be clearly recognized, as it is these annual rounds which allow for
identification of small, early, yet aggressive lung cancers which have high cure rate with surgical
resection despite their aggressiveness.60–62
Nodule growth is also important. Growth of a nodule is defined as: (1) enlargement of the overall
nodule size regardless of consistency, (2) growth of the solid component of a part-solid nodule, (3)
development of a solid component within a nonsolid nodule, and (4) increased attenuation of nonsolid
components of a nonsolid nodule.63–66
Other findings on the CT scan of the chest should also be reported and these include emphysema,
interstitial lung disease, mediastinal masses, breast masses, coronary artery calcification, and upper
abdominal lesions.
CT EVALUATION OF THE PLEURA
PLEURAL THICKENING
At the turn of the century asbestos was touted as the wonder material with its novel fire retardant and
insulating capabilities. In 1970, it was one of the first substance placed on a watch list to protect
individuals from exposure. There are two forms of thoracic asbestos disease: asbestos-related pleural
disease and asbestosis. Asbestosis affects the lung parenchyma with subpleural lines and parenchymal
bands. Asbestos-related pleural disease, however, is much more common and, as shown in Figure 12.31,
causes areas of pleural thickening, or plaques, that are rectangular in shape. Asbestos-related plaques
typically begin posterior and laterally.
FIGURE 12.31 Pleural plaques.
FIGURE 12.32 Mesothelioma.
The pleural plaques will often calcify. Unilateral disease is atypical for asbestos-related pleural
disease and should suggest an alternate diagnosis such as prior hemothorax.
PLEURAL NODULARITY OR MASS

People exposed to asbestos are at increased risk for mesothelioma, which is the most common primary
pleural-based tumor.67,68 In Figure 12.32, mesothelioma is seen to circumferentially encase the left lung
and decrease the volume of the ipsilateral lung parenchyma. Mean survival is 12 months, with poorer
prognosis with extrapleural extension to the chest wall or mediastinum. Staging by CT is essential in the
surgical decision-making algorithm when considering pleurectomy/decortication versus extrapleural
pneumonectomy.69
Pleural metastases can be distinguished from pleural plaques by their round-shaped contour, as shown
in Figure 12.33 for a patient with melanoma metastases to the pleura.
PLEURAL EFFUSION
Most fluid in the pleural space is associated with heart disease, and has an average HU of between 0 and
20. In contrast, when blood is in the pleural space the HU increase to between 20 and 60 (Fig. 12.34).
Sometimes, the site of bleeding can be identified because of heterogeneity of the fluid, or focal increased
attenuation on arterial phase imaging to suggest an actively extravasating vessel. Long-standing
hemothorax may demonstrate a hematocrit level, with higher attenuation blood products settling to the
dependent portion of the lung.
EMPYEMA
Empyema should be considered when a pleural effusion is loculated, especially if adjacent to an area of
pulmonary consolidation (Fig. 12.35). Air within pleural fluid also supports the diagnosis, but is not
specific to empyema as it can be seen secondary to instrumentation, such as a biopsy or thoracentesis. If
fluid in a collection is ventrally located, it suggests that the fluid is viscous and may be difficult to drain
with a chest tube. Contrast-enhanced CT imaging demonstrates enhancement of the visceral and parietal
pleura in a patient with empyema, known as the “split pleura” sign. Recognizing empyema is clinically
important as drainage, thoracotomy, video-assisted thoracoscopy, or open drainage is required.70
FIGURE 12.33 Pleural metastases.
CHEST WALL TRAUMA

Rib fractures are commonly noted on CT examinations and the patient may provide a remote history of
trauma. Patients who receive radiation treatment are at increased risk of developing rib fractures in the
radiation port. When rib fractures occur in more than one location on multiple contiguous ribs, the patient
is at risk for flail chest, that is, paradoxical movement of the intervening chest wall segment with
respiration. CT is important in the diagnosis of rib fractures, and may aid in preoperative planning in
instances of flail chest.71
FIGURE 12.34 Hemothorax.
FIGURE 12.35 Empyema.
CHEST WALL INFECTION

Any infection can extend beyond the pleura to involve the chest wall but Nocardia and Actinomyces are
most frequently associated with extrapulmonary chest wall involvement. When pneumonia with
associated empyema spreads contiguously beyond the pleura and into the chest wall, it is known as
empyema necessitans. The patient shown in Figure 12.36 has Nocardia of the left anterior chest wall.
CHEST WALL MASSES
Chest wall tumors include sarcomas, myelomas of the bone, and neurogenic tumors. Figure 12.37 is an
example of a neurogenic tumor (schwannoma), which is growing inward from the left chest wall within
the posterior mediastinum.
Extramedullary hematopoiesis occurs when there is long-standing anemia and the bone marrow, unable
to keep up with the demand, gives rise to hematopoietic cells outside of the marrow. In the chest, this is
typically encountered as unilateral or bilateral paraspinal masses near the costovertebral junctions.72,73
Figure 12.38 shows a patient with thalassemia in which we see homogeneous, paravertebral soft tissue
masses are noted with accompanying heterogeneous bone marrow.
STRUCTURAL DEFECTS OF THE CHEST WALL

Pectus excavatum is the most common chest wall anomaly. It is a congenital defect of the anterior chest
wall wherein the sternum lies posterior to its typical anatomic location. It is more often seen in men, and
associated with scoliosis. The Haller index reflects the extent of the pectus deformity, and is obtained by
measuring the transverse versus AP dimension of the thorax, with a ratio greater than 2.5 diagnostic of
pectus excavatum. The larger the Haller index, the greater the deformity and the increased likelihood of
right heart compression, as is evident in Figure 12.39. Strong correlation has been shown between the
radiographic and CT-derived Haller indices and surgical correction is indicated with an index greater
than 3.5.74,75 Pectus carinatum is the reverse, with the sternum protruding anterior to its expected location.
FIGURE 12.36 Nocardia.
THE RIBS AND BEYOND

When looking at the chest wall it is important to consider the soft tissues. Gynecomastia is frequently seen
on CT scans of men and can be associated with certain medications as well as liver diseases. The breast
parenchyma of women cannot only be easily identified but breast density can be qualitatively assessed as
well.76 Women with increased breast density are at increased risk for breast cancer.77 Nodules in the
breast can be seen and patients with breast nodules should be referred for mammography for further
characterization. Figure 12.40 demonstrates a 1.5-cm upper outer quadrant left breast nodule.
FIGURE 12.37 Schwannoma.

FIGURE 12.38 Extramedullary hematopoiesis.
FIGURE 12.39 Pectus excavatum.

FIGURE 12.40 Breast nodule.
CONCLUSION
Chest CT allows noninvasive evaluation of the lung parenchyma, pleura, and chest wall. A systematic
review of the images and a patterned approach to the evaluation of abnormalities allows for a narrow
differential diagnosis. When combined with clinical history and physical examination, the findings can be
very specific with important clinical ramifications for diagnosis, staging, prognosis, treatment, and
surgical planning.
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13
Magnetic Resonance Imaging of the
Thorax
Prabhakar Rajiah ■ Ritu R. Gill
INTRODUCTION
Magnetic resonance imaging (MRI) is an important imaging modality in evaluation of cardiothoracic
abnormalities, including that of mediastinum, lung, pleura, diaphragm, and cardiovascular structures. It is
useful as a primary imaging modality in several abnormalities, as a problem solver in other diseases, and
often used as a complementary modality as part of multimodality workup in surgical planning. The
advantages of MRI include ability to characterize tissue composition, high soft tissue contrast, multiplanar
imaging capabilities, high spatial and temporal resolution, and wide field-of-view. This modality
obviates the utilization of ionizing radiation or potentially nephrotoxic contrast media. However, MRI
may be contraindicated in some patients, particularly in those who have indwelling metallic devices not
compatible with magnetic fields and in patients with claustrophobia. High cost and limited availability
are additional factors that limit the use of MRI. In the thorax, challenges include cardiac and respiratory
motion, heterogeneous magnetic susceptibility of lung, and pulsatile blood flow. However, technical
advances, both in hardware and in pulse sequences have enabled overcoming most of these challenges
and provide high-quality MRI images. Nephrogenic systemic fibrosis is a debilitating fibrosing condition
that is associated with the use of gadolinium-based contrast media in patients with severe renal
dysfunction, thus limiting post gadolinium imaging in this cohort. Black-blood imaging and several
noncontrast MRA- and MR-based perfusion techniques can be used to visualize vasculature and map
perfusion.
In this chapter, we review the technical aspects of Thoracic MRI, review state of the art MR protocols
used in imaging thoracic abnormalities, illustrate the utility of MRI in cardiothoracic abnormalities and
disease processes.
TECHNICAL PRINCIPLES AND ASPECTS OF MRI

MRI depends on the interaction between atomic nuclei containing odd number of protons/neutrons
(typically hydrogen), external magnetic field, and applied radiofrequency (RF) waves. In the absence of
an external magnetic field, the magnetic spins are randomly oriented. However, with an external magnetic
field, the spins are oriented either parallel or antiparallel to the main magnetic field. At equilibrium, there
is a slight excess of spins aligned along the direction of main magnetic field (B0), with the longitudinal
magnetization pointing in the direction of B0. At equilibrium, there is no transverse magnetization in the
xy plane. In addition, the protons are also precessing around the axis of magnetic field in a manner similar
to wobble of a spinning top. The precession frequency is called Larmor frequency and is proportional to
the B0. Using dedicated coils, RF pulse is applied, which results in change of orientation of the net
magnetization to variable degrees. For example, a 90-degree RF pulse tips the longitudinal magnetization
into the transverse plane. MR signal is derived exclusively from transverse magnetization, which
produces free induction decay and signal in a wire loop receiver, which is then digitized, amplified,
combined, and Fourier-transformed to yield the MR images. A 180-degree RF pulse rotates transverse
magnetization from the +x to the x direction, in which case it is called a 180-degree refocusing pulse.
Spin-echo and fast spin-echo sequences use both 90- and 180-degree RF pulses. Gradient-echo sequences
use RF pulses <90 degrees, but do not use 180-degree RF pulse. T1 is the time taken for spins to restore
longitudinal magnetization, also called spin–lattice relaxation, whereas T2 is the time taken for decay of
transverse magnetization, also called spin–spin relaxation. The T1 and T2 values of different tissues vary,
and this property can be utilized to highlight different tissues using T1- and T2-weighted sequences. This
can be done by varying the TR, which is the time between RF pulses and TE, which is the time between
the initial RF pulse and the echo, which occurs when dephasing spins are refocused in a spin echo
sequence or by magnetic gradient reversal. To localize these various spins in the body, spatial encoding is
performed using magnetic field gradients, which is a magnet whose strength varies with position. By
exciting hydrogen nuclei only within a single slice, the spatial encoding problem is reduced to two
dimensions and these two dimensions are spatially mapped using frequency encoding in one direction and
phase encoding in the other direction. The number of phase (NP) and frequency (NF) encoding steps is
called the matrix, and this, in combination with the field of view (FOV) determines the in-plane spatial
resolution of the MR image.1
MRI PULSE SEQUENCES

MRI pulse sequence refers to the sequence of RF pulses and magnetic gradients that produce MR images
at a specified location, in a special anatomic plane, and with a specified soft tissue contrast. For example,
in the conventional 2D spin echo sequence, a train of 128 near identical units are applied, one unit for
each phase-encoding step. This begins with a slice-selective 90-degree RF pulse that plays out while a
gradient is on. Next a 180-degree refocusing pulse is applied at a time TE/2, which forms an echo at TE
after the 90-degree pulse. The echo is acquired in the presence of a frequency-encoding gradient (readout
gradient). While the echo is evolving, phase-encoding gradient is applied on for a brief period, with the
strength of this gradient stepped with one step for each phase encode, from negative to positive values.
The next unit begins with 90-degree pulse at time TR after previous 90-degree pulse. The pulse sequence
ends after 128 units of 90- and 180-degree pulse echoes are completed. This sequence can either be T1,
T2 or proton density weighted based, on the TR and TE. Gradient-echo sequences are ultrafast due to
stronger and faster gradients and faster receivers.2
MRI SEQUENCES IN THORACIC IMAGING

Several sequences are available for thoracic imaging, depending on the clinical indication. Several
strategies are available to minimize or eliminate motion artifacts from cardiac and respiratory motion.
Cardiac gating synchronizes MR acquisition with ECG tracing and is more reliable when R-R interval is
nearly constant as in normal sinus rhythm. Respiratory motion can be minimized by breath-hold
acquisition for short sequences, but for long sequences other techniques are available, which reorder
phase-encoding steps to minimize respiratory motion artifacts. Bellows placed around the chest or upper
abdomen senses respiratory excursion and transmits information to MR scanner; this technique performs
well when respiration is regular. With respiratory triggering, image data is collected during quiet period
of expiration. This increases the time of acquisition and does not work well with apnea or irregular
respiration. MR navigator is a technique where a gradient echo is used to monitor diaphragmatic position
and imaging is acquired only during expiration.
Ultrafast spin-echo T2 is a rapid sequence, which can be used to localize and characterize lesions
without need for ECG gating or breath-hold, but the spatial resolution is not high. Balanced steady state
free precession (b-SSFP) is a type of gradient-echo sequence in which the gradients are balanced in all
the directions. The signal depends on T2/T1 ratio of the tissue. Static images acquired through the chest
can be used for lesion localization and characterization. T1- and T2-weighted images are typically
performed using a ECG-gated double inversion recovery (DIR) (initial inversion pulse throughout the
imaged volume and a second slice selective inversion pulse) to minimize motion artifacts and can be
performed either with T1 or T2 weighting. Fat saturation is obtained using STIR or a triple inversion
recovery, which is an additional inversion pulse to the DIR sequence. T1-weighted (T1W) ultrafast
gradient echo can be obtained both in-phase, and out-of-phase, which is helpful in identifying
microscopic fat (shows signal drop in out-of-phase sequence), useful in distinguishing thymic hyperplasia
from thymic neoplasms. Dixon sequence with in-phase, out-of-phase, water-only, fat-only images
obtains several types of images bringing out different tissue characteristics using a single sequence.
Chemical shift ratio (CSR) is calculated as CSR = [Thymus SI in out of phase (OP) imaging/paraspinal
muscle SI on out of phase (OP) imaging]/ [Thymus SI on in phase (IP) imaging IP/paraspinal SI on in
phase (IP) imaging].
Diffusion-weighted echoplanar imaging is utilized for identifying lesions with restricted diffusion
such as neoplasms show high signal on high b value images and low signal on the apparent diffusion
coefficient (ADC) map plotted by logarithmic plotting of multiple b values. 3D ultrafast gradient echo
with automated subtraction is a rapid 3D volumetric sequence, which is useful in the evaluation of
contrast enhancement (VIBE, LAVA, THRIVE). Subtracted images are obtained by subtracting the
precontrast acquisition from postcontrast sequence.3
Multiple sequences are also available for evaluation of cardiovascular structures.4–6 Cine SSFP
images are obtained by segmented k-space acquisition, in which the k-space is filled in a segmented
fashion across multiple R-R intervals. The final image is a composite of images acquired across many
heartbeats. This is useful for evaluation of cardiac morphology and function and can quantify the
ventricular function. This sequence requires regular R-R interval. With arrhythmias, prospective ECG
triggering can be used. Real-time cine SSFP images are cine SSFP images which are not averaged, but a
true representation of cardiac motion. This is useful for evaluating ventricular septal motion and also for
evaluating chest wall or mediastinal invasion of tumors. Velocity-encoded phase contrast sequence is a
type of gradient echo sequence, in which the signal depends on the velocity of a pixel. This is used for
quantifying flow and velocity of different vascular structures. Following contrast administration, dynamic
first-pass perfusion images are useful in the evaluation of myocardial ischemia. This along with early
post-contrast T1W fast spin echo is useful for evaluating contrast enhancement in thoracic abnormalities.
MR angiography is performed using a T1-weighted spoiled gradient echo sequence following
gadolinium-based contrast administration. The image acquisition is timed when the contrast is in the
vessel of interest and the central portions of k-space is filled. Time-resolved MR angiographic
sequences (TWIST) perform high frequency sampling of the central k-space and are able to obtain high
temporal resolution images of the vascular system, while at the same time obtain perfusion images,
particularly that of the lung.7 Pulmonary perfusion is obtained during parenchymal phase of contrast
enhancement in MR angiography, particularly time-resolved MR angiography.8 Pulmonary perfusion can
also be performed using arterial spin labeling, for which no exogenous contrast is required. Localized
adiabatic RF pulses are used to invert the magnetization of blood in the pulmonary arteries. By subtracting
images acquired with and without the arterial labeling pulses, perfusion images of the lungs can be
obtained. Dynamic contrast enhanced (DCE) MRI is 2D or 3D volumetric acquisition of the whole or
part of the chest during injection of contrast at a fixed rate with multiple acquisitions over time to map
enhancement over time. The data obtained can be plotted and used to calculate pharmacokinetic
parameters of tissues and tumors. The commonly calculated indices include area under the curve
(AUC), permeability coefficient kep, elimination coefficient kel, and amplitude (amp).
3D-SSFP sequence is a volumetric acquisition, in which images are obtained in a particular phase of
cardiac cycle and in one particular phase of respiration which is detected using a navigator pulse. Fat
saturation and T2 prep are used to suppress fat and myocardial signal, to optimally detect coronary
arteries. This sequence can be used to evaluate any vascular bed, without the need of intravenous contrast,
which is useful in patients with renal dysfunction. Delayed enhancement imaging is performed in 10 to
15 minutes after contrast administration, when contrast washes out from normal myocardium, but is
retained in scar or fibrous tissue, which is useful in the evaluation of myocardial infarction and other
types of cardiomyopathies. It is also useful in the evaluation of thrombus and other neoplastic masses.
Myocardial tagging is a type of T1-weighted images, in which grids are applied over myocardium using
saturation pulses. This is used for evaluation of regional myocardial function and pericardial tethering.
Other methods for evaluation of myocardial strain include- Feature tracking, DENSE and SENC.
Multiecho gradient echo sequences are gradient echo sequences obtained at different TEs in the same
slice. Using signal intensity at different TEs, the T2 value can be obtained, which is very low in patients
with iron deposition. T1 mapping is a technique where the absolute T1 value of the myocardium is
obtained using images at different inversion times. This is useful for quantification of myocardial fibrosis,
edema, and amyloidosis.9 T2 mapping is similarly obtained by using images at different TE. The absolute
T2 value is useful in the evaluation of myocardial edema in acute myocardial infarction and acute
myocarditis.
Hyperpolarized (HP) Helium (3He) and Xenon (129Xe) imaging of the lungs is acquired after the
inhalation of hyperpolarized gases using specialized coils to map pulmonary ventilation and gas exchange
and the data collected then can be used to evaluate the microstructure of the lungs. DWI imaging can be
used along with HP imaging to calculate ADC of the hyperpolarized gas, which then be used to calculate
the number and size of alveoli and also to calculate the thickness of the alveolar septae.10 Oxygen-
enhanced MR is also based on similar principals and can provide both structural and functional
information.11
CLINICAL APPLICATIONS OF THORACIC MAGNETIC RESONANCE

IMAGING
MEDIASTINUM
The International Thymic Malignancy Interest Group (ITMIG)12 recently proposed classification of
mediastinal compartments delineated by cross-sectional imaging that extends from the thoracic inlet to the
diaphragm: Anterior mediastinal or prevascular compartment includes all structures anterior to the
pericardium including thoracic aorta; Middle or visceral compartment includes all mediastinal visceral
structures extending from the posterior aspect of anterior pericardium to a vertical line drawn 1 cm from
the anterior margin of the spine, includes trachea and esophagus; and the posterior or paravertebral
compartment includes all structures posterior to the anterior margin of the spine.
The mediastinal mass protocol is optimized to characterize the mediastinal mass and also assess
resectability, it includes coronal and axial T2W images, axial T1W in- and out of phase images to
evaluate for microscopic fat, and pre- and post contrast GRE images in all three planes. Cardiac gating
with T1W or T2W DIR sequences are useful in identifying invasion of mediastinal vascular structures and
for surgical planning.
ANTERIOR MEDIASTINUM OR PREVASCULAR COMPARTMENT

MRI is used for tissue characterization in mediastinal masses, to distinguish cystic and solid lesions and
for surgical planning in order to determine resectability. Often due to poor tissue contrast on CT scans, it
is hard to discern if a mass is solid or cystic. MRI can help distinguish solid from cystic lesions and can
help differentiate water, hemorrhage, proteinaceous material, and calcium oxalate within the cystic lesion.
DWI imaging can help differentiate benign from malignant tumors, Razek et al. have proposed that a
threshold ADC value of 1.56 × 10−3 mm2/sec can be used as a cut-off value to separate benign from
malignant mediastinal masses.13 DCE MRI can also be used to characterize mediastinal masses by
evaluating peak enhancement times; a peak enhancement time of 1.5 minutes can be seen in low risk
thymomas, 2.5 minutes in stage III thymomas and up to 3.2 minutes can be observed in nonthymomas,
thereby proposing a potential cut off of 2 minutes to separate low risk from high-risk thymomas.14 The
most commonly seen anterior mediastinal masses include substernal thyroid, parathyroid adenomas,
thymic lesions, enlarged lymph nodes/lymphoma and germ cell tumors. Some other etiologies including
sarcomas, lymphangioma, infections, and inflammatory pathologies such as fibrosing mediastinitis can
also be seen in this compartment.
Substernal Thyroid
A substernal thyroid mass can present as a mediastinal mass and may be present in the anterior
mediastinal compartment; however, majority of these are located in the paratracheal space behind the
innominate vessels and thus are in the visceral compartment of the mediastinum. Goiters extend from the
neck into the mediastinum, sometimes the substernal goiter is attached to the thyroid with a fibrous
septum. These masses are heterogenous on T1W and T2W images and show heterogenous enhancement
post contrast administration. Coronal and sagittal reformats are helpful in delineating relationship with
adjacent structures. In multinodular goiters, multiple fluid-containing lesions can be seen within the
enlarged thyroid, these tend to be have high signal intensity on T1W images indicating proteinaceous or
hemorrhagic content. Breach of capsule and presence of regional adenopathy and loss of fat planes are
pathognomonic of malignant thyroid tumors. Differentiation between the malignant subtypes and presence
or absence of calcification are limited by this technique.14–16
Parathyroid Adenomas
An ectopic parathyroid adenoma is suspected if there is recurrent hyperparathyroidism after surgical
resection of parathyroid glands. MRI is not the primary imaging modality used in the evaluation of ectopic
parathyroid adenomas. Ultrasound or scintigraphy are more helpful in screening for parathyroid
adenomas. MR evaluation is performed when scintigraphy is inconclusive or non-diagnostic. Screening
MR evaluation extends usually from the thyroid to the base of the heart. These lesions are small well-
defined lesions with low signal on T1W and high signal on T2W images with avid enhancement. If
hemorrhage is present then these lesions are high on T1W sequences as well. The differential diagnosis
includes necrotic lymph nodes and parathyroid carcinoma. High-resolution T1W and T2W images are
also acquired to identify the recurrent laryngeal nerve and surgical planning.
Thymic Hyperplasia
Normal thymus gland is bilobed, undergoes fibrofatty involution, and decreases in size with age. In
subjects less than 30 years of age, normal thymus can be well visualized on T1-weighted MR images as it
is outlined by mediastinal fat, which has higher signal intensity and on out phase imaging there is up to
60% drop in signal due to the presence of macroscopic fat, which can vary with age. In thymic
hyperplasia, the thymus increases in size after having undergone involution, etiologies include myasthenia
gravis, thyrotoxicosis and secondary to stress to the body. Ten to fifteen percent of patients with
myasthenia gravis have been known to have thymomas. The anatomical shape of the thymus is maintained
in these patients and the chemical shift ratio is less than 0.50 to 0.60. CSR between 0.80 and 0.90 is
deemed indeterminate in solid lesions and warrants follow-up or biopsy to exclude neoplastic
process.17–19 A CSR of greater than one is seen in malignant thymic epithelial neoplasms. Chemical shift
ratio can help differentiate thymic masses; however, when using this parameter, one must remember that
normal thymus can have variable amounts of intracytoplasmic fat which varies with age and gender. When
assessing a thymic cyst or a cystic neoplasm, CSR can be misleading and is not applicable. In diagnostic
evaluation of teratomas and thymolipomas, CSR is not helpful as these lesions have macroscopic fat,
which is better evaluated by fat saturated sequences (Fig. 13.1).
FIGURE 13.1 Thymic hyperplasia. The triangular soft tissue lesion in the anterior mediastinum (A) on in-phase images and (B)
out-of-phase images shows a 60% drop in signal consistent with thymic hyperplasia [CSR = (tSI op/mSI op)/(tSI in/mSI in) =
0.60].
Thymic Epithelial Neoplasms

Thymic epithelial neoplasms include thymoma, thymic carcinoma and thymic carcinoids. The primary
role of MRI in evaluation of patients suspected of having thymic epithelial neoplasms is staging, when
patients are allergic to iodine-related contrast agents, for surgical planning and tissue characterization,
either to eliminate cystic lesions or using novel techniques such as DWI to calculate ADC values which
can help characterize histological subtypes.15,17
Thymomas are the most common thymic epithelial neoplasm and are generally well-encapsulated
slow-growing neoplasms, with areas of calcification and necrosis and myxoid degeneration. Therefore,
thymomas demonstrate lower T1 and higher T2 signal intensity and show heterogenous contrast
enhancement. A cystic variant has also been reported; these are high signal on T2W images and can mimic
mediastinal cysts but show heterogenous enhancement.15,19 Fibrous septae are low signal on T1W and
T2W images. The drop metastases and pleural metastases have similar signal characteristics as the
primary tumor. Black-blood or white-blood techniques are additionally helpful along with cardiac gating
to exclude invasion of mediastinal vascular structures and determine resectability. Phrenic nerve
involvement can be seen in invasive thymoma and can be assessed with the addition of multishot spiral
sequences utilizing real-time imaging, thus allowing for evaluation of paradoxical movement of the
diaphragm and measurement of diaphragmatic span.20 Multiplanar images help in optimal staging and
determining invasion of other mediastinal structures such as pericardium.
Thymomas present as lobulated masses with or without capsular invasion. Other features associated
with aggressive subtype include mediastinal extension, vascular encasement, regional adenopathy, and
drop pleural metastases. Lung, pleural, and even bone metastases have been reported. Newer techniques
such as determination of CSR and ADC values provide complementary information and have been used to
distinguish thymomas from other mediastinal masses.
Thymic carcinomas are similar to invasive thymomas in appearance; however, they tend to
demonstrate higher signal intensity on T1W and T2W sequences. Mediastinal adenopathy and pleural
effusions are also more commonly seen with the former. Cystic degeneration and hemorrhagic change are
seen and manifest as heterogenous appearance on both T1W and T2W sequences. These also demonstrate
intense to heterogenous enhancement. It is important to cover the whole chest when evaluating these and
not to limit the FOV to exclude pleural metastases.
Thymic carcinoids, can be typical or atypical defined by the degree of mitosis on histopathology;
however, on imaging they can be very similar to thymic carcinomas and invasive thymomas. They are
relatively rare but are associated with MEN syndromes.21 Differentiation between the two on imaging is
limited and may be only suspected if there is capsular breach and association with adenopathy and
presence of metastases.
Thymolipomas are benign tumors seen in younger individuals composed of fat with some fibrous
septae. They can grow to a very large size and can occupy the whole hemithorax. On MRI, they have high
signal intensity on T1- and T2-weighted images without significant enhancement (Figs. 13.2 to 13.4).19
Germ Cell Tumors

The majority of anterior mediastinal germ cell tumors are benign, with most of these being dermoid cysts
and benign teratomas and comprise varying amounts of fluid, fat, soft tissue, and calcifications. The
malignant teratomas are the most common malignant germ cell tumor. Other less common germ cell tumors
include seminomas and nonseminomatous germ cell tumors (choriocarcinomas, embryonal carcinomas,
and endodermal sinus tumors); the former are common in young males. These tend to be well
encapsulated with varying compositions of fluid, fat, calcium, and soft tissue, with presence of internal
septations that are T2 hyperintense with heterogenous enhancement, presence of adenopathy, and capsular
invasion is suggestive of the malignant counterpart. DWI and DCE techniques have been used to assess
response to therapy. MRI is also useful in determining resectability (Fig. 13.5).15
FIGURE 13.2 Thymoma. A 5-cm mass in the anterior mediastinum, (A) isointense to muscle on axial T1W image, (B) slightly
hyperintense to muscle on axial T2W image with heterogeneous enhancement on (C) axial post-contrast VIBE image.
FIGURE 13.3 Pleural drop metastases. (A) Axial CT image, (B) axial T2W (hypointense), (C) axial T1W (isointense), and (D)
post-contrast axial VIBE (enhancing) image showing a pleural drop metastases in a patient with thymoma.
FIGURE 13.4 Thymic carcinoid. (A) Large well-encapsulated anterior mediastinal mass, slightly hyperintense on T2W images;
(arrow) large draining vein, (B) coronal T2W image showing the mass is well encapsulated and keeps the shape of the thymus,
(C) and, (D) axial post contrast VIBE images showing heterogeneous enhancement with a large draining vein (arrow) in the
lateral aspect.
FIGURE 13.5 Germ cell tumor. Axial T1W (A) T2W, (B) and post-contrast VIBE, (C) images showing a large heterogeneous
mass in the anterior mediastinum with areas of fat and necrosis showing heterogeneous enhancement.
FIGURE 13.6 Lymphoma. Moderate left chylous pleural effusion with (A) isointense soft tissue mass encasing the descending
aorta on T1W axial image, (B) hyperintense to muscle on T2W images, (C) restricted diffusion on ADC map with ADC value
comparative with an epithelial neoplasm, (D) mild heterogeneous enhancement on post-contrast VIBE image consistent with
lymphoma.
Lymphoma
Primary thymic lymphomas are rare and in majority of these cases tend to be B cell lymphoma, a type of
non-Hodgkin lymphoma. These are low signal on T1W and T2W images and demonstrate homogenous
enhancement; necrosis may be present. T cell lymphoma can also involve the thymus and can be
associated with paraneoplastic syndrome. Nodular sclerosing Hodgkin lymphoma can also present as a
lobulated anterior mediastinal mass with or without other sites of adenopathy, there tends to be an overlap
of imaging features; other clinical features combined with histopathology are needed to confirm diagnosis.
DWI can be used to help narrow the differential diagnosis but there can be an overlap of ADC values of
various mediastinal tumors. MRI is useful to evaluate areas of concern on CT scans and PET CT scans
post treatment to identify residual or recurrent disease and guide biopsy. Viable tumor is bright on T2W
images as compared the fibrotic tissue which is dark on both T1- and T2-weighted images (Fig. 13.6).15,17
Thymic Cyst
Thymic cysts can be congenital or acquired and are often asymptomatic but can present with severe chest
pain due to sudden distension of the thymic capsule. These are well encapsulated within the thymus and
can be associated with varying amounts of normal thymic tissue and demonstrate low signal on T1W and
high signal on T2W images and demonstrate capsular enhancement. Varying amounts of hemorrhage,
protein, and fat present as high signal on T1W sequences. Absence of enhancing mural nodules and lack
of enhancing internal components favor benign thymic cysts rather than cystic thymomas (Fig. 13.7).17,20
Hypervascular Mediastinal Masses

Hypervascular mediastinal lesions include paragangliomas, hemangiomas, sarcomas, and Castleman
disease. Paragangliomas are intermediate on T1W and hyperintense on T2W sequences with intense
enhancement, areas of necrosis can be seen. MR imaging features along with association with
hypertension and in combination with biochemical tests can help confirm the diagnosis. Majority, 97% of
these are benign and only rarely (3%) are malignant, the latter can metastasize. The MR characteristics of
pheochromocytomas are similar to paragangliomas. Castleman disease can also present with
hypervascular masses which are low on T1W and have high signal intensity on T2W sequences.
Hemangiomas and epithelial hemangioendotheliomas are rare mediastinal tumors that also tend to have
low signal on T1W and high signal on T2W sequences with intense enhancement (Fig. 13.8).21,22
FIGURE 13.7 Thymic cyst. (A) A hypodense mass in the anterior mediastinum post contrast enhanced axial CT (B) is
hyperintense on T1W, (C) and T2W images and (D) shows minimal enhancement post gadolinium administration, consistent with
a hemorrhagic thymic cyst.
MIDDLE VISCERAL COMPARTMENT

The visceral or middle mediastinal compartment contains blood vessels, lymph nodes, lymphatics, the
trachea and esophagus, and a variety of neural structures. Cardiac and respiratory gating are needed to
decrease artifacts and optimize imaging of tumor and pathologies in the middle mediastinum. The
nonvascular pathologies include lymphoma, foregut duplication cysts, tracheal and esophageal neoplasms,
paragangliomas, Castleman disease, and benign pathologies such as fibrosing mediastinitis, hemangioma,
and lymphangioma. The vascular pathologies include cardiac and paracardiac masses and diseases,
coronary artery anomalies, thoracic aorta disorders, cardiomyopathies, and acquired cardiovascular
diseases. MR also plays a vital role in evaluating both congenital and acquired cardiovascular disorders
and also traumatic injuries of the aorta.
HEART
Cardiac and Paracardiac Masses
Although echocardiography is the primary imaging modality used in the detection of cardiac masses, MRI
is more useful in providing additional information about the masses.23 MRI protocol for cardiac mass
includes sequences that are useful in highlighting different tissue characteristics through the mass
including T1W, T2W, STIR, diffusion, early contrast enhancement, and delayed contrast enhancement
sequences. Cine SSFP sequences can evaluate the position of mass with cardiac chambers and valves and
also evaluate ventricular function.
Thrombus is the most common nonneoplastic mass, with others being pericardial cyst, lipomatous
hypertrophy of the interatrial septum, vegetations, and caseous mitral annular calcification. Malignant
lesions are more common than benign neoplastic lesions. Secondary tumors are much more common than
primary neoplasms. Metastasis, lymphoma, leukemia, and sarcoma are the common malignant lesions
while myxoma, lipoma, fibroelastoma, hemangioma, and paraganglioma are the common benign lesions.
Neoplastic lesions from adjacent structures such as lung, esophagus, and mediastinum can extend to the
heart.24
Using a combination of T1, T2, STIR, early and delayed enhancement, the differential diagnosis of the
mass can be narrowed, particularly a benign lesion can be distinguished from malignant lesion. T1- and
T2-weighted images can define tissue characteristics such as fat, hemorrhage, or fluid. Benign lesions are
smaller, have smooth margins, may have a stalk, involve single chamber and a single compartment
(chambers, myocardium, pericardium), while malignant lesions are larger, irregular, broad-based,
infiltrative, involve multiple chambers or multiple compartments, with pericardial effusion/thickening.25
Myxoma is classically attached to the fossa ovalis and protrudes into the left atrium (Fig. 13.9). Lipoma
has fat signal in all sequences. Hemangioma and paraganglioma have high signal in T2-weighted images
with flow voids seen in paraganglioma. Fibroelastomas are common in valves, are smooth, and may have
delayed enhancement. Metastatic lesions and lymphoma can present as multiple nodules, solitary nodule,
diffuse infiltration, or pericardial effusion. Sarcoma is the most common primary malignant tumor of the
heart. Angiosarcoma is more common in the right atrium, while osteosarcoma and spindle cell sarcoma
are more common in the left atrium. Thrombus has no contrast enhancement, both in early and delayed
phases (Fig. 13.10), with the rare exception of a chronic vascularized thrombus. In suspicious cases,
where a thrombus has to be distinguished from a neoplasm, a delayed enhancement sequence is performed
at longer inversion time (e.g., 600 ms). At this time, only thrombus remains dark, whereas neoplasms will
show at least some signal. Pericardial cyst is a fluid-containing lesion, more commonly seen in the right
cardiophrenic angle. Lipomatous hypertrophy is a fat-containing thickening of the septum, with
characteristic sparing of the fossa ovalis. Vegetations affect the leaflet tips and have irregular margins.24
FIGURE 13.8 Castleman disease. 58-year-old with progressive dyspnea and cough. (A) Axial T2W hyperintense mass with
flow voids in the middle mediastinum, (B) sagittal T1W post contrast MRI showing an enhancing heterogeneous mass in the
superior aspect of the right main pulmonary artery, (C) the posterior aspect of the ascending aorta, the inferior aspect of the
aortic arch, and the anterior aspect of the descending aorta.
FIGURE 13.9 Myxoma. Three-chamber delayed enhancement MRI image shows a heterogeneously enhancing mass in the left
atrium (arrow) attached to the atrial septum.
FIGURE 13.10 Thrombus. Short-axis SSFP image shows a mass in the posterior wall of the left atrium (arrow), which did not
show any contrast enhancement consistent with a thrombus.
FIGURE 13.11 Lung cancer invading heart. T1-weighted mass shows a large mass in the right lung (arrow), which is invading
the heart, particularly the right atrium.
MRI is very useful in determining the involvement/infiltration of cardiovascular structures from

adjacent tumors such as lung and esophagus. T1 and T2 images show the presence or absence of fat plane
between the neoplasm and heart (Fig. 13.11). Cine MRI scans can demonstrate the movement of a mass
relative to the heart, providing information about the site of attachment. In suspicious cases, a real-time
cine MRI with free breathing can be performed to see if the mass is moving separately or along with the
heart. Cine images can also demonstrate compromised valve function.
Pericardial Disorders
MRI is valuable in the evaluation of various pericardial disorders, particularly pericardial constriction.
MRI protocol for pericardial disorders includes T1- or T2-W black-blood images for evaluating
pericardial morphology, particularly thickening and effusion. STIR images are used for evaluating
myocardial edema. Cine SSFP images evaluate cardiac chambers and functional features. Myocardial
tagging is used for pericardial tethering. Velocity-encoded sequences are used for evaluating inflow and
other flow parameters. Delayed enhancement is used for evaluating pericardial inflammation. Real-time
cine SSFP sequence is used for evaluating septal motion and ventricular interdependence.26
Pericarditis can be seen in several stages, such as acute, chronic inflammatory, and chronic fibrosing
pericarditis. In acute pericarditis, there is pericardial thickening (>2 mm), with fluid, pericardial edema,
and delayed enhancement (Fig. 13.12). In chronic inflammatory pericarditis, there is pericardial
thickening with resolution of effusion and no delayed enhancement. In chronic fibrosing pericarditis, the
pericardium becomes fibrotic/calcified. The pericardium is thickened and has low signal due to fibrosis
or calcification. In addition, MRI demonstrates physiological features of pericardial constriction. Cine
SSFP images show diastolic septal bounce and abrupt cessation of diastolic filling (Fig. 13.13). There is
tubular shape of the left ventricle and conical shape of the right ventricle. Real-time cine SSFP image
shows exaggerated diastolic septal flattening/inversion with inspiration compared to expiration, which is
a feature of ventricular interdependence. Pericardial constriction is managed by surgical pericardiectomy;
however, recent studies show that in the presence of constriction associated with inflammation (as seen
by delayed enhancement), intense medical therapy (colchicine, NSAID, steroids) is beneficial.
Pericardial effusion is seen as low signal in T1- and T2-weighted images and has high signal with
complex/loculated effusion. Cardiac tamponade can be seen as flattening of the anterior surface of the
heart, collapse of the right ventricle free wall in early diastole and collapse of right atrium free wall
during late diastole and early systole (Fig. 13.14), compression of cardiac chambers and dilation of SVC,
IVC, and hepatic veins.26,27
FIGURE 13.12 Acute pericarditis. (A) Short-axis T2-weighted black blood image shows circumferential thickening of the
pericardium (arrow), (B) two-chamber delayed enhancement image in the same patient shows diffuse circumferential pericardial
enhancement (arrow), which is consistent with inflammation seen in acute pericarditis.
FIGURE 13.13 Constrictive pericarditis. A: Short-axis black blood T2-weighted image shows thickening of the pericardium
(arrow) due to calcification. B: Four-chamber cine SSFP image shows pericardial thickening (straight arrow). There is also
deformity of the ventricles and diastolic septal flattening (curved arrow), which are features of pericardial constriction. C:
Short-axis real-time cine SSFP imaging in inspiration shows that the ventricular septum is flattened in diastole in inspiration, which
is indicative of exaggerated ventricular interdependence, which is a feature of pericardial constriction.
FIGURE 13.14 Tamponade. Four-chamber cine SSFP image shows a loculated pericardial effusion (curved arrow) adjacent to
the right atrium and also adjacent to the left ventricle. There is collapse of the free wall of the right atrium (straight arrow),
which is consistent with cardiac tamponade.
Cardiomyopathies
MRI is a valuable tool in the evaluation of cardiomyopathies, not only in the diagnosis, but also in risk
stratification, prognostic determination, and determining suitability for surgery and other interventions.
MRI is also the most accurate and reliable method of quantifying ventricular function, with ventricular
function <35% often considered as indication of ICD placement. Delayed enhancement MRI is useful in
detecting scar and fibrosis, the pattern of which can be used in the diagnosis of cardiomyopathies.
Regardless of etiology, the presence of scar is an adverse prognostic factor.28 Other sequences used in
MRI protocol for cardiomyopathies include cine SSFP sequences for ventricular function, both global and
regional; velocity-encoded sequence for quantifying valvular function; and STIR sequences for
myocardial edema. Recently T1 mapping is used for determining absolute myocardial T1 value as an
indicator of myocardial fibrosis and T2 mapping is used for quantifying absolute myocardial T2 value as
an indicator of myocardial edema, both of which are more sensitive than delayed enhancement and STIR
images respectively.
In myocardial infarction, a subendocardial or transmural enhancement is seen in a vascular distribution
(Fig. 13.15). MRI is the most sensitive technique in the diagnosis of this scar and is useful in the
diagnosis of cases, which present in atypical situations. The technique is also useful in the detection of
viable myocardium in patients who are being considered for coronary artery bypass grafting (CABG).
Delayed enhancement <50% of myocardial thickness is considered viable myocardium, whereas
enhancement >75% is considered viable and hence not suitable for CABG. MRI can also identify
complications of MI including aneurysm (Fig. 13.16), pseudoaneurysm (Fig. 13.17), thrombus,
pericarditis, free wall rupture, and ventricular septal rupture.29 Idiopathic dilated cardiomyopathy is seen
as ventricular dilation, global systolic dysfunction, and may have a linear mid myocardial scar.
Hypertrophic cardiomyopathy has several phenotypical presentations, the most common of which is
asymmetric thickening of the ventricular septum (Fig. 13.18A). Apical, mid ventricular, mass-like, and
concentric types are less common. MRI shows the hypertrophy, quantifies the hypertrophy, quantifies
LVOT obstruction, and demonstrates systolic anterior motion of the mitral valve and mitral regurgitation.
MRI also identifies delayed enhancement due to interstitial fibrosis, which is seen in a patchy mid
myocardial distribution in the hypertrophied segments, or in the right ventricular insertion points (Fig.
13.18B). The extent of fibrosis indicates the risk of arrhythmia and sudden cardiac death and may be an
indicator of ICD placement. MRI is useful in surgical planning for myomectomy. Papillary muscle
abnormalities which can also produce obstructive features are best diagnosed using MRI and this is
managed by papillary muscle plication. Occasionally, a long mitral valve can produce similar symptoms
and is managed by repair of the mitral valve. Acute myocarditis manifests as myocardial edema in T2-
weighted images and mid myocardial or subepicardial pattern of delayed enhancement, typically
associated with pericardial involvement. Sarcoidosis has similar features in the acute stage with mid
myocardial or subepicardial enhancement (Fig. 13.19) but in chronic stages can have transmural pattern
of enhancement with wall thinning. Left ventricular noncompaction presents with prominent
nontrabeculated myocardium, with a ratio of >2.3 between noncompacted and compacted myocardium,
which may show delayed enhancement. Arrhythmogenic right ventricular dysplasia (ARVD) shows fat in
the RV free wall, with major wall motion abnormalities (aneurysm, akinesis, dyskinesia) with either
severe systolic dysfunction (ejection fraction <40%) or ventricular dilation (end diastolic volume >110
L/m2). Fabry disease shows mid myocardial or subepicardial pattern of enhancement typically in the
basal inferolateral segment, often associated with concentric thickening. Low values are seen in T1-
mapping. Amyloidosis shows concentric LV thickening with biatrial and atrial septal thickening. There is
diffuse subendocardial to transmural enhancement of the ventricles (Fig. 13.20). There is also altered T1
kinetics, where the myocardium nulls before the blood pool in inversion recovery images with T1 scout.
In stress-induced cardiomyopathy, there is vigorous contraction of the basal segments, but
hypokinesis/akinesis of the apical segments, resulting in systolic cardiac failure. There may be
myocardial edema, but no delayed enhancement is seen.28 In iron overload cardiomyopathies, there is low
signal of the myocardium, which gets worse with longer TE values. This can be quantified with multiecho
gradient echo sequence and calculation of T2 .30
FIGURE 13.15 Infarct. Short-axis delayed enhancement MRI image shows full-thickness delayed enhancement in the lateral
and inferior wall (arrow), consistent with infarct in the left circumflex artery distribution. Due to an extensive full thickness
infarct, this segment is not viable, indicating that this is not a suitable candidate for revascularization procedure.
FIGURE 13.16 Aneurysm. Short-axis cine SSFP image in a patient with myocardial infarction shows a large wide-mouthed
aneurysm originating from the lateral wall of the left ventricle (arrow).
FIGURE 13.17 Pseudoaneurysm. Coronal SSFP image shows a narrow-mouthed pseudoaneurysm (arrow) originating from the
inferior wall of the left ventricle.
FIGURE 13.18 Hypertrophic cardiomyopathy. A: Short-axis cine SSFP image shows hypertrophic cardiomyopathy, with
asymmetric thickening of the ventricular septum (arrow). The lateral wall is of normal thickness. B: Two-chamber delayed
enhancement MRI image in the same patient shows heterogeneous, patchy mid myocardial enhancement in the apical region
(arrow), which is consistent with interstitial fibrosis in hypertrophic cardiomyopathy.
FIGURE 13.19 Sarcoidosis. Short-axis delayed enhancement image shows diffuse subepicardial enhancement (arrow),
consistent with cardiac sarcoidosis.
FIGURE 13.20 Amyloidosis. A: Short-axis black blood image shows concentric LV thickening (curved arrows). B: Short-axis
delayed enhancement image shows diffuse enhancement of the left ventricular (straight arrow) and right ventricular (curved
arrow) myocardium and dark blood pool, which is consistent with cardiac amyloidosis.
Valvular Disorders
MRI is a valuable complementary imaging modality to echocardiography in the evaluation of valvular
abnormalities. MRI protocol for evaluation of valves includes velocity-encoded sequences targeted
toward the valve of interest. Cine SSFP images are utilized to evaluate morphology, evaluate valvular
regurgitation/stenosis, and quantify ventricular function and volumes. If a valvular mass is suspected, then
additional sequences are added similar to a cardiac mass protocol. Delayed enhancement can be used to
evaluate myocardial scar or cardiomyopathies.
Velocity-encoded phase contrast imaging can quantify both regurgitation and stenosis. On MRI, the
regurgitation is graded as mild (<15%), moderate (16% to 25%), moderate severe (25% to 45%), and
severe (>45%). The velocity of stenotic jet is measured and using this, pressure gradient can be
calculated using modified Bernoulli equation, Δp = 4v2. Valvular disease is often seen as thickening of the
leaflets. Aortic stenosis is characterized by restricted systolic opening of the leaflets, with systolic flow
acceleration. The leaflets are thickened and calcified, which has low signal in MRI. The valve
morphology is also exquisitely demonstrated using MRI, including abnormalities such as bicuspid,
quadricuspid, and unicuspid valves. Aortic regurgitation is seen as a retrograde jet through the aortic
valve in diastole. Pulmonic stenosis is shown during systole and regurgitation in diastole. MRI is the most
valuable imaging modality in the quantification of pulmonary valvular abnormalities. Mitral stenosis is
seen as thickened leaflets with flow acceleration during diastole, whereas regurgitation is seen as a
backward jet into left atrium during systole. A posterior eccentric regurgitant jet is often seen in
hypertrophic cardiomyopathy, while an anterior regurgitant jet is often seen in mitral valve prolapse.
Stenotic lesion of the tricuspid valve is seen as leaflet thickening with flow acceleration in diastole,
whereas regurgitation is seen as backward flow in right atrium during systole. MRI also evaluates the
consequences of valvular abnormalities such as ventricular hypertrophy, dilation, and systolic
dysfunction.31,32
Congenital Cardiac Abnormalities

MRI is a valuable modality in the evaluation of various congenital cardiac abnormalities. It provides
comprehensive anatomic and functional evaluation of these cardiac abnormalities and provides a
roadmap for surgical evaluation. MRI is also the most useful modality in the evaluation of adult
congenital heart disease, including in adults who had pediatric congenital heart surgery.33 MRI is
especially useful in the evaluation of right ventricular volumes, which is evaluated only in a limited
fashion with echocardiography. Tetralogy of Fallot has right ventricular obstruction, right ventricular
hypertrophy, overriding aorta, and ventricular septal defect (Fig. 13.21). MRI is useful in the evaluation
of major aortopulmonary collaterals (MAPCAs) in patients who have severe RV obstruction such as
pulmonary atresia. MRI is useful in the evaluation and quantification of pulmonary regurgitation, right
ventricular dilation, and right ventricular function in patients who had surgical repair. Transposition of
great arteries can be of dextro and levo types. In D-TGA, there is ventriculoarterial discordance, with the
aorta originating from the right ventricle and the pulmonary artery from the left ventricle (Figs. 13.22 and
13.23). MRI is useful both in pre- and postsurgical states, including arterial switch and atrial switch
procedures including Mustard and Senning procedures. In Ebstein anomaly, there is apical displacement
of the septal leaflet of the tricuspid valve, resulting in atrialization of a portion of right ventricle,
decreased right ventricular systolic function, and tricuspid regurgitation (Fig. 13.24). In single ventricle
type of abnormalities, MRI is useful in delineating the anatomy and quantifying ventricular and valvular
function. There are several types of abnormalities that produce a single ventricle physiology, including
hypoplastic left heart syndrome, tricuspid atresia, AV canal defect, double outlet right ventricle, and
double inlet left ventricle. MRI is also useful in the evaluation of shunts used in several stages of these
patients including aortopulmonary shunts (Blalock-Taussig, modified Blalock-Taussig, Potts, Waterston),
Glenn shunt (SVC to right pulmonary artery) and Fontan shunt (IVC to right pulmonary artery). Ventricular
septal defects can either be membranous, muscular, inlet, or outlet types. Atrial septal defect can be
ostium primum, ostium secundum, sinus venosus (superior, inferior), and coronary sinus types.34
FIGURE 13.21 Tetralogy of Fallot. Three-chamber cine SSFP image shows a malalignment ventricular septal defect (curved
arrow), with overriding of aortic root (AO). There is also right ventricular hypertrophy.
FIGURE 13.22 D-TGA. Axial black blood image shows that the aorta is anterior and to the right of pulmonary artery, which is
a classic feature of D-TGA.
FIGURE 13.23 Mustard. Axial cine SSFP image shows a baffle in the left atrium, which diverts the flow from the right atrium
toward the left ventricle and the flow from left atrium toward the right ventricle, which is indicative of an atrial switch procedure
for D-TGA.
Coronary Artery Abnormalities

MRI is a good imaging modality in the evaluation of coronary artery abnormalities. Although CT is more
commonly used in the evaluation of coronary artery abnormalities, MRI has also been showing to be
effective in the evaluation of coronary arterial abnormalities, including stenosis.35 3D whole-heart
navigator-gated free-breathing coronary MRA using SSFP sequence with fat saturation and T2 preparation
is the sequence used in the evaluation of coronary artery abnormalities.35 MRI is also useful in the
evaluation of coronary arterial anomalies. Anomalous origin of coronary arteries is usually from the
opposite sinuses (Fig. 13.25). The course of coronary arteries can also be abnormal, either interarterial
(between aorta and pulmonary artery), retroaortic (behind aortic valve), prepulmonic (anterior to
pulmonary artery), or transeptal (through ventricular septum). Coronary arteries may drain into a cardiac
chamber or vein or pulmonary artery in coronary artery fistula. Coronary ectasia is a diffuse dilation of
coronary arteries, seen in atherosclerosis. Coronary aneurysm is focal dilation, with the vessel measuring
1.5 times its normal diameter (Fig. 13.26). This is commonly caused by atherosclerosis in adults, and by
Kawasaki disease in children.
FIGURE 13.24 Ebstein anomaly. Four-chamber cine SSFP image shows Ebstein anomaly with apical displacement of the septal
leaflet of tricuspid valve (arrow). The right ventricle is atrialized. There is diastolic septal bounce due to tricuspid regurgitation.
FIGURE 13.25 Anomalous origin of coronary artery. 3D volume rendered image shows anomalous origin of the right coronary
artery (arrow) from left coronary artery.
THORACIC AORTA
MRI has become the modality of choice for the evaluation of thoracic aortic pathologies. Thoracic aortic
protocols include cine SSFP images in multiple planes to evaluate the thoracic aorta and the aortic valve.
In patients with suspicion of vasculitis, T2-weighted images with and without fat saturation are used to
evaluate wall thickening and edema. Flow quantification sequences are used to quantify aortic flow and
valvular abnormalities. 3D MR angiography is utilized for evaluation of aortic anatomy and to make
measurements. 3D whole-heart navigator-gated SSFP sequence is a noncontrast alternative to evaluate the
thoracic aorta, especially in patients with severe renal dysfunction.
Several anatomical variants are encountered in the arch branching vessel pattern. The most common, is
a two-vessel aortic arch (Bovine arch) in which there is a common trunk supplying the right
brachiocephalic and left common carotid arteries. Another variant is a left vertebral artery originating
directly from the aortic arch. Aberrant origin of the right subclavian artery as the arch is less common. In
this anomaly, the right subclavian artery originates as the last branch from the aortic arch distal to the left
subclavian artery and crosses behind the esophagus to reach the right side. The aberrant vessel can
originate directly from the aorta or from an outpouching called the diverticulum of Kommerel, which can
rarely become aneurysmal.
FIGURE 13.26 Coronary aneurysm. 3D volume-rendered MR angiography image shows diffuse coronary artery aneurysm
(arrows).
Double aortic arch is the most common symptomatic vascular ring, in which two arches originate from
the ascending aorta, cross on either side of the trachea and esophagus, and joint the descending thoracic
aorta. A complete ring is formed with encirclement of the trachea and esophagus (Fig. 13.27). A right-
sided aortic arch is seen in 0.1% of the population. This can have either a mirror image branching pattern,
which is associated with other cardiac defects in 90% of cases or may have an aberrant left subclavian
artery, which is not commonly associated with other cardiac defects. Coarctation of aorta is characterized
by discrete narrowing of the proximal descending thoracic aorta (Fig. 13.28). In hypoplasia, there is
diffuse narrowing of the arch. MRI can exquisitely demonstrate all these vascular rings and help in
surgical planning.
Aneurysm is a common acquired disorder to involve the thoracic aorta and is defined as a permanent
localized dilation >2 standard deviations than normal diameter. Atherosclerosis is the most common
cause. Less common causes include ankylosing spondylitis, rheumatoid arthritis, rheumatic fever, SLE,
scleroderma, Behçet disease, psoriasis, ulcerative colitis, Reiter syndrome, and radiation therapy.
Aneurysm can either be fusiform when it involves the entire circumference of the vessel wall with a
spindle shape or saccular, when only a portion of the vessel wall is involved resulting in an eccentric
outpouching. Aneurysms are classified as true aneurysms if all three layers of the vessel, intima, media,
and adventitia, are intact or as false or pseudoaneurysms if disruption of one or more layers occurs.
Alternatively, a false aneurysm can be considered as a contained rupture. An isolated aneurysm of the
ascending aorta, especially in a younger patient, should prompt a search for another etiology, such as
Marfan syndrome or a bicuspid aortic valve. Sinus of Valsalva aneurysm is usually congenital (Fig.
13.29). MRI can identify, characterize, and accurately measure the aneurysm, assess extension to branch
vessels, relationship of aneurysm to adjacent structures, and detect associated abnormalities including that
of aortic valve. Large thoracic aortic aneurysms can become symptomatic from congestive heart failure
caused by aortic insufficiency, from compression of the trachea or esophagus, from hoarseness caused by
compression of the recurrent laryngeal nerve, or from erosion of bony structures with subsequent pain.
Annuloaortic ectasia is symmetric dilation of the aortic root and ascending aorta with effacement of the
sinotubular junction. The ascending aorta has a pear-shaped appearance, but the arch and descending
aorta is of normal caliber. This is caused by Marfan syndrome, other connective tissue disorders,
syphilis, bicuspid valve, and aortitis. MRI and gadolinium-enhanced 3D MR angiography in particular
offer alternatives to CT in the evaluation of patients being considered for endovascular stent graft. In fact,
MR may be the only suitable imaging modality for patients with impaired renal function or allergies to
iodinated contrast media. Many commercially available stent grafts are constructed with Nitinol support
struts, which, unlike most metals, produce little MR artifact. MRI can also be used to evaluate patients for
complications of stent graft placement such as endoleak.
FIGURE 13.27 Double aortic arch. 3d volume rendered posterior MR angiography image through the aorta shows a double
aortic arch, with the right (curved arrow) and the left (straight arrow) arches encircling the trachea and esophagus and forming
a complete ring.
FIGURE 13.28 Coarctation. A: MR angiographic image shows a severe coarctation in the proximal descending aorta (arrow).
There are also prominent collaterals in the mediastinum and intercostal region. B: Sagittal cine SSFP image shows narrowing of
the proximal descending aorta, with flow acceleration (arrow) seen at the level of obstruction.
FIGURE 13.29 Sinus of Valsalva aneurysm. Short-axis image through the aortic valve shows a sinus of Valsalva aneurysm
originating from the noncoronary sinus (arrow).
Aortic pseudoaneurysms can form secondary to penetrating trauma, as a surgical complication, or as a

complication of an untreated aneurysm. Common locations for postoperative aortic pseudoaneurysms
include the cannulation site, the aortotomy site, and the graft suture line. Acute and subacute
pseudoaneurysms are generally considered a surgical emergency. Mycotic aneurysm is infectious
aneurysm caused by nonsyphilitic organisms, including Streptococcus, and staphylococcus (Fig. 13.30).
These are more common in the ascending aorta, and are saccular, wide-necked and multiple. Associated
soft tissue thickening may be seen.
Traumatic aortic injury is seen as a sequel of blunt chest trauma. This commonly affects the ascending
aorta, but this is typically fatal, and hence the most common location in patients who survive in the arch at
or near ligamentum arteriosum due to rapid deceleration. The most common imaging findings are
deformity of aortic contour, intimal flap, intraluminal debris, pseudoaneurysm, and intramural hematoma.
Mediastinal hematoma is not specific. Pseudoaneurysm is a chronic manifestation of aortic trauma. A
normal MRI does not completely exclude traumatic aortic injury, especially when the clinical suspicion is
high. MRI and CT can identify blood in the mediastinal fat around the site of an aortic laceration, and the
absence of such blood decreases the likelihood of traumatic aortic injury. In chronic traumatic aortic
aneurysms, MRI can be used for follow-up and to determine the need for surgical intervention.35
Acute aortic syndrome can be caused by dissection, intramural hematoma, penetrating ulcer, or rupture.
Dissection is characterized by a tear in the intima of the aorta, with leak of blood into tunica media and
formation of true and false lumen. The Stanford classification divides dissection into Type A (75%),
which involves the ascending aorta, and Type B (25%), which does not involve the ascending aorta. On
MRI, the flap, true and false lumen are demonstrated (Fig. 13.31). Complications such as thrombus, aortic
rupture, hemothorax, mediastinal hematoma, hemopericardium, acute aortic regurgitation, branch vessel
obstruction, and end organ ischemia can also be evaluated using MRI. Intramural hematoma is caused by
spontaneous hemorrhage into the tunica media of the aorta, usually due to rupture of vasa vasorum and
less commonly due to penetrating atherosclerotic ulcer. On MRI, IMH is seen as a crescenteric area of
abnormal signal within the aortic wall, extending circumferentially. The signal depends on the stage of
hematoma, with intermediate signal in acute phases due to oxyhemoglobin (Fig. 13.32) and high signal in
subacute stage due to methemoglobin. This is also classified into type A and B similar to that of
dissection. The hematoma can extend along the aorta, rupture or cause cerebral, mesenteric, vascular, or
renal ischemia.36
FIGURE 13.30 Mycotic aneurysm. Axial SSFP image shows large mycotic aneurysm of the descending aorta (dotted circle),
with destruction of the vertebral body.
FIGURE 13.31 Aortic dissection. Axial SSFP image shows Type B dissection with a flap (arrow) separating the true and false
lumen.
FIGURE 13.32 Intramural hematoma. Axial black-blood T1-weighted image shows a crescenteric area of high signal in the
lateral wall of the aorta (arrow) consistent with intramural hematoma.
Penetrating atherosclerotic ulcer is characterized by ulceration of the aortic wall, which begins as an
intimal ulcer, but results in full-thickness penetration of the aortic wall. It is usually caused by
atherosclerosis and is commonly seen in the descending aorta. MRI shows an outpouching from the aortic
lumen (Fig. 13.33). The aortic wall may be thickened and show contrast enhancement. A penetrating ulcer
should be distinguished from atherosclerotic ulcer, which is confined to the intima, lacks intramural
hematoma, and is asymptomatic. Complications include aneurysm, dissection, embolization, and rupture.
Rupture can occur in penetrating ulcer, dissection of intramural hematoma. It can either be contained or
extend into mediastinum, pericardium, pleura, extrapleural space, esophagus, or bronchus. With rupture,
hematoma is seen extending from the aneurysm, dissection, intramural hematoma, or ulcer. With
aortoesophageal fistula, contrast is seen in esophagus and air may be present in aorta.37
Aortitis is characterized by reactive damage to the aortic wall from leucocytes and other inflammatory
mediators in the aortic wall. Giant cell arteritis is the most common cause in older patients and Takayasu
arteritis is the most common cause in younger patients. On MRI, the angiography can show aneurysms and
stenosis which are complications of arteritis. In addition, MRI can also potentially help in evaluating the
disease activity. MRI shows wall thickening in both acute and chronic stages; however, wall edema is
seen in STIR images in the acute phase, whereas no edema is seen in chronic stages. Similar contrast
enhancement of the wall is also a feature of active diseases. Syndromes such as Marfan syndrome, Loeys–
Dietz syndrome, and Ehler–Danlos syndrome also affect the thoracic aorta.37
FIGURE 13.33 Penetrating ulcer. Sagittal MR angiographic image shows multiple wide-mouthed penetrating ulcers (arrows) in
the descending aorta.
PULMONARY VASCULATURE
MRI is a valuable imaging modality in the evaluation of the pulmonary vasculature. The pulmonic valve
can be evaluated by using cine SSFP images in the short-axis plane and sagittal view. Flow quantification
sequence is used for evaluating and quantifying pulmonic valvular and flow abnormalities. 3D MR
angiography is useful in the evaluation of pulmonary vascular anatomy. Time-resolved MR angiography
using techniques such as TWIST helps in evaluation of pulmonary vascular flow with high temporal
resolution. This enables evaluation of not only pulmonary vascular anatomy but also pulmonary
hemodynamics including pulmonary perfusion. 3D whole-heart navigator-gated SSFP sequence is a
noncontrast alternative to evaluate pulmonary artery, especially in patients with severe renal
dysfunction.38
Pulmonary hypertension is characterized by abnormally elevated pulmonary arterial pressure and
pulmonary vascular resistance. Common causes of pulmonary hypertension are cardiac disorders, chronic
lung disease, chronic pulmonary emboli, and shunts. Pulmonary hypertension is called primary or
idiopathic when all known etiologies have been excluded. MRI shows the anatomic changes of
pulmonary hypertension including dilated central pulmonary arteries, tapered pruned peripheral
pulmonary arteries, right ventricular hypertrophy, and systolic bowing of the interventricular septum. The
main pulmonary artery is considered dilated when it is >2.9 cm or greater than the size of ascending aorta.
The size of the central pulmonary arteries correlates with the degree of pulmonary hypertension, although
the correlation is imperfect. The severity of pulmonary hypertension has been correlated with increased
intraluminal signal intensity in the pulmonary arteries on spin-echo dark blood images.38 While in normal
patients, there is signal void in systole and early diastole, in pulmonary hypertension there is high signal
intensity in the lumen in systole and early diastole due to slow blood flow in diastole. MR angiography
may also show dilated bronchial arteries. MRI is also accurate in evaluation of RV function, including
stroke volume, end diastolic volume and ejection, which have important prognostic value.39 There is also
decreased myocardial perfusion reserve, which inversely correlates with RV workload and ejection
fraction.39 Reduced biventricular regional function by strain imaging has been shown to be associated
with increased RV overload.39 Dynamic MR angiogram can identify abnormalities in pulmonary
perfusion, seen as peripheral wedge-shaped or mottled defects which is sensitive in the detection of
chronic pulmonary embolism. This is also useful in the evaluation of pulmonary veno-occlusive disease.
Delayed enhancement MRI may show mid myocardial enhancement in the RV insertion points of
interventricular septum in patients with pulmonary hypertension due to increased stress. Altered
hemodynamics detected with time-resolved MRA has been shown to be independently associated with
pulmonary arterial pressure and pulmonary vascular resistance.40
Pulmonary embolism is the third most common acute cardiovascular disease. The etiology of PE is
usually deep venous thrombosis (DVT), most commonly from the lower extremities. However, the
frequent use of central venous catheters has increased the incidence of upper extremity DVT. Chronic PE
represents an uncommon complication of acute PE. Acute emboli become organized and incorporated into
the pulmonary arterial wall, essentially forming mural thromboemboli. Patients with chronic PE often
develop progressive pulmonary hypertension.
CT is the most commonly used imaging modality in the evaluation of pulmonary embolism, but MRI
shows comparable diagnostic accuracy. Advances in scan technology including the use of parallel
imaging, view-sharing, time-resolved MR angiography, and pulmonary perfusion have increased the
diagnostic accuracy of MRI in detecting pulmonary embolism. MRI protocol for diagnosis of PE includes
single-shot SSFP images in multiple planes, MR angiography, and pulmonary perfusion. On MRI, acute
embolism is seen as central/occlusive filling defect within pulmonary arteries, partial filling defect
surrounded by contrast material, peripheral filing defect which makes an acute angle with the arterial
wall, abrupt decrease in vessel diameter, and absence of contrast material in the vessel segment distal to
obstruction. Chronic pulmonary embolism is characterized by tapered pulmonary arteries, peripheral,
eccentric filling defects or webs. Pulmonary perfusion defects are seen as wedge-shaped peripheral
defects in MR pulmonary perfusion. Pulmonary infarctions can also produce peripheral wedge-shaped
defects which can progress to scars, bands, nodules, cavities, or irregular opacities. Mosaic pattern of
perfusion can also be seen.41 Meta-analysis has shown that MRI has a sensitivity of 100% for detecting
PE in central and lobar arteries, 84% in segmental arteries, and 40% in subsegmental arteries.42 PIOPED
III trial showed sensitivity of 92%, specificity of 96% in diagnosis of PE.43 IRM-EP study showed
sensitivity of 84.5% and specificity of 99.1% for detection of PE. However, MRI has to be performed in
an experienced center since 52% of patients were shown to have technically inadequate study.43 The
technique may not be widely available in all institutions. There is limited sensitivity for distal PE and
inconclusive results may be seen in 30% to 50%.44 MRI may not be able to detect pulmonary lesions
which could be the cause of acute chest pain.
Pulmonary aneurysm is focal dilation of the pulmonary artery. Causes include trauma, congenital
diseases, iatrogenic, vasculopathy or vasculitis, chronic pulmonary embolism, pulmonary hypertension,
infection, and neoplasm. Congenital causes include deficient vascular wall, pulmonic valvular stenosis,
and left-to-right shunts. Idiopathic aneurysm is a diagnosis of exclusion. Pseudoaneurysm results from
iatrogenic injuries or infection. Pulmonary arteriovenous malformation is a congenital vascular
anomaly of the lung, with communication of the pulmonary arteries and veins. They are common in the
periphery of the lower lobes and their large feeding arteries and draining veins. Multiple pulmonary
AVMs are seen in one-third of patients and in association with hereditary hemorrhagic telangiectasia
(Osler-Weber-Rendu disease). More than one feeding artery is present in 20% of patients. MR
angiography shows the AV malformation, with demonstration of feeding artery.
Pulmonary sequestrations are rare congenital malformations of lung that have no communication with
the tracheobronchial tree. Two types occur: intralobar and extralobar. Intralobar sequestrations are
surrounded by the visceral pleura, whereas extralobar sequestrations are surrounded by their own pleura.
Intralobar is most common in the posterior segment of the left lower lobe or the right lower lobe.
Extralobar sequestrations are common near the left dome of diaphragm in 90% and occasionally
infradiaphragmatic. Intralobar are usually asymptomatic unless infected, whereas extralobar type is
usually asymptomatic. Both types of sequestrations derive their arterial supply from aorta or its branches,
most commonly the descending thoracic aorta. The venous drainage of intralobar sequestrations is usually
to the left atrium, while the venous drainage of extralobar sequestrations is always systemic, most
commonly the inferior vena cava or azygos hemiazygos system (Fig. 13.34).45
MEDIASTINAL VEINS
MRI is an excellent modality for the evaluation of mediastinal veins and can delineate venous
obstructions in the internal jugular, subclavian, and brachiocephalic veins and SVC. MR can usually
differentiate intraluminal thrombus or tumor from extrinsic compression. In contrast to conventional
venography, MR can fully depict a mass lesion responsible for extrinsic venous compression. MRI
protocol for evaluation of venous abnormalities includes 3D MR venography and volumetric interpolated
3D sequences in axial and coronal plane. SSFP images are also helpful. Masses can be evaluated with
T1W, T2W, and diffusion-weighted sequences. MRA is obtained in neutral position and with arms
elevated in patients suspected of thoracic outlet syndrome (TOS). MR venography is useful for evaluation
of congenital anomalies such as persistent left SVC, anomalous pulmonary venous return, retroaortic left
innominate vein, scimitar syndrome, and interruption of IVC with azygos or hemiazygos continuation.
Anomalous pulmonary vein is usually partial, but can be total. In scimitar syndrome, there is partial
anomalous pulmonary vein, typically on the right side, associated with hypoplasia of the right lung.
MEDIASTINAL CYSTS
Mediastinal cysts can be can be congenital or acquired and include bronchogenic cysts, pericardial cysts,
neurenteric cysts, meningoceles, esophageal duplication cysts, thymic cysts, cystic hygromas, colloid
cysts related to thyroid goiter, pancreatic pseudocysts, abscesses, and hematomas. These are often
incidentally found on radiographs or CT scans and MR is used primarily as a problem-solving tool to
characterize contents and define relationship to adjacent structures. Simple cysts are low on T1W and
high signal on T2W sequences with capsular enhancement, the nature of contents (hemorrhagic, protein,
and colloid) can influence the signal characteristics. MR is superior to CT in depicting septations and
enhancing mural components. Enhancement characteristics can help distinguish benign from complex
cysts.
FIGURE 13.34 Intralobar sequestration. A: Axial post contrast image showing nonenhancing cystic lesion with wall
enhancement in the left lower lobe (arrow); (B) coronal oblique MIP image showing direct supply from the aorta (arrow).
Bronchogenic cysts can either be intrapulmonary or mediastinal, the latter are generally located either
in the paratracheal or subcarinal regions, but do not communicate with the bronchial tree.46 They are
usually asymptomatic when small but can compress critical adjacent structures such as airways or blood
vessels if large in size. The foregut duplication cysts, closely abut the esophagus and are mostly
asymptomatic, can have slightly thicker walls when compared with bronchogenic cysts.47 Neurenteric
cysts and meningoceles are closely associated with the spine and can be associated with vertebral
anomalies.48 Pericardial cysts are closely associated with the pericardium and a “beak sign” or
communication with the pericardium may be demonstrated on multiplanar images. Rarely echinococcal
cysts may be seen in the pericardiac region mimicking a pericardial cyst; these tend to have internal cysts
and daughter cysts within the primary cyst with enhancement of the septations. These can also be seen in
the lung and rarely transdiaphragmatic extension of a ruptured liver cyst into the lung can occur.49
POSTERIOR COMPARTMENT: PARAVERTEBRAL SPACE

MRI is superior to CT in evaluating pathologies of the paravertebral space or posterior mediastinum. The
most common tumors of this space are neurogenic tumors such as neurofibromas, schwannomas, and
malignant peripheral nerve sheath tumors from peripheral nerves; ganglioneuromas, neuroblastomas, and
ganglioneuroblastomas from sympathetic nerves; and paragangliomas and pheochromocytomas from
neuroectodermal cells closely associated with autonomic nerves. Paravertebral masses include
paraspinal abscesses, commonly related to tuberculosis and discitis; lymphoma, usually non-Hodgkin’s
lymphoma; extramedullary hematopoiesis; and primary and metastatic vertebral body neoplasms can also
be seen.50
Neurofibromas can be intradural, extradural, or both, and can present as a dumbbell-shaped tumor with
expansion of the neural foramina. Multiplanar images help delineate the extent of tumor and association
and compression of adjacent soft tissue structures. CT is superior to MRI in depicting bony abnormality,
and provides additional complementary information. On MRI, neurogenic tumors are low to intermediate
signal on T1W sequences, high signal on T2W sequences, and demonstrate marked contrast enhancement
(Fig. 13.35). Differentiation of benign from malignant neurogenic tumors is difficult on MR signal
characteristics alone; however, regional adenopathy and distant metastases would suggest malignant
nature of an otherwise indeterminate mass. Note should be made that plexiform neurofibromas can have
an aggressive appearance, whereas early peripheral nerve sheath tumors can have a nonaggressive
appearance.51
Both Hodgkin and non-Hodgkin lymphoma can involve the posterior mediastinum. Nodal masses can
encase the aorta and the vertebral bodies and can present as part of multistation adenopathy. Metastatic
lymph nodes can also occur in this space. Primary bone tumors arising from the vertebral bodies such as
giant cell tumor, osteoblastoma, and chondrosarcoma can occur in this space. CT is superior to MRI in
evaluating bone; however, MR plays a vital role in surgical planning by illustrating marrow involvement,
and surgical planning by identifying fat planes and extent of invasion.50
FIGURE 13.35 Neurogenic tumor. A: Axial T1W image showing a hypointense mass (arrow) in the left paraspinal region. B:
Hypointense on axial T2W image with areas of hyperintensity representing myxoid degeneration. C: Intense heterogenous
enhancement on post contrast T1W images biopsy proven to be a schwannoma.
Approximately 10% of pheochromocytomas are extra-adrenal, and 1% are located in the mediastinum,
most commonly in the paravertebral sympathetic nerves. Another rare site for this tumor is the
pericardium, particularly near the aortopulmonary window. Mediastinal pheochromocytomas can be
difficult to detect, however can be identified due to their classic MR signal characteristics (high T2W
signal). The primary imaging modality for tumor localization is the iodine-131 (131I)
metaiodobenzylguanidine scan. Although these scans have high sensitivity and specificity, they suffer from
low anatomic resolution. MRI can be used as a complementary modality for accurate localization to guide
resection.52,53
Lung Cancer
Lung cancer continues to have high morbidity and mortality. It is estimated that in 2013, in United States
alone, there will be about 228,190 new cases of lung cancer (118,080 in men and 110,110 in women) and
159,480 deaths from lung cancer (87,260 in men and 72,220 among women) accounting for about 27% of
all cancer deaths.54 The National Lung Screening Trial55 involving more than 53,000 heavy smokers
resulted in 20% fewer lung cancer deaths among trial participants56; however, most of the nodules
detected by CT were not cancer, and required interval follow-up or biopsies for definitive diagnosis,
potentially translating to a large and technically challenging diagnostic burden. DWI and DCE MRI can
help characterize indeterminate masses into benign or malignant.
Pulmonary Nodule Assessment

Most pulmonary nodules are incidentally detected and are usually followed till either benign character is
established or are resected as they are deemed either malignant or suspicious for malignancy. PET CT can
be equivocal for lesions less than 8 mm and biopsy may not yield a diagnosis when they are less than 1
cm.57 MRI is emerging as an adjunctive modality to CT and helps characterize nodules as benign or
malignant. DCE MRI has been evaluated as a diagnostic tool and four types of enhancement curves have
been reported.58 The diagnostic performance of DCE MRI in distinguishing benign from malignant
nodules has been reported to have sensitivity of 94% to 100% and specificity of 70% to 96% and
accuracy of up to 94%.58 ADC values from DWI have also reported 70% to 88.9% sensitivity and 61.1%
to 97% specificity in distinguishing benign from malignant nodules. Mori et al. have reported higher
signal intensity of lesion to spinal cord ratio on STIR turbo SE to have a higher accuracy than ADC
values in distinguishing benign from malignant lesions (85.5% vs. 50%).59 Hence, evaluation of SPN by
MR may benefit from inclusion of STIR turbo SE along with DWI and perfusion imaging in the SPN MRI
protocol (Fig. 13.36).
FIGURE 13.36 Solitary pulmonary nodule. (A) A 2-cm isointense nodule on axial T1W image, (B) is hyperintense on axial T2W
and, (C) shows mild peripheral enhancement post contrast administration, was subsequently biopsied and found to be consistent
with a hamartoma.
STAGING AND ASSESSING RESECTABILITY

CT is the primary modality to evaluate lung cancer, followed by FDG-18 PET CT for staging prior to
treatment allotment. MRI is used as a problem-solving tool and is superior to CT in determining
resectability in advanced stage lung cancers and in determining response to therapy in some instances.
The Radiologic Diagnostic Oncology Group showed that CT and MR had similar diagnostic accuracy in
staging lung cancers.60 The sensitivity and specificity of MR in comparison to CT when differentiating
T3–T4 from T1–T2 tumors was 56% versus 63%; 80% versus 84%.
When assessing “T” status by MR, the most useful sequences are T1W and T2W axial images
combined post contrast T1W sequence. Dynamic cine MR imaging when combined with static MR
imaging are useful in predicting chest wall invasion. Contrast-enhanced MRA (CE MRA), along DIR
sequences with cardiac and respiratory gating are helpful in determining invasion of mediastinal and hilar
vascular structures and in also depicting mediastinal fat planes. Accurately assessing nodal (N) status by
any imaging modality continues to be problematic with significant false positives and false negatives
reported by PET CT. Evaluation for early involvement and microscopic disease is limited by even
multimodality approach. Several MR techniques have been used to improve the diagnostic performance of
MRI. STIR turbo SE sequence has been used to distinguish benign from malignant nodes, the malignant
nodes depict high signal intensity in comparison with the benign nodes which have low signal intensity.
DWI is also being increasingly used since 2008 to help identify nodes harboring tumor. Ohno et al.61
compared the qualitative and quantitative performance of STIR turbo SE and DWI and found the former to
have higher quantitative sensitivity (82.8%/74.2%) and accuracy (86.8%/84.4%). MR imaging using
superparamagnetic iron oxide nanoparticle (SPION)-based MRI contrast agent, is being used to identify
lymph nodes involved with tumor in the GI and prostate malignancies and breast cancer. MR also plays an
important role in confirming intrathoracic metastasis. Contiguous spread to the chest wall, mediastinum,
and abdomen is more easily identified on MR than CT scans. MRI is also more sensitive in identifying
marrow involvement by tumor. In some institutions, whole-body MR and PET MR is being used to
identify occult extrathoracic metastasis. Adrenal masses are often discovered incidentally on 21% of
staging CT examinations for lung cancer; majority of these are benign adrenal adenomas, but CT is unable
to characterize the adrenal mass as benign or malignant in approximately 40% of cases. Chemical shift
imaging consists of paired gradient-echo MR images with TE values of 2.1 and 4.2 ms, the former is said
to be out of phase or opposed phase, and the latter is in phase because of the relative direction of the
magnetization vectors for fat and water protons. CSI is used to identify microscopic fat in adenomas, and
is more reliable than CE T1 and T2W sequences.62
Postoperative predicted lung function is always assessed prior to surgical resection and in majority of
institutes, VQ scans are used to assess suitability for planned resection. In recent times, pulmonary
functional MR imaging, using 3D CE perfusion MRI and oxygen-enhanced MRI have shown promise in
predicting ventilation and perfusion.63,64 Therapeutic response assessment (RECIST and modified
RECIST) has traditionally been done using CT scans in clinical trials. 18-FDG PET CT also allows for
quantitative and qualitative assessment of treatment in response to patients with thoracic malignancies.
However, differentiation between tumor, fibrosis, and inflammation can be difficult on CT scan and
fibrosis. CE T1W and T2W images can help differentiate fibrosis from residual tumor. Unfortunately,
significant overlap occurs in the MRI appearances of active fibrosis, inflammation, and recurrent tumor.
DCE MRI and calculation of pharmacokinetic parameters along with ADC values from DWI showing
promising results when assessing post treatment MRI scans (Fig. 13.37).
FIGURE 13.37 Predicting resectability in lung cancer. A,B: Axial post contrast VIBE images showing a left upper lobe mass
encasing the left upper lobe bronchus (straight arrow). The mass does not invade the left subclavian artery (curved arrow). C:
Coronal post contrast image showing thrombus (arrow) in the left upper lobe pulmonary artery branch. The mass was
successfully resected with a left upper lobectomy.
SUPERIOR SULCUS TUMORS (PANCOAST TUMORS)

Tumors arising in the lung apex or the superior sulcus of the lung, were named after Dr. Henry Pancoast in
1924.65 These are mostly non–small cell lung cancers, and are characterized by local invasion into the
chest wall, brachial plexus, and encasement and invasion of subclavian vessels, and erosion of adjacent
ribs and vertebral bodies and extension into the spinal canal. These tumors are associated with Horner
syndrome (anhidrosis, miosis, ptosis, and enophthalmos), hoarseness of voice and symptoms related to
involvement of brachial plexus. These tumors can be missed on radiographs and the primary modality of
choice for evaluation is MR. CT scans are helpful in characterizing the extent of bone involvement. These
tumors are best evaluated by the use of a combined neurovascular and body coil with a brachial plexus
protocol. This includes high-resolution T1W and T2W in all three planes, coronal STIR sequence, and
post contrast images in multiple planes. Sagittal images are particularly useful in evaluating for
involvement of the brachial plexus and neural foramen involvement. Marrow involvement of the vertebral
bodies are also better assessed by T1W images. Addition of MR angiography and black-blood sequences
such as DIR can be used to evaluate the integrity of the arteries and veins. Posttreatment MR imaging can
help identify and quantify residual tumor. Extent of involvement helps define treatment strategy, it is
important to identify extent of involvement of brachial plexus (Figs. 13.38 and 13.39).65
FUNCTIONAL IMAGING OF THE LUNGS

Lung Parenchyma
CT is the modality of choice for evaluating lung parenchyma, as MR imaging of lung parenchyma is
limited by low intrinsic proton density of the lung parenchyma and is further compromised by
susceptibility gradients due to intravoxel dephasing and signal loss, when strong magnetic gradients are
applied.66 Recent innovations in MRI techniques have widened the potential for evaluating parenchymal
lung diseases.67–70 These include very short echo times, ultrafast turbo-spin-echo acquisitions, projection
reconstruction techniques, breath-hold imaging, ECG triggering, contrast agents (perfusion imaging,
aerosols, oxygen), sodium imaging, and hyperpolarized noble gas imaging. Several studies are evaluating
the potential of MR in imaging: (a) acute alveolar processes in chronic infiltrative lung disease, (b)
detection and characterization of pulmonary nodules, (c) detection, characterization, and follow-up of
pneumonia, (d) differentiation of obstructive atelectasis from nonobstructive atelectasis and infarctions,
and (e) measurements of lung water content. An area of emerging utility is evaluation of cystic fibrosis;
MR is capable of depicting anatomical hallmarks of cystic fibrosis with enhanced tissue characterization
and when combined with perfusion imaging, can help characterize inflammation and infection and assess
treatment response earlier than perceptible by CT scans.71 These techniques allow for imaging chronic
bronchitis, bronchiectasis, and emphysema without the use of ionizing radiation as in CT scans. More
sophisticated techniques such as Fourier decomposition, arterial spin labelling, and proton imaging are
under investigation for MR imaging of pulmonary ventilation and perfusion without the administration of
contrast.72 Thus, combining static and dynamic MR imaging without the use of intravenous contrast allows
for repeat imaging over time without the worry of radiation exposure and also enables functional imaging
of the lung. These techniques have the potential to provide information on regional lung function,
including ventilation, perfusion, V/Q ratio, intrapulmonary oxygen partial pressure (PO2), gas exchange,
and spirometric and biomechanical parameters, throughout the individual lobes and even at an alveolar
level. The majority of these techniques are still in the research arena but are gaining momentum as they
have the ability to quantify disease processes, identify imaging phenotypes, help identify disease early,
and can aid in monitoring therapeutic interventions (Fig. 13.40).
FIGURE 13.38 Resectable Pancoast tumor. Right superior sulcus tumor (A) coronal, (B) sagittal post contrast VIBE images
showing a large enhancing mass in the right apex without evidence of chest wall invasion. The brachial plexus is not involved
(arrow).
Ventilation Imaging
Conventional MR imaging has limited value in evaluating lung parenchyma as the lungs have very few 1H
as compared with other structures. Hyperpolarized gases (Hyperpolarized 3Helium and 129Xenon) when
inhaled allow for evaluation of pulmonary ventilation, microstructure, and gas exchange within a single
breath scan. This technique requires the use of a polarizer, special coils, and minor commercially
available hardware and software modifications to the conventional scanners.69
Laser-polarized 3He MR images can yield very high signal with functional displays of the 3He
ventilated airspaces with high spatial and temporal resolution and thus enables multiple scans to be
repeated serially over time. The magnetic properties and extreme chemical inertness of 3He in
comparison with 129Xenon leads to higher polarization, longer storage time, improved visualization of
surrounding structure, and a very attractive safety profile, however is being replaced by 129Xenon due to
cost. The latter on the other hand allows imaging of all three compartments of the lung—airspace, septae,
and red blood cells—thus can map ventilation and perfusion (Fig. 13.41).
The 3He MRI are applied to produce spin density of images of the gas distribution within the lungs to
map ventilation defects.73 As data acquisition is completed with a single breath hold after the inhalation
of a hyperpolarized gas, using a fast pulse sequence, such as gradient-echo or echo-planar sequences.
Moreover, the relatively fast in vivo depolarization rates of hyperpolarized nuclei (on the order of 10 to
20 seconds) and the lack of magnetization recovery demand a well-practiced and well-defined workflow
in combination with special coils and ultrafast MR sequences.67
FIGURE 13.39 Unresectable Pancoast tumor. Right superior sulcus tumor. (A) Coronal, (B) sagittal post contrast VIBE images
showing a large enhancing mass in the right apex with invasion of the chest wall and right brachial plexus (arrow), (C,D) axial
pre- and post contrast DIR images showing the tumor is inseparable from the trachea (T) and the right carotid artery (arrows),
the tumor was deemed unresectable and was treated with radiotherapy.
Diffusion-weighted MR imaging has been extensively studied in hyperpolarized gas imaging to

calculate ADC values. The average distance travelled by the gas atoms during a given time is determined
by the diffusion coefficient D, specific to the gas or gas mixture. For pure 3He gas under standard
conditions (and without restricting wall and barriers), D is 2.05 cm2/s and approximately 0.88 cm2/s in an
atmospheric concentration. However, D is much smaller than predicted from free diffusion and is
heterogenous in the lungs. The majority of this difference and the heterogeneity indicate diffusion
hindrance by the lung structure itself; thus, the measured value of D is termed the ADC and is a measure of
the alveolar gas motion rather than a measure of gas diffusion across the alveolar capillary membrane and
serves as a surrogate for gas distribution that is altered by changes in the lung microstructure and thus
indirectly gives information about changes in function. ADC appears to be a sensitive and reproducible
marker for early detection and progression of disease and other processes affecting the size of alveoli and
small airways. Thus, can be used to calculate pulmonary microstructure (alveolar size and wall
thickness), regional oxygen partial pressure, regional oxygen uptake, and V/Q matching.74
Oxygen-sensitive imaging represents another potential application of 3He MR. Molecular oxygen,
being paramagnetic, shortens the T1 of hyperpolarized 3He, thereby destroying its signal. Regions of lung
with high PO2 will therefore lose 3He signal more rapidly than those with lower oxygen concentrations.
Thus, 3He MR can be used to map oxygen partial pressures quantitatively in the lungs as well as to assess
regional oxygen uptake and V/Q alveolar–capillary transfer of oxygen can be evaluated by measuring the
decrease in regional PO2 during a breath hold. Interrupted uptake of oxygen from the alveoli into the
blood due to either pulmonary arterial obstruction or a significant diffusion defect can be detected as an
area of abnormally high V/Q using the oxygen-sensitive 3He MR technique.64,71
FIGURE 13.40 Fourier decomposition images from a healthy subject at 3T. (A) Perfusion map and, (B) ventilation map.
Molecular oxygen, which is weakly paramagnetic, can also be used as an MR agent to assess
ventilation in proton MRI. The diffusion of oxygen from the alveoli into the capillary blood and binding to
hemoglobin results in a reduction in the T1 of the blood and thus an increase in lung signal on a T1-
weighted sequence. By subtracting an image acquired with room air from one acquired with 100%
oxygen, oxygen-enhanced MR lung scans are obtained. Unlike hyperpolarized 3He, in which the signal is
obtained directly from the gas itself, the signal obtained using molecular oxygen as a ventilation agent
results from its paramagnetic effect on the alveolar capillary blood and other interstitial water.
Hyperpolarized 129Xe readily diffuses into interstitial tissues and alveolar blood; therefore, MR
spectroscopic techniques can be used to measure separately the 129Xe signal in alveolar gas, interstitial
parenchyma, and alveolar capillary blood. By following the diffusion of the gas from the alveoli into the
blood and/or the interstitium, the hyperpolarized 129Xe scans have the potential to map regional
ventilation, perfusion, and V/Q all within a single examination. Moreover, the kinetics of gas transfer
from airspace to capillary could potentially be used to calculate a host of other parameters, including
alveolar wall thickness, capillary blood volume, mean alveolar transit time, and pulmonary perfusion.
These techniques are still in the research arena and translation to clinical care will need improvement in
workflow and improved patient compliance.
Pulmonary Perfusion
Pulmonary perfusion can be assessed using ultrashort-TE T1-weighted sequences after the administration
of gadolinium contrast agents and acquiring multiple runs in 2D or 3D while tracking the passage of the
contrast through tissues. The time-intensity curve obtained from a dynamic contrast-enhanced study is
fitted to a γ-variate function, flow parameters such as peak time, apparent mean transit time, and blood
volume can then be calculated. These semiquantitative perfusion indices can be used to calculate
treatment response in tumors.74 Quantitative pulmonary perfusion can be combined with MRA to enhance
the accuracy of MR for detecting pulmonary emboli and evaluate the functional consequences of
pulmonary emboli on lung parenchyma and hemodynamics. Arterial spin labeling (also known as arterial
spin tagging) is another emerging technique to map perfusion. This method requires no exogenous contrast
agent.75 Instead, localized adiabatic RF pulses are used to invert the magnetization of blood in the
pulmonary arteries. By subtracting images acquired with and without the arterial labeling pulses,
perfusion images of the lungs can be obtained. Although the resulting spatial resolution is less than that of
gadolinium-enhanced technique, the arterial spin-labeling technique can provide nearly real-time
volumetric imaging of pulmonary perfusion. Moreover, because no contrast agent is injected and no
ionizing radiation is involved, the scans can be repeated as often as desired. Arterial spin tagging
provides a very powerful tool for investigating the effects of various interventions or agents on regional
pulmonary perfusion (Fig. 13.42).
FIGURE 13.41 Hyperpolarized Xenon scan demonstration of “opening volume” effects. A ventilation defect is seen with
inhalation is started from a low lung volume (RV) and disappears when starting the 129Xe inhalation from a higher lung volume
(FRC). Reproducibility is demonstrated on a repeat scan 1 week later.
FIGURE 13.42 Lung perfusion with Fourier decomposition technique at 3 T and perfusion map post gadolinium administration in
the same patient. (A) Ventilation map, (B) perfusion map, (C) compared with a perfusion map post gadolinium administration.
Imaging of Lung Mechanics

Several MR studies have evaluated lung mechanics. The high temporal and spatial resolution of the
volumetric MR image data sets can be used to obtain regional rather than global spirometric parameters
and other measures of lung mechanics. Potential uses include the mapping of abnormal regional
compliance in patients with pulmonary fibrosis or emphysema. Two MR approaches have been used to
quantify tissue deformation and localized lung inflation: tissue tagging to track lung motion and
displacement of vector maps derived from the registration of serial images acquired during breathing
using the pulmonary vasculature and parenchymal structures as inherent spatial markers.76 Mapping of
regional lung mechanics using these new techniques can add unique, previously unavailable functional
information beyond the imaging.
CHEST WALL
MR imaging is useful in evaluating chest wall tumors due to superior spatial and contrast resolution when
compared with CT scans. Most primary neoplasms of the chest wall except for skin are of mesenchymal
origin. Fat suppression techniques are helpful in characterizing chest wall tumors. MR is often used as an
adjunct to CT scans when evaluating bone tumors, a multidisciplinary approach combined with patient
demographics, pattern of bone mineralization, and extent and pathology.77 Some osseous and soft tissue
tumors can have characteristic findings on MRI; however, often a multidisciplinary approach is needed
for management. There can be an overlap of signal characteristics on T1W and T2W images, and majority
of the lesions show variable enhancement, thus limiting further characterization. Differentiation between
benign and malignant can be done by evaluating fat planes, invasion of adjacent structures, and presence
of capsule. MR can help characterize fat, fluid, and solid components within chest wall lesions. Akata et
al. have used dynamic and fast field echo sequence (repetition time = 8, echo time = 3, flip angle = 100)
and 25 consecutive images taken while the patient takes deep breaths, to evaluate invasion of chest wall
by tumors.78 Cine MR imaging has also been used to study chest wall dynamics.
TOS comprises of impingement of subclavian vessels and brachial plexus, in the region of thoracic
cavity and axilla. TOS can be classified into the following types neurogenic, vascular, arterial, or
combined. Arterial TOS is always associated with bone abnormalities such as cervical ribs, exostosis,
and callus formation. Venous TOS however is caused by repetitive injury to the subclavian vein by the
first rib,79 clavicle, subclavius muscle, anterior scalene muscle, and costoclavicular ligament and is
referred to as Paget–Schroetter syndrome. A typical TOS protocol includes 3D MRA, equilibrium phase
venography, and T2W images with provocative maneuvers including abduction and adduction of the arms
and multiphase acquisition of post contrast images in three planes with inclusion of arterial and venous
phases.80 Equilibrium phase images help identify presence of venous thrombus, stenosis, and help
characterize extrinsic masses. High-resolution imaging using T1W and T2W sequences can help identify
fibrous bands and anomalous ligaments.80 A detailed TOS evaluation will include details on the affected
vessel during hyperabduction, degree of luminal narrowing both for artery and vein, location, and cause
of compression and other associated findings (Fig. 13.43).81
FIGURE 13.43 Coronal MIP image in hyperabduction showing narrowing of both subclavian arteries (arrows) consistent with
thoracic outlet syndrome. The diagnosis is made by comparing MR images acquired with arms up and down.
PLEURAL DISEASES
Primary and secondary pleural pathologies can be assessed by CT and PET CT, MRI is usually used as an
adjunct modality to help characterize the lesions, predict resectability, and to assess treatment response.
Multiplanar capability of MR when combined with ability for tissue characterization, allows pleural fluid
to be classified into transudate and exudate and distinguish fluid from solid pleural masses.
Differentiation between transudate and exudate pleural effusions on MR is based on the presence or
absence of specific morphological features (pleural thickening, “split pleura sign,” loculations,
nodularity, internal septations, and enhancement post gadolinium administration).82 DWI is an emerging
technique that is being increasingly used to classify effusions and masses based on cellularity and water
content. As the cellularity of masses increases, the water content decreases and the ADC value decreases.
Therefore, the transudative effusions have a higher mean ADC value of 3.42 ± 0.76 × 10−3 mm2/s when
compared with the exudative effusions, which have a mean ADC value of 3.18 ± 1.82 × 10−3 mm2/s.27
Thus, using a cut off value of 3.6 × 10−3 mm2/s, transudate effusions can be separated from exudative
effusions with a sensitivity of 71% and specificity of 63%.83 MR can also be used in evaluation of
hemothorax and chylothorax both in localization of the thoracic duct prior to embolization procedures
characterization of the fluid and also in identification of the thoracic duct. The thoracic duct can be best
identified axial T2W images.
Chronic pleural effusions and pleural thickening can cause the adjacent area of lung to collapse and is
termed as “round atelectasis,” which can remain stable or even grow over a period of time. It tends to
have a very characteristic “comet tail appearance” on CT scans; however, nonresolution and potential
change in morphology can raise concern for underlying malignancy and lead to unnecessary invasive
procedures. DCE MRI can be utilized to characterize round atelectasis, by plotting signal intensity curves
from the lung consolidation and comparing it with normal lung.84 The signal intensity curve in round
atelectasis is similar to normal lung and pulmonary artery blood flow and has a steeper slope during
wash-in and wash-out, and higher relative signal increase when compared with tumors. Pleural thickening
can be secondary to a number of causes such as mycobacterial tuberculosis infection, empyema, trauma,
drug exposure, collagen vascular disease, and asbestos exposure. MRI can help differentiate malignant
pleural thickening from benign pleural plaques, which have low signal intensity on T1W- and T2W-
weighted sequences and show minimal to no enhancement post gadolinium administration, and identify
associated anatomical features such as extrapleural fat hypertrophy, diffuse pleural thickening, and pleural
effusions. DWI and DCE when combined with conventional MRI can increase the accuracy of
differentiation.
Pleural Tumors
Malignant involvement of the pleura is most commonly related to metastatic disease; primary
bronchogenic carcinoma is the most common tumor metastatic to the pleura followed by breast (20%) and
lymphoma (10%). Primary pleural tumors include fibrous tumor of the pleura, malignant pleural
mesothelioma, and sarcomas.
The MR signal characteristics of pleural metastases are generally similar to the primary tumor but in
some cases, the metastases are more aggressive. Hence, can have more necrosis and areas of high
cellularity. ADC values from DWI can potentially be used to characterize histological subtypes of pleural
tumors.82 STIR images can help delineate the extent of the lesion and are very helpful in extent of chest
wall invasion and help plan resection margins.84,85
Fibrous tumors of the pleura have a very characteristic appearance on MR. They tend to be isointense
to muscle on T1W and T2W sequences with areas of necrosis and myxoid degeneration (hyperintense on
T2W) and tend to have intense enhancement post gadolinium administration. The malignant counterpart is
hyperintense on T2W and STIR images with intense enhancement. ADC values can help areas of
malignant transformation. Synovial sarcomas depict the “triple sign” on T2W sequence with areas of
hypointensity, isointensity, and hyperintensity (Figs. 13.44 and 13.45).82 Focal liver herniation both
congenital and postsurgical or trauma can mimic pleural based tumors. In these cases, using a liver
specific agent such as Eovist with delayed imaging can help differentiate the two.82
Malignant pleural mesothelioma (MPM) is a rare but very aggressive primary pleural neoplasm
related to asbestos exposure. MRI plays a crucial role in treatment planning by both anatomical
delineation due to superior signal-to-noise ratio and depiction of fat planes. MPM is generally
intermediate to slightly high signal intensity on T1W1 images, moderately high signal intensity onT2W
images as compared to adjacent musculature and chest wall, and shows moderate enhancement after
contrast administration.82 MRI is superior to CT in detecting early chest wall invasion, diaphragmatic
involvement, and vascular invasion (Fig. 13.46). DWI and DCE MRI can further help characterize and
identify histological cell types of mesothelioma.86,87 The epithelial subtype has a higher ADC value than
the sarcomatoid subtype and an ADC value of 1.1 × 10−3 mm2/s can be used as a cut off to differentiate
the two histological cell types (Fig. 13.47).88,89 Perfusion parameters can be used to quantify angiogenesis
within these tumors.
FIGURE 13.44 Synovial cell sarcoma of the right pleura. “Triple sign”’ presence of iso, hypo, and hyperintense areas within the
tumor, on T2W image pathognomonic of synovial cell sarcoma.
FIGURE 13.45 Fibrous tumor of the pleura. (A) Axial T1W image showing two masses isointense to muscle; (curved arrow)
arising from the posterior pleura, (straight arrow) from the fissure, (B) hypointense on T2W images and showing, (C)
heterogenous enhancement on post contrast VIBE images, was resected and proved to be a fibrous tumor of the pleura.
FIGURE 13.46 Malignant pleural mesothelioma. Axial T2W images showing a small volume right pleural effusion and a large
lobulated right pleural tumor (A) arrow shows area of mediastinal fat invasion, (B) and, (C) arrows showing areas of multifocal
endothoracic fascial involvement.
FIGURE 13.47 ADC maps of epithelial, sarcomatoid and biphasic mesothelioma patients showing restricted diffusion within the
tumor.
MRI is used for planning resectability in primary pleural tumors, key areas that are assessed are chest
wall, diaphragm, endothoracic fascia, mediastinal fat, and vascular involvement. Parallel MRI techniques
allow for quantification of tumor mobility and local lung motion, thus evaluating for invasion of
mediastinum and chest wall. Generalized auto calibrating partially parallel acquisition (GRAPPA), true
fast imaging with steady state precession (FISP), and fast low angle shot (FLASH) can also help in
delineating subtle invasion of the mediastinal structures such as the myocardium and chest wall. Fat
suppression and subtraction images especially coronal images can be helpful in identifying subtle
endothoracic fascial involvement.90
Perfusion assessment from DCE MRI after the administration of gadolinium can be used to map
pharmacokinetics of tumors. The signal intensity curve can be plotted by tracking flow of contrast from
the circulation into and out of the tumor, and can be used to determine whether the blood supply is from
the aorta or the pulmonary artery or both. Pharmacokinetic parameters can be derived and utilized to
predict the probability to respond to chemotherapy and can also can be used to assess response to therapy.
Giesel et al.90 showed that patients who had lower a permeability coefficient (kep <2.6 min) were less
likely to respond to chemotherapy than those with a higher kep (>3.6 min) and enjoyed a survival
advantage (460 vs. 780 days) (Fig. 13.48).
DIAPHRAGM
The dome-like complex shape of the diaphragm is best assessed on sagittal and coronal images. Breath-
hold imaging techniques, such as fast gradient echo and single-shot fast spin echo, eliminate respiratory
motion artifact while providing adequate soft tissue contrast. Dynamic gradient echo images can be used
to assess mobility of the diaphragm and can help assess paralysis secondary to phrenic nerve involvement
and determine suitability for lung reduction procedure. Multiplanar MRI is useful in the preoperative
planning for repair of traumatic diaphragmatic rupture and congenital diaphragmatic hernias.
Diaphragmatic cyst and hematomas can be seen and T1W and T2W images can be used to characterize
these lesions. Diaphragmatic involvement and transdiaphragmatic extension of pleural malignancies can
be assessed by MR imaging. Sagittal images are most useful to assess the extent of diaphragmatic
involvement (Fig. 13.49).91
PET/MR
PET/MRI is a novel hybrid imaging technology that involves the fusion of two powerful imaging
modalities, namely PET and MRI. As discussed above, MRI has high tissue characterization abilities,
multiplanar imaging capabilities, and functional capabilities without the use of ionizing radiation,
whereas PET enables highly sensitive and accurate imaging of metabolism. The MRI also provides
attenuation correction and anatomical localization for PET scan. This novel PET/MRI imaging technology
provides one-stop shop evaluation of structure, function, and metabolism, which improves throughput and
patient comfort. There are three different types of PET/MRI systems. In the integrated or concurrent
system, the PET ring detector is located within the MRI magnet (Biograph mMR, Siemens Healthcare,
Erlangen, Germany). In the sequential scanner (Philips Healthcare, Cleveland, OH), the MRI and PET
scanners are separate but located within the same root, 10 feet apart with the patient moved on a table and
images are obtained by hardware fusion. In another model (GE Healthcare, Milwaukee, WI), the PET/CT
and MRI scanners are located in different rooms with a shared patient transport system. A table moves
between the rooms and fusion of images is provided by software.
FIGURE 13.48 Coronal post-contrast and multiparametric maps depicting perfusion parameters of the tumor. MR-determined
pharmacokinetic parameters: AUC, area under the curve and represents blood volume, k trans, transfer constant (min−1), k ep,
rate constant (min−1), Ve, elimination constant (dimensionless).
In the chest, there are several utilities of PET/MRI, particularly in the evaluation of lung cancer.
PET/MRI is not used in the evaluation of lung nodules, although it has a high sensitivity in detection of
nodules >5 mm, with low sensitivity for non-FDG avid nodules (Li Fan). Combining PET and MRI helps
in distinguishing benign from a malignant nodule, by using the metabolic information of PET. Although
PET/CT is the current imaging modality of choice in the staging of lung cancers, PET/MRI is also being
increasingly used. For T staging, PET/MRI is particularly useful in the evaluation of invasion to adjacent
structures, particularly the mediastinum, chest wall, pulmonary vasculature, and bronchial tree. PET/MRI
has been shown to have similar performance to PET/CT in N staging.92 PET/MRI is also as good as
PET/CT in M staging. Overall, it has been shown that PET/MRI has similar lesion characterization and
tumor stage as compared with PET/CT.93 PET/MRI is also useful in evaluation of prognosis, therapeutic
response, and recurrence detection. PET/MRI is a noninvasive imaging modality for evaluating
pharmacokinetics and pharmadynamics profile of novel drugs. PET/MRI is also useful in the evaluation
of mediastinal tumors. PET/MRI is particularly useful in the evaluation of neoplastic lesions in children,
such as lymphomas, due to absence of radiation and availability of comparable information.
FIGURE 13.49 Diaphragmatic cyst. (A) Axial T2W image showing a hypointense lesion in relation to the diaphragmatic crus
(white arrow), (B) hyperintense on T1W image and shows (C) no restricted diffusion on ADC map, consistent with a
proteinaceous cyst in the left diaphragmatic crus.
FIGURE 13.50 PET/MRI for lung cancer. Axial PET/MRI image shows a large hypermetabolic mass in the right upper lobe,
which is invading the mediastinum. There is also a right lower paratracheal lymph node (curved arrow).
PET/MRI also has potential applications in cardiovascular imaging. In cardiac and paracardiac
tumors, PET/MRI provides a one-stop evaluation of metabolism, tissue characterization, anatomical
localization, and functional quantification (Fig. 13.50). It is useful in the local staging and evaluation of
distal metastatic disease. Complementary information is obtained from MRI and PET in the evaluation of
inflammatory disorders such as myocarditis and sarcoidosis. Disease activity can be evaluated in
arteritis. PET/MRI also has utility in the evaluation of myocardial infarction, both in the assessment of
perfusion and viability. PET/MRI is also useful in the evaluation of plaque inflammation, which is a
feature of vulnerable plaque, both with FDG uptake in PET and tissue characterization with MRI.94
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14
Radionucleotide Studies of the Lung
Perry Gerard ■ Amrita K. Arneja ■ Yachao Zhang
INTRODUCTION
Since the introduction over a half-century ago of radionucleotides into the evaluation of thoracic diseases,
nuclear imaging continues to provide unique and useful diagnostic information. PET scanning has
overshadowed (covered in chapter 14) many of the other diagnostic studies that radionucleotides provide.
This chapter concentrates on the special contributions of nuclear medicine to a multitude of thoracic
diseases.
VENTILATION AND PERFUSION STUDIES OF THE LUNG

Pulmonary embolism (PE) is relatively common and has the potential to be fatal if patients do not receive
prompt diagnosis and treatment. The classic triad of dyspnea, pleuritic chest pain, and hemoptysis is not
commonly encountered. The incidence of pulmonary emboli is approximately 1 in 1,000 per year and
approximately 10% of these patients die within 1 hour of the episode. Clinical grading systems such as
the Modified Wells Criteria have been used to assess the clinical probability for having a pulmonary
embolus. Overall mortality in untreated patients is approximately 30%. Therefore, making the correct
diagnosis and instituting appropriate therapy is vital and lowers mortality to between 2.5% and 8%.
Although anticoagulant therapy is an effective treatment, it is not without risks. Major hemorrhagic
complications can be as high as 10% to 15% among patients receiving anticoagulants or thrombolytic
therapy. Therefore, making the accurate diagnosis is essential for improved outcomes in patient with
pulmonary emboli.
Lung perfusion and ventilation scintigraphy have been used for the diagnosis of PE for the past half
century.1 It is a safe and noninvasive way to evaluate for regional pulmonary perfusion and ventilation.
Lung scintigraphy is considered a valuable diagnostic imaging procedure using ventilation and perfusion
scintigraphy and to evaluate for cardiovascular and pulmonary disorders.2
The most common clinical indication for lung scintigraphy is to determine the likelihood of PE (Fig.
14.1). Less common clinical indications may be to document the degree of resolution of PE, quantify
differential pulmonary function before pulmonary surgery for lung cancer,3 evaluate lung transplants,4
evaluate congenital heart or lung disease such as cardiac shunts, pulmonary arterial stenosis, and
arteriovenous fistulae and their treatment,5 confirm the presence of bronchopleural fistula,6,7 evaluate
chronic pulmonary parenchymal disorders such as cystic fibrosis,8 and to evaluate the cause of pulmonary
hypertension.9
The use of computed tomography angiography (CTA) for diagnosis of PE is sometimes a preferred
modality by clinicians. CTA has a sensitivity of 83% and 95% specificity for diagnosing lung embolism.10
Lung scintigraphy is an alternative to CT pulmonary angiography (CTPA) in patients with contrast
intolerance, poor renal function, individuals who are obese or claustrophobic, pediatric patients, and
pregnant patients. Lung scintigraphy may be the first choice when there is low clinical suspicion of
disease, since the perfusion lung scans are associated with very low morbidity and can select out patients
with a higher likelihood of PE for CT angiography. The effective radiation dose for a CT angiogram is
also significantly higher than that of V/Q scanning by approximately five times.11 In-patients that have
received numerous prior CT scans, the additional radiation risk of receiving a CT angiography
examination may be unwarranted.
Ventilation scans are most commonly performed with Xenon-133. Xenon has a half-life of 5.3 days and
gamma ray energy of 81 keV. Xenon is utilized to assess all phases of ventilation which includes the
single wash-in, equilibrium and the washout phase. Therefore Xenon-133 can be used to detect and
evaluate airway disease. However it is limited as it is usually performed before the perfusion study and
with posterior upright views (which allows evaluation of the most pulmonary segments). Another agent
called Tc-99m Technegas contains ultrafine carbon particles but is not currently available in the United
States. However, by far the most commonly used agent is aerosolized 99mTc-DTPA. It is readily available
and does utilize a nebulizer and aerosol delivery system, and performed with the patient supine after
breathing for 3 to 5 minutes. Perfusion scans are typically performed by embolizing 99mTc-
macroaggregates of albumin (MAA) into the lungs. The MAA particles that are injected should always be
below 500,000. When performing perfusion scintigraphy, it is recommended to reduce the number of
particles used in patients with known pulmonary hypertension, extensive lung disease, known right to left
shunts, or those that have had a prior pneumonectomy or single lung transplantation. In pregnant patients
and children, reducing the radioactivity from 4 to 2 mCi is also recommended. The half-life of the
macroaggregates is approximately 3 hours.
The pretest probability plays a large factor in determining the likelihood of pulmonary embolus.
Significant predictors of PE include recent surgery, thromboembolic disease, history of PE or
thromboembolic disease, malignancy, older age, hypocapnia, hypoxemia, tachycardia, and band
atelectasis or elevation of the diaphragm on the chest x-ray. A low pretest probability together with a
negative D-dimer test effectively rules out acute PE.12
After the perfusion scintigram is performed, images are acquired via a low-energy, large field of view
gamma camera, in six projections: anterior, posterior, left and right posterior oblique, and left and right
lateral projections.13 After the perfusion scan, the ventilation scan is performed with the same six views
obtained.13 The results are combined to determine if there is a match between the defects seen on the
ventilation and perfusion scans. If there is a perfusion defect with a normal ventilation study in the same
region, this represents a mismatch and is suspicious for a pulmonary embolus. If both studies show
defects in the same region, then a PE is considered less likely. Classification for PE grading has been
categorized into very low, low, indeterminate, normal, and high probability for PE.14–16 The PIOPED
study validated the PE probability estimates based on ventilation/perfusion scintigraphy and chest x-ray
findings. The PIOPED investigators confirmed that a normal perfusion study excludes pulmonary emboli
with a 97% negative predictive value. Subsegmental or small perfusion defects, matched by ventilation
with or without chest x-ray abnormalities larger than the perfusion defects, have a low probability for
pulmonary emboli (<20% probability), while scans that do not fit into the high- or low-probability
categories almost always require additional tests for diagnosing PE.
FIGURE 14.1 V/Q scan for diagnosis of pulmonary embolism. A: Multiplanar imaging of the thorax obtained after inhalation of
30.7 mCi of aerosolized Tc-99 DTPA and intravenous administration of 3.1 mCi of Tc-99 MAA. There are segmental defects
noted in the right lower lobe (yellow dotted line), right upper lobe (red dotted line), and a region of the left lower lobe (blue
dotted line) on the perfusion study which are mismatched on the ventilation study. Findings are consistent with high probability of
pulmonary embolism in these regions. (RPO, right posterior oblique view; LAO, left anterior oblique view; LPO, left posterior
oblique view; RAO, right posterior oblique view.) B: Follow-up CT thorax of the same patient demonstrates arterial filling
defects (red arrow) within the lobar and segmental arteries supplying the right upper (axial image; left) and right lower lobe
(coronal image; right). The left lower lobe filling defect is not shown. The CT findings are consistent with V/Q scan results.
Since 2009, the trinary interpretation and reporting strategy has also been gaining favor as a simpler
method of interpretation of ventilation–perfusion scans for pulmonary embolus. The strategy divides
outcomes into three categories: no PE, PE present, and nondiagnostic. This strategy was developed in
order to facilitate clearer communication and decrease confusion among clinicians regarding the results of
a V/Q scan. Given the prevalence and clinician preference of CTPA for diagnosis of pulmonary embolus,
a similar reporting system was developed. Trinary reporting systems have traditionally been used for
CTPA. In both modalities, the patient’s pretest probability highly affects the predictive value and
likelihood of having a PE. Therefore, a trinary reporting system is becoming an effective way to simplify
and standardize the reporting of pulmonary embolus in patients that receive a ventilation–perfusion
scintigraphy.17
There are numerous causes of pulmonary emboli; therefore, lung perfusion studies should be
interpreted with knowledge of the clinical findings and compared with a standard chest x-ray obtained
within 24 hours. Although the chest radiograph may be normal in patients with pulmonary embolus,
pertinent findings such as consolidation, atelectasis, effusions, masses, or cardiomegaly can confound the
scintigraphy results. Pregnancy and lactation status should also be considered prior to ventilation–
perfusion scan to minimize the radiation exposure. History of prior deep venous thrombosis or PE should
also be determined and any prior scintigraphy should be made available for review by the nuclear
medicine physician.2 Although the presence or lack of deep venous thrombosis in the lower extremities
does not determine if pulmonary embolus is present, obtaining a positive sonogram increases the
likelihood of pulmonary embolus.
Quantitative lung scans are utilized for planning of preoperative patients prior to lung resection most
commonly for malignancy, but also used for lung volume reductions in COPD and prior to lung
transplantation and correction of pulmonary stenosis (Fig. 14.2). These are used in conjunction with
pulmonary function tests. The examination is performed obtaining a right to left differential lung function
after obtaining anterior and posterior views and drawing regions of interest around the right and left lungs
and calculating a geometric mean to correct for attenuation.18 Issues include that anterior and posterior
imaging fail to adequately separate the upper and lower lobes for evaluation.
FIGURE 14.2 V/Q scan demonstrating split lung function. A: V/Q scan of a patient with right lower lobe consolidation. V/Q
scan demonstrates the split lung function with relatively decreased ventilation and perfusion to the right lower lobe. The
functional split for ventilation is 43.5% in the right lung and 56.5% in the left lung and the functional split for perfusion is 47.1% in
the right lung and 52.9% in the right lung. Findings suggest decreased ventilation to the right lung disproportional to decreased
perfusion to the right lung. B: Finding from the V/Q scan shown in Figure 14.2A is consistent with the chest radiograph shown,
which demonstrates right lower lobe mass. C: PET imaging demonstrates increased uptake in the right lower lobe, confirms the
lesion shown in Figure 14.2B. In addition, there is increased uptake in a right hilar lymph node.
RADIONUCLIDE EVALUATION OF NEOPLASTIC AND NONNEOPLASTIC

LUNG DISEASES
Radionuclide lungs scans can be an important diagnostic tool for certain neoplasms, infections, and other
pathologic findings. Although increasing use of PET imaging has resulted in decreasing use of other types
of radionuclide scintigraphy, certain types of scans are still valuable for diagnosis of specific pathology.
Gallium scintigraphy can be used for infection and inflammation in certain cases. Thallium can also be
used for diagnosis of Kaposi sarcoma in HIV patients. It can also be used in conjunction with gallium
scintigraphy to differentiate between Kaposi sarcoma, opportunistic infection, and malignant lymphoma in
HIV patients. MIBG is valuable for diagnosis of tumors of neuroendocrine origin, such as
pheochromocytomas, paragangliomas, and neuroblastomas. Increasing favor of PET imaging in oncology
have limited the use of radionuclide scintigraphy using gallium, thallium and MIBG, however, several
useful indications remain as important diagnostic tools.
GALLIUM SCINTIGRAPHY
Gallium-67 citrate binds to plasma transferrin when in the free state. It is taken up by tumors,
inflammation, and infection through the porous capillary endothelium. Gallium uptake can also depend on
the presence of bacteria and macrophages, as it can bind to leukocyte-derived tissue lactoferrin and
circulating leukocytes.19 Therefore, gallium scintigraphy is used for a variety of diagnostic purposes,
including localizing source of fever in patients with fever of unknown origin (FUO), detection of
pulmonary and mediastinal inflammation/infection, evaluation and follow-up of active lymphocytic or
granulomatous inflammatory processes such as sarcoidosis or tuberculosis, and diagnosing osteomyelitis
and/or discitis (Fig. 14.3).20,21 Imaging is typically performed 18 to 72 hours after the administration of
the radioisotope.
In oncology, gallium scintigraphy becomes irrelevant with the introduction of positron emission
tomography (PET) 18F-fluorodeoxyglucose (18F-FDG) imaging.67 Ga citrate is not useful for diagnosing
or staging lung tumors in spite of several early optimistic studies.22,23 Although in the past gallium
radiotracer along with SPECT/CT was used for the evaluation of neoplastic lung disease, especially
lymphoma, the increasing use of the PET imaging has resulted in limited use of gallium scintigraphy for
this purpose. Gallium-positive patients had also previously been followed with gallium scintigraphy to
evaluate response to therapy or recurrent disease; however, PET imaging has now become the study of
choice for lung neoplasms. The use of gallium when PET is not available, however, is well justified for
lymphomas and hepatomas (Fig. 14.4).
THALLIUM SCINTIGRAPHY
Kaposi sarcoma is the most common neoplasm seen in HIV patients.24 Studies have found that the
frequency of pulmonary involvement in Kaposi sarcoma varied between 21% and 44%.25 Although
thallium scintigraphy is typically used for myocardial perfusion imaging, it has also been found to be
positive in Kaposi sarcoma (Fig. 14.5). If used in conjunction with gallium, thallium scintigraphy can
typically differentiate Kaposi sarcoma, opportunistic infections, and malignant lymphoma. Kaposi
sarcoma is thallium positive; however, it is gallium negative and this combination of findings is highly
specific for Kaposi sarcoma. Opportunistic infections are found to be gallium positive and thallium
negative. Malignant lymphoma, on the other hand, is both thallium positive and gallium positive.26
MIBG SCINTIGRAPHY
MIBG scintigraphy is used to image tumors of neuroendocrine origin, particularly those of the
neuroectodermal (sympathoadrenal) system (pheochromocytomas, paragangliomas, and
neuroblastomas).27 MIBG also accumulates in other neuroendocrine tumors, such as carcinoid and
medullary thyroid carcinoma. Nononcologic indications for MIBG scintigraphy include investigation of
disease of sympathetic innervation, such as the innervation of myocardium or salivary glands,28,29 or
functional studies of the adrenal medulla (hyperplasia), and study of movement disorders.
MIBG can be labeled with either I-131 or I-123. I-123 is the preferred radiopharmaceutical as it is
more suitable for SPECT imaging and results are available sooner. However, I-131 is more widely
available and preferred when MIBG therapy planning is indicated.30 Discussion of risks and benefits must
be included in the clinical decision when undergoing MIBG scintigraphy in patients that are pregnant,
breastfeeding, or taking certain medications that could interfere. Patients may be receiving alpha- or beta-
blockers for metabolically active catecholamine-secreting tumors and the need to discontinue these agents
in order to complete the study should be thoroughly evaluated with the referring physician to ensure
accuracy of the examination.31 Doses should also be reduced in children and thyroid blockade must be
performed 1 to 3 days prior to administration of the radiotracer in order to prevent thyroid uptake of the
iodine.
FIGURE 14.3 Whole body gallium scan of a patient with infected pacemaker. Following the intravenous administration of 6 mCi
gallium-67 citrate, anterior and posterior whole body images were obtained approximately 48 hours after injection. The right
anterior oblique (RAO) view and the left anterior oblique (LAO) view of a patient with pacemaker demonstrates focal intense
uptake at the superior aspect of the pacemaker, consistent with clinical suspicion of infection in this area (red arrow). The
pacemaker overlying the left upper lung field projects as a focal defect of tracer uptake (yellow arrow).
FIGURE 14.4 Pretreatment staging and posttreatment monitoring of lymphoma patient using gallium scan. A: Gallium scan of
the patient with anterior and posterior views (from left to right) demonstrates increased uptake within the mediastinum. B: In
posttreatment monitoring, gallium scan of the same patient free of disease demonstrates no uptake of radio tracer in the same
location. C: Pretreatment axial CT scan of the chest of the same patient demonstrates the large softy tissue mass in the anterior
mediastinum encasing the pericadium and the major vessels, characteristic of lymphoma.
The imaging interpretation is always performed with the understanding of the patients’ clinical history,
presence of symptoms, and localization based on other radiologic imaging. Uptake in nonphysiologic
areas raises suspicion for a neuroendocrine tumor or metastasis. False-negative results can occur based
on lesion size, tumor physiology, or pharmaceutical interference. False-positive results can occur due to
artifact, uptake related to another pathologic process such as pneumonia (Fig. 14.4), or benign uptake.30
THYROID
The thyroid gland is an H-shaped endocrine gland in the neck with two lobes that creates hormones that
regulate multiple bodily functions. Hyperthyroidism is a common condition that causes excess levels of
thyroid hormone to be produced by the thyroid gland and is a major health concern causing a variety of
symptoms including nervousness, anxiety, tremors, heart palpitations, weight gain, and muscle weakness.
It can become a debilitating disease. Thyroid adenomas and neoplasms can also arise from the thyroid
gland and result in significant morbidity and mortality. Thyroid scintigraphy examinations are valuable for
use in patients with hyperthyroidism as well as thyroid cancer, thyroiditis, and other conditions. They
allow the direct visualization of functional and hyperfunctioning thyroid tissue. Thyroid scintigraphy is
also widely used in evaluating for residual thyroid tissue after thyroidectomy or radioactive thyroid
ablation. Five-year survival rates for thyroid cancer are 97.8%, therefore confirming accurate therapy and
follow-up through thyroid scintigraphy is vital to patient survival.32
FIGURE 14.5 Thallium scan. A: Anterior view of the whole body thallium scan in a patient with Kaposi sarcoma. Multiple foci
of increased uptake are seen in the thorax. Physiologic uptake is seen in the bowel and collecting system. B: Axial SPECT/CT
image at the level of the heart demonstrates three lesions, which are located in the bilateral posterior upper lobes. C: SPECT/CT
coronal reconstruction images provide additional anatomical detail.
Both radioactive iodine 123I and 131I can be used for evaluation of the thyroid gland. In conjunction
with other diagnostic modalities, thyroid scintigraphy is used to determine the nature of thyroid lesions
and guide therapy. Radioactive iodine has the ideal physical characteristics for thyroid tissue uptake as it
relates the general structure of thyroid gland to its function. Thyroid follicular cells take up radioiodine,
organify, and store them as thyroglobulin.33 Thyroid scintigraphy is therefore a useful tool in determining
the functional status of an abnormal nodule or the entire thyroid gland in patients with abnormal serum
TSH and can be used to select nodules for fine-needle aspirations. Thyroid cancer or benign nodule
concentrate less avidly and appears as “cold,” as opposed to “hot nodules,” which is often autonomous
and less likely to be cancerous. Some hot nodules can be indeterminate as scintigraphy generates two-
dimensional images. In a situation when normal thyroid tissue and a nodule overlap in a 2D image, the
averaging of the two densities place the nodule into an indeterminate range. Recombinant TSH (rTSH)
sometimes is given to patients prior to the examination to enhance radioactive iodine uptake, especially
for detecting recurrent or residual differentiated thyroid cancer.34 SPECT/CT may also be utilized to
localize lesions with added z-axis of the axial CT images. It is often used in conjunction with scintigraphy
to localize metastatic thyroid disease (Fig. 14.6).35 Normal ectopic thyroid tissue can also be localized by
thyroid scintigraphy (Fig. 14.7).
Thyroid scintigraphy is recommended for preablation staging and posttreatment follow-up for
differentiated thyroid cancer that meets the criteria for maximum tumor diameter greater than 1.0 cm or
smaller with high-risk pathology.36 SPECT/CT maybe used to facilitate more accurate localization of
metastasis and for staging as mentioned earlier.
Pretest preparation includes avoiding iodinated contrast as well as other iodine rich food as they
saturate iodine uptake in the thyroid gland and interferes with the diagnostic and therapeutic use of
radioiodine. If patient has significant iodine intake, procedure should be postponed for 4 to 6 weeks.37
Thyroid scintigraphy is also used for posttreatment monitoring of patients who have undergone total
thyroidectomy with or without adjuvant therapy of radioactive iodine ablation for thyroid cancer.
In benign thyroid disease, radioactive iodine may also be used for differentiating diffuse enlargement
in Grave disease from toxic nodular goiter. Often, the results are used to determine the dose for
radioactive iodine therapy, which may provide symptom relief for patients. Radioactive iodine ablation
takes several months to reduce the size of thyroid goiter. Surgical removal sometimes is performed for
immediate relief of symptoms in patients with multinodular goiters that are too large. 131I is the isotope
used for therapy with therapeutic dosimetry ranging from 20 to 100 mCi as opposed to 2 to 4 mCi in
diagnostic scintigraphy.
FIGURE 14.6 I-131 whole body scan in a patient with recent total thyroidectomy for papillary thyroid cancer. Approximately 48
hours after 2 mCi of I-131 was administered, images were obtained. Several foci of uptake in the neck may represent cancer
recurrence or residual tissue (red arrow). There are multiple foci of increased uptake in the lungs, compatible with metastatic
disease.
FIGURE 14.7 I-131 whole body thyroid scan of a patient with suspected recurrence of papillary thyroid cancer approximately 1
year posttotal thyroidectomy. A: Following the oral ingestion of 2.8 mCi of I-131 in a capsule, a delayed whole body thyroid scan
was performed at 48 hours post administration of radiotracer. Anterior and posterior views demonstrate multiple foci of intense
uptake clustered in the neck region (red arrow). There is physiologic uptake within the collecting system (yellow). B: SPECT
and SPECT CT images provide 3D localization and delineation of the lesions. Intense focus of increased radiotracer activity in
the right lateral anterior neck at the level of the false vocal cords (yellow arrow) may represent a positive lymph node. A second
area of increased uptake noted in the region of the mid neck, which crosses the midline, may represent residual thyroid
parenchyma in the region of the surgical bed (green arrow).
It is important to be aware of the posttreatment side effect of 131I therapy. Patients develop
hypothyroidism and should be closely followed and treated with thyroid hormone replacement after
radioiodine therapy if not already taking it after thyroidectomy. Another important consideration is thyroid
stunning with pretreatment scintigraphy, a not-well-understood phenomenon of decreased dosage uptake
following diagnostic scintigraphy. Inflammation in other vulnerable organs such as oral mucosa, parotid
gland, and salivary gland are to be watched out for.38 Fertility issue may be a late side effect.39 Other late
side effects to be aware are permanent damage to the salivary glands and radiation-induced malignancies.
Many of these effects are yet to have established threshold values.
PARATHYROID
The parathyroid glands produce parathyroid hormone produced by the chief cells and control calcium
homeostasis. Eighty percent of normal adults have four parathyroid glands. In most instances, there are
two pairs of parathyroid glands located on the posterolateral surface of the upper and lower lobes of the
thyroid gland. Parathyroid hormone is produced by the parathyroid gland and functions in regulating
calcium and phosphate levels. Hyperparathyroidism is caused by excess production of parathyroid
hormone from overactive parathyroid glands and results in hypercalcemia. The most common cause of
primary hyperparathyroidism is a parathyroid adenoma.40 Approximately 80% to 85% of parathyroid
adenomas are adjacent to the thyroid; however, the remainder may be ectopic in position in regions such
as the mediastinum, within or adjacent to the thymus, along the esophagus or carotid sheath or
bifurcation.41 In 85% of cases of primary hyperparathyroidism, there is a single or multiple
hyperfunctioning adenomas; 12% to 15% are due to hyperplasia, and 1% to 3% are carcinomas.42
Surgery for the parathyroid has progressed from wide neck exploration to minimally invasive with the
improved precision in preoperative localization based on 99mTc-sestamibi scintigraphy, a gold standard
preoperative imaging modality for parathyroidectomy planning.43
Parathyroid scintigraphy is performed utilizing dual-phase imaging protocol, which refers to early and
delayed images acquired with 99mTc-sestamibi, or dual isotope or subtraction imaging, which refers to
scans utilizing two radio-isotopes.42
99mTc-sestamibi, Hexakis-2-methoxy-isobutyl-isonitrile labeled with technetium-99m, is a lipophilic
cation that gets distributed to tissue based on blood flow and passively accumulates in the cytoplasm and
mitochondria, driven by transmembrane electrochemical gradient.44 Sestamibi accumulates in the
hyperfunctioning parathyroid glands due to the increased blood supply to the region as well as higher
number of mitochondria.45 After intravenous injection of 99mTc-sestamibi, a double-phase image is often
obtained at 10 to 15 minutes and 1.5 to 3 hours. The delayed image usually demonstrates improved signal
to noise ratio, as thyroid activity in the background is washed out. However, not all thyroid activities
wash out early and not all parathyroid lesions retain the radiotracer. Occasionally, coexisting thyroid
nodules may retain 99mTc-sestamibi and be mistaken for a parathyroid lesion.
Dual tracer subtraction scintigraphy can be utilized as many 99mTc-sestamibi avid thyroid lesions also
found to accumulate pertechnetate iodine.46 The thyroid scintigraphy can then be subtracted digitally from
the 99mTc-sestamibi scan, or be used for direct visual comparison of the pair of images for the assessment
of parathyroid abnormalities (Fig. 14.8).
FIGURE 14.8 Dual isotope technique for localization of parathyroid adenoma. A: Dual isotope imaging was performed utilizing
10 mCi Tc-99 pertechnetate and 25 mCi 99mTc-sestamibi, which were administered intravenously. Anterior scintigraphic imaging
of the neck and upper thorax was performed in the thyroid phase approximately 10 minutes and 30 minutes after the injection.
Additional anterior imaging was performed during the parathyroid phase approximately 2 hours postinjection. There was an
increased focus of uptake located just below the inferior left thyroid gland. It is best identified on the image obtained during the 2-
hour delayed phase, after partial washout of thyroid gland uptake (red arrow). B: SPECT/CT images obtained to provide 3D
localization of the parathyroid adenoma, which is identified within the posterior inferior left lobe of the thyroid gland.
SPECT and SPECT/CT imaging is often performed following the initial scans to improve sensitivity in
diagnosis and in determining a more precise anatomic location. This is most helpful in cases of ectopic
parathyroid tissue and can aid in surgical planning. In combination with functional imaging, SPECT/CT
for anatomic purposes can result in a more optimal study.
SOMATOSTATIN RECEPTOR SCINTIGRAPHY

Somatostatin (SST), a small peptide, is a neurotransmitter in the central nervous system (CNS) and
gastrointestinal tract with inhibitory hormonal actions. SST has an antiproliferative effect on tumors by
inhibiting growth and angiogenesis and the release of growth factors and hormones. It also has an
inhibitory effect on inflammatory cells and acts as an immunomodulator. There are five SST receptor
subtypes identified in normal tissues and neuroendocrine tumors.47 Tumors known to have high expression
of SST receptors are adrenal medullary tumors including pheochromocytoma, neuroblastoma, ganglioma,
and paraganglioma (Fig. 14.9). GI neuroendocrine tumors such as carcinoid, gastrinoma, and exocrine
pancreatic tumors include the nonfunctioning neuroendocrine tumors. Pituitary adenoma and small-cell
lung cancer may also have high expression.48 A small amount of SST receptors are discovered in
astrocytoma, benign and malignant bone tumors, breast carcinoma, and differentiated thyroid carcinoma.
However, tumors show various degree of SST expressions especially found in medullary thyroid and
insulinoma cancer.49 The commonly used Indium-111 pentetreotide is a [In-111 DTPA-D-Phe] conjugate
of octreotide, an SST analog that binds to predominantly SST receptor subtypes SST2 and SST5.49
Octreotide scans therefore have limited sensitivity and specificity depending on the types of tumor and
their SST expression status. Not uncommonly, autoimmune disease such as Grave’s, rheumatoid,
infectious processes such as bacterial pneumonia, granulomatous disease such as TB or sarcoidosis, and
postradiation inflammation may all have various degrees of uptake without having known receptor
expressions.50 Occasionally, tumors without SST receptors also demonstrate uptake. SST-bound tracers
can clear through the renal collecting system, biliary system, and bowels. Knowing patent’s history is
essential in minimizing false-positive results.
111In-pentetreotide was approved as a radioactive SST in 1994 in the United States for use in the
diagnosis and management of a wide variety of neuroendocrine tumors.51 Lung tumors found to have
neuroendocrine differentiation include carcinoid, large-cell cancer, and small-cell lung cancer. Pulmonary
carcinoid accounts for 1% to 2% of all lung malignancies and falls into low-to-intermediate grade lung
tumor; however, lymph node and distant metastasis may occur overtime.52 SST scintigraphy, therefore,
may be needed for staging.
Prior to the examination, a thorough history and review of patient’s prior studies should be performed.
When possible, octreotide therapy should be discontinued before radioisotope administration. The time
prior to discontinuation varies from 1 day to 6 weeks depending on the type for octreotide formula.
Patients should be well hydrated and a mild oral laxative can also be considered.53
FIGURE 14.9 111In-pentetreotide scan of a patient with carcinoid tumor of the lung. A: Anterior and posterior views of whole
body 111In-pentetreotide scan. Increased focal region of uptake of 111In-pentetreotide in the right lung abutting the mediastinum
is demonstrated (red arrow). Finding corresponds to the posterior upper lobe lung mass abutting the mediastinum. B: The mass
was confirmed to be carcinoid on pathology.
After administration of 111In-pentetreotide, the planar scintigraphy and SPECT/CT is performed at 24

hours postinjection. Additional images can be obtained at 4 and 48 hours; however, this is optional but
may aid in diagnosis. The tracer accumulates in organs that express SST receptors as discussed earlier.
The SNMMI-recommended administered activity is 6 mCi in adults and 0.08 mCi/kg in children. The
amount of 111In-pentetreotide injected per dose of octreotide scan is not expected to have a clinically
significant pharmacologic effect in majority of the tumors. 111In-pentetreotide is cleared rapidly from the
blood pool (⅓ of injected dose remains in the blood pool at 10 minutes, 1% at 20 hours after injection).
Excretion is almost entirely via the kidneys with 2% via hepatobiliary system.
Despite the favorable biodistribution, the sensitivity and specificity varies considerably attributed to
the variable expression of SST receptor types, levels, and the diversity of organs and tissue involved.
More recent study has shown that utilizing 18FDG PET/CT in conjunction improves the diagnostic
accuracy of SST receptor scintigraphy in primary staging and monitoring of pulmonary carcinoids.54
SURGICAL APPLICATIONS OF RADIONUCLIDE TRACER METHODOLOGY

PREOPERATIVE LUNG SCINTIGRAPHY AND INTRAOPERATIVE
PROCEDURES
Radionuclide-guided procedures have revolutionized the operating room with the wide use of handheld
detectors during routine surgical procedures. The solid-state scintillation detector probe is connected
through a flexible fiberoptic cable to the photomultiplier tube and appropriate electronics, including a
digital display and an audible signal that changes pitch according to the intensity of the radioactivity. The
probe is selected according to the intended clinical use, the size and depth of the region of interest, and
the type of radionuclide emissions used with gamma being the most common. The radioactivity detected
by the probe, expressed in number of counts per second (cps) or counts per minute (cpm), is corrected by
the background radioactivity. Spots with net count rates higher than 3 standard deviation of background
activity are considered true findings. Gamma rays can be detected at a distance from the source of
radioactivity. Therefore, the radioactivity deposited at the injection site can interfere with the survey of
less-active targets. To avoid this problem, the probe should be shielded from gamma rays coming at
undesirable angles; when in use, the face of the detector should always be directed away from the
injection site. Accurate detection is obtained when the face of the probe is perpendicular to the source of
activity and at close range. Avoid sweeping movements during use, as fewer counts will be recorded and
the origin of the radioactivity cannot be accurately determined.55
Radio-guided procedures have major application in oncology. In surgeries of the chest, preop and
postop scintigraphy as well as intraoperative detector use can guide lymph node mapping in breast cancer
detection and staging. Radio-guided Lymph Node Mapping and Sentinel Lymph Node Biopsy (RGSLNB)
rely on the natural physiology of lymphatic drainage, which picks up small particles and delivers them to
local lymph nodes. Radiotracers can be injected close to malignant lesions, and they follow the lymph
drainage to help identify the sentinel lymph node, which can be identified using a handheld gamma probe.
After initially being used in breast and cutaneous melanoma, RGSLNB gained wide acceptance and is
now being used in many other types of oncology surgeries including thyroid cancer and parathyroid
cancer.56 In more recent years, as interventional radiology and minimally invasive procedures progressed,
radio-guided procedures also expanded to aid in mapping of vessels and intravascular delivery of
radiotherapy.57,58 Advancement in localization of breast cancer was made with the introduction of
radioactive seeds in the early 2000, which requires a sealed seed of radioactive isotope to be placed
inside the patient a few days prior to surgery; this technique has reduced operating room schedule
conflicts and improved workflow compared to the traditional wire localization by Radiology immediately
prior to scheduled surgery time.59
RADIATION ISSUES
The operating room will need to follow a protocol for radioactive waste disposal and monitoring, similar
to that being performed in the nuclear medicine department. The amount of radiation the surgeon and staff
will be exposed to depend on the type of activities performed and radioactive isotopes used. For
intraoperative localization of tumor tissue or lymph node detection, the staffs generally are exposed to a
small amount of radiation. The maximum allowable exposure recommended by the U.S. Nuclear
Regulatory Commission is 50,000 mrem/yr for extremities and 5,000 mrem/yr for the whole body. To put
this number in perspective, using 99mTc, one of the most commonly injected agent, in radio-guided
parathyroidectomy as an example, this number translates to several thousands of parathyroidectomies per
year without exceeding the maximum dose using a standard operating time of less than 2 hours.60 The total
calculated radiation of the whole body dose to the surgeon was approximately 8.78 to 11.00 μSv from an
1 mCi injection. Most other surgical staff in the OR will be of slightly less exposure due to longer
distance from the source. The duration of time of surgery to time of radiotracer injection will slightly
affect the radiation dose. With many variables to be considered, a dedicated radiation safety team
composed of medical physicists, nuclear medicine physician, surgeons, operating room administrative
staff in the facility is necessary to carefully monitor the radioactivity of the surgical staff.
As intraoperative radiation therapy became an option, intraoperative delivery of radiation therapy to
the tumor bed during surgery has been a growing interest.61,62 While those radiations are of high dosage,
they often come within a protective seal and lead aprons are worn in the operating room during these
procedures to protect the staff administering the radioactive therapy.63
Handling of operating room radioactive waste material is a vital component of the radiation safety
protocol. Contaminated equipment and samples containing high radioactivity such as the pathology
specimen should be stored in designated area to allow adequate periods of decay before disposal.
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15
Thoracic PET CT
Perry Gerard ■ Neil Kapadia ■ Jay Acharya
INTRODUCTION
Cancer is one of the leading causes of morbidity and mortality in the United States. Specifically, lung
cancer is the leading cause of oncologic mortality in the United States.1 Lung cancer causes more deaths
than the next three most common cancers combined (colon, breast, and pancreatic). An estimated 159,260
Americans are expected to die from lung cancer in 2014, accounting for approximately 27% of all cancer
deaths.2 Advancements in radiology have led to the increased use of imaging to guide treatment in lung
cancer patients, whether metastatic or primary in etiology. Conventional radiography and CT have been
used as measures to evaluate the anatomy of thoracic tumors, but do not provide any information regarding
metabolic activity. Positron emission tomography (PET) has become the examination of choice for
evaluation and staging of lung tumors and indeterminate pulmonary lesions. In this chapter, we provide a
practical review of PET and PET CT in evaluation of patients with disease in the thorax. More
importantly, we will provide a variety of examples of false negatives and false positives which should
always be considered in the interpretation of PET CT given the specific clinical scenario.
PRINCIPLES OF PET IMAGING

The most common radioisotope utilized in PET imaging is 18F-fluoro-2-deoxy-D-glucose (FDG). FDG is
a radiolabeled glucose molecule that operates on the principle that many lung tumors require increased
glucose metabolism. PET has been used with increasing frequency for diagnosis, staging, and
posttherapeutic follow-up imaging for various tumors. PET-CT has been used in the evaluation of various
tumors including non-small–cell lung carcinoma (NSCLC), lymphoma, solitary pulmonary nodules, breast
cancer, colorectal cancer, and other malignancies.3
Neoplastic cells require increased uptake of glucose. Furthermore, once the FDG is transported into
the cell, it remains metabolically trapped after phosphorylation by hexokinase. Thus, the FDG
accumulates within all cells requiring glucose, but will accumulate to a higher degree in highly
metabolically active cells, such as many lung tumors. This differentiation in glucose uptake is the basis
behind the utility of PET imaging. Quantitative information regarding the FDG uptake activity is obtained
and serves as a measurement tool.
PET is routinely performed in conjunction with CT, which allows for precise anatomic correlation
between the FDG uptake activity and anatomic structures. Current recommendations regarding the use of
FDG PET-CT include the diagnosis of lung cancer and locoregional and distant staging of NSCLC,
evaluation of the solitary pulmonary nodule, melanoma, lymphoma, and esophageal, colorectal, head and
neck, and breast cancer.
In addition to FDG, there are multiple other PET tracers available which are useful for specific
diagnostic purposes. An example of this is 18F-Fluoride which uptakes within the skeletal system and can
provide information about skeletal metastasis. PET tracers such as 13N-Nitrogen and 82Rb-rubidium
chloride are used for myocardial imaging. Other specialized tracers are also available which are not in
the scope of this chapter.
STANDARDIZED UPTAKE VALUE

PET scanners are designed to measure in vivo radioactivity concentration which is related to FDG
concentration. However, it is not the absolute value of FDG concentration which is useful, it is the
relative FDG concentration that is important. There are two main variables which affect the radioactivity
concentration in any given part of the body: the initial amount of FDG administered and the volume of
distribution in which the FDG is deposited. A convenient substitution for volume is to use the patient
weight which can be readily measured. There needs to be standardization for these main variables during
a PET scan. The standardized uptake value (SUV) is used to take these variables into account and allow
for comparison of different areas of the scan with respect to their FDG concentration. The SUV is
calculated by:
where c(t) is the concentration of radioactivity (kBq/mL) measured by the PET scanner in a specific
region of interest at time t, a(t) is the decay corrected activity (kBq) administered to the patient at time t,
and w is the weight of the patient (g). This formula assumes the patient is the density of water at 1 g/mL.
Since the SUV is determined with variables that change with time, and variables that change with each
study, comparing SUV values from one study to the other should be avoided when evaluating disease.
However, SUV values are useful in evaluating relative metabolic activity of a region of interest at a given
point in time during a single study.
INDICATIONS FOR PET CT

PET CT demonstrates high sensitivity to pick up abnormally high metabolic tissues. However, increased
uptake in tissues is not specific in order to make diagnoses. The main indications for PET CT are to
detect other foci of known tumor or disease to describe its extent or in the case of treatment, describe
residual tumor burden or treatment response. For example, in the case of lung cancer, PET CT is indicated
for staging of diagnosed non-small–cell lung cancer and to delineate gross tumor volume in patients
undergoing radiation therapy. Similarly, PET CT is used for initial staging of lymphoma and then utilized
for reassessment after chemotherapy and/or radiation. Although metastatic staging and treatment response
are the primary uses for PET CT, it can occasionally also be used for further characterization of
pulmonary nodules which are large enough to be imaged by PET (8 to 10 mm in size)4 or a partially solid
mass with the solid component >8 mm in size which are low to moderate probability for malignancy.5
Although a decision must be made with a combination of factors in mind such as patient smoking history
and features of the lesion, PET may be used to further characterize the metabolic nature of the nodule. If
the nodule is highly hypermetabolic, the surgeon may be swayed in favor of doing a resection while in the
case of a low metabolic nodule, serial follow-up with serial CT may be appropriate. However, this
method of characterization is still not specific since there are various false positives and false negatives
for PET which we will discuss in further detail subsequently in this chapter.
Once a diagnosis of lung cancer is made, PET CT may be used to find and localize extrathoracic lymph
nodes which may then be biopsied to evaluate for metastasis in order to prevent exclusion of the patient
from potential treatment. If a PET scan is obtained, a bone scan is not necessary to evaluate for bony
metastasis. Intracranial lung cancer metastasis shows variable uptake on PET6 and therefore, PET-CT is
not recommended for the evaluation of metastasis to the brain. In addition, in patients with peripheral
stage cIA tumors, a PET scan is not required for staging.5
TECHNIQUES AND PROTOCOL FOR PET CT

When ordering a PET scan for a patient, it is important to keep in mind the preparation involved and the
requirements that must be met for a diagnostic scan to take place. Patients who cannot maintain these
requirements may not be able to tolerate the examination and either nondiagnostic images, or worse yet,
confounding results may occur in the setting of an inappropriate radiation dose.
The main goals of patient preparation prior to PET are to limit physiologic uptake of FDG radiotracer
into normal tissues such as skeletal muscle. This will allow better detection of abnormal uptake within
neoplastic disease. Patients should fast except water for at least 4 to 6 hours prior to imaging to decrease
physiologic glucose and insulin levels within the blood. Parenteral nutrition and intravenous fluids
containing dextrose should also be stopped for 4 to 6 hours. The blood glucose should be checked prior to
administration of FDG radiotracer.7 If the blood glucose level is greater than 150 to 200 mg/dL, the
preferred method is to reschedule the test when the blood glucose level is under better control. Insulin
may be given, however administration of FDG must be delayed until serum insulin and blood glucose
levels have reached equilibrium which depends on the route and type of insulin administration. The
patient should be quietly sitting or lying supine during the injection and uptake phase to minimize uptake
in skeletal muscle and vocal cords. The patient should also be placed in a warm room prior to radiotracer
administration to minimize brown fat uptake. The room should be quiet and dimly lit, especially for brain
imaging. Usually, the patient should sit quietly and comfortably in the room for about 1 hour. Hydration
and allowing the patient to urinate prior to image acquisition avoid high bladder activity and allow better
pelvic imaging.
The patient must be able to tolerate the examination. The patient required to lay still for the duration of
the image acquisition which ranges from 15 to 45 minutes. In addition, keeping the patient’s arms
overhead is preferred. History of claustrophobia must also be evaluated to assure the patient will be able
to stay in the scanner for the required amount of time without moving. If the patient is able, performing
deep inspiration breath holds during the CT portion of the study can greatly increase the accuracy of
matching the PET images and low-dose CT images.8,9 Much of the time, a “whole body” PET scan is
ordered. In this case, the scan goes from the base of the skull through the proximal femurs. Although this is
institution dependent, the brain and much of the lower extremities are excluded from the field of view.
This is important to consider when using the PET CT to replace bone scan to evaluate for metastasis,
since the lower extremities and skull may not be evaluated.
PHYSIOLOGIC UPTAKE IN PET IMAGING
18F-FDG follows the metabolic pathways of glucose and therefore serves to act as an energy metabolite.
The FDG is transported into cells through membrane glucose transporters where it is subsequently
converted to 18F-FDG-6-phosphate by hexokinase. At this point, the 18F-FDG-6-phosphate is negatively
charged and cannot exit the cell. Furthermore, it is not significantly enzymatically active. Glucose-6-
phosphatase will mediate dephosphorylation, which is a slow process, and particularly slow in most
tumors, myocardium, and brain tissue. Thus, during imaging, 60 minutes after injection, these are highly
active sites of radiotracer deposition. The brain demonstrates high uptake of FDG, as the brain
metabolizes significant glucose. Spleen, liver, and bone marrow demonstrate mild physiologic uptake
with the liver normally appearing slightly more intense compared to the latter two. Lymphatic tissue may
show moderate uptake, particularly involving the tonsils in adults and adenoids in children. Thymic tissue
may demonstrate activity in children. Thymic tissue can also demonstrate uptake in young adults, which
may be sequela of a rebound thymic hyperplasia secondary to chemotherapy.10
In the chest, there is variability of activity, with greater activity in the inferior and posterior segments
of the lungs, which may decrease sensitivity of lesion detection in these areas.11 Cardiac activity is highly
variable due to cardiac myocyte utilization of fatty acids for energy in the fasting patient with low insulin
levels. Mild mediastinal activity is physiologic. Gastrointestinal tract activity is also variable in nature.
The esophagus generally will show no significant uptake unless there is inflammatory or neoplastic
change. Mild radiotracer activity in the stomach is often seen. Small intestine activity is low grade.
Colonic activity is generally moderate, most predominantly in the cecum and rectosigmoid region.
18F-FDG is excreted in the urine, unlike its analog glucose, which allows for the presence of
radiotracer activity at any point along the course of the urinary system. Thus, there are limitations in
evaluation of the renal and urothelial tumors.
Skeletal muscle activity is also highly variable and the activity can be multifactorial and nonspecific.
Exercise or even mild activity before imaging can yield indeterminate results.
Symmetric activity within the neck, supraclavicular, and paraspinal regions can be seen in the presence
of brown fat. This is generally seen in children and young adults. Patients can be pretreated with
benzodiazepines to reduce activity in the brown fat. Also, performing the examination in a warm room
will decrease FDG uptake into the brown fat.12 Correlation between the PET findings and the CT can
facilitate in the diagnosis and recognition of the brown fat (Fig. 15.1).
FIGURE 15.1 A: Axial, sagittal, and coronal PET images. There are focal areas of increased FDG uptake within the lower
neck and upper mediastinum. This is a classic example of brown fat FDG uptake. Treatment with benzodiazepines or warming
the patient prior to scanning will decrease brown fat activity. B: PET with color overlaid on axial CT which demonstrates
localization of the FDG activity within the regions of fat in the neck confirming the finding of brown fat.
FALSE-NEGATIVE FINDINGS IN THE THORAX

Small lesion size (less than 1 cm) can lead to false negative regardless of intrinsic tumor FDG affinity.
Also, if proper breath-holding techniques are not followed, or the patient is not able to comply with
breath holding, small nodules will not be visible on PET CT due to motion blur.13 As mentioned
previously, protocols for hyperglycemia should be followed to minimize competition for FDG uptake in
surrounding tissues. Furthermore, a number of thoracic masses are known to have poor FDG uptake and
can lead to false negatives. This should be considered when working up a patient for possible
malignancy. As previously mentioned, approximately half of bronchoalveolar carcinomas (BACs) or
adenocarcinoma in situ (AIS) will demonstrate a false negative on PET CT. Well-differentiated
adenocarcinomas also demonstrate poor FDG uptake as do carcinoid tumors. In these cases, PET CT
should be used in conjunction with other imaging modalities to confirm results and to minimize the
repercussions of false-negative findings.
Another instance in which a lung lesion may not be FDG avid is when there is a metastatic lesion from
a tumor of relatively low cellularity or tumors that produce mucin. Examples include mucinous carcinoma
of the breast, mucinous adenocarcinomas of gastrointestinal origin, and renal cell carcinoma metastasis to
the lungs. It is important to also obtain a thorough clinical history. In the case of a patient recently treated
with chemotherapy, decreased FDG uptake will be seen in tumor deposits especially if the chemotherapy
is effective which will lead to a decreased number of metabolically active tumor cells. Although this may
show treatment response, tumor cells may still be viable and will continue to grow if therapy is stopped
even with little to no FDG uptake (Fig. 15.2).
FALSE-POSITIVE FINDINGS IN THE THORAX

As mentioned previously, proper technique must be followed to minimize uptake in normal tissue such as
brown fat which may lead to confusion and false-positive results. Inflammatory cells at the site of
inflammation or infection may demonstrate increased FDG activity.14 Additionally, active granulomatous
processes, other infectious conditions, and active fibrotic lesions may also show increased 18F-FDG
activity and serve as a false positive for malignancy.15
Tuberculosis is a disease that may cause intense FDG uptake due to activated inflammatory cells
stimulated to undergo phagocytosis. Phagocytosis is known to stimulate the hexose monophosphate shunt
which causes increased glucose metabolism and high FDG uptake. This leads to a nodular region of
increased activity. Occasionally, there may be central necrosis or cavitation, which demonstrate a
relatively hypometabolic central focus surrounded by high radiotracer activity.16 Lymphadenopathy in
association with tuberculosis may also show increased radiotracer activity in these areas as well, which
can be of particular importance in the hila and mediastinum. Tuberculosis is particularly confounding
because it can cause extrapulmonary sites of infection as well which can be mistaken for metastasis.
Other granulomatous disease can also represent false-positive results such as infection with
histoplasmosis. Other atypical lung infections will also show increased FDG uptake such as in areas
infected with blastomycosis or aspergillosis (Fig. 15.3).
FIGURE 15.2 A: PET with color overlaid on CT axial, coronal, and sagittal reconstructions. Multiple lung metastasis seen in a
45-year-old patient with no known primary. Note, normal uptake within the heart and liver and activity within the urine in the
bladder. B: Coronal slices through the PET images only on the same patient demonstrating multiple lung metastasis. Notice
additional areas of normal uptake within the bowel, bony structures, kidneys, and spleen. C: Single PET with color overlaid on
CT slice through the level of the upper lungs demonstrating multiple lung metastasis in the same patient. Although not difficult to
localize in this case, increased activity within the masses allows for increased sensitivity of finding metastasis in more difficult
cases.
Sarcoidosis is a multisystem process which leads to development of very specific noncaseating

granulomas. Aggregation of T lymphocytes and mononuclear phagocytes in sarcoidosis results in
increased FDG uptake. Within the thorax, abnormal increased FDG activity may be seen predominantly in
the mediastinum, hila, and even sometimes within the lung parenchyma.17
Essentially, any infectious or inflammatory process that results in leukocyte infiltration and
propagation of inflammatory tumor markers will yield increased 18F-FDG uptake. Other infectious
etiologies include cryptococcosis from the fungus Cryptococcus neoformans which also leads to
granulomatous inflammation within the lungs. Paragonimiasis, which is a foodborne parasite, also shows
increased FDG uptake. Paragonimiasis is caused by a liver fluke and may penetrate through the diaphragm
and pleura and enter the lungs. Abscess formation from any cause will also demonstrate increased
radiotracer activity within the thorax.
FIGURE 15.3 A,B: Coned down axial CT examination and corresponding PET images. There are slightly lobular soft tissue
density masses within the right upper lobe and left upper lobe which demonstrate avid FDG uptake. Multiple other FDG avid
masses were also seen throughout the lungs as well, and were suspicious for metastasis. However, this patient had no primary
tumor and further investigation with biopsy proved these masses were tuberculous granulomas.
FIGURE 15.4 A: PET CT coronal projection in a patient with sarcoid. There are multiple lymph nodes in a “lambda”
configuration within the mediastinum and bilateral lung hila which is often seen in the setting of sarcoidosis. B: Axial CT and
PET image through the same level through the mid lungs. The CT portion of the examination allows for detection of
granulomatous sarcoid nodules in the lungs in addition to the previously mentioned mediastinal lymph nodes.
Other FDG-avid lesions which may result in false-positive findings in FDG PET are etiologies which
result in fibrosis. An important example is radiation fibrosis in which inflammatory cells infiltrate the
area in the acute setting. Fibrosis caused by pneumoconiosis especially in the setting of progressive
massive fibrosis is another important cause of false-positive findings in FDG PET.
Fibrosis and inflammation may also be seen in the setting of recent surgery with increased uptake at the
site of associated inflammation or hematoma. Radiation-induced inflammation may also produce a false-
positive result. In a similar fashion, talc pleurodesis may also develop pneumonitis/fibrosis which can
uptake FDG and lead to a false positive.
Another pitfall when interpreting PET CT scans is errors in localization due to misregistration of the
PET and CT portions of the examination. This is where breath holds and restricting motion discussed
earlier in the chapter play a role in imaging quality. If the patient moves between the PET portion and CT
portion of the examinations, the change in distance can cause difficulty in localizing FDG-avid lesions,
especially in areas such as ribs or the spine where a soft tissue component may not be readily visible on
the CT images. It has been shown that shallow breathing is inadequate for comprehensive staging in the
setting of lung cancer especially in the evaluation of the lower lobes of the lung.13 Good technique and
patient cooperation is paramount in obtaining diagnostic quality images.
As mentioned previously, there is FDG uptake in sarcoidosis due to the inflammatory nature of
granuloma formation. This is especially true in the case of active sarcoidosis which demonstrates a
characteristic pattern on PET CT. Sarcoid classically demonstrates uptake in the right paratracheal and
bilateral hilar lymph nodes in a “lambda sign.” Although FDG uptake is not particularly useful for making
the initial diagnosis, PET CT can be helpful for monitoring therapy (Fig. 15.4, Table 15.1).17
TABLE 15.1 False Negatives and False Positives in Interpreting PET CT
False Positive—Inflammatory False Negative—Technical
Post-surgical hematoma/biopsy Small lesions <0.8 cm

Post irradiation Misregistration
Post chemotherapy
Local inflammatory disease (granulomatous, fungal, mycobacterial disease)
Thyroiditis
Esophagitis
Acute and chronic pancreatitis
Acute cholangitis
Osteomyelitis
Lymphadenitis
Recent fracture sites
False Positive—Physiologic False Negative—Physiologic
Salivary glands Low Grade Tumors

Brown fat Bronchoalveolar Carcinoma
Thymus Carcinoid
Lactating breast/areola Metastasis to Lung from:
Skeletal and smooth muscle Mucinous Carcinoma (Breast, Gastrointestinal)
Esophagus Renal cell carcinoma
Urinary tract structures, Invasive ductal and lobular breast carcinoma
Uterus during menses
Corpus luteum cyst
EVALUATION OF THE SOLITARY PULMONARY NODULE

A solitary pulmonary nodule is defined as an opacity within the lungs less than 3 cm in size. These lesions
may be categorized into malignant or benign classification by imaging characteristics such as calcification
or quality of their margins in some cases. Most of the time, solid soft tissue density nodules are usually
indeterminate with their imaging characteristics and their risk is stratified by clinical information such as
patient age and smoking history. These lesions can be caused by multiple etiologies including
inflammatory, infectious, and neoplastic causes. Information about the metabolic activity of a solid soft
tissue density nodule can be found utilizing PET CT to aid in determining the etiology. For example, two
similar-appearing 1-cm soft tissue lung nodules in a patient with smoking history may be differentiated by
their SUV value, the nodule with the higher SUV value being more suspicious for malignancy18 and which
should be biopsied first.
Even in the setting of biopsy proven non–small cell lung cancer, false-positive results can occur in the
setting of concurrent inflammatory processes especially in the case of mediastinal lymph node uptake. In
these cases, mediastinoscopy and biopsy should be obtained when a pathologic lymph node is suggested
by PET CT in the mediastinum.19
One of the primary reasons to get PET imaging in the chest is to stage or follow-up lung cancer.
However, it is important to realize that BAC/ALS and adenocarcinoma with BAC features, especially the
mucinous type, may demonstrate little or no uptake and result in a false-negative scan. It has been
suggested that false-negative results occur in approximately 50% of cases of BAC.20 In addition, if the
lesion is less than 0.8 cm, there is even greater chance of a false-negative result. A false negative is seen
in up to two-thirds of cases.21 Otherwise, PET is a valuable method of staging and follow-up evaluation.
Staging of NSCLC, using FDG PET-CT imaging, dictates clinical management in this patient
population. Treatment options vary based on the tumor stage and include the use of surgery, radiation
therapy, or chemotherapy. 18F-FDG PET-CT is the accepted first-line staging tool in patients who may be
treatment candidates, as determined by the TNM staging classification.22
The T designation is based on the size of tumor, involvement of contiguous structures, and the presence
or absence of satellite nodules which can be evaluated with PET/CT if sufficient size. T1–T3 lesions are
potentially resectable lesions. T4 lesions are often inoperable. Using PET in conjunction with CT allows
for better prediction of the N and M values. The accuracy of lymph node staging (N) by PET and PET/CT
was 56% and 78%, when compared to mediastinoscopy or surgical staging.23 NSCLC most commonly
metastasizes (M) to the brain, liver, adrenal glands, bone, and lung. PET CT provides an accurate method
to evaluate for both local and distant metastatic disease (Figs. 15.5 to 15.7).24
FIGURE 15.5 A: PET with color overlaid on CT axial, sagittal, and coronal reconstructions. Increased peripheral uptake is seen
about a cavitary lesion within the right upper lobe of the lung. This was later demonstrated to be squamous cell carcinoma of the
lung. B: PET with color overlaid on axial slice through the right upper lobe cavitary lesion. Once again this demonstrates
increased FDG activity in the periphery of the lesion indicating a metabolically active process and is consistent with a cavitary
squamous cell carcinoma. C: PET with color overlaid on axial slice through the right hilum. Significantly increased soft tissue
density with associated increased FDG uptake within the right hilum suggests metastatic right hilar lymphadenopathy. The left
hilum does not demonstrate increased FDG activity which suggests lack of contralateral disease. D: PET with color overlaid on
axial CT slice through the lung bases. FDG uptake within pleural effusions most commonly indicates pleural metastasis,28
however in this case there is no appreciable FDG uptake within the right pleural effusion which suggests a bland effusion rather
than a malignant pleural effusion.
FIGURE 15.6 A: PET overlaid with axial CT through the level of the mid lungs. Another example of a squamous cell lung
cancer this time with FDG uptake seen in the adjacent pleura suggesting pleural metastasis. B: PET overlaid with axial CT
through the level of the mid lungs. FDG avid mediastinal activity is seen compatible with metastatic mediastinal lymphadenopathy
which would also affect staging.
FIGURE 15.7 A: PET CT with color overlaid on coronal CT images. There is an FDG avid lung carcinoma in the right lung
apex. Focal FDG uptake is also seen in a mid-thoracic vertebra which is highly concerning for bone metastasis. B: Axial CT
through the level of the liver in the same patient. PET increases the sensitivity for lesions greatly. As an example, on the low
dose CT portion of the examination it is impossible to see the FDG avid lesion within the liver. The FDG uptake allows for
localization of the hepatic metastasis while it may have been missed on CT alone.
LYMPHOMA
FDG PET is an integral part of staging, detection of recurrence, and monitoring of treatment response in
patients with non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma.25 Intrathoracic involvement is more
common in Hodgkin disease than in NHL.26 Studies show that there is median sensitivity of 90.3% and
median specificity of 91.1% for staging of lymphoma using 18F-FDG PET imaging.27 Anatomic
correlation with CT increases the overall sensitivity and specificity of FDG PET-CT for initial staging of
NHL and Hodgkin lymphoma to 97% and 100%, respectively. Therapeutic response for NHL and
Hodgkin lymphoma can also be monitored using PET CT.28 The sensitivity and specificity for the
detection of residual disease after completion of first-line therapy are 84% and 100% for Hodgkin
lymphoma and 72% and 100% for aggressive NHL, respectively.29
The advantages of FDG PET/CT for the staging and restaging NHL and Hodgkin lymphoma can be
primarily attributed to the detection of FDG-avid, normal-sized lymph nodes (usually <1 cm), and of
extranodal sites that were previously missed on CT evaluation. These most commonly involve the liver,
spleen, bone, and skin.30 Current recommendations suggest the following regarding FDG PET in
lymphoma:
1. PET is recommended for the staging of patients with FDG-avid, potentially curable lymphoma, such as
large B-cell lymphoma and Hodgkin disease, to more accurately delineate disease extent.
2. PET is not recommended prior to treatment for incurable, non–FDG-avid or indolent histologic
subtypes, such as mantle cell or grade-1 follicular lymphoma, or for lymphomas with variable FDG
activity, unless the medical oncologist is seeking to assess response to the chemotherapy regimens or
new experimental drugs.31,32
FIGURE 15.8 A: PET with color overlaid on axial CT at the level of the lung hila. Increased FDG uptake is seen within
mediastinal and bilateral hilar lymphadenopathy in this patient with CLL. B: PET with color overlaid on axial CT at the level of
the lower lungs in the same patient. Increased FDG uptake is also seen scattered throughout the lung parenchyma within the
lower lobes. This increased metabolic activity was proven to be due to infiltration of the lung with CLL.
Although rare in the thorax, marginal zone lymphomas such as mucosa-associated lymphoid tissue
(MALT) demonstrate heterogeneous FDG avidity because of their indolent nature and may represent
another false-negative opportunity.26
Lymphoma can also involve the thymus gland; however, it does not affect staging and is considered a
nodal organ. A majority of cases in proven Hodgkin lymphoma, the thymus demonstrates FDG avidity due
to thymic hyperplasia.33
Lymphomatous infiltration of the myocardium and pericardium can also occur but very rarely. This
often presents a diagnostic dilemma since there is normal physiologic FDG uptake in the heart. FDG
uptake within a pericardial effusion may also be seen in the setting of lymphoma (Fig. 15.8).34
MESOTHELIOMA
Mesotheliomas are tumors associated with exposure to asbestos. These pleural-based tumors commonly
show intense FDG uptake.35 One of the applications where PET CT has been researched is to try to
differentiate benign inflammatory pleuritis or asbestos-related pleural thickening versus mesothelioma
utilizing SUV values.36 Although, specific diagnosis cannot be made as to benign and malignant disease,
PET CT can be useful for guiding the location for pleural biopsy in a metabolically active region.
Although this is not completely specific, PET CT can be used after tissue diagnosis to evaluate for
metastatic lymph nodes or for staging and surgical planning for procedures such as aggressive
pleuropneumonectomy.
ESOPHAGEAL CANCER
Esophageal cancer consists of either squamous cell carcinoma or adenocarcinoma. Squamous cell
carcinomas usually originate from the proximal esophagus. Adenocarcinomas originate in the distal
esophagus near the gastroesophageal junction and are related to metaplasia and Barrett esophagus.
Another very rare pathologic process within the esophagus is involvement by diffuse large B-cell
lymphoma which demonstrates diffusely increased FDG uptake. Since most primary esophageal cancers
are diagnosed by clinical symptoms and by endoscopy, PET CT is not tremendously useful in the primary
diagnosis of esophageal cancer; however, it has been shown to be effective in staging and evaluating
extent of disease. EUS is the most sensitive method of regional node staging in esophageal cancer and
allows assessment of depth of invasion in the case of stage III disease. Tumor- and node-stage accuracy of
PET CT is comparable to EUS. PET CT can be utilized for identifying the extent of the esophageal mass
and spread within pathologic lymph nodes as an adjunct to EUS. Primary esophageal lesions and
metastatic lymph nodes >0.8 cm can be detected with PET CT and PET CT is useful for detecting
systemic metastasis. In the case of esophageal cancer, metastasis to the supraclavicular, cervical, and
celiac nodes are considered distant stage-IV disease and precludes surgery. Also, PET CT is less
invasive than EUS and may be used in patients where esophageal stricturing prevents the passage of the
scope making EUS technically difficult or impossible.37
INCIDENTAL FINDINGS ON PET-CT

Although there may be no significant FDG uptake on a PET-CT, it is important to carefully evaluate the
CT portion of the examination since critical information and/or clinically important incidental findings
may be seen. One study describes 12% of their studies had findings indicating a second primary
malignancy.38 In addition, just as in CT solely performed for other reasons, there may be critical results
such as pneumothorax or pulmonary embolism. These findings may change future management or in the
cases of critical values, these patients may need further emergent inpatient care (Figs. 15.9 and 15.10).
FIGURE 15.9 PET with color overlaid on axial, sagittal, and coronal CT reconstructions. This patient had a history of small cell
carcinoma of the lung and was status post recent removal of an infusaport. There was a significant chemotherapy response with
no significant uptake of FDG radiotracer, however an incidental nonocclusive left internal jugular vein thrombus is seen. The
patient was hospitalized and temporarily anticoagulated with heparin.
FIGURE 15.10 A: Coronal PET images through multiple levels. In this patient with bone metastasis (not pictured), there is a
circumferential photopenic ring around the region of the heart. B: PET with color overlaid on coronal and axial CT
reconstructions. There is a large pericardial effusion seen around the heart. The effusion does not demonstrate significant FDG
tracer uptake which suggests bland versus malignant effusion.
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restaging-do we need contrast-enhanced CT? Radiology. 2004;232:823–829.
31. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586.
32. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus
of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007;25:571–578.
33. Even-Sapir E, Lievshitz G, Perry C, et al. Fluorine-18 fluorodeoxyglucose PET/CT patterns of extranodal involvement in patients with
non-Hodgkin lymphoma and Hodgkin’s disease. Radiol Clin North Am 2007;45:697–709.
34. Weijs LE, Arsos G, Baarslag HJ, et al. Pericardial involvement in a non-Hodgkin lymphoma patient: coregistered FDG PET and CT
imaging. Eur Heart J 2007;28:2698.
35. Gerbaudo VH, Sugarbaker DJ, Britz-Cunningham S, et al. Assessment of malignant pleural mesothelioma with (18)F-FDG dual-head
gamma-camera coincidence imaging: comparision with histopathology. J Nucl Med 2002;43(9):1144–1149.
36. Zhuang H, Pourdehnad M, Lambright ES, et al. Dual time point 18F-FDG PET imaging for differentiating malignant from inflammatory
processes. J Nucl Med 2001;42:1412–1417.
37. Lee G, Hoseok I, Kim SJ, et al. Clinical implication of PET/MR imaging in preoperative esophageal cancer staging: comparison with
PET/CT, endoscopic ultrasonography, and CT. J Nucl Med 2014;55(8):1242–1247.
38. Beatty JS, Williams HT, Aldridge BA, et al. Incidental PET/CT findings in the cancer patient: how should they be managed? Surgery
2009;146(2):274–281. http://dx.doi.org/10.1016/j.surg.2009.04.024
Section
IV
DIAGNOSTIC PROCEDURES
16
Laboratory Investigations in the Diagnosis
of Pulmonary Diseases
Erin A. Gillaspie ■ Dennis A. Wigle
Lung pathology is varied and diagnosis, at times, can be challenging. This chapter focuses on diagnostic
techniques that can help to differentiate between disease types. The chapter is arranged in a manner that
first discusses the methods for acquiring samples for analysis and the second focuses on laboratory
processing, stains, and adjunctive assessments that may assist in diagnosis.
FLUID SPECIMENS
SPUTUM
The tracheobronchial tree produces small amounts of secretions daily that are generally handled by
mucociliary clearance mechanisms. Secretions are made up of water, electrolytes, proteins, lipids, and
mucus glycoprotein. The mucus serves to trap and eliminate inhaled particles. Unfortunately, many
pathologic states can perturb the natural balance between production and clearance of secretions.1
Expectorated sputum contains endogenous mucus, ciliated cells, alveolar macrophages along with
debris, and foreign particles including bacteria. Examination of sputum may be helpful in diagnosis.
Adequacy of sampling is important. Alveolar macrophages should be present in the specimen, while too
many epithelial cells within a sample (>10 cells/hpf) represent contamination and should not be sent for
culture.1
Evaluation of sputum appearance is the first step in analysis. Healthy individuals have clear,
translucent, viscous sputum containing minimal microscopic elements. Purulent sputum is opaque or off-
white, yellow, or green, indicating high leukocyte content. Carbon particles may also discolor sputum in
chronic smokers.1
Sputum may be sent for Gram stain and culture to help diagnose and identify the causal organism of
pneumonia. Cytologic examination may also be performed to diagnose a malignancy. It should be noted
that large studies such as the Mayo Clinic Lung Project evaluated chest x-ray and sputum as a screening
tool for lung cancer and did not find this to be effective in screening.2,3
BRONCHOALVEOLAR LAVAGE
Bronchoalveolar lavage (BAL) is another excellent diagnostic tool, which may help in the diagnosis of
malignancy, infection, or interstitial lung diseases. A BAL is performed in conjunction with a
bronchoscopic procedure. Patients are generally sedated and bronchoscopic examination of the airway is
completed. The bronchoscope is wedged into the desired subsegmental bronchus—the right middle lobe
and lingula are used most commonly. Saline is flushed through the bronchoscope and gently aspirated into
a collection trap. Steps are repeated as needed to collect several aliquots, each typically measuring 20 to
40 mL of fluid.4
First washings are felt to be most representative of tracheobronchial epithelial cells and bronchial
proteins. This should be sent for microbiology. Subsequent washings are more representative of distal
airspaces. These specimens may be pooled and sent for cellular analysis.5
Fluid from a BAL should always be processed immediately if possible; otherwise specimens may be
stored for up to 24 hours in nutrient-supplemented media (e.g., MEM+25mM HEPES or RPMI
1640+25mM HEPES) at 4°C.5
Occasionally, samples must be washed to remove excess mucus. Cellular elements are isolated for
study by centrifugation. A viability of greater than 90% of cells is considered acceptable; less than 80%
suggests compromise of the sample. At least 400 white blood cells should be evaluated to give a
meaningful analysis of cell differential populations.5 A “normal” BAL in clinically well individuals has
been shown to contain macrophages (>80%) and lymphocytes (<15%).
Depending on clinical suspicion, a variety of additional studies may be performed on the sample. BAL
fluid specimens may be sent for quantitative culture or stained to detect the presence of bacteria,
mycobacteria, or fungi. Polymerase chain reaction (PCR) methods are also commonly used to facilitate a
more rapid diagnosis for certain pathogens including pulmonary tuberculosis.6
According to Meyer,7 cell differential on BAL is also very useful in categorizing disease types. An
elevated neutrophil count (>50%) strongly supports acute lung injury or a suppurative infection.
Eosinophil count of >25% is diagnostic of parasitic lung disease. Lymphocyte counts >25% strongly
suggests granulomatous lung disease such as sarcoidosis, hypersensitivity pneumonitis (HP), a drug
reaction, or viral infection. A lymphocyte count >50% may also suggest HP or a drug reaction but may
also support a diagnosis of cellular nonspecific interstitial pneumonia (NSIP).
In the case of interstitial lung disease, BAL has taken a secondary role to high resolution CT scanning
(HRCT). Although HRCT may be diagnostic in many cases, in nonspecific scans, BAL with cellular
analysis may help to narrow the diagnosis.8
Welker et al.9 have performed the largest investigation to date, evaluating the diagnostic utility of BAL
in the setting of interstitial lung disease. They studied 1,748 patients, each of whom underwent BAL with
cell counts. The study confirmed that in frequent diseases such as sarcoidosis and usual interstitial
pneumonia (UIP), the disease left a reproducible cellular fingerprint that could be easily identified.
BAL analysis has proven to be a useful adjunct in posttransplantation surveillance. Many studies have
shown that elevated proteins, cytokines, and specific cells (CD8, CD4, and NK) in samples correlate
well with acute rejection. However, this does not replace the need for histologic study of lung tissue.
Neutrophil predominance (>20%) has been observed in patients who are at high risk for chronic rejection
and predicts response to treatment in certain subtypes of chronic allograft dysfunction.10
BRONCHIAL BRUSHING
Bronchial brushing is another minimal-risk procedure that may be performed in conjunction with flexible
bronchoscopy. A sheathed brush is passed through the bronchoscope; the brush is extended into the airway
and gently rubbed over a lesion to collect cells and organisms within the bristles of the brush. The brush
is retracted and removed from the bronchoscope.11 Brush contents are smeared onto slides, which may be
placed in 95% alcohol or immediately air-dried for hematoxylin and eosin (H&E) staining. Alternatively,
the whole brush may be submitted for cytologic analysis.
In the third edition of the American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines, diagnostic utility of brushings was compared with biopsy in the analysis of centrally located
lung tumors. The sensitivity of forceps biopsy was 88% while washings and brushings were somewhat
lower at 48% and 59%, respectively.12 When possible, biopsy is certainly the superior form of tissue
sampling.
TABLE 16.1 Modified Light Criteria

Transudative Exudative
Appearance Clear Cloudy
Specific gravity (SG) <1.012 >1.020
Protein Content <2.5 g/dL >2.9 g/dL16
Ratio fluid:serum protein <0.5 >0.517
Difference to blood albumin content >1.2 g/dL <1.2 g/dL18
LDH upper limit of serum <2/3 >2/317
Cholesterol content <45 mg/dL >45 mg/dL16
PLEURAL FLUID
Pleural fluid is continually produced by the body to serve as a lubricant between the parietal and visceral
pleura. The volume produced daily for a 100 kg patient is approximately 300 mL.13 The volume,
appearance, and cellular content of pleural fluid can be quite informative and assist in narrowing
diagnoses. Pleural fluid can be categorized as transudative or exudative based on Light criteria (Table
16.1).14 Transudative effusions occur secondary to elevated hydrostatic pressures in capillaries. This may
be caused by congestive heart failure, cirrhosis (hepatic hydrothorax), nephrotic syndrome, peritoneal
dialysis, hypoproteinemia, urinothorax, and superior vena cava obstruction.15 Exudative effusions,
conversely, are due to increased capillary permeability with increased spillage of cells and fluid into
surrounding tissues or decreased capillary resorption. Common causes of exudative effusions include
infections (bacterial, fungal, and viral), infarctions, neoplasms, and pleural diseases.15 Pleural fluid is
collected most commonly by thoracentesis. Thoracentesis is a simple procedure that can remove excess
fluid from the pleural space for diagnostic and therapeutic purposes. A small catheter is introduced into
the pleural space using Seldinger technique. A gentle negative pressure is applied and fluid is collected.19
Ultrasound may be added to help localize and sample smaller effusions (Fig. 16.1).
Fluid may be sent for a variety of studies including cell count, differential, protein, LDH, cholesterol,
albumin, specific gravity, culture, and cytology.
FIGURE 16.1 Ultrasound view of pleural effusion. Needle is being advanced into the fluid with imaging guidance.
TISSUE SPECIMENS
Tissue specimens are distinct from fluid specimens in that they allow for identification of cells or bacteria
but in some cases can also provide details of tissue architecture. Tissue may be collected by
bronchoscopic biopsy, image-guided biopsy, or surgical resection.
When selecting an approach to the biopsy several things should be considered. First is the location of
the lesion. Central masses are more amenable to endoscopic and transbronchial approaches whereas
peripheral lesions are often better suited to image-guided biopsy or surgical biopsy. Certain diagnostic
work-ups may require larger volumes of tissue or higher number of samples and this may also help to
guide approach to tissue sampling. For interstitial lung disease, pathologists may request samples of 3 to
4 cm in size from different regions of varying severity to provide adequate information for making a
diagnosis. Tissue biopsy is also sometimes required if bronchoscopy, BAL, and other fluid analyses fail
to make a diagnosis.
ENDOBRONCHIAL AND TRANSBRONCHIAL BIOPSY

Endobronchial and transbronchial approaches to biopsy are minimally invasive with low morbidity and
low cost. Just as with BAL and bronchial brushings, biopsies can be obtained through a flexible,
fiberoptic bronchoscope, or a rigid bronchoscope. Generally, four to five pieces of tissue are collected,
each measuring 1 to 2 mm in diameter. Samples may be sent for frozen section or submitted in formalin
fixative for permanent section analysis. Although the procedure is low risk, a careful history and physical
should be obtained ahead of time to ensure no anesthetic or bleeding risks exist for a patient.
Endobronchial lesions are visible within the bronchial tree and direct tissue sampling may be
performed. A biopsy forceps is advanced through the bronchoscope and takes samples of the lesion in
question. Unfortunately, the biopsy may lack quality due to crush artifact. Newer techniques (discussed
below) help to reduce crush and may improve diagnostic yield.
Transbronchial biopsy is also performed with the assistance of a flexible bronchoscopy. At minimum,
a chest x-ray is required and preferably, a CT scan is performed prior to the procedure to help guide
tissue sampling. Fluoroscopy may be used intraprocedurally to help locate and target a particular area for
biopsy. While fluoroscopy does not reduce the incidence of pneumothorax, it has been shown to increase
diagnostic yield.20
Cryobiopsy is a newer technology that may be used for both endobronchial and transbronchial
biopsies. Comparative studies in the last 5 years have shown that cryobiopsy can achieve large samples
and artifact-free tissue sections with greater preservation of tissue and architecture. This has led to
diagnostic yield of greater than 90%.21 Hetzel et al.22 in a multicenter study randomized 600 patients with
endobronchial tumors to forceps biopsy or cryoprobe biopsy. Blinded histologic evaluation yielded a
definitive diagnosis in 95% of patients with cryoprobe versus 85% in conventional (p <0.001).
Importantly, there was no difference in major morbidity including bleeding complications.
Navigational bronchoscopy, unlike cryoprobe, makes use of imaging technology to better localize
nodules prior to biopsy. Electromagnetic navigational bronchoscopy (ENB) allows a practitioner to use
CT scan to plot the most efficient course through the bronchial tree to a lung nodule or desired biopsy
location.23 This technology is particularly effective in more difficult-to-reach nodules that require
transbronchial sampling. Gex et al.24 performed a meta-analysis and found that a definitive diagnosis was
obtained in 65% of patients with a diagnostic accuracy of 74%. Complication rates were no higher than
other diagnostic techniques. They concluded that ENB is effective and safe (Fig. 16.2).
FIGURE 16.2 Electromagnetic navigational bronchoscopy can be used to inject a pulmonary nodule with methylene blue. A
catheter is advanced into the lung parenchyma and location is confirmed on fluoroscopy (A). The dye is injected into the
parenchyma surrounding a lung nodule. The methylene blue is easily visualized at the time of video assisted thoroacoscopic
surgery (B) and final pathologic examination confirms removal of nodule and demonstrates the methylene blue dye staining the
nodule and adjacent tissue (C).
Endobronchial ultrasound (EBUS) is another adjunctive technology that may be used to help localize
and direct precise sampling of tissues. Yoshikawa and colleagues25 discuss the benefits of using
ultrasound for peripheral nodules in their review. In each patient, an ultrasound image visualized target
lesion, a sheath was advanced, and biopsy performed. Diagnosis was successfully obtained in 61% of
peripheral nodules biopsied using this technique. The study showed that larger nodules (>2 cm), solid
nodules, and nodules in the right middle lobe or lingula had greater diagnostic yield. Many other studies
have confirmed the benefit of EBUS-guided biopsies in nodules that are fluoroscopically invisible.26
LUNG FINE NEEDLE ASPIRATION AND NEEDLE BIOPSY

Fine needle aspiration (FNA) and needle biopsy are alternative methods for sampling pulmonary tissues
or nodules and are performed in a similar manner (Table 16.2).27 Ultrasound is commonly used for
image-guided procedures of the pleura, but is less useful for parenchymal lesions. CT scans are the
imaging modality of choice as they allow clear visualization of the nodule, distance from the chest wall,
relationship to adjacent structures, and, most important, show the biopsy needle advancing within the
nodule or area of abnormality. Multiplanar, reformatted scans are particularly useful for lesions that are
less than 1 cm.29 Reported accuracy for CT-guided biopsies range from 64% to 97%. A trend toward
lower diagnostic accuracy was noted for lesions that were less than 1.5 cm in diameter, and subpleural
nodules (Fig. 16.3).28
FNA is performed by advancing a needle through the chest wall into a radiographically localized
region. Once the needle is confirmed to be within the tissue of interest, negative pressure is applied and
the needle is gently advanced and retracted to collect cells. Generally, an 18- to 25-gauge needle is used.
The cell sample is applied directly to slides which may be air-dried and immediately stained for analysis
or fixed in 95% alcohol. Any remaining fluid may be sent for cell-block analysis. Just as with trans-
bronchial biopsy, the complications of trans-thoracic procedures include both pneumothorax and
hemoptysis.28
Lung needle biopsy shares the same indications as an FNA and is useful for the assessment of
pulmonary nodules, mediastinal masses, pleural abnormalities, and diagnosis of infection. Considerations
prior to biopsy should include position of the lesion, adjacent structures, severe pulmonary disease
(bullous emphysema), or patients unable to cooperate or lay flat. CT guidance is used to advance a needle
(usually 18 to 22 gauge) into the lesion. The stylet is removed and the needle is advanced through the
nodule or area of interest to take a core of tissue. The procured cylindrical fragments of tissue are sent to
pathology for evaluation.28
TABLE 16.2 Reliable and Unreliable Diagnoses on Lung Biopsy
High Yield and Reliable
Malignancy
Sarcoidosis
Infection
Transplant rejection
Low Yield and Reliable
Lymphangioleiomyomatosis
Pulmonary alveolar proteinosis
Eosinophilic granulomatosis
Chronic transplant rejection
Nonspecific and Unreliable
Idiopathic interstitial pneumonias
Allergic alveolitis
Pneumoconioses
From Churg AM. Lung biopsy, lung resection and autopsy lung specimens: Handling and diagnostic limitations. In: Churg AM, Myers JL,
Tazelar HD, Wright JL, eds. Thurlbeck’s Pathology of the Lung. 3rd ed. New York: Thieme; 2005:95–108. Copyright © Georg Thieme
Verlag KG. With permission.
FIGURE 16.3 CT-guided biopsy of a small right sided pulmonary nodule.
The most common complications are pneumothorax and hemorrhage. Risk factors for complications
include smaller size of lesions, length of intrapulmonary needle path, trans-fissural course, and a wider
trajectory angle.30,31
In 2010, Yao et al.29 set out to answer whether FNA or core needle was superior based on diagnostic
ability and rate of complications. The meta-analysis found no difference in diagnostic accuracy for benign
or malignant lesions and no difference in complication rates. More recently in 2014, Capalbo et al.32
again compared the two methods of tissue acquisition in 121 patients. In their experience, FNA resulted in
fewer complications—pneumothorax in 18% versus 31% and parenchymal hemorrhage in 9% versus
34%—and diagnostic accuracy of FNA was 94.8% when performed in the presence of a pathologist who
could confirm adequacy of tissue sampling.
PLEURAL BIOPSY
A percutaneous pleural biopsy is a minimally invasive method of obtaining pleural tissue for diagnosis of
a pleural process. Pleural biopsy is recommended for evaluation and exclusion of infectious etiologies
such as tuberculosis, connective tissue disorders, or malignant disease, particularly malignant
mesothelioma. Pleural biopsy can also help to understand the etiology of pleural effusion which can
remain unclear in 20% to 40% of cases.33 In patients with no focal abnormality, a nondirected biopsy may
be taken. Image guidance is recommended in those who have a mass or thickening as it has been shown to
improve diagnostic sensitivity to 86%.34,35 The procedure is carried out much in the same way as a lung
biopsy. Skin is prepared and draped, anesthetized, and a small incision is made and the needle advanced
into the pleural space. The cutting edge of the needle is seated in the pleura and biopsy is taken.
Complications include pneumothorax, hemothorax, and laceration of the diaphragm, lung, liver, or spleen.
Rarely, tumor seeding has been reported along the needle track.36
SURGICAL LUNG BIOPSY

Open lung biopsy has taken on new meaning in the minimally invasive era. Standard video-assisted
thoracoscopic (VATS) and uniportal VATS have supplanted open thoracotomy approaches for diagnosis of
lung nodules. No matter the approach, the tissue yield is similar. A surgeon has the ability to visualize the
whole lung, palpate abnormal areas, and directly select regions to biopsy.
Early in the experience, outcomes were compared between diagnostic efficacies of thoracotomy versus
VATS approach. The two methods were demonstrated to be equivalent in diagnostic yield.37–39
Palpating lesions is more challenging in VATS than open as the surgeon is unable to fit his hand through
incisions and must rely on single digit palpation through port sites. For small lesions, or ground glass
opacities where identification can be difficult, localization may be performed preoperatively. ENB (as
described above) may be used to identify and map a lesion to bronchoscopically inject blue dye or place
a fiducial prior to thoracoscopy. An alternative and equally effective method as described in a paper by
Grogan et al.40 is preoperative CT-guided radionucleotide labeling of a lesion with technetium 99.
Intraoperatively, a collimated probe connected to a gamma detector can be used to isolate the lesion. The
lesion may be wedged out and then background counts can then be assessed to confirm specimen removal.
Localization has been described to be successful in 95% of cases.
Selecting a biopsy location for diagnosis is easy in the setting of a discrete abnormality or nodule.
Interstitial lung disease is a more diffuse process. Accepted guidelines for selecting sites for biopsy
include: (1) more than one biopsy from more than one site, (2) avoid areas of end-stage fibrosis, (3) areas
of intermediate abnormality or normal lung should be biopsied adjacent to areas with established
radiographic abnormality.41
Generally a diagnostic procedure is limited to a wedge resection or biopsy. Therapeutic treatment of a
lung nodule that is malignant generally mandates an anatomic resection—a segmentectomy, lobectomy, or
pneumonectomy. A frozen section may be helpful in guiding amount of resection and confirming
completeness of resection. Some samples will be held over for fixation and further review with special
staining. This will be discussed later in the chapter.
ANALYSIS OF SPECIMENS
PULMONARY CYTOLOGY
As was just described, there are many methods for obtaining cell samples for study. These include
everything from sputum sample and BAL to fine-needle aspirations. Please see Table 16.342 for complete
list.
SLIDE PREPARATION
There are different methods for preparing slides for evaluation. A touch prep technique directly applies
cellular aspirate or fluid onto slides. Slides may be air-dried and immediately stained and evaluated or
fixed in alcohol. With adequate sampling, slides can be prepared for both immediate viewing and fixed
for additional special staining.
TABLE 16.3 Cytology Specimens

Cytology Specimens
Pleural fluid (thoracentesis)
Sputum
Bronchial washing
Bronchoalveolar lavage
Transbronchial FNA
Transthoracic FNA
Respiratory cytology. Hologic, 2015. http://www.cytologystuff.com/study/nongynintro2.htm. Accessed April 15, 2015. Copyright © 2015
Hologic, Inc. All Rights Reserved.
Cell blocks are also very valuable in the evaluation of cytologic specimens. In this technique, cell
samples are centrifuged to create pellet of cells. The pellet is fixed in formalin and paraffin embedded.
This allows pathologists to examine the architectural details of the specimen and perform additional tests
such as immunocytochemistry, FISH, and PCR. Cell blocks have been shown to improve diagnostic
ability of cytology and are particularly useful in samples with a paucity of cells.43
The College of American Pathologists has published strict criteria on the preparation of slides to
maintain high fidelity amongst laboratories and to continually achieve a high level of diagnostic
accuracy.44
DIAGNOSTIC ACCURACY
In the last 40 years, cytologic methods have improved along with the diagnostic value of cytologic
specimens. Sensitivity and specificity of cytology has been studied extensively, especially in the setting of
lung cancer. Diagnosis of lung cancer can be achieved in 50% of sputum samples, 65% of bronchial
lavages or brushings, and FNA. Image-guided biopsies, in particular, have 90% specificity. The largest
study analyzing FNAs was reported by the College of American Pathologists Q-Probe Quality Assurance
Program. Over 13,000 fine needle aspirates were performed and analyzed. The diagnostic sensitivity was
98% and specificity 99%.45
DIAGNOSTIC CRITERIA
Understanding and interpreting normal is essential to interpreting abnormal. Normal cells found in a
respiratory sample include columnar cells that are ciliated or nonciliated, macrophages, epithelial cells,
and inflammatory cells. Epithelial cells will exhibit changes in response to infection, inflammation,
malignancy, and treatment effect.
Infections can cause cytomorphologic alterations or sometimes the organisms themselves can be
visualized. Some viruses such as Herpes Simplex and Cytomegalovirus (CMV) have characteristic
intranuclear or intracytoplasmic inclusions that are diagnostic if visualized. Fungal hyphae may be
commonly identified on cytology from appearance. Aspergillus, Candida, Cryptococcus, Histoplasma,
Mucormycosis, and Blastomyces all have key morphologic features.
SOLID TISSUE SAMPLES

In many cases, a pathologist will freeze and immediately review pathology to give confirmation of
removal, of negative surgical margins, adequacy of specimen, and may confirm cell type. To perform a
frozen section, tissue must be sent fresh. The pathologist will select a portion of the specimen, place it on
a metal disk, and embed the tissue in gel, rapidly freezing it to about –20°C. The specimen is cut with a
microtome to 5 to 6 microns thick, and placed on a glass slide where it can be stained and analyzed under
light microscopy.
Frozen section is beneficial in that it gives surgeons enough information to perform an appropriate
oncologic resection, and allows a pathologist to decide what additional studies should be performed to
assist in diagnosis.
As with any test, there are some detriments to frozen section. Frozen section may fall prey to sampling
errors—sampling nonmalignant surrounding areas rather than the truly malignant portion—and errors of
interpretation. Interpretation can be difficult, in particular differentiating metastatic disease from primary
disease, differentiating between tumor in the setting of poor differentiation, and at times differentiating
between neoplastic versus inflammatory or reactive histologic patterns.47 Pathologic features to
differentiate primary lung cancer from metastatic disease are listed in Table 16.4.48
TABLE 16.4 Pathology Features of Metastatic Disease

Features of Primary Adenocarcinoma Versus Metastatic Adenocarcinoma
Lung primary
Mixed patterns with solid, acinar and or bronchoalveolar architecture
Adjacent atypical adenomatous hyperplasia
Metastases
Complex or cribriform architecture
Cytologically bland or uniform cells
Dirty necrosis
Adapted from Sienko A, Allen TC, Zander DS, et al. Frozen section of lung specimens. Arch of Path and Lab Med 2005;129(12):1602–1609.
PERMANENT SECTION
A specimen that does not require rapid analysis or tissue remaining after frozen section may be processed
as fresh or placed in a fixative.
There are some studies that can only be performed on fresh specimens, that is, cultures for
microorganisms, flow cytometry, electron microscopy, and certain types of immunohistochemistry. It is
always important to discuss diagnostic concerns and goals with a pathologist to identify appropriate
studies and guide tissue handling.
Most solid tissue samples will be fixed in formalin. Specimens should be fully submerged in the
fixative. Some studies describe inflating larger pulmonary resections with formalin by infusing the fluid
through a red rubber catheter in the bronchus to facilitate superior fixation. Samples are then embedded in
paraffin wax as a supporting medium and then sectioned. Preparation of specimens takes about 12 to 24
hours and then they can be stained. The benefit to permanent section is that it avoids freeze artifacts, and
permits greater certainty of interpretation. The majority view is that permanent section is superior if only
a small amount of tissue is available.49
MALIGNANT PATHOLOGIC FEATURES

Pathologists are relied upon in thoracic surgery to determine malignancy of a pulmonary nodule and tumor
subtype to help guide treatment efforts. This section reviews some of the features of the most common
malignant pulmonary lesions.
Squamous cell carcinomas are composed of cells with keratinized, eosinophilic cytoplasm and
hyperchromatic irregularly shaped nuclei in a background of necrosis. The nuclear envelope is thickened
and nucleus enlarged with clumped and dense chromatin (Figs. 16.4 and 16.5).
This cancer is distinguished immunohistochemically by staining negative to thyroid transcription
factor-1 (TTF-1) and positively to p63.46 Benign conditions which can mimic squamous cell carcinoma
include treatment effect by chemotherapy or radiation, inflammatory conditions such as Aspergillus
infection, and pulmonary infarction. Poorly differentiated squamous cell cancer may be difficult to
discriminate from other cancers and metastatic disease.
Adenocarcinomas are composed of clusters of rounded, epithelial cells with enlarged nuclei. Cells
have abundant cytoplasm which can be vacuolated or bubbly in appearance. The nuclei may have
prominent nucleoli and chromatin is vesicular. The differential diagnosis includes reactive bronchiolar
epithelium, well-differentiated adenocarcinoma, or metastatic adenocarcinomas often of gastrointestinal
origin. Adenocarcinomas from lung origin will commonly stain positively for TTF-1 (Fig. 16.6).46
FIGURE 16.4 An example of a well-differentiated squamous cell carcinoma with formation of keratin pearls. A keratin pearl
typically has a pink, whirled appearance on H&E staining, surrounded by epithelial cells.
Large cell carcinomas lack the keratinized eosinophilic cells of squamous carcinoma and glandular
features of adenocarcinoma. Large cell carcinomas are distinguished by giant cells with moderate
cytoplasm, large nuclei, and prominent nucleoli. Malignant nuclear figures include coarsely clumped
chromatin, macronucleoli, and multiple nuclei (Fig. 16.7).46
Carcinoid tumors are well-differentiated neuroendocrine tumors that most commonly arise in the
intestines but may also be found in other organs including the lungs. These tumors are distinguished by
their uniformity, the lack of prominent nucleoli, and coarse, granular chromatin, which is often described
as “salt and pepper” appearance. Carcinoids have typical neuroendocrine architectural patterns with
organoid nests, trabeculae, and rosettes. Typical carcinoids are defined as having only 1 mitosis per high-
powered field while atypical have 2 or more mitoses or may have necrosis. To help with diagnosis,
common immunohistochemical stains include synaptophysin, chromogranin A, and CD56/NCAM.
Carcinoid tumors do stain positive in some cases for TTF-1; however, this staining is focal and weak
(Fig. 16.8).50
FIGURE 16.5 At higher magnification, squamous cell carcinoma can be diagnosed by pink cytoplasm, the nests of polygonal
cells with intercellular bridges or desmosomes, and the distinct cell borders.
FIGURE 16.6 Pulmonary adenocarcinoma has three variants based on pathologic findings—solid type, acinar type, and papillary
tumor. This is an example of acinar adenocarcinoma. Note the presence of numerous, irregularly shaped glands.
FIGURE 16.7 An example of large cell carcinoma. Tumor cells contain abundant cytoplasm, pleomorphid nuclei, and no
evidence of glandular differentiation or squamous differentiation.
FIGURE 16.8 Carcinoid tumors feature uniform tumors with salt and pepper chromatin pattern and small nucleoli. Cells are
often arranged in nests surrounded by a rich capillary network.
FIGURE 16.9 Small cell carcinoma features small cells with scant cytoplasm, ill-defined borders, and finely granular nuclear
chromatin. Mitotic count is usually high.
Small-cell carcinoma is a high-grade, malignant, epithelial neoplasm. Cytologically, this tumor is

defined by small cells, scant neoplasm, and small nucleoli with fine, “salt and pepper” chromatin. A key
morphologic feature is the molding of cells to one another as a result of rapid growth and necrosis of
individual cells within clusters. Most small-cell carcinomas are positive for TTF-1 as well as
synaptophysin, with about half showing positivity for chromogranin (Fig. 16.9).46
SPECIAL STAINS
H&E staining is the cornerstone of tissue examination. Virtually all specimens will be evaluated initially
with H&E staining and in many cases, this is the only stain required to make a diagnosis. Special stains
refer to any other empirical and histochemical staining that is performed to confirm a diagnosis. These
stains allow a pathologist to confirm the presence of specific chemical constituents, cellular components,
or infectious agents such as bacteria or fungi. Please see Table 16.5 to review stains.
IMMUNOHISTOCHEMICAL STAINS
Cancer can often be diagnosed and even differentiated by type on routing staining and light microscopy. In
cases where the diagnosis is difficult, immunohistochemical staining can help to clarify the diagnosis. The
most common stains are reviewed below.
Thyroid Transcription Factor 1

TTF-1 is a member of the homeodomain transcription factor family NKX-2. These transcription factors
regulate the production of surface proteins in type II alveolar cells and bronchial cells. TTF-1 is usually
retained in lung carcinomas derived from these cells. TTF-1 can be detected in thyroid and lung tumors—
namely adenocarcinomas, large cell, and small-cell cancers. This stain is particularly useful in
differentiating primary lung from metastatic adenocarcinoma.51,52
Cytokeratin
All normal and malignant epithelial cells contain cytokeratin (CK). There are 19 different polypeptide
CKs, which form intermediate filament cytoskeleton within epithelial cells. The CKs expressed within a
cell are specific to the region and cellular differentiation and therefore staining for specific subtypes of
CKs can give clues as to the origin of a cell.53 For lung cancer diagnosis, the most important subtypes of
CK for analysis are 5, 6, 7, and 20.
TABLE 16.5 Special Stains
Useful Stains for Diagnosing Infections and Pulmonary Disease Processes
Stain Infection
Infectious Agents
Gram stain Bacteria
Ziehl–Neelsen Mycobacteria
Auramine or rhodamine Mycobacteria
Coates modified Fite Nocardia and atypical mycobacteria
Grocott–Gomori methenamine silver (GMS) Fungi or pneumocystis
Giemsa Trophozoites of pneumocystis and toxoplasma
Periodic acid–Schiff (PAS) Fungi
Mucicarmine Cryptococcus
Dieterle, Warthin–Starry, Steiner Legionella and spirochetes
Noninfectious
Congo Red Amyloid
Elastic Van Gieson (EVG) Elastic fibers
Trichrome Collagen, smooth muscle, lymphangioleiomyomatosis
von Kossa, alizarin-red Calcium
Oil-Red-O Cholesterol, chyle
Many groups have set out to study effective pathologic differentiation of metastatic colorectal versus
lung cancer. The combination of CK 7/20 has repeatedly been shown to be of value in differentiating
tumor origin. CK7 generally arises from epithelium of the breast or lung while CK20 is found to be
expressed in intestinal cells.54 Therefore, CK7 (+)/20(−) cells represent a lung primary and the reverse is
colorectal primary.54,55
Studies for squamous cell carcinomas have shown that these tumors consistently stain positively with
CK5/6. Therefore, stains for CK5/6 are used commonly in conjunction with p63 to make the diagnosis of
squamous cell cancer.56
Calretinin
Calretinin (also called neuron-specific calcium-binding protein) is a calcium-binding protein that belongs
to the troponin-C family and is strongly expressed in mesothelial cells. Both cytoplasm and nuclei are
positive in mesothelioma in a pattern described as “fry-egg-like.” Studies have shown that serous fluid
effusions stain positively for calretinin in 58% to 100% of cases. Staining with calretinin is often used in
combination with others to help increase sensitivity and specificity.57
Napsin
TTF-1 is the mainstay of immunohistochemical stain for lung cancer. However, as previously mentioned,
it also stains other tissues such as thyroid, and metastatic breast and neuroendocrine tumors such as small-
cell lung cancer. Unfortunately, the expression of TTF-1 in cells is also less predictable in more poorly
differentiated tissues.58 Therefore, additional markers have been identified to help with diagnosis through
combined staining.
Napsin A is an aspartic proteinase that is involved in the maturation of surfactant proteins. Expression
is regulated by TTF-1. Napsin is abundant in the cytoplasm of type II pneumocytes and like TTF-1,
continues to be expressed in malignancy. Napsin A has been studied extensively and proven to be a good
surrogate marker in the setting of very poorly differentiated lung adenocarcinoma or tumors of unknown
origin.58 This stain has shown to be very effective in FNA59 and pleural effusions60 in addition to tissue
samples when used in combination with TTF-1.
p63
p63 is a gene that encodes for six different protein isoforms including tumor protein p63, which is a
member of the p53 family of transcription factors. These proteins are expressed predominantly in the
lungs, specifically within reserve cells of the ciliated bronchial epithelium. p63 expression is consistently
found at high levels in squamous cell carcinoma.61
In some institutions, TTF-1/p63 is used as a first line panel to differentiate between adenocarcinoma
and squamous cell carcinoma. This combination achieves excellent accuracy and only occasionally needs
additional staining to confirm diagnosis. This is particularly important in small sample sizes where tissue
conservation is essential to perform additional genetic markers which could be helpful in determining a
treatment strategy.62
Neuron-Specific Enolase, Chromogranin, and Synaptophysin

Neuroendocrine tumors all display typical arrangements of cells—nesting, palisading, trabeculated or
rosette-like—variable mitoses and contain cytoplasmic granules. In some cases, the diagnosis of
neuroendocrine tumors may be made by light microscopy, in other cases, immunohistochemical traits help
to differentiate between subtypes.
Neuron-specific enolase (NSE) is a glycolytic enzyme that catalyzes the conversion of glycerate to
pyruvate and is present in neuroendocrine cells. NSE levels are frequently increased in patients with
small-cell lung cancer and may be used as a diagnostic tool and to measure disease progression and
success of treatment.
Chromogranins are a family of glycoproteins that are normally found in the dense-core granules of
neuroendocrine cells. Chromogranin will stain all four pulmonary neuroendocrine tumor subtypes
including typical and atypical carcinoids, large cell and small-cell carcinomas. The specific degree of
staining depends on density of the granules.
Synaptophysin is a transmembrane protein found in presynaptic vesicles of neural cells. The protein is
variably expressed by the four pulmonary neuroendocrine tumors. This is one of the most specific markers
of neuroendocrine differentiation.63
Neural Cell Adhesion Molecule

Neural cell adhesion molecules (NCAMs) are cell-surface adhesion proteins that belong to the
immunoglobulin family. These proteins are involved in cell adhesion and importantly are expressed in
neuroendocrine cells and tumors. Small-cell lung cancers stain positive for NCAM in nearly 100% of
cases (Table 16.6).64,65
Special staining and lung cancer genomics will be presented separately. In addition, molecular biology
of lung cancers is described in future chapters.
TABLE 16.6 Pulmonary Immunohistochemical Stains
Summary of Immunohistochemical Stains
Marker Stains
Keratin Carcinoma
CK7 (cytokeratin) Carcinoma (lung origin)
CK20 (cytokeratin) Carcinoma (intestinal origin)
TTF-1 (thyroid transcription factor–1) Carcinoma of pulmonary or thyroid origin, small-cell carcinoma
P63 Squamous carcinoma
Chromogranin Neuroendocrine tumor
Synaptophysin Neuroendocrine tumor
NSE Neuroendocrine tumor
CD56 Small-cell carcinoma
Desmin Lymphangioleiomyomatosis
S-100 Melanoma, malignant peripheral nerve sheath tumor
CD45—leukocyte common antigen (LCA) Lymphoid tissue
CD20, CD79a B-cell lymphocytes
CD3, CD4, CD8 T-cell lymphocytes
CD34 Solitary fibrous tumor
MOLECULAR PATHOLOGY AND MICROBIOLOGY

This section of the chapter introduces some basic concepts of molecular pathology and laboratory studies.
The latter portion of this section focuses on specific tests in the diagnosis of pulmonary infections.
TERMINOLOGY OF MOLECULAR BIOLOGY

Human cells are composed of 23 paired chromosomes—22 autosomes and 1 sex chromosome.
Chromosomes reside in the nucleus, are made up of DNA, and encodes the genetic information of an
organism in “genes.” In transcription, a DNA segment unwinds, a transcription factor attaches to the
relevant DNA strand, and a particular segment is copied to create a messenger RNA (mRNA).
Importantly, not all portions of DNA code for genes. Sequences called exons are coding regions that can
be transcribed into mRNA and proteins. Introns (noncoding regions) make up the majority of DNA and are
not fully understood. While once considered “junk,” they are now thought to help in controlling gene
expression. After transcription, mRNA dissociates from DNA and transfers information from the cellular
nucleus to the cytoplasm where translation into proteins takes place.
Molecular diagnostic techniques are based in detecting specific sequences of nucleic acids (DNA or
RNA). There are extensive clinical applications in the fields of oncology, pharmacology, genetics, and
infectious disease. Importantly, in pulmonology and thoracic surgery, molecular diagnostic techniques may
be used to identify nucleic acid sequences that are particular to an infectious agent, or to a particular
malignancy to assist in classification and guide treatment.
This section discusses some of the basics of diagnostic tests which can be performed with cellular and
tissue samples. Table 16.7 summarizes available tests.
TABLE 16.7 Nucleic Acid Studies

Techniques Used to Analyze Nucleic Acids (DNA and RNA)
Electrophoretic separation
Hybridization
Amplification
Target amplification
Polymerase chain reaction (PCR)
Transcription-mediated amplification (TMA) and nucleic acid sequence–based amplification (NASBA)
Strand-displacement amplification (SDA)
Probe amplification
Ligase chain reaction
Cleavase/invader technology
Signal amplification
Branched DNA
Hybrid capture
Q-beta replicase
Combination of the above
HYBRIDIZATION AND ELECTROPHORESIS

Hybridization
There are three main tests that may be used for the detection of nucleic acid sequences: hybridization
assays, amplifications, and DNA/RNA sequence analysis.
Nucleic acid hybridization is a technique that detects the presence of a particular segment of DNA or
RNA within a sample. Hybridization is especially useful in the identification of infectious agents that
cannot be cultured in vitro. This method is effective for bacteria, fungi, protozoa, or viruses and is the
simplest of the three diagnostic tests.
There are several types of hybridization. Blotting, as described below are examples of hybridization
using extracted DNA that is cleaved with a restriction enzyme. In situ hybridization (ISH), conversely
detects presence of a segment on intact chromosomes.
Hybridization begins with unwinding nucleic acid, and this may be accomplished with application of
heat, salt, or other chemicals. Complementary probes are added to the nucleic acids and allowed to
anneal to their target sequences if present. Probes are generally short and specific. Probes are typically
labeled with radioactively, fluorescently, or with an antigen and may be detected with fluorescence
microscopy, chemiluminescence, or autoradiography.
Probes may be amplified or unamplified. Unamplified probes are less sensitive but can be used for the
detection of a sequence. Many authors favor at least one round of amplification to maximize the quality of
detection for genes that may have differential expression within a cell. Methods exist to amplify the DNA
target or the hybridized probes and are discussed in the next section.
Electrophoresis and Blotting

Electrophoresis is a method that applies an electromotive force to move nucleic acids or proteins through
a gel, separating them according to size.
Molecules are selected for study and a gel is prepared. Generally agarose is used for the study of
nucleic acids and acrylamide is used in protein analysis. The size of the pores within a gel can be
controlled by varying the chemical composition of the gel and therefore the degree of separation of
fragments can be selected. In most cases, DNA is digested by restriction endonucleases to create multiple
fragments. Nucleic acid fragments or protein samples are then loaded into wells and an electrical charge
is applied. Recall that DNA and RNA have a sugar-phosphate backbone which is negatively charged and
will migrate toward a positive charge.
TABLE 16.8 Blotting Methods by Molecule Studied

Types of Blotting
Blotting Type Molecule Studied
Southern DNA
Western Protein
Northern RNA
Electrophoresis is complemented by blotting which transfers nucleic acids or proteins onto a

nitrocellulose sheet and labeled fragments for identification. Table 16.8 summarizes types of blotting.
Southern Blotting
Southern blotting is a method that was developed for the detection of a specific DNA sequences. DNA is
digested with restriction endonucleases, separated by gel electrophoresis, and transferred onto a porous
(nitrocellulose) membrane. The nitrocellulose is bathed in nucleic acid probes which are labeled and
allow for detection of specific DNA targets.66 Detection of the probe may be performed by
autoradiography if the probe is radioactive or by enzymatic development of a chromogenic substrate.67
AMPLIFICATION
There are several methods to accomplish amplification; however, they all share a fundamental basis:
enzymes are used to synthesize millions of copies of a target sequence. The three major types of
amplification include target, probe, and signal.68
Target Amplification
Target amplification is an enzyme-mediated process that reproduces a unique sequence of a nucleic acid,
creating 108 to 109 copies. Target amplification can be realized through PCR, nucleic acid sequence–
based amplification (NASBA), transcription-mediated amplification (TMA), and strand displacement
amplification (SDA).
PCR was originally developed by Kary Mullis in the 1980s and is a simple method of amplification.
DNA is heated to unwind and expose target sequence. A DNA primer is added and anneals to the
complementary strand of DNA. DNA polymerase builds a copy by adding deoxynucleotide triphosphate
to the 3’ end of the primer. Heat is again applied to the solution to separate new copy of DNA from the
parent strand. After 30 to 50 cycles of PCR, a million-fold amplification is achieved. Variations of the
technique include reverse transcriptase PCR, nested PCR, multiplex PCR, quantitative PCR, and real-
time PCR.68
PCR can help in the identification of infectious agents, especially fastidious organisms which could
otherwise take weeks to grow. Each micro-organism contains a unique sequence of RNA or DNA which
can be targeted. Many companies now provide premade master mixes to test for specific bacteria and
viruses.69
Transcription-Mediated Amplification Methods and Nucleic Acid Sequence Based

Amplification
TMA and NASBA are RNA-specific amplifications that are modeled after retroviral replication methods.
An RNA target is reverse transcribed into DNA. The new DNA sequence then serves as a template to
synthesize RNA copies with the help of RNA polymerase. The replicated RNA is what will ultimately be
detected. This method is particularly effective for the diagnosis of Mycobacterium tuberculosis,
Chlamydia trachomatis, hepatitis C, and HIV.70
FIGURE 16.10 Strand displacement amplification.
Stand Displacement Amplification

SDA, in contrast to TMA and NASBA, requires multiple primers in a specific order to amplify the target
sequence and then displace the copied sequence (Fig. 16.10). An engineered primer with a restriction
enzyme site binds to a complementary target. Strand extension uses thiolated deoxynucleotide base. A
restriction enzyme then creates a nick at the restriction site and a bumper primer displaces the newly
generated strand. The process continues with nicking, extension, and displacement resulting in
amplification.71
Probe Amplification
Probe amplification is unique in that the product contains only the DNA or RNA sequence of the original
probe. This method makes use of a ligase chain reaction (LCR).
DNA is denatured into single strands. Two separate probes anneal to two distinct, but close target
areas on a DNA strand. The two probes are ligated together by DNA ligase creating a continuous DNA
sequence. DNA ligase will only ligate probes that have perfectly annealed to the sample DNA. The
probes are separated from target DNA by heating and the steps are repeated. Gel electrophoresis is used
to separate the LCR products and autoradiography is most commonly used to detect the presence of
selected DNA or RNA sequence.68
Signal Amplification
Signal amplification does not increase the number of targets or probes. Rather, this method focuses on
increasing the number of labeling molecules at the target sequence. There are three techniques: branched
DNA, hybrid capture, and Q-beta replicase.
Branched DNA assay begins with single strand DNA molecules called “capture probes.” These
capture probes are embedded in a solid support medium. An extender DNA molecule is added that
contains two domains: the first hybridizes to the capture probe and the second domain will hybridize to
the target molecular sequence from the patient sample. Now, signal amplification can take place by adding
a second extender which has one domain that attaches to the target molecular sequence and a second
sequence that contains sites for hybridization for enzyme labels for detection. Most tests rely on
chemiluminescence.71
The hybrid capture assay involves an RNA probe hybridizing to a DNA target or vice versa. The
RNA–DNA hybrids are captured by antibody that is labeled with a chemiluminescent enzyme. When the
enzyme is activated, it emits detectable light.71
Finally, Q-beta replicase system is an RNA dependent RNA polymerase derived from bacteriophage
Q-beta. This technique was first described in 1988 by Lizardi et al.72 and amplifies a specific template
molecule that hybridizes to a target sequence. The signal component of the hybridized probe is then
amplified.
SEROLOGY
The basis of serology is to test for an antigen or a person’s response to an antigen, i.e. antibodies.
Serology may be used to diagnose infection, monitor efficacy of treatment, and identify auto-immune
disorders. Investigations include enzyme immune assay (EIA), agglutination, precipitation, complement
fixation (CF), and fluorescent antibodies.
Quantification is an important aspect of serology and serves to distinguish a past infection from a
current one. Quantification is performed by serial dilutions and will be reported as a titer (i.e., 1:4, 1:16,
or 1:256). An active infection will result in a higher titer or an increase in titer over time.
Class of antibody detected is also important. IgM appears early in the course of an infection and will
generally disappear by 6 months. Conversely, IgG class of antibodies will appear later and persist for
years. Therefore, IgG can represent both an active infection and previous exposure.68
EIA or enzyme-linked immunosorbent assay (ELISA) are methods of detection and quantification of
specific antigens or antibodies in a sample. The test uses enzyme labeled antigens and antibodies to bind
to specific biologic molecules. If bound, a chromatographic substance will yield a visible color change or
the enzyme will fluoresce indicating the presence of antigen of interest.73
Ouchterlony immunodiffusion, also called agar gel immunodiffusion is a technique that allows for the
detection and quantification of antibodies and antigens. Wells within a gel plate are separately instilled
with antigens and antibodies. As the antigens and antibodies diffuse out of their wells, some will bind and
form immune complexes that will precipitate in the gel leaving behind a think white line giving a positive
visual result.
CF has been largely superseded by EIA/ELISA and PCR, but is still used occasionally in the
identification of some fungi.
MOLECULAR TECHNIQUES IN MICROBIOLOGY

The relevance of molecular techniques in microbiology is endless. Some of the more common
applications include: classification of organisms, confirmation of an isolate obtained in culture, early
detection of a pathogen, rapid detection of antibiotic resistance, detection of mutations, differentiating
toxigenic strains, and determination of viral load. An accurate and timely diagnosis can be of paramount
important in initiation of proper treatment and preventing the spread of a contagious disease.
The aforementioned techniques are uniquely suited to microbiologic studies as they can identify
sequences that are unique to each organism (Table 16.9).
TABLE 16.9 Infectious Agents Difficult to Identify by Culture

Nonculturable agents
Human papilloma virus
Hepatitis B virus
Fastidious or slow growing organisms
Mycobacterium tuberculosis
Legionella pneumophila
Highly infectious agents too dangerous to culture
Francisella tularensis
Brucella sp.
Coccidioides immitis
Present in low numbers
HIV in antibody negative patients
CMV in transplanted organs
Intracellular pathogens
Viruses
LEGIONELLA PNEUMOPHILA
In July 1976, a virulent form of pneumonia struck 182 members of the Pennsylvania branch of the
American Legion during their annual meeting in Philadelphia; 18 legionnaires died. An intensive
investigation ultimately led to the isolation of a new bacterial organism that went on to be called
Legionella pneumophila. Legionella is now recognized as a major cause of serious or fatal pneumonia in
immunosuppressed or immunocompromised patients.74
The identification of Legionella pneumophila presented a diagnostic challenge as the organism does
not stain by traditional methods and will not grow on standard culture media. Legionella requires
cysteine, iron, and elevated CO2 to grow in culture and even in a perfect microenvironment, still takes 7
to 12 days to multiply sufficiently for identification.75
Diagnosis relies on clinical suspicion based on physical symptoms and radiologic findings. Laboratory
diagnosis makes use of culture, serologic assays, and rapid detection assays. Culture is performed on
buffered, charcoal-yeast extract agar. Unfortunately, as mentioned, growth is slow. Serologic studies,
while great for epidemiologic studies, have proven to be suboptimal for acute diagnosis as it relies on
high titers to make a diagnosis. Therefore, for rapid diagnosis, clinicians must rely on direct detection of
organisms.75
Many companies now provide preprepared assays that use PCR amplification and ISH for diagnosis.
Amplification is performed directly on the clinical specimen; then nucleic acid probes are added and may
be identified via chemiluminescence or fluorescence. Studies have confirmed that PCR–ISH detection
gave a positive result in 100% of known cases and therefore has been deemed the best method for
detection of Legionella in lung tissue and BAL specimens.76
Legionella may also be detected in urine, sputum, and serum samples using EIA/ELISA.75
NOCARDIA
Nocardia is an aerobic filamentous bacterium that belongs to order Actinomycetales. When Nocardia
infects the lung it may develop into an abscess or necrotizing pneumonitis. Sinus tracts may form in the
lung, mediastinum, or subcutaneous tissues. Disseminated disease may manifest with brain abscesses.
Nocardia is an opportunistic pathogen which principally affects immunosuppressed patients.
Like Legionella, Nocardia cannot be stained by routine methods; Gram stain or methenamine silver
must be used. Nocardia does grow well on media for bacteria, fungi, and mycobacteria, however growth
is slow. Serologic assays are under development. Several laboratories have created serologic panels;
however this is not widely used in clinical practice.77,78
TABLE 16.10 Clinical Classification Scheme for Mycobacteria

Species Potentially Pathogenic in Humans
M. tuberculosis
M. avium–intracellulare
M. kansasii
M. fortuitum–chelonae complex
M. scrofulaceum
M. xenopi
M. szulgai
M. malmoense
M. simiae
M. genavense
M. marinum
M. ulcerans
M. haemophilum
M. celatum
From Koneman EW, Win WC. Koneman’s Color Atlas and Textbook of Diagnostic Microbiology. 6th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2006.
MYCOBACTERIA
MYCOBACTERIAL IDENTIFICATION
There are 100 different strains of Mycobacteria. The species most pathogenic to humans are listed in
Table 16.10.79 In addition to confirming mycobacterial infection, identification of the isolate with
susceptibilities must be performed to help guide treatment. Unfortunately, mycobacteria are fastidious
growers, making conventional testing for diagnosis insufficient.
Tuberculin Skin Test
Mantoux tuberculin skin test is the traditional way to diagnose latent M. tuberculosis. M. tuberculosis
purified protein derivative (PPD) is injected under the skin and reaction assessed in 48 to 72 hours. The
presence and size of induration determines positivity (Table 16.11).80
Blood Test
QuantiFERON-TB Gold In-Tube (QFT) is a blood test that is effective in the diagnosis of M.
tuberculosis infection. QFT is an in vitro ELISA test and measures cell-mediated immune response;
specifically interferon-gamma release from sensitized lymphocytes that react to PPD from M.
tuberculosis. The test is nonspecific and indirect. Patients with latent or active infections will both have a
positive QuantiFERON-TB test. Also, the test is based on measurement of cell-mediated immune
response of the patient, rather than direct detection of an antigen.81
FIGURE 16.11 Mycobacterium avium–intracellulare stained with acid fast.
Sputum Sampling
Respiratory samples should also be collected for culture. The World Health Organization recommends
collecting two sputum samples, with at least one being early morning. Early morning samples have
repeatedly shown to have improved diagnostic accuracy.82
Specimens may also be collected bronchoscopically. It should be noted that sputum is contagious and
appropriate isolation precautious should be taken.
MYCOBACTERIAL STAINING
Staining Mycobacterium samples and light microscopy can be helpful in establishing the diagnosis. The
ability to detect Mycobacterium varies with the sample type and the species of Mycobacterium present.
In order to succeed, stains must be taken up by the lipid and mycolic acid components in the
mycobacterial cell wall. Mycobacteria spp. are classically acid-fast positive and are effectively stained
with Ziehl–Neelsen acid-fast technique or by fluorochromes (e.g., auramine–rhodamine). Acid-fast stains
are examined under light microscopy and fluorochrome stains under fluorescence. Both may be quite
sensitive but are dependent on specimen type, species, thickness of smear, the laboratory technologist, and
interpreting pathologist (Figs. 16.11 and 16.12).83
TABLE 16.11 Interpretation of Tuberculin Skin Test

Induration of 5+ mm is considered positive in the Induration of 10+ mm is considered positive Induration of 15+ mm is considered
following: in the following: positive in any person
HIV patients Recent immigrants for high prevalence
Recent contact with TB areas
People with fibrotic changes on CXR Injection drug users
consistent with prior TB Employees high-risk settings
Organ transplant Children <4
Patients on immunosuppressants Infants, children, and adolescents
exposed to adults
Adapted from American Thoracic Society and CDC. Diagnostic standards and classification of tuberculosis in adults and children. This official
statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors,
July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, Sept. Am J Respir Crit Care Med
2000;161:1376–1395. http://ajrccm.atsjournals.org/cgi/ content/ful/161/4/1376
FIGURE 16.12 Auramine–rhodamine stain of mycobacterium tuberculosis. The fluorescent stain specifically identifies and
lights up acid-fast organisms.
MOLECULAR TECHNIQUES
Nucleic acid amplification using PCR can help with rapid identification of Mycobacterium. The assay
replicates the nucleic acids until they are sufficient to be detected by standard hybridization techniques.
This has become commonplace for the detection of Mycobacteria.
The commercially available detection kits have a sensitivity and specificity that approaches 100%.
There are two FDA approved tests in the United States: the enhanced amplified mycobacterium direct test
(Gen-Probe Inc., San Diego, CA) and Amplicor M. tuberculosis test (Roche Diagnostic Systems Inc.,
Branchburg, NJ).84
Some authors feel PCR-based sequencing should be considered the “gold standard” for identification
of Mycobacteria as the test can be performed rapidly and with high sensitivity.
The CDC released a consensus expert statement in late 2009 with recommendations for nucleic acid
testing in patients suspected of having M. tuberculosis. The conclusions were: all US clinicals and public
health TB programs should have access to molecular tests to aid in the diagnosis of TB and nucleic acid
testing for TB should become standard practice. They further stated that nucleic acid testing should
always be a priority with a short interval from specimen collection to testing.85
MYCOBACTERIAL CULTURES
Mycobacteria are fastidious growers. Specimens must be released from mucin, decontaminated and
concentrated to allow for growth without contamination. Most samples come from nonsterile sites and
sample contamination is common with molds, yeast, bacteria, and nontubercular mycobacteria. The
preferred culture media are Lowenstein–Jensen (egg based), Middlebrook (agar based), and additives to
suppress nonmycobacterial organisms. Incubation of media in CO2 improves yield. Many laboratories use
one liquid- and one solid-type media. Cultures are incubated for 6 weeks in liquid media and for 6 to 8
weeks in solid media before they can be officially deemed negative. Positive cultures are reported back
as soon as growth occurs.86
Broth media (BACTEC 460) contains glucose tagged with carbon-14 and antibiotic additives.
Mycobacterium metabolizes palmitic acid and releases CO2 which is detected in the BACTEC system.
The test has a fast turnaround of 3 to 4 days versus 10 to 14 days minimum for conventional cultures. The
drawbacks of this system are the need to dispose off the radiolabeled samples properly and the constant
puncturing of the tube diaphragm to sample the vial head space for 14C which can cause contamination.87
Newer BACTEC 960 Mycobacterium Growth Indicator Tubes (MGIT, Becton Dickinson
Microbiology Systems) depend on fluorescence rather than radioactivity. As Mycobacteria grow and
oxygen is depleted, the indicator fluoresces when exposed to ultraviolet light at 365 nm.
The BACTEC culture media may also be supplemented with antibiotics to suppress contaminant
growth. For example, the PANTA/F contains the antibiotics polymyxin B, amphotericin B, nalidixic acid,
trimethoprim, and azlocillin.88
RAPID MYCOBACTERIAL IDENTIFICATION TESTS

Rapid identifications tests include cell wall lipid analysis by high-pressure liquid chromatography
(HPLC), nucleic acid probes, and para-nitro-acetylamino-hydroxypropiophenone.
HPLC was first described in the late 1960s and is still widely applied for separation and purification
in a variety of industries. The objective of HPLC is to identify Mycobacteria by analysis of mycolic
acids which make up part of the cell wall. Specimens are suspended in solution, saponified, and mycolic
acids are separated by acidification and extracted. UV spectrophotometer is able to analyze
chromatographic patterns and compare these to reference standards—a variety of known Mycobacteria
species.89,90
Perhaps the most promising of diagnostic techniques is that of nucleic acid hybridization. Nucleic acid
probes that are specific to a unique sequence are labeled with radioactive iodine labeled for
chemiluminescence detection. Rapid assay kits are available for M. tuberculosis, M. avium, M.
intracellulare, and M. gordonae (Gen-Probe. Inc., San Diego, CA).91 The tests are approved only for
pulmonary specimens. Pooled analysis of results in the literature reveals a sensitivity of 85% and a
specificity of 97%.92
ELISA testing, gas chromatography, and mass spectrometry to detect tuberculostearic acid and DNA
amplification and hybridization may also be used.
FUNGAL INFECTION OF THE LUNG

Fungal lung infections are encountered frequently in pulmonary medicine, thoracic surgery, and in critical
settings due to the increased number of susceptible individuals—cancer patients, HIV, organ
transplantation, immunosuppressive therapy for systemic inflammatory diseases, prolonged corticosteroid
use, and diabetics. There is also an increased awareness and improved methods for detecting a fungal
infection. Aspergillus and Candida, in particular, are on the rise. Fungal diseases are diagnosed in much
the same way as mycobacterial diseases: by visualization, culture, molecular techniques, serology, and
antigen detection (Table 16.12).
FUNGAL CULTURES
Fungal cultures may be performed on sputum, bronchial lavage or aspirates, pleural fluid, or any tissue
samples. Fungi are slow and fastidious growers. Samples should be inoculated on several different types
of culture media to try to optimize recovery. Some fungal cultures take weeks to become positive.
Sabouraud agar medium was developed in the late 1800s with the sole purpose of culturing fungi. This
media is selective in that it facilitates the growth of fungi and inhibits the growth of bacteria. Glucose is
in high concentration (4%) and results in vigorous fermentation and subsequent acid production by any
bacteria present. The pH of the medium drops to 5.6 and inhibits all bacterial growth. The agar can be
made more selective by also directly adding antibiotics—commonly gentamicin, chloramphenicol, and
cycloheximide which will inhibit Gram-negative, Gram-positive, and saprophytic fungi, respectively.
Plates are incubated at room temperature (22° to 25°C) and at 37°C because different fungi will grow
preferentially at different temperatures. Fungi with more than one form are called dimorphic and may
grow in different morphologies at different temperatures. Coccidioides, Histoplasma, and Blastomyces
are all dimorphic fungi with yeastlike morphology at warmer temperatures and mycelial growth at room
temperature.94
TABLE 16.12 High-Risk Clinical Scenarios for Fungal Infection
Traditional Immune Suppression
Significant neutropenia
Hematologic malignancy
Transplant
Chemotherapy
Emerging-Immune Compromising Condition
Corticosteroid use
Biologic immune suppression
Cirrhosis
Renal insufficiency
COPD
Diabetes
Exposure or recent travel to endemic geographical regions
Nonresolving lung infiltrates and fever despite antibacterial antibiotics
Adenopathy with skin bone or CNS findings
Adapted from Limper AH. The changing spectrum of fungal infections in pulmonary critical care practice: Clinical approach to diagnosis. Proc
Am Thorac Soc 2010;7(3):163–168.
Diagnostic criteria for the identification of fungal species include appearance, rate of growth, colony
pigmentation, growth on specific media, and dimorphic growth. Microscopic examination and special
staining can be performed.93
MICROSCOPIC EXAMINATION AND STAINING

Microscopic examination can rapidly aid in diagnosis of some fungal infections and may be adequate for
diagnosis without a culture. A first diagnostic step should always include both plating for culture and
staining with light microscopy.
There are many diagnostic techniques and stains that may be used for specific fungi. Mucicarmine,
periodic acid–Schiff (PAS), or India ink stains are helpful in documenting carbohydrate capsules which
are present in cryptococcal organisms. Methenamine or calcofluor assist with Aspergillus, Pneumocystis,
Histoplasma, Coccidioides, and Candida. Wright Giemsa and silver staining are particularly useful for
Pneumocystis.
If the organism is present, it can be identified on the basis of morphology.
MOLECULAR TECHNIQUES FOR DETECTING FUNGUS

Antigen Detection Tests
Antigen testing relies on the detection of components of the fungal wall that shed into the bloodstream or
other body fluids the organism proliferates. Rapid PCR-based tests have been devised for all the most
common fungal infections. These tests are highly specific and have been shown to be very helpful in the
diagnosis of Pneumocystis, coccidioidomycosis, and histoplasmosis. Unfortunately these tests are not
available in all centers.93,95
Serologic Testing
Serologic testing seeks to detect host antibodies that are reacting to the fungal infection. Diagnostic
usefulness of serologic testing varies dramatically with fungal organisms. Further, many patients may
present with subclinical infections, thereby making a positive serologic test of little significance in this
situation. It is important to differentiate between resolved and clinically significant active infections.
Complicating matters, fungal infections are common in immunocompromised hosts who have altered
humoral and cellular immune responses and may invalidate serologic tests.
DIAGNOSTIC CONSIDERATIONS OF SPECIFIC FUNGI

Aspergillus
Aspergillus may be detected as colonization or an invasive pulmonary infection. Sputum or bronchoscopy
with BAL may be used to collect specimen for evaluation. BAL has inconsistent diagnostic yield, but
reportedly carries a sensitivity and specificity of 50% and 97%, respectively, with adequate sampling.
Culture and microscopy should standardly be performed. H&E stains and GMS stains show Aspergillus
with a classic 45-degree branching pattern (Figs. 16.13 and 16.14).
Serologic studies have been created for the identification of Aspergillus antigens in body fluids.
Galactomannan and beta-D-glucan are specific cellular constituents which may be detected by EIA with a
sensitivity of 71% and specificity of 89% in proven cases of invasive pulmonary aspergillosis (Table
16.13).96
Coccidioidomycosis
Coccidioidomycosis is the cause of “River Valley Fever” and is endemic to southwest United States and
may manifest with mild, nonspecific symptoms or lethal, diffuse lung disease in an immunocompromised
host.
Culture is difficult to obtain as patients with pulmonary coccidioidomycosis generally do not produce
significant sputum and shed fungi in this manner. Microscopy has low sensitivity but positive staining
reveals spherules with multiple endospores.
FIGURE 16.13 Aspergillus stained with GMS. Aspergillus has a branching patter with 45-degree angles.
FIGURE 16.14 Invasive Aspergillus stained with GMS. Aspergillus can be seen invading an artery, making this angioinvasive
aspergillosis.
Serology is the most effective means for diagnosis. EIA for detection of antigen in urine, serum, and
CSF are available. These tests are generally most effective once the patient has disseminated disease.
Immunoassays are available for the detection of IgM and IgG antibodies of Coccidioides. IgM appears
first indicating acute infection and over subsequent months IgG begins to appear in increasing levels.
Serology is useful not only in diagnosis, but it can also follow response to therapy. A drop in antibody
during treatment is an indication of good response.97
PCR is still experimental but may hold a promising future (Fig. 16.15).98
Candida
There is still expert debate as to whether candidal infections present an infection or even play a role in
the development of pneumonia. Isolation of Candida spp. in culture remains a diagnostic dilemma. In
contrast to the defined culture threshold for bacteria, there is no such standard to distinguish fungal
colonization from fungal infections.
TABLE 16.13 Diagnostic Criteria for Invasive Pulmonary Aspergillosis
Diagnosis Criteria
Proven Histopathologic or cytopathologic examination of lung tissue showing hyphae from needle aspiration or biopsy specimen with
evidence of associated tissue damage
OR
Positive culture result for Aspergillus from a sample obtained by sterile procedure from the lung
AND
Clinically or radiologically abnormal site consistent with infection
Probable Host factor
AND
Mycologic evidence (positive Aspergillus microscopy or culture from the sputum or BAL or positive antigen assay)
AND
Clinical criteria consistent with infection
Possible Host factor
AND
Clinical criteria consistent with the infection
From Kousha M, Tadi R, SoubaniAO. Pulmonary aspergillosis: A clinical review. Eur Respir Rev 2011;20(121):156–174. © European
Respiratory Society. Reproduced with permission from the European Respiratory Society.
FIGURE 16.15 Coccidiodes immitis stained with GMS. The fungal organisms vary in size. The endospore is the structure to the
left containing small circular structures and the pehrule is the folded, larger circle to the right.
Early diagnosis of an invasive candidal infection is difficult. Over the years, a “Candida score” has
been developed to try to help physicians differentiate who will benefit from treatment. The score is based
on four factors including use of TPN, surgery, multifocal Candida species colonization, and severe sepsis.
A linear and significant association between a higher “Candida score” and invasive candidiasis has been
repeatedly demonstrated for a score of 3 or higher.98,99
Candida can be isolated from sputum, BAL, TBNA, or tissue samples. Generally, Candida grows and
identifies easily. In cases with high clinical suspicion and poor growth, tissue biopsy can be very helpful.
Tissue biopsy can be fixed, embedded in paraffin, and stained with PAS or methenamine-silver stain to
detect hyphal structures consistent with Candida. Blood cultures are vital in the diagnosis of invasive
disease and estimated to be positive in 50% to 70% of cases.98
EIA detection of serum beta-D-glucan has a diagnostic sensitivity varying between 57% and 90% and
specificity of 44% to 92%. This test is used less frequently due to the very effective identification of
candida on light microscopy and culture.
Several PCR tests have also been developed and validated, but the clinical significance is still under
study (Fig. 16.16).98
FIGURE 16.16 Candida albicans stained with GMS. Candida exists in both yeast form and hyphae form which are both seen
in this section.
Histoplasmosis
Histoplasmosis is endemic in the Ohio and Mississippi River Valley. Disease manifestations vary greatly
depending on the number of inhaled organisms and a host’s immune system. Pulmonary infection is the
principal manifestation and may present with a mild pneumonitis or severe acute respiratory distress
syndrome. Dissemination may occur and is life-threatening.101
Culture is performed on Sabouraud dextrose agar and incubated at 25°C. Cultures from patients who
have disseminated disease have the highest yield.
Cytology and histopathology have limited sensitivity. In patients who are acutely ill with high level of
suspicion, a tissue biopsy should be performed and tissues stained with methenamine silver or PAS stain.
The narrow-budding yeast can be seen free in tissues and within macrophages. Routine H&E stains are of
little use.
Detection of antigen in the urine or sputum has been available since the mid-1980s. Currently, an EIA
using a peroxidase label is the standard assay. Urine is more sensitive than sputum. It should be noted,
however, that the test is only well studied in disseminated disease and sensitivity significantly declines in
acute, isolated pulmonary infections.
Studies for the detection of host antibodies are also diagnostically helpful with reported sensitivity of
greater than 90%. Unfortunately just like with any serologic test, there are some limitations. The antibody
response to histoplasma takes several weeks to be positive, the response may be negative in
immunosuppressed patients, and finally positive serology may represent an old rather than active
infection.
Immunodiffusion and CF are two tests that measure antibody response to infection and are used in the
diagnosis of Histoplasmosis. Immunodiffusion has a high specificity and qualitatively measures
precipitating antibody–antigen complexes: H precipitin band or M precipitin band. M precipitin is
present in up to 75% of patients with acute infection and all patients with chronic Histoplasmosis.
Importantly, H bands will disappear after 6 months thereby helping to differentiate in some cases between
acute and chronic infections.102
CF measures antibodies to yeast or mycelial antigen. Diagnosis of active infection requires a fourfold
rise (1:32 or greater). A low titer may be an indication of old exposure. This assay will be positive in
95% of patients who have been infected with histoplasmosis.102
Skin tests are not very helpful in diagnosis due to cross-reactions with other fungi and they interfere
with subsequent CF antibody assays and therefore should be avoided (Fig. 16.17).101
FIGURE 16.17 Gomori methenamine silver (GMS) stain. Histoplasmosis appears black and rice-like.
FIGURE 16.18 Cryptococcus neoformans stained with GMS. Each organism is black and surrounded by a thick, gelatinous
capsule.
Cryptococcus
The two principal pathogenic species of Cryptococcus are C. neoformans and C. gattii. Pulmonary
infection is the principal manifestation, but the infection may spread to other parts of the body.
Dissemination requires immunosuppression and fungal organisms may involve the central nervous system,
skin, lungs, and bone.
Just like with Histoplasmosis, conventional tests like culture and histopathology have limitations that
make diagnosis difficult. Specific probes have been generated to test tissue or liquid specimens for
specific gene sequences that are unique to Cryptococcus. PCR can be used for amplification of genomic
regions and electrophoretic analysis performed.103
Saubolle and McKellar85 described latex agglutination and EIA to detect cryptococcal polysaccharide
in the urine, serum, or CSF in patients with dissemination or meningeal disease. The tests have a high
sensitivity (95%) and specificity (98%) in the disseminated form of the disease. If the infection is limited
to the lungs, the sensitivity for serum antigen detection drops to 50% (Figs. 16.18 and 16.19).103
FIGURE 16.19 Cryptococcus neoformans stained with mucicarmine. Organisms here are highlighted by the mucicarmine
stain.
FIGURE 16.20 Blatsomycosis stained with GMS. Blastomycosis is round, with broad based budding.
Blastomycosis
Blastomycosis is another soil dwelling fungus that can cause pulmonary infection in patients who inhale
spores from the environment. In most cases, people are asymptomatic; however, in some the disease can
become invasive and disseminated.
Blastomycosis is best stained with GMS or PAS. The broad-based, budding yeast have thick refractile
walls. Blastomycosis may be isolated from sputum, BAL, FNA, or surgically resected tissues.
EIA antigen detection has good sensitivity (90%) for urine, serum, BAL fluid, and CSF. Unfortunately,
there is cross-reactivity with Histoplasma and therefore testing should be performed simultaneously for
both fungi.98
Martynowicz and Prakash104 attempted to diagnose 25 patients with known blastomycosis with
immunodiffusion and CF. Immunodiffusion was positive in 10 of 25 patients (40%), and CF was positive
in 4 of 25 patients (16%). These results again confirm that serology is not useful for the diagnosis of
blastomycosis.105 EIAs for antibody detection have much higher sensitivity and specificity but remain in
testing phase and are not clinically available (Fig. 16.20).
Mucorales
Mucormycosis is an aggressive, fatal fungal infection that targets immunocompromised hosts.
Mucormycosis is notoriously difficult to diagnose as samples often fail to grow in culture. Histology has
historically been the gold standard for diagnosis; however, this requires an expert pathologist.
Morphologic features of Mucormycosis are nonpigmented pauciseptate ribbon-like hyphae with right
angle branching.98
Detection of Mucormycosis DNA in samples by PCR sequencing was studied by Hammond et al.106
and has shown comparable diagnostic sensitivity to culture. PCR was even more likely to confirm
Mucormycosis in pathologically defined cases. Unfortunately, serologic tests for invasive disease have
not been shown to be clinically useful.98
Pneumocystis
Pneumocystis spp. is a fungal infection principally seen in immunocompromised hosts, in particular,
AIDS patients prior to the advent of HAART therapy. The organism was first described by Carlos Chagas
and Antonio Carini for whom Pneumocystis carinii was originally named.
Pneumocystis is difficult to identify because it cannot be grown in culture. The diagnosis is
established by the presence of cysts in respiratory secretions or tissue. Gomori methenamine silver,
Gram–Weigert, and toluidine-blue-O stain the wall of the cyst for viewing under light microscopy.107
FIGURE 16.21 Pneumocystis carinii stained with GMS. This organism has a round appearance with a central darkening that
looks like a nucleus, but is not.
PCR-based diagnostic assay now exists as well. PCR is able to correctly diagnose Pneumocystis in
75% of cases compared with 15% diagnostic accuracy by traditional staining. This has increased
diagnostic yield fivefold (Fig. 16.21).108
PARASITIC LUNG INFECTIONS
Pulmonary parasitic infections are uncommon in the United States. They are often found in travelers who
have visited parts of the world where parasitic infections are endemic. Immunosuppressed patients are at
highest risk.
A summary of the more common parasitic infections and presenting symptoms can be found in Table
16.14. Specific diagnostic studies will be discussed below.
HYDATIDOSIS
Hydatid disease is caused by the larvae of the Echinococcus tapeworm species. Most infections are
caused by Echinococcus granulosus. Dogs are the definitive host and harbor adult worms in the GI tract.
Eggs are shed in dog feces and may contaminate food sources, ultimately infecting humans as an
intermediate host. The eggs may travel to the lungs or to the liver where they develop into cysts.
Travel and characteristics signs on X-ray are diagnostic clues. Laboratory confirmation is more
challenging. Peripheral blood eosinophilia is present in only about half of cases. Serologic tests are
available at some reference laboratories but are poorly sensitive for isolated lung disease.
Cyst aspiration, although perhaps helpful in attaining diagnosis, should not be performed as leakage of
the cyst may precipitate an anaphylactic reaction (Fig. 16.22).109
DIROFILARIASIS
Pulmonary dirofilariasis is caused by the dog heartworm. Heart worms live in the right ventricle of the
heart and may be spread by mosquitos to humans. Worms may be swept through circulation into the
pulmonary arteries. A coin lesion is classically seen on chest x-ray.
TABLE 16.14 Comprehensive List of Parasitic Infections of the Lung
Condition Presentation Imaging Geographical Incubation Period Investigations
Distribution
Hydatidosis Compression Single or multiple Mediterranean Months to decades Blood eosinophilia
Chest pain lung cysts borders, East and uncommon
Cough Pleural effusion Central Asia, sub- Microscopy
Hemoptysis Pneumothorax Saharan Africa, Hydatid serology
Hypersensitivity Russia, China, positive in 50–
reaction South America 60%
Dirofilariasis Chest pain, cough, Coin lesion with or Pulmonary Years after exposure Blood eosinophilia
hemoptysis, without dirofilariasis uncommon
wheezing calcification reported from Biopsy usually
Fever USA, Japan, diagnostic
Malaise Australia, South
America
Paragonimiasis Pleuritic chest Pulmonary infiltrates Asia, West Africa, 1–27 mo Eggs in stool or
pain, cough, Consolidation Central and South sputum
fever, Cystic lesions America Eosinophilia in
hemoptysis Pleural effusion peripheral
Pneumothorax blood, pleural
fluid, or
bronchoalveolar
lavage
Serology
Amoebiasis Right upper Pleural effusion, Widely distributed Weeks to years after Neutrophilia
quadrant or atelectasis, exposure Serology (may be
shoulder tip Empyema negative,
pain Amoebic lung especially in
Cough abscess early disease)
Bile expectoration Hepatobronchial
fistula
Pneumonia
Ascariasis Cough, wheeze, Transient pulmonary Worldwide in areas 1–2 wks from infection to Larvae in
dyspnea, chest infiltrates where sanitation is onset of pulmonary pulmonary,
pain, fever Bacterial pneumonia poor (fecal–oral symptoms gastric
Loeffler syndrome Eosinophilic transmission) secretions
Hemoptysis pneumonia Blood eosinophilia
Pneumothorax during larval
migration
Hookworm Cough, wheeze, Transient pulmonary Widely distributed: Pulmonary manifestations Blood eosinophilia
infection dyspnea, chest infiltrates (infection usually by start within 10 days of during migration
pain, fever Eosinophilic contact of bare feet exposure, can continue Eggs in stool in
Loeffler syndrome pneumonia with fecally for more than 1 mo established
contaminated soil) infection with
adult worms
Toxocariasis Cough, dyspnea, Pulmonary infiltrates Worldwide distribution Weeks Eosinophilia
wheeze, asthma Secondary bacterial (adult worms live in common in
or bronchitis pneumonia gut of cats and blood
Hepatomegaly, dogs) Eosinophilia in
splenomegaly, BAL
ocular lesions Toxocara serology
Schistosomiasis Acute disease: Acute disease: Africa, South Acute disease: 5–7 wks Acute disease:
Katayama fever transient America, south east after exposure blood
with cough, reticulonodular Asia, China Chronic disease: years eosinophilia
dyspnea, rash, changes after exposure common
and arthralgias Chronic disease: Eggs in sputum, or
Loeffler granulomatous BAL after 6
syndrome, lung disease, wks
pneumonitis pulmonary Chronic disease:
Chronic disease: hypertension, eggs in stool
dyspnea, pulmonary AV and/or urine
pulmonary fistulae after 6 wks
hypertension Serology positive
6–12 wks
Strongyloidiasis In hyperinfection In hyperinfection Worldwide distribution Pulmonary symptoms may Blood eosinophilia
syndrome: syndrome: where sanitation is occur days after acute common
asthma, ARDS, pulmonary poor infection; hyperinfection Larvae in stool or
intra-alveolar infiltrates, miliary may occur up to duodenal
hemorrhage nodules, airspace decades after infection aspirate but not
opacities in sputum unless
ARDS in severe hyperinfection
disease, rarely Microscopy
granulomatous Culture
changes Serology
Filariasis Fever, malaise, Mediastinal No microfilariae in
weight loss lymphadenopathy peripheral
blood
Filarial serology
(IgG)
Reproduced from Kunst H, M ack D, Kon OM , et al. Parasitic infections of the lung: a guide for the respiratory physician. Thorax 2011;66:528–536. With permission from
BM J Publishing Group Ltd.
Unfortunately there are no reliable serologic tests available. In addition, eosinophilia is only present in
a small number of patients. Most cases will be diagnosed after resection of the lesion (Fig. 16.23).109
PARAGONIMIASIS
Fluke worms may infect humans though ingestion of sea food that is raw or lightly cooked.
Paragonimiasis is endemic to Korea, Japan, China, and other parts of Southeast Asia. Generally patients
will describe a history of travel to these regions and a history of eating raw crayfish or crab.
The fluke worm larvae migrate to lung parenchyma. A CT scan may be diagnostic if intracystic worms
can be seen; however, Paragonimiasis is often misdiagnosed as tuberculosis or malignancy.
Peripheral eosinophilia is present during acute infection and IgE may be elevated. In addition, elevated
eosinophil counts will be appreciated in pleural effusions or BALs. Operculated eggs isolated from
sputum or BAL is diagnostic.
FIGURE 16.22 A protoscolex is seen from an excised hydatid cyst, in this case of pulmonary echinococcosis. Note the
characteristic central hooklets, which are refractile by bright field microscopy (stained with hematoxylin and eosin, original
magnification 400×).
ELISA testing can detect specific IgM and IgG antibodies (Fig. 16.24).109
AMOEBIASIS
Entamoeba histolytica is a protozoan that is found worldwide and causes invasive amoebiasis. E.
histolytica is seen most commonly in regions with poor sanitation as the parasite which lives in the
human large intestine is transmitted by fecal–oral route. Pulmonary involvement occurs secondarily as a
complication of amoebic liver disease.
Routine hematologic tests are not useful in diagnosis of E. histolytica. Microscopic stool examination
for trophozoites is diagnostic. The parasite may also be cultured from stool on Robinson medium.
Unfortunately only about one-third of patients have the organism present in their stool. When an abscess is
drained, it has a characteristic appearance—thick, opaque, and reddish resembling anchovy paste. Pus
may also be examined microscopically for trophozoites.
FIGURE 16.23 Degenerating segments of an adult nematode are seen in a background of granulomatous inflammation, in this
case of pulmonary dirofilariasis (stained with hematoxylin and eosin, original magnification 200×).
FIGURE 16.24 A yellow to brown, ovoid but asymmetrical egg, with a thick shell and one slightly flattened end is seen in a
background of granulomatous inflammation, in this case of pleuropulmonary paragonimiasis (stained with periodic acid—Schiff,
original magnification 400×).
Nonpathogenic species of Entamoeba can also be isolated from stool and are morphologically
indistinguishable from E. histolytica. Therefore, specific identification of the parasite is necessary to
guide treatment.
EIA antibody and antigen detection tests are commercially available. IgM may be detected as early as
1 week after infection and testing carries a sensitivity of 95%. Antibody detection is most useful in
patients with extraintestinal disease. If original sample is negative, and suspicion remains, a second
serum sample should be assessed 7 to 10 days later. Antigen detection tests target galactose-inhibitable
adherence protein (GIAP) which is unique to E. histolytica.
Molecular analysis by PCR is the study of choice to distinguish between E. histolytica which is a
pathogenic species from nonpathogenic (Fig. 16.25).111
FIGURE 16.25 Intra-alveolar amebic trophozoites are seen among numerous inflammatory cells, in this autopsy case of
pulmonary amoebiasis. Note the abundant bubbly cytoplasm with central round nucleus and prominent central nucleolus (stained
with hematoxylin and eosin, original magnification 630×).
PULMONARY MALARIA (PLASMODIUM)

Malaria is a serious disease spread to humans through infected mosquitoes. Mild forms of malaria may
manifest with flu-like symptoms, while severe cases may develop jaundice, hepatomegaly, cerebral
symptoms, and acute respiratory distress syndrome. There are approximately 1,500 to 2,000 cases
annually in the United States according to the CDC. There are four Plasmodium spp. that infect humans:
Plasmodium falciparum, P. malariae, P. vivax, and P. ovale.
Rapid and accurate diagnosis is essential to treat affected individuals and prevent transmission of
disease.
Microscopic examination of thick and thin peripheral blood smears stained with Giemsa reveal the
distinctive appearance of the parasite. This remains the gold standard of laboratory confirmation of
diagnosis.111
In 2007, the first rapid diagnostic test for malaria was approved by the FDA for use in the United
States. This immunochromatography test is in dipstick format and can provide results in 15 minutes. The
kits detect unique antigens derived from Plasmodium. It is recommended that positive tests be followed
up with microscopy for confirmation.112
Plasmodium nucleic acids may be detected using PCR amplification and electrophoresis. Due to the
time it takes to complete the examination, generally this is used as a confirmatory test after the diagnosis
has been made, rather that initial testing.113
SCHISTOSOMIASIS
Schistosomiasis is one of the most prevalent parasitic infections, infecting an estimated 200 million
people worldwide. The parasitic eggs are excreted in urine or feces and humans are infected by cercariae
which directly penetrate the skin. The flukes generally live in target venous plexuses, but to get there must
pass through the heart and lungs. Chronic disease states present with portal hypertension and
hepatomegaly which may lead to diversion of eggs into pulmonary vasculature resulting in obliterative
arteritis.
Blood tests generally reveal eosinophilia. In addition, eggs may be found in feces, urine, sputum, or
BAL. Terminal urine samples maximize sensitivity of the test.109
Serologic diagnosis relies on detecting antibodies or circulating antigens. Unfortunately patients with
Schistosomiasis have a prolonged seronegative window; therefore, early studies may return negative. IgG
antibodies to egg antigens become detectable 7 to 12 weeks following infection. IgG remains positive for
years and is therefore not particularly helpful in measuring response to treatment.109
Indirect hemagglutinin assays to worm antigens and ELISA to soluble egg antigen have proved
repeatedly to have high sensitivity for the diagnosis of Schistosomiasis mansoni. Commercially available
kits are also offered for the detection of cercarial antigen and adult worm antigen, but these are less
sensitive.114
STRONGYLOIDIASIS
Strongyloides is prevalent in tropical and subtropical regions including the southeastern United States.
The filariform larvae penetrate skin directly and enter blood vessels. The larvae then migrate into alveoli
and may ascend into the trachea and be swallowed into the intestinal track. In the intestine, larvae mature
into adult worms and reproduce. Many patients will have few manifestations of disease, but
immunosuppressed patients can develop severe infections manifesting with ARDS, intra-alveolar
hemorrhage.
Blood eosinophilia is common. Definitive diagnosis is made by finding the larvae in stool, body
fluids, or tissue biopsies. The larvae may be identified on microscopy and may also be cultured.
Antibody assays are available and have a sensitivity of 90%; however, immunocompromised patients
may not mount a great response and therefore have a false negative result.109
PULMONARY FILARIASIS
Tropical pulmonary eosinophilia is a hypersensitivity reaction to filarial parasites that are found in
Southeast Asia, India, China, and Africa. These organisms are recognized for causing elephantiasis due to
blockage of lymphatic outflow.
Blood eosinophilia is common. BAL will also have elevated eosinophils. Diagnosis is based on the
presence of filarial-specific IgE and IgG antibodies.109
PULMONARY ASCARIASIS
Ascariasis is a round worm infection commonly found in areas of poor sanitation with food and water
contamination. Larvae invade lung tissues during the second week of infection and cause Loeffler
syndrome manifesting with cough, wheezing, dyspnea, fever, and hemoptysis.
Eosinophilia is present in the blood and respiratory secretions. Diagnosis is made by finding eggs
within stool on microscopy. There is no serologic testing available.109
VIRAL INFECTIONS OF THE LUNG

Respiratory viral infections of the upper or lower respiratory tract are among the most common illnesses
in humans. In most cases, the infection is self-limited. The most common causes are influenza,
parainfluenza, adenoviruses, and respiratory syncytial viruses (RSVs).
In patients who are immunocompromised, viral infections may be life-threatening. In addition to the
aforementioned viruses, immunocompromised hosts are also more susceptible to picornavirus, RSV,
CMV, herpesvirus, varicella zoster virus (VZV), and Epstein–Barr virus (EBV).
INFLUENZA
Influenza virus is an RNA virus from the family Orthomyxoviridae. The virus is spread from person to
person through respiratory droplets. Uncomplicated influenza is characterized by fever, myalgias,
headache, cough, sore throat, and rhinitis and will resolve on its own. Influenza can have secondary
complications including pneumonia, otitis media, and sinus infections or it can have a particularly virulent
course manifesting with respiratory failure/ARDS, encephalopathy, myelitis, myocarditis, and Reye
syndrome. There were 142 deaths associated with the virus in the 2014–2015 flu season.
Conventional viral cell culture may be performed on a throat swab or collection of respiratory sample.
Results take anywhere from 3 to 10 days. This is the gold standard by which all other tests are measured.
Rapid cell culture shortens the time to detection to around 1 to 3 days. This method uses single or mixed
cell lines and enhances infectivity of cells by centrifugation. The presence of viruses may be detected
more quickly with maintained, high sensitivity.
Rapid influenza detection tests (RIDTs) are directed against influenza A or B viral nucleoprotein
antigens. There are a number of commercially available kits and both the CDC and WHO endorse the use
of RIDT to assist in the diagnosis of influenza. RIDT take less than 30 minutes and may be performed on
swab or aspirate. It is a qualitative test with sensitivity ranging from 60% to 90% and specificity 65% to
99%. The predictive value of the test is most useful during peak influenza season. Other times of the year,
confirmatory tests are important.
Immunofluorescence antibody staining can be done on swabs, washes, or aspirates. Either direct
fluorescent antibody staining or immunofluorescent antibody staining can be performed. IFA provides
higher sensitivity approaching 100%.115
PARAINFLUENZA
Parainfluenza has types 1 to 4 and manifests with bronchiolitis, croup, and pneumonia in children and the
elderly.
PCR is an adequate for the detection of parainfluenza virus and proves especially helpful in
immunocompromised patients. PCR has a sensitivity of 100% and specificity of 95% to 98%. Rapid and
multiplex real time PCR assay for detection of the four serotypes are available.116
ADENOVIRUS
Adenovirus is a DNA virus that is classified according to major capsid antigens. These viruses are also
spread by respiratory secretions. Infection is asymptomatic in most immunocompetent hosts. In some,
fever, sore throat, and rhinorrhea may occur.
PCR is a highly specific and sensitive test for detecting adenovirus DNA. Quantitative real-time PCR
is used commonly for the detection of the virus in immunocompromised patients and also in assessing
response to treatment. The test is most studied and commonly used for adenovirus type 4.116
RESPIRATORY SYNCYTIAL VIRUS

RSV is an important cause of infection and death in transplant patients. Most information regarding RSV
has emerged from the hematopoietic stem cell recipient population. In this group of patients, infection
with RSV progresses to pneumonia 80% and overall mortality is 15%. Other groups at increased risk
include the elderly, COPD, asthma, cardiac disease, and cancer patients. High suspicion should be
maintained and antiviral therapy should be initiated immediately.
Traditionally, diagnosis has been by culture. This remains the standard by which sensitivity and
specificity of other tests is compared. Unfortunately, this does not capture all patients and takes time for
results.
Antigen detection in respiratory secretions with IFA or EIA methods can be lifesaving when positive.
Unfortunately, the sensitivity of this test decreases as a patient ages because adults secrete fewer plaque
forming units per mL in respiratory secretions. EIA antibody testing against F and G glycoproteins are
positive in approximately 85% of adults who are culture positive.117
RT-PCR using nucleic acid probes specific to N gene can help to most quickly amplify and identify
RSV subgroup A or B. This has been studied extensively in children, but reports are scarce in adults. This
carries the highest sensitivity (97%) of molecular and serologic testing.117,118
HERPESVIRUSES
The family of herpesviruses is unique in that many people carry the virus in its latent form. The family
includes CMV, EBV virus, VZV, Herpes simplex 1 and 2, and human herpesviruses 6 to 8.
Viruses may remain dormant in a host for years. Each virus subtype hibernates in a particular area
within the body: EBV within lymphocytes, VSV and HSV in nerve ganglia. In the immunocompromised
state, the virus may become reactivated and lead to overwhelming disease.
Transplant patients are at particular risk of infection and early diagnosis and treatment is of paramount
importance. Improved diagnostic techniques over the years and more potent antiviral medications for
prophylaxis and treatment have helped to reduce morbidity and mortality.119
HUMAN HERPESVIRUS
Among the numerous human herpesvirus (HHV) serotypes, 6 and 8 are the most important to know.
HHV6 is a member of the Roseolovirus genus. Disease usually manifests as a febrile illness that
affects children. Transplant patients are also at risk, but infection occurs in less than 1% of patients.
Symptoms include pneumonitis, encephalitis, colitis, or hepatitis. Diagnosis is made by direct detection of
viral nucleic acids by PCR amplification and electrophoresis. Due to the ubiquitous nature of the virus,
most serologic tests are of limited use.120
HHV8 is also known as Kaposi sarcoma–associated herpesvirus. In healthy adults an HHV8 infection
is mild with no obvious signs of disease. In transplant patients the prevalence of Kaposi sarcoma is about
0.5%. Diagnosis is made by IFA and EIA to detect antibodies directed against viral proteins.119
HERPES SIMPLEX
Herpes simplex virus (HSV) 1 and 2 can cause a number of diseases in humans ranging from
mucocutaneous ulcers to ARDS. The initiation of appropriate therapy depends on prompt and accurate
diagnosis.
Light microscopy can be used to make the diagnosis of HSV. Mucocutaneous scrapings are stained with
Giemsa, methylene blue, or Wright stain and are examined for HSV cytopathic effects. This method of
testing relies on proper sampling. Unfortunately microscopy lacks the ability to differentiate between
HSV 1 and 2 and can often look similar to other members of Herpesvirus family.
Cell culture is used as an adjunct and like microscopy is heavily dependent on adequate sampling.
Traditionally, cultures took too long to be helpful in patients who needed acute treatment. Rapid culture
with enzyme-linked virus inducible systems has improved turnaround time with good performance.
Direct immunofluorescence assays may be performed directly on specimens and has 100% specificity.
The FDA has approved PCR nucleic acid amplification for HSV 1 and 2 isolated from oral or genital
lesions. Many of the commercially available kits are highly sensitive, but lack the ability to differentiate
between HSV 1 and 2. There are no approved assays presently for testing CSF, blood, or other secretions.
Western blotting assays are useful in differentiating between HSV 1 and 2 as each has a specific
antigen banding pattern. Unfortunately this method is time consuming and expensive.
Newer methods employ ELISA for the specific detection of gG-1 and gG-2 proteins. Sensitivity and
specificity approaches 100% and the test takes only 2 to 3 hours. However, most laboratories do not have
the specialized equipment to run this assay.
Rapid ELISA is available for point-of-care usage and can provide result in as little as 6 minutes.
Specificity is high, but the test lacks sensitivity due to subjective visual interpretation of test results.121
CYTOMEGALOVIRUS
CMV, also known as HHV5, is another member of the Herpesvirus family. In most developed countries
more than half the population has been infected with the virus. Transmission requires contact with the
virus via bodily secretions, blood, organ transplantation, or pregnancy. Infections are generally
asymptomatic in immunocompetent patients; however, it can cause significant morbidity and mortality in
immunocompromised hosts. In transplant patients, infection may result from contact with an infected
person, reactivation of a latent infection, or transmission from the donor.122
Diagnostic studies include culture (which may take up to weeks), a rapid culture shell assay,
microscopy from a tissue biopsy or cytology, and serologic studies or molecular assays. Microscopy
characteristically shows intranuclear inclusions described as an “owl’s eye.” Immunostaining and ISH
can be performed on these samples and slides as well.
Nucleic acid amplification has evolved into the commonly used diagnostic test. Amplification helps
with diagnosis, helps to monitor the effectiveness of treatment, and can prognosticate relapse.
The challenge as with many of these infections lies in proving the infection is active and does not
represent prior exposure.122
EPSTEIN–BARR VIRUS
EBV is ubiquitous, with 90% of the world’s population being infected with the virus. The virus causes
infectious mononucleosis, seen most commonly in younger patients, and manifesting with fever,
lymphadenopathy, and pharyngitis. EBV is also associated with several malignancies including non-
Hodgkin lymphoma, posttransplantation lymphoproliferative disorder (PTLD), nasopharyngeal
carcinomas, and gastric cancers. PTLD can affect transplanted lungs, thereby making this virus another
important pathogen to consider for thoracic surgeons.123
Serology is most useful in the diagnosis of mononucleosis-related EBV infection. The most widely
used assay is called the Monospot (heterophile antibody) test and was introduced in 1932. Indirect
fluorescent antibody tests and antibody EIA are also used. Antibody class and titers will help to
determine if the infection is acute or remote. Early in infection, serum contains viral capsid antigen
(VCA) IgG and VCA IgM. Over time, IgM decreases, IgG antibodies persist, and EBV nuclear antigen
increases.
ISH can be used to detect EBV RNA within infected cells. EBER1 and EBER2 are the most abundant
viral transcripts in infected cells thereby making them excellent markers of latent infection. In fact, ISH of
biopsied tissue is the gold standard for determining whether cancers are EBV related.
Western blot, flow cytometry, and ELISA can all be used to detect specific viral proteins.
Finally, PCR amplification allows not only for diagnosis of infection but also for viral load
measurement.124
VARICELLA ZOSTER VIRUS

VZV is renowned for causing chicken pox in children and may be reactivated later in life as shingles.
VZV rarely involves the lung in immunocompetent patients; however, in VZV pneumonia in
immunocompromised patients can be life-threatening. This may be caused by primary infection or
reactivation of VZV.
Diagnosis of VZV can be made on clinical presentation alone. Cultures take weeks for a positive
result. Consequently molecular and serologic tests have been developed to assist in a more timely
diagnosis.
Antibody titers and class (IgM and IgG) help to determine acute infection versus prior exposure versus
immunity postvaccination.
Immunofluorescent straining with monoclonal antibodies and PCR assays have both been studied
extensively for the diagnosis of VZV. Immunofluorescent staining can be completed efficiently. While
PCR has higher overall sensitivity, cost and complexity are higher, making it a less desirable test. Wilson
et al.125 directly compared immunofluorescent staining, culture, and PCR for sensitivity, specificity,
positive predictive value, negative predictive value, ease of study, and cost. They concluded that
immunofluorescent staining should be the test of choice with the addition of PCR only when staining was
negative with a maintained high clinical suspicion.
New ELISA assays to VZV IgG have been developed to detect antibody response after vaccination.126
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SUGGESTED READINGS
Churg AM, Myers JL, Tazelar HD, et al. Thurlbeck’s Pathology of the Lung. 3rd ed. New York: Thieme; 2005.
Connolly JL, Schnitt SJ, Wang H, et al. Role of the Surgical Pathologist in the Diagnosis and Management of the Cancer Patient. 6th
ed. Hamilton, Ontario: Holland-Frei Cancer Medicine; 2003.
Corrin B. Pathology of the Lungs. London: Churchill Livingstone; 2000.
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Dabbs DJ, Thompson LDR. Diagnostic Immunohistochemisty Elsevier. 2014.
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Methods. 20th ed. Philadelphia, PA: Saunders; 2001:1273.
Katzenstein A-LA, ed. Katzenstein and Askin’s Surgical Pathology of Non-Neoplastic Lung Disease. 4th ed. Vol 13. Philadelphia, PA:
Saunders; 2006.
Koss LG, Melamed MR, eds. Koss’ Diagnostic Cytology and Its Histopathologic Bases. 5th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2005.
Murray PR, et al. Manual of Clinical Microbiology. 9th ed. Washington, DC: ASM Press; 2007.
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PA: Lippincott Williams & Wilkins; 2006.
17
Molecular Diagnostic Studies and Genomic
Studies in Pulmonary Disease
Jacob A. Klapper ■ Chadrick E. Denlinger
INTRODUCTION
In the last 10 years the impact of advances in molecular diagnostic techniques has led to a rapid evolution
in our understanding of the genomics, proteomics, and epigenetics of almost all malignancies, including
lung cancer. For example, in the last few years there has been a 100-fold reduction in the cost of
sequencing the complete genome and exome of a tumor (previous cost $100,000/tumor).1 These advances
in technology coupled with diminished cost have translated into the quick ascent from identifying the
original somatic activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase
domain to the treatment of many thousands of patients with the EGFR tyrosine kinase inhibitors (TKIs).2,3
As both the most common cause of cancer death in the United States and a worldwide scourge that is
responsible for 1.38 million deaths a year, the impetus for formulating a better understanding of the
molecular framework of lung cancer is imperative.4 The complexities of this task are enormous as
investigators have determined that lung cancers can have up to 200 nonsynchronous mutations per tumor.
This is far more than other common malignancies and reflects the many ways that environmental
exposures and genetic susceptibility can lead to cellular immortality. As an example of these
complexities, scientists have shown that just because different histologies share similar mutational
profiles it does not mean that targeted therapies will work equally.5
While the primary focus of this chapter is to describe the various methods of molecular diagnosis, it is
vital to understand the treatment implications of accurate mutational analysis. There are currently six
targeted therapies that are being used for patients with locally advanced, recurrent, or metastatic non-
small cell lung cancer (NSCLC), and this number is expected to rise rapidly. For instance, erlotinib, an
EGFR TKI, has demonstrated significant improvements in progression-free survival and response rate.6
Meanwhile, in what was a first of its kind, the BATTLE trial adaptively randomized patients to targeted
therapies based on relevant biomarkers obtained from tissue biopsies.7 Studies of this kind represent the
future of oncologic care and consequently it is imperative that the thoracic surgical oncologist understand
the molecular biology of this disease.
Because tissue can be difficult to procure and typically involves invasive procedures, it seems
inevitable that molecular diagnostic studies will eventually include a detailed evaluation of alternative
specimens. For instance, whereas historical studies examining sputum as a method for screening for lung
cancer were not deemed beneficial, new methods of enhanced analysis may revitalize interest in using
sputum as a screening tool.8–10 Along these same lines, the search for biomarkers indicating the presence
of lung cancer have led many to evaluate blood and plasma. The development and application of
technologies, such as microarrays, have greatly enhanced our ability to understand the cancer genome and
to potentially, in the future, establish biomarkers with true clinical import.11,12
In addition to enhanced screening, molecular studies can help us clarify a patient’s histologic
diagnosis. For example, patterns of gene expression are emblematic of certain histologies and can help a
pathologist differentiate a metastatic colonic adenocarcinoma from a lung primary. Of course, as
mentioned previously, the most profound implications of these studies are in selecting therapies for
patients. As the options for small molecule therapy continue to expand, one can easily conceive of a future
where cancer becomes a chronic disease in which resistant lesions are biopsied, analyzed for new
mutations, and treatments adjusted accordingly. Consequently, molecular studies and the mutations within
tumors will invariably be incorporated into the workup and current staging system and may one day assist
in stratifying patients within the various stages (i.e., high risk Stage I vs. low risk).13
There are several key elements to this chapter and no discussion of these complex molecular studies
can proceed without an explanation of some basic biologic terms. Likewise, it is advisable to provide a
brief overview of cell signaling and the cell cycle as mutations at various stages from the cell membrane
to the nucleus impact a cell’s mortality. From a more clinically relevant standpoint, it is also important to
review the various procedures for collecting tissue and their reliability in terms of subsequent genomic
analysis. Next, it is essential to provide a broad overview of the myriad of technologic breakthroughs that
have accelerated our understanding of cancer biology. Finally, the chapter will summarize the current
recommendations for molecular testing, what more “personalized” oncology will look like, and what
challenges lay ahead in this new era of molecular medicine.
GENOMICS, EPIGENETICS, AND PROTEOMICS

Genomics is the study of the structure and function of the genome. The discovery of mutations and their
implications in cellular development define this discipline of molecular biology. Germline mutations are
inherited while somatic mutations occur in any nongerm cell of the body after conception and it is these
that are commonly involved in tumor genesis. Two primary examples of somatic mutations include
missense and nonsense mutations. Missense mutations involve the substitution of a single nucleotide
which results in a change in the amino acid that is produced. A nonsense mutation meanwhile is a single
nucleotide substitution that results in the production of a stop codon which results in the production of a
truncated protein. Somatic mutations have been discovered that affect numerous oncogenes such as EGFR
and tumor suppressor genes (TSGs) such as p53.
As a byproduct of in-depth mutational analysis, scientists are realizing an ever-growing appreciation
for genetic heterogeneity. We have long known and appreciated that tumors of similar tissue types behave
differently between patients (interpatient heterogeneity), but now mutational analysis has shown that one
individual’s tumor can be populated by multiple distinct subclones each with their own potential
predilection for aggressive behavior (intratumoral heterogeneity). Some of these subclones will
metastasize and predominate in certain metastatic sites (intermetastatic heterogeneity). While initially
susceptible to targeted therapy, additional mutations of cells within these metastatic sites will confer
resistance (intrametastatic heterogeneity).1,14–16
Epigenetics, unlike genomics, is the study of the changes in gene expression that occur, not as a result
of a direct alteration in the gene’s DNA sequence but rather secondary to molecular events that impact that
gene’s expression. Much of the focus in epigenetics and cancer has centered on changes in the promoter
region of the gene. Promoters are the area within or near the gene that regulates its expression.
Investigators have repeatedly noted that methylation of specific gene promoter regions has the effect of
silencing certain genes. These changes profoundly influence cellular processes such as cell cycle
regulation, apoptosis, invasion, epithelial mesenchymal transition, and cell cycle regulation.
Proteomics, meanwhile, focuses on the analysis of tumor protein expression profiles. A better
understanding of protein expression is valuable in that it ultimately reflects a tumor’s phenotype and
provides the potential for additional targeted therapies. Recent advances in technologies related to
proteomics, specifically mass spectrometry, have broadened our understanding of not only this field but
specifically how proteomics can be applied to lung cancer.17
CELL SIGNALING
Molecular analysis of human cancer over the last 20 years has vastly improved our understanding of the
cell signaling pathways involved in lung cancer. The impetus for proliferation and other functions begins
at the level of the cell surface. A primary example of cell signaling in lung cancer begins with EGFR
which is a member of the ErbB/HER family of ligand-activated receptor tyrosine kinases (RTKs) that
extend across cell membranes. Other RTKs include AXL, MET, IGF-1, HER2. ALK, and ROS1. In the
normal cell, ligands binding to the extracellular domain of EGFR (or another receptor) results in the
phosphorylation of the tyrosine residues on the cytoplasmic side of the receptor which act as docking sites
for “adaptor” proteins. These adaptors then recruit “effector” proteins such as H-Ras, N-Ras, and the
well-known KRAS. When these proteins are bound by GTP, Ras interacts with and initiates a cascade of
downstream signaling that includes the RAF-MEK-ERK (also known as MAPK/ERK) and PI3K-AKT
pathways. In normal cells, each upstream kinase phosphorylates tyrosine residues on its downstream
targets. This results in a conformation change in protein structure and initiation of enzymatic activity. In
mutant cells, however, point mutations within individual proteins in the signaling cascade can result in
constitutive activation that is no longer dependent upon upstream activation events. Given that the
eventual target of these pathways is the nucleus, uninhibited enzymatic activation has broad implications
in cell replication and proliferation.18–20
DRIVER MUTATIONS
Driver mutations are specific oncogenes that are recognized with increasing frequency among lung
cancers (Fig. 17.1). An understanding of their role in cell signaling has evolved in the past decade and
their importance is expected to escalate rapidly as more targeted agents become available. Mutations in
many of the elements involved in cell signaling have been implicated in lung cancer. KRAS was the first
and is the most common molecular mutation recognized in NSCLC (found in 30% of adenocarcinomas and
5% of squamous cell carcinomas). In normal cells it remains bound and inactive until extracellular stimuli
induce the activated GTP-bound form. However, mutant forms of KRAS are insensitive to GTP-
dependent activation and thus KRAS continues to stimulate the downstream effectors RAF and PI(3)K.18
Likewise, mutations in the EGFR receptor result in alterations in the ATP-binding site of the cytoplasmic
kinase domain. The result is unabated downstream signaling via the aforementioned pathways. Attempts
to suppress this activity have led to the development of the TKIs, erlotinib and gefitinib, which
competitively inhibit the binding of ATP to the kinase domain.21–23 EGFR, like KRAS, is commonly seen
in patients with adenocarcinoma. Less common than the two previous mutations is the genetic alteration in
the ALK receptor which is found in 5% of patients with NSCLC. A result of a gene rearrangement that
produces fusion of the 5′ end of the echinoderm microtubule-associated protein-like gene (EML4) with
the 3′ end of the ALK gene, this transmembrane RTK is a member of the insulin receptor family which
transduces growth signals through the downstream activation of STAT3 leading to the MAPK–ERK
activation pathway (Fig. 17.2).24
Associations between certain demographic sectors and specific driver mutations have been made. For
example, EGFR mutations are most common among women, Asians, and nonsmokers.25 In contrast, KRAS
mutations occur most commonly among patients with a smoking history and ALK rearrangements are
associated with younger age, never smoking status, and the presence of liver metastases.26
Additional less common “driver” mutations in lung cancer involve the genes encoding HER2,
phosphatidylinositol 3-kinases (PI3KCA), AKT, BRAF, and MAP2K1. HER2, like EGFR is an RTK that
is mutated in 2% of patients with NSCLC again occurring predominantly in women, nonsmokers, Asians
with adenocarcinoma.27 Interestingly, HER2 mutations are not present in tumors harboring EGFR or
KRAS mutations. Slightly more common at 1% to 3% are mutations in BRAF, a gene whose product links
Ras GTPases to downstream proteins of the MAPK family. PI3KCA is a member of a family of lipid
kinases that regenerate phosphatidylinositol-3-phosphate. Mutations in this gene result in a gain of
function and activation of the protein kinase B (also known as AKT) signaling pathway in the absence of
growth factors. The AKT gene, meanwhile, encodes protein kinase B which when mutated results in
unchecked protein kinase B activation. Both PI3KCA and AKT are very rare in lung cancer, each with a
1% prevalence. While in 95% of cases driver mutations are mutually exclusive, PIK3CA mutations have
also been identified in patients who possess EGFR or KRAS mutations. Identification of concomitant
PIK3CA mutations in patients being considered for EGFR TKIs has clinical bearing as these individuals
tend to have an innate resistance to targeted therapy.28–31
FIGURE 17.1 Driver mutation progress.
FIGURE 17.2 Cell signaling.
FIGURE 17.3 Progression from the G1 phase to DNA synthesis in the S phase is dependent upon the activation of Cyclin D
and the cyclin-dependent kinases (Cdk). Mitogenic signals such as increased Ras stimulate Cdks to drive progression from the
G1 to S phase. Meanwhile, tumor suppressor genes (Rb, p53, and CDK2A) downregulate Cdk activity thus halting progression of
the cell cycle.
Unfortunately despite impressive initial response rates with TKIs, like erlotinib and gefitinib,
resistance to these medications inevitably occurs due to the development of additional mutations. Our
understanding of the methods by which cancers overcome these targeted therapies has grown
exponentially in recent years. For instance, identification of the T790M (point mutation at codon 790,
threonine [T] is replaced with methionine [M]) mutation within the EGFR gene of resistant cell lines
leads to the expression of a receptor whose kinase domain has enhanced affinity for ATP at the exclusion
of the drug designed to target it.32 Alternatively, in other individuals, resistance is the result of the cell’s
increased activation of other RTKs such as HER2 or second messengers such as MET. Engelman33 was
the first to show that amplification of MET in patients with gefitinib resistant lung cancers led to the
subsequent phosphorylation of ERBB3 which then leads to activation of the PI3K/AKT pathway. Most
recently, investigators have identified an upregulation in the protein nuclear factor kappa B (NFκB) in
patients with EGFR-mutant NSCLC that have become unresponsive to TKI treatment.34,35
CELL CYCLE
The consequences of mutant cell signaling are realized at the level of the nucleus where the increased
activity of these pathways has direct impact on nuclear transcription and proliferation by promoting the
cell’s passage through the cell cycle. For instance, there is now substantial evidence demonstrating how
increased activity of the Ras-Ref-MEK and PI3K pathways promotes passage through the G1/S transition.
Briefly, there are four components to the cell cycle: M phase, S phase, G1 phase, and G2 phase. The G1
phase separates nuclear division (M phase) from DNA synthesis (S phase) while the G2 phase is a gap
between the S and M phases. Cell signaling interactions at G1 are of particular interest to investigators as
a number of proteins are active in monitoring progress through to the S phase, the most prominent being
the cyclin-dependent kinases (cdks).18 It is these proteins that upstream effectors like Ras-Ref-MEK target
and empower to drive the G1/S transition.36,37 In normal cells, efforts to halt the cell’s progression to
DNA synthesis are controlled by such notable TSGs as Rb and p53.38 Perhaps less well known but of
equal importance are the tumor suppressors, p16Ink4a (also known as CDK2A) and p14ARF. The former
of these TSGs protects the cell against hyperactive Ras-ERK activity by blocking Cdk4/6 and thereby
inducing cell quiescence or senescence (Fig. 17.3).39
Changes in the expression of TSGs like CDK2A and p14ARF have been directly linked, not to
mutations, but rather to epigenetic alterations that are exemplified by methylation. In the case of these
TSGs, hypermethylation, or the addition of a methyl group to DNA at the 5-carbon of the cytosine
pyrimidine ring results in the silencing of these genes.40 It has been proposed that the effects of
hypermethylation are mediated either directly, by the repression of transcription, or by recruiting binding
proteins that then downregulate or silence the TSGs.41,42 Hypermethylation of CDKN2A is widely
recognized in lung cancer occurring in 67% of adenocarcinomas and 70% of squamous. The
consequences of an inactivated CDKN2A is that p16 is no longer transcribed which results in a lack of
inhibition of the kinases CDK4 and 6. Unabated, these proteins then bind and phosphorylate the RB TSG
and cell cycle progression (CCP) proceeds.43–45
MOLECULAR DIAGNOSTIC TECHNIQUES

As thoracic surgeons, our services are commonly called upon to operate for cure or to establish a
diagnosis. Up until recently, biopsies served the purpose of distinguishing cancer from a benign process,
but this is no longer the case as yields from various tissue acquisition techniques must be considered
when one wants to perform molecular testing. Recently, the Lung Cancer Mutation Consortium (LCMC)
reported that when needle biopsies of lung cancers were performed with the intention of analyzing 10
specific driver genes, the tissue obtained was inadequate in 25% to 35% of the cases while surgical
biopsies were inadequate in 5% of cases.46 Thus, as the number of assays necessary for complete
molecular assessment of a tumor increases, adequacy of the tissue sample will likely become even more
critical. In addition, surgeons must bear in mind that successful analysis is predicated, not only on the
acquisition of viable tumor, but also on handling and preserving tissue correctly. Finally, as the resistance
to targeted therapies inevitably develops in patients, the surgeon should expect that in the future he or she
may be asked to perform additional procedures for further study.
As part of selecting the appropriate technique for molecular analysis, it is important to understand the
difference between “screening” and “targeting” methods. For instance, EGFR mutations that are
associated with sensitivity to TKI therapy are found in exons 18 to 21. However, two types of mutations,
short in-frame deletions in exon 19 and a specific exon 21 point mutation, make up 90% of all activating
EGFR mutations. Available screening modalities are designed to detect all known and novel mutations
between exons 18 and 21 whereas targeted techniques detect only known or common mutations. The
advantages of screening are the aforementioned while the disadvantages tend to be lower sensitivity and
the need for technical expertise in accurately executing these labor intensive technologies. In contrast, the
appeal of targeted methods is that they tend to be less time-consuming with improved sensitivity and
technologies that are more widely available.47,48
With DNA sequencing, the mutation must be present in approximately 20% of all DNA in a sample to
be detected.49 Attempts to improve upon the sensitivity and specificity of sequencing includes such
techniques as high resolution melting analysis (HRMA) which enables the detection of mutant genes at
very low levels.50 Other approaches utilize technologies such as macrodissection and laser capture
microdissection for DNA extraction but these are again labor intensive and very time consuming.
Recently, investigators have developed a multiplexed PCR-based assay (SNaPshot) which can
simultaneously identify more than 50 mutations in several key NSCLC genes, doing so with a respectable
turnaround time of less than 3 weeks. Again, however, the limitation of this technology is that it is not
entirely comprehensive. For example, designed to detect only the most common mutations in p53,
SNaPshot runs the risk of underreporting mutations and denying patients chances at alternative therapies
or important diagnostic information.51
Methylation-specific PCR is a recent technologic advance that has had significant implications in our
understanding of the epigenetic mechanisms involved in cancer. For example, much of what is known
about the impact of hypermethylated CDK2A and its regulation of the cell cycle comes from this assay.
Using very small samples amounts of DNA (i.e., nanograms), MSP can be used to detect gene-specific
promoter hypermethylation in surgically resected tissues as well as sputum and plasma.52
As opposed to mutational analysis, fluorescence in situ hybridization (FISH) is designed to detect
gene copy number rather than the presence or absence of the mutation. The basic principles behind this
technology include using fluorescently labeled DNA probes to bind to specific genomic regions in the
tumor nucleus. One of FISH’s assets is the ability for it to be conducted on very small samples of fresh
frozen or paraffin-embedded (FFPE) tissue. In addition, a number of studies have demonstrated that gene
copy number, as measured by FISH, can be a useful predictive marker of tumor response and patient
survival with TKIs.53,54 EGFR gene copy number, however, is not universally accepted as a predictive
marker, which may be due to differences in laboratory methodologies used for performing and interpreting
the assay results.55–57 In order to help standardize how FISH results are reported, the University of
Colorado has created a “scoring system” that helps more specifically define an EGFR FISH-positive
tumor from a negative one.58
Accurate FISH assay analysis is particularly important when it comes to screening patients for the
ALK gene rearrangement given the high clinical benefit that comes from crizotinib. Weickhardt and
colleagues expertly summarize the various techniques for detecting the ALK rearrangement in patients
with NSCLC, concluding that polymerase chain reaction (PCR) and immunohistochemistry (IHC) both
have their limitations and that FISH analysis should be the gold standard. In addition, they note that the
FDA has established what constitutes a positive gene rearrangement so that patients are accurately
selected for crizotinib therapy.47
The role for standard IHC in mutational analysis is very appealing in that it is fast, cost-effective, and
the technical infrastructure for its application already exists in academic and community settings.
Unfortunately, the widespread use of IHC has not been established due to questions about its sensitivity
and specificity in comparison to DNA-based molecular techniques. What is known about IHC testing is
primarily centered on EGFR mutation analysis. Two mutant-specific rabbit monoclonal antibodies have
been developed against the exon 19 A746_A750 deletion and the L858R point mutation. Using these
antibodies, several studies comparing IHC to direct sequencing have reported similar sensitivity and
specificity.59–61 However, as mentioned previously, IHC for detection of ALK gene rearrangement has not
proven to be as reliable. While, IHC ALK screening in lymphomas is standard, but in NSCLC, where the
expression of the fusion protein is lower, IHC has been less reliable. Certain centers have been more
successful using IHC in part due to their technical expertise, but multi-institutional success has yet to be
seen.62,63
Investigators, however, have long been cognizant of the complex biology of cancer and have sought
techniques for better understanding global gene expression in tumors, and this may be more useful than
single gene analysis. DNA array technology, or microarray, is very exciting in that it allows for molecular
profiling of the tumor so that we can better understand the expression of thousands of genes at one time. In
essence, a DNA array starts with multiple rows of oligonucleotide strands and complementary DNA
arranged on a glass slide or silicon chip. To complete the array, RNA is extracted from tumor tissue,
amplified and labeled with a fluorescent dye and hybridized to the array. The fluorescence from each spot
on the array signifies expression of the RNA’s corresponding gene. The knowledge garnered from these
arrays provide valuable insights into a tumor’s heterogeneity.11 For instance, Wigle and colleagues64 used
molecular profiling to subtype various stage I adenocarcinomas and were able to identify molecular
signatures that predicted different patterns of patient survival. In addition, they used DNA array to
differentiate adenocarcinomas of lung primary from colonic metastases. Thus, the potential of this
technology for both histologic subcategorization and differentiation is just beginning to be fully
appreciated.
Proteomic analysis of tissue relies heavily on mass spectrometry, in particular new technologies such
as matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and imaging mass
spectrometry (IMS). The former has significantly increased the sensitivity and accuracy for establishing
protein, lipid, glycan, and ceramide profiles from very thin frozen section specimens. As an adjunct to
MALDI, IMS can then be applied producing valuable images that detail the tissue distribution of these
species as well as low molecular weight compounds such as drugs and metabolites using standard
histologic tissue sections. This latter point is particularly interesting as IMS may become increasingly
useful in the assessment of drug penetration into targeted tissues.15,65,66
TISSUE ACQUISITION FOR MOLECULAR ANALYSIS

Perhaps most clinically relevant for the thoracic surgeon is an understanding of what tissue sampling
techniques will yield adequate tissue for molecular analysis. Clearly, surgically resected specimens
provide the pathologist with ample tissue for study, but many times resections of primary lesions or
metastasectomies are not clinically indicated. In these cases the surgeon must be cognizant of which less
invasive approach will be most likely to produce tissue sufficient for testing.
It is generally accepted that it is unknown what percentage and absolute number of tumor cells need to
be present in a sample for reliable mutation detection. In addition, with less tissue for analysis one has to
be concerned about how representative the sample is given the heterogeneity of the tissue. In a review of
EGFR mutation analysis, Gately67 recommended at least two cylinders of tissue from a CT-guided biopsy
and eight FNA passes/samples per cell block and eight smears from a brush biopsy. Meanwhile, a
European EGFR Workshop Group suggested that the ideal sample should contain between 200 and 400
tumor cells, noting that the percentage of the tumor cells in the specimen should be at least 50% for
accurate DNA sequencing.68 A CT-guided core needle biopsy is a popular approach for the nonsurgical
acquisition of tissue for diagnosis and genotyping. In general, this technique will generally yield more
than 500 tumor cells per biopsy. In the European working group study, it was suggested that at least two to
three cores should be performed in order to garner adequate tissue for diagnosis.
Fine-needle aspiration (FNA) either via transthoracic approach or bronchoscopy has been established
as a reliable method for acquiring tissue for mutational analysis. In general, an FNA performed with a 21-
gauge needle will typically yield more than 100 cells per biopsy, whereas a 19-gauge needle will yield
more than 150 cells. Current recommendations are that at least four biopsies be performed regardless of
the needle size. Navani and colleagues were amongst the first to demonstrate the reliability of FNA;
successfully completing EGFR mutational analysis in 90% of the cases. Overall, the ability to do EGFR
mutation testing with endobronchial ultrasound–transbronchial needle aspirate (EBUS-TBNA) appears to
range from around 72% to as a high as 96%.69–74
FNA aspirates have also been shown to be very valuable in the evaluation of metastatic lesions. It is
known, for instance, that EGFR mutational status is not static and that discordance between the primary
lesion and the metastatic site is common. As Bozzetti demonstrated in a study of 31 patients with
metastatic NSCLC who underwent FNA of a distant lesion, previously EGFR negative tumors can become
EGFR positive. In this specific study, 8 of the 31 patients developed an EGFR mutation. Thus, FNA
should be strongly considered in the evaluation of patients with recurrent or metastatic NSCLC as they
may become candidates for TKI therapy.75,76
Since the publication of the initial reports of the detection of malignant cells, sputum analysis for the
diagnosis of NSCLC has been regarded as a potentially ideal method for screening because of the limited
cost and risk for complications associated with obtaining these specimens.77 Proving its effectiveness,
however, has proven elusive as the consistent detection of malignant cells from the sputum has been
difficult. With the advent of more advanced technologies for evaluating sputum, renewed interest now
exists in examining this fluid for potential biomarkers. As Hubers and colleagues78 clearly state, a sputum
biomarker test would have one if not more clinical applications: identifying high risk patients who should
be screened (i.e., with low-dose CT scan), diagnosing patients who have a nodule discovered on CT, and
risk stratifying patients with semisolid lesions in order to determine high or low risk for developing
malignancy. As of now, the sensitivity and specificity of these assays are not acceptable for clinical
implementation. Still, there has been a rapid expansion in the study of the wide molecular milieu that
exists in the sputum. For instance, extensive research has been done on mutational analysis and assessing
DNA hypermethylation, while more limited investigations have begun looking at the presence of
messenger RNA, microRNA, and tumor-related proteins.
KRAS and p53 mutations in the sputum have been the focus of much research. While investigators have
been able to detect KRAS mutations in the sputum of patients with confirmed lung cancer, the success of
KRAS as a biomarker for eventual cancer development has been less encouraging. In a large study of 803
asymptomatic heavy smokers, Baryshnikova assessed the frequency of both KRAS and p53 mutations. In
follow-up, eighteen patients developed lung cancer but no KRAS mutation was detected while fifteen
patients had a p53 mutation detected and one of these individuals went on to develop malignancy. Sputum
analyses for EGFR mutations and EML4-ALK rearrangements have also been done but again with limited
success. Thus, mutational studies of sputum remain very much in their infancy with no immediate clinical
relevancy at this time.79–82
While the mutational analysis of sputum has not yet been shown to be useful in identifying at-risk
patients, the study of gene hypermethylation in the sputum has been somewhat more encouraging. For
example, Palmisano and colleagues83 were able to detect methylation of CDKN2A and MGMT in the
DNA from sputum in 100% of patients with squamous cell carcinoma from anywhere between 5 and 35
months prior to diagnosis. In additional small studies, Kersting and colleagues84 and Honorio and
colleagues85 found hypermethylation of CDKN2A and RASSF1A in patients a year or more before their
diagnosis. Meanwhile in the examination of patients with known malignancies, the median concordance of
methylation between tumor and matched sputum is 78% thus suggesting that DNA methylation status in the
sputum reasonably reflects what is found in the tumor.
While this literature is encouraging, no single gene is hypermethylated in 100% of tumors and, as
demonstrated in the Palmisano study, hypermethylation is not unique to patients with cancer as nearly 20%
of smokers without cancer also demonstrated hypermethylation of CDKN2A. Nevertheless, investigators
remain focused on generating panels of genes that can produce a sensitivity and specificity that meets
acceptable standards for clinical implementation.86–88
MicroRNA (also referred to as miRNA or miR) are a class of small single-stranded noncoding RNA
molecules which have been implicated in a broad range of disease processes including cancer
development and progression, cardiovascular disease, the inflammatory response of sepsis, and COPD.
miRs function by annealing to complementary strands of mRNA which blocks its function through one of
two mechanisms. First, the resulting double stranded RNA may be recognized by the cell as a viral
product and therefore degraded. The second mechanism by which miRs block mRNA is that the double
stranded RNA is not able to pass through the translational machinery and therefore synthesis of this
specific protein is aborted. A number of studies have demonstrated that miRs can be detected in the
sputum and investigators have successfully created “panels” of miRs that are signifiers of lung cancer. In
addition, there is now evidence that different miR panels can be detected in the sputum and used to
differentiate between squamous and adenocarcinoma of the lung.89,90
As with sputum, blood and serum as a source of potential markers for lung cancer has significant
appeal. For example, Kimura and colleagues91 noted significantly higher levels of the mutant of EGFR in
patients with response to gefitinib than in patients who developed progressive disease thus suggesting that
the serum may be used for tracking a clinical response. Andriani evaluated the plasma DNA of 64 patients
with NSCLC looking at three markers: p53, FHIT, and microsatellite alterations at the loci on
chromosome 3. In this study, at least one of the three genetic markers were altered in the plasma of greater
than 50% of the all the patients and in 64.4% of the patients the mutations detected in the plasma
corresponded to those seen in the tumor.92 While these reports are encouraging, there are inherent
limitations to the clinical implementation of blood and serum analysis. These fluids, unlike sputum, are
not organ specific and thus the mutations discovered within them may be representative of a malignant
process other than lung cancer.36
CURRENT GUIDELINES FOR MOLECULAR TESTING

Because the most common mutations (i.e., EGFR) are not found in the overwhelming majority of patients,
clinical guidelines have been created for selecting patients for testing. Clearly, lifelong nonsmokers who
are female with adenocarcinomas are ideal candidates for testing, but there has been some debate over the
cost/benefit of testing everyone with adenocarcinoma. In addition, debate exists over testing for patients
with squamous and mixed histology. The following paragraphs highlight the current recommendations of
the various professional societies.
An initial report by the European EGFR Workshop Group suggested that screening should be limited to
those in whom the frequency of mutations is high. Recently, the European Society of Medical Oncology
(ESMO) published guidelines discouraging such selection and now recommends that “all nonsquamous
tumors in patients with advanced/recurrent disease should be tested for EGFR mutation.” In addition, they
encourage testing in patients with squamous histology who have minimal or distant smoking history.
Identical recommendations were also made for screening for ALK rearrangements. In comparison, the
guidelines set forth by the College of American Pathologists, International Association for the Study of
Lung Cancer, and Association for Molecular Pathology are more specific in their recommendations.
While they endorse testing for EGFR and ALK in all patients with adenocarcinoma or tumors with an
adenocarcinoma component, they are more skeptical of testing in patients with pure squamous histology.
Nevertheless, they do acquiesce to testing in patients with squamous cell carcinoma if “an
adenocarcinoma component” cannot be excluded or the patient is a young, nonsmoker.93,94
Aside from whom to test, it is important to know when to test patients with NSCLC. Lindeman suggests
that EGFR and ALK testing should be routinely done in any patient at the time of diagnosis of advanced
adenocarcinoma or at the time of recurrence or progressive disease. Currently, the recommendations from
multiple professional societies is that EGFR and ALK testing should be encouraged but is not mandated in
patients with stage I, II, and III disease.84,85
What about testing for other mutations or targetable gene alterations? The ESMO suggests that as of
now there is no indication for routine testing for markers such as KRAS, BRAF, HER2, ROS1 fusion, and
RET fusion.84 KRAS testing is an interesting subject as it was the most common mutation discovered in
over 800 adenocarcinomas that were analyzed by the Lung Cancer Mutation Consortium and it is easy to
identify.95 Unfortunately, no current targeted therapies exist for KRAS and thus the question becomes: do
we need to test for it? KRAS has been associated with a poor prognosis but is this enough to validate the
cost of performing the mutational analysis?96 Secondly, while past data has suggested that KRAS is
predictive of response to chemotherapy, current data do not support this notion.97,98 Third, while there has
been interest in using KRAS to select patients for EGFR TKI therapy, mutational analysis of EGFR alone
has been proven to be sufficient. Finally, the primary advantage to KRAS testing appears to be that a
KRAS mutation effectively rules out other mutations such as ROS1 and ALK. Thus, the necessity of
KRAS remains questionable.99–101
In addition to creating treatment plans, clinicians are optimistic that testing for molecular markers may
help predict eventual response to chemotherapy. Some potential markers that have been mentioned include
ERCC1, BRCA1, RRM1 and thymidylate synthase. Unfortunately, the predictive accuracy of these
markers has not been strong and currently the ESMO does not recommend routine testing for these
mutations.102–105
While in the future novel technologies for the assessment of blood and sputum may simplify mutational
analysis, the current recommendations of the international professional societies are that EGFR testing
should be PCR based and should ideally be done on formalin-fixed, paraffin-embedded specimens. EGFR
mutation specific antibodies for IHC do exist but given that the number of clinically relevant mutations far
exceeds the number of antibodies, IHC is discouraged as the primary test. Similarly, while the ESMO
suggests that IHC may be used for prescreening for ALK mutations, FISH analysis should be the primary
assay utilized. In the future, there is no doubt that more extensive and thorough methods for analysis will
become clinically available. Next generation sequencing that allows for the study of large numbers of
DNA templates with a single test has real potential for clinical implementation (high sensitivity at a
reasonable cost).84,85,106
Because roughly 50% of patients with EGFR mutations who develop disease progression do so
because of a second mutation, repeat molecular testing can be important.27 No current standard guidelines
exist, but more than 90% of these mutations are due to a substitution of a methionine for threonine at
position 790 in exon 20 of the EGFR kinase domain.25 Investigators have shown that in these patients with
acquired resistance there is an increase in amplification of MET and therefore these patients may become
candidates for second-line therapies.107 Newer evidence on the development of adaptive resistance has
noted that the cells of patients treated with TKIs undergo an upregulation of several RTKs which help
overcome selective inhibition. Finally, data is emerging that suggests that the overexpression of the kinase
AXL and MED12 can be used to measure resistance to EGFR TKIs.108,109
PERSONALIZED ONCOLOGY AND FUTURE CHALLENGES

Modern oncologic care has been dominated by cytotoxic agents that were designed for application across
the general patient population. As of now, once the histologic diagnosis of cancer has been made, these
agents are administered and response is assessed based on follow-up imaging. We are however on the
cusp of a major paradigm shift in how we select a patient’s therapy, all of which is due to the rapid
expansion in our appreciation of cancer’s molecular heterogeneity. As a result, the era of personalized
oncology will likely replace the traditional generic approach.
Our transition into this new era is exemplified by the creation of such entities as the Cancer Cell Line
Encyclopedia (CCLE). The CCLE is a large scale genomic dataset of 947 human cancer cell lines that
analyzed the mutational status of more than 1,600 genes creating a compilation of gene expression,
chromosomal copy number, and massive parallel sequencing data. This information was then coupled
with the pharmacologic profiles of 24 anticancer drugs across 479 of the lines in order to identify
molecular correlates of pharmacologic response. Thus, with entities such as the CCLE and others, it
becomes possible to create genetic predictors of drug response that can then be used to individualize
patient care.110
In addition to personalizing patient treatment, genomic characterization of tumors is likely to influence
histologic subtyping and staging. A collaborative study conducted by the Clinical Lung Cancer Genome
Project (CLCGP) and the Network of Genomic Medicine (NGM) initially retrospectively analyzed 1,255
fresh-frozen human lung tumor specimens and was able to detect genomic alterations specific to the
various histiologic subtypes. For example, adenocarcinomas tended to express mutations in ALK, BRAF,
EGFR, ERBB2, KRAS, and STK1 while DDR2 and FGFR1 mutations were more specific for squamous
cell carcinoma. Also interestingly, they discovered that large cell carcinoma did not have genomic
alterations that were specific to its cohort. As a result, investigators were able to reclassify many of these
large cell carcinomas as squamous cell or adenocarcinoma solely on the basis of their genomic profile.
Finally, the NGM prospectively evaluated these histology specific mutations across 5,145 lung cancer
patients finding that they correlated well with the aforementioned retrospective data.111
The traditional American Joint Commission on Cancer TNM staging system is an important component
of risk stratification. As of now, the molecular analyses of tumors are not included in the current staging
system, but this seems likely to change as we learn more about the predictive nature of molecular
mutations. In the past decade using large panel gene array, numerous molecular signatures have been
identified to stratify patients with lung cancer into low and high risk groups for recurrence. Unfortunately,
many of these studies were single institution with limited specimens available for analysis. The result
was the identification of prognostic signatures that varied widely between institutions and shared little
common ground. Large scale multi-institutional studies, like the one conducted by Shodden and
colleagues, are of particular importance as they have demonstrated that using uniform methods of data
acquisition and analyses one can more reliably generate gene expression profiles with clinical
applicability. As proof of this principle, Bueno and colleagues,112 in a multi-institutional study of 650
patients with stages I and II adenocarcinoma, evaluated the prognostic capabilities of 31 cell cycle
related genes whose expression was used to create a CCP score for each tumor. Individually and when
combined with the patient’s pathologic stage, the CCP was a significant predictor of lung cancer specific
mortality.113
Gene expression profiles are not the only way investigators are using current technologies to predict
prognosis. For instance, it is well known that the process of epithelial to mesenchymal transition is a
hallmark of malignant behavior. Reka and colleagues, using proteomic analysis of tissue culture, were
able to generate a panel of proteins that are commonly secreted during this process. This panel was then
used to stratify patients with lung cancers into with low, medium, and high risk groups. Others have used
proteomic analysis of tumors to predict which patients are most likely to benefit from small molecule
therapy. As an example, Gregorc115 found that patients with advanced stage lung cancer, who were being
treated with second-line chemotherapy regimens, were much less likely to benefit from erlotinib as
opposed to traditional cytotoxic agents if they had an unfavorable proteomic profile.114
TABLE 17.1 Identified Driver Mutations in Non-Small Cell Lung Cancer

Gene Class Alteration Frequency (%) Drug: Investigational Drug: FDA Approved
AKT1 S/T kinase Mutation 1 Perifosine No
ALK RTK Rearrangement 3–7 Ceritnib Crizotinib
BRAF S/T kinase Mutation 1–3 Vemurafenib No
Dabrafenib
DDR2 RTK Mutation 4 Dasatinib No
EGFR RTK Mutation 10–35 Dacomitinib Erlotinib
Neratinib Afatinib
FGFR1 RTK Amplification 20 Ponatinib No
Dovitinib
HER2 RTK Mutation 2–4 Trastuzumab No
Afatinib
KRAS GTPase Mutation 15–25 None No
MEK1 S/T kinase Mutation 1 Selumetinib No
Trametinib
MET RTK Amplification 2–4 Crizotinib No
Cabozantinib
NRAS GTPase Mutation 1 None No
PIK3CA Lipid kinase Mutation 1–3 None No
PTEN Lipid/protein phosphatase Mutation 4–8 None No
RET RTK Rearrangement 1 Cabozantinib No
ROS1 RTK Rearrangement 1 Crizotinib No
Trastuzumab
Afatinib
As of now, an EGFR mutation based on DNA sequencing is evidence enough for commencing treatment
with a TKI. Unfortunately, less than 60% of patients with EGFR mutant NSCLC actually respond to these
medications. Resistance to these therapies can come in many forms and extend beyond the aforementioned
T790M mutation, which is a well-known form of adaptive resistance.82,116 Overexpression of AXL, a
member of the tyrosine kinase subfamily, has recently been discovered as a new mechanism by which
cells gain resistance to TKIs. Likewise, evidence now exists that loss of the MED12 mediator complex
results in resistance to EGFR inhibitors. An important modulator of response to TKIs, MED12 negatively
regulates TGF-βR2 thus maintaining responsiveness to therapy. In the absence of MED12, TGF-βR2 is
upregulated and resistance develops.99,100 In contrast to these examples of adaptive resistance, innate
resistance is becoming even better understood. As an example, BCL2L11 is a pro-apoptotic protein that is
part of the intrinsic mitochondrial-mediated apoptosis pathway. Response rates to EGFR TKI of 100%
have been reported among patients expressing high levels of BCL2L11 mRNA. In contrast, patients who
expressed low levels of BCL2L11 apparently were not able to complete the process of programmed cell
death and a poor response to targeted therapy was observed. In summary, our increased appreciation for
resistance will, in the future, further allow us to delineate patients that are likely to respond to EGFR
TKIs from those who are not likely to respond.117
Given the pace at which our knowledge of genetic alteration is rapidly evolving several aspects of this
chapter will likely be outdated by the time of its publication. In fact, with advances in knowledge and the
explosion in drug development, it can be difficult for the clinician to remain current on a month to month
basis. For this reason, resources such as My Cancer Genome (www.mycancergenome.org), a website
supported by Vanderbilt University, have been created to continually update newly identified driver
mutations and the agents being evaluated in clinical trials. Table 17.1 summarizes the current mutations,
rearrangements, and amplifications known to occur in lung cancer.
As Vogelstein explains in an excellent review of cancer genomics and the challenges that lay ahead, the
small molecule inhibitors that currently exist are designed to target protein kinases and inhibit their
enzymatic activity or interaction with activating ligands. This inhibition has profound effects on cell
signaling and by consequence cell proliferation. Unfortunately, only 31 oncogenes are tyrosine kinases
that are targetable in this manner and the vast majority that remain have less enzymatic activity and
involve more complex and less robust interactions with associated gene products. Consequently, drugs
targeting these oncogenes results in less significant tumor kill. Another important challenge to consider is
the preponderance of TSG mutations in comparison to oncogene-activating mutations in solid tumors.
Logically, it is easier to develop therapies that target the product of these oncogenes, while it is far more
difficult to develop effective therapies that can replace the function of these TSGs. So what is the answer
to this sober reality? In the opinion of Vogelstein, it will be an even greater understanding of the
downstream effects on cell signaling. Therefore, we must develop a better appreciation for the effects of
loss of TSGs on kinase activity and then target these pathways accordingly.1
CONCLUSIONS
Molecular profiling of lung cancer has led to an ever increasing appreciation for the complexity of this
disease. It is now well understood that mutations in driver genes and changes in the methylation status of
TSGs have widespread implications in the life cycle of a cell. At the same time, the byproducts of this
new knowledge have allowed clinicians to offer more personalized approaches to their patients in the
form of directed therapies tailored to the individual’s tumor. In essence, we now know that one
individual’s pulmonary adenocarcinoma is not the same as another’s and that generic traditional
chemotherapy may not be the ideal treatment. Meanwhile, advances such as mass spectrometry,
microarray, and next generation sequencing provide a more in-depth analysis of the patient’s tumor which
has the potential to yield important prognostic information. Likewise, these technologies may finally
allow us to pinpoint a biomarker or panel of biomarkers from sources such as the sputum and blood that
can identify at-risk patient’s months to years before their diagnosis. In summary, a new “molecular” era in
the treatment of lung cancer has arrived and with it new and exciting opportunities to effectively prevent
and treat this sobering disease.
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Section
V
DIAGNOSTIC PROCEDURES IN
PULMONARY DISEASES
18
Bronchoscopic Evaluation of the Lungs and
Tracheobronchial Tree
Dominik Harzheim ■ Felix J. F. Herth
Visual inspection of the airways was once an art performed by a handful of highly skilled surgeons using
rigid instrumentation. It was almost always performed in the operating theater under general anesthesia. In
the early 1970s, fiberoptic bronchoscopy was introduced, revolutionizing examination of the airways.
Over the ensuing years, flexible bronchoscopy has almost completely replaced the rigid bronchoscope as
the diagnostic instrument of choice. Flexible bronchoscopy is now performed by pulmonologists,
anesthesiologists, otolaryngologists, critical care specialists, and thoracic surgeons in a variety of clinical
settings, including the hospital ward, intensive care unit, and operating room. The well-trained thoracic
surgeon must have a clear understanding of all aspects of both flexible and rigid bronchoscopy, including
indications, anesthetic techniques, instrument options, and the management of complications.
RIGID BRONCHOSCOPY
The indications for rigid bronchoscopy include examination and management of obstructing airway
lesions, massive hemoptysis, retrieval of foreign bodies, suctioning of inspissated secretions, and
obtaining tissue biopsy specimens of endobronchial lesions more generous than those provided by the
flexible bronchoscope. A rigid bronchoscope should always be available when tracheal lesions are
examined. Bleeding from biopsy sites or edema from tissue trauma can obstruct a compromised lumen,
which can be forcibly dilated with a rigid instrument, and ventilation can be restored through the
instrument.
The rigid bronchoscopes most commonly used in adults have an internal diameter of 6 to 13 mm and
are manufactured in various lengths from 33 to 43 cm (Fig. 18.1). Traditional models provide only a
tunnel view, but modern rigid bronchoscopes also can be used with telescopic lenses. Illumination is
supplied from a halogen light source. A fiberoptic cable is attached to a light carrier that passes down the
side wall of the bronchoscope, through the telescope, or both. With the help of the telescope, generous
biopsy specimens can be taken without compromising visualization. Both models have a ventilating side
port permitting assisted ventilation (Fig. 18.2). Contrary to rigid bronchoscopes, rigid tracheoscopes do
not permit access to the left and right main bronchus and exhibit no side ventilation fenestrations.
FIGURE 18.1 Standard 8-mm rigid bronchoscope with light carrier, rigid biopsy forceps, and glass eyepiece.
FIGURE 18.2 A: Jackson ventilating rigid bronchoscope with eyepiece in place. The patient is ventilated through the side port.
B: Dumon–Harrell rigid bronchoscope. The surgeon looks down the Hopkins rod and can simultaneously suction and obtain a
biopsy through the various side ports. C: Dumon–Harrell rigid bronchoscope. The telescope, suction catheter, and semirigid
biopsy forceps are simultaneously passed down the rigid bronchoscope. A neodymium:yttrium-aluminum-garnet (Nd:YAG) laser
fiber can also be passed without compromising ventilation.
Rigid bronchoscopy is almost always performed under general anesthesia, with all of its attendant
risks. Despite the clearer view provided with telescopes, sampling of the upper lobe or distal airway
cannot easily be accomplished through the rigid bronchoscope (Fig. 18.3). However, these disadvantages
can easily be overcome by combining flexible and rigid bronchoscopy. In this approach the rigid scope is
used as a conductor for the flexible bronchoscope, providing a fast and secure access to the
tracheobronchial tree. Advantages and disadvantages of isolated rigid bronchoscopy are listed in Table
18.1.
FIGURE 18.3 Rigid ventilating bronchoscopy with biopsy performed using general anesthesia and open-tube technique.
Under general anesthesia, the multifunctional head, situated at the proximal tip of the rigid scope,
allows for simultaneous ventilation and airway instrumentation. The ventilation port can be either used
for volume ventilation or jet ventilation. Jet ventilation offers the advantage of free introduction of
instruments by warranting an open ventilation. In case of volume ventilation a fenestrated cap has to be
attached to the end of the scope to ensure adequate ventilation. The anesthesiologist must monitor the
adequacy of ventilation continuously; increased minute ventilation and tidal volumes may be required.
To pass the bronchoscope, the patient is placed in a supine position with the head slightly flexed in
order to achieve anterior alignment of the oral and the pharyngeal axis. The endoscopist elevates the
epiglottis with the tip of the bronchoscope and passes the lubricated instrument through the glottis into the
upper trachea. Once the vocal cords are visualized, the scope is rotated 90 degrees with the bevel
parallel to the cords to prevent vocal cord trauma. After passing the cords, the 180-degree rotation of the
scope is completed while smoothly advancing the scope to the mid-trachea. Injuring the vulnerable distal
wall of the trachea should be avoided by a continual elevation of the tip of the scope. It is important that
the patient’s upper teeth are being protected with the operator’s thumb or long finger and that the vocal
cords are viewed by an anterior displacement of the bronchoscope rather than a lever motion on the teeth.
Telescopes provide a magnified field of vision. Examination of the trachea is performed as the
bronchoscope passes through the glottis and advances down to the carina. The carina is assessed for
sharpness and mobility during ventilation. Splaying or fixation suggests the presence of a subcarinal mass.
Biopsy of the bronchial mucosa on the carina is performed if mucosal or submucosal changes are
observed. Thirty- and ninety-degree angle-viewing telescopes allow the endoscopist to view the upper
lobe bronchi. Alternatively, a flexible bronchoscope can be passed through an appropriately sized rigid
instrument to view upper lobe orifices and all segmental bronchi (Fig. 18.4).
TABLE 18.1 Rigid Bronchoscopy
Advantages
Foreign body removal
Massive hemoptysis
Infant endoscopy
Dilate strictures
Tracheal obstruction
Laser bronchoscopy
Disadvantages
General anesthesia
Visualize segment
Biopsy segment
Peripheral biopsy upper lobe
FIGURE 18.4 Flexible bronchoscope passed through a rigid bronchoscope to examine upper lobe orifices and airways beyond
the tip of the rigid bronchoscope.
The risks of rigid bronchoscopy include injury to the gums and tooth dislodgment, hypoventilation,
airway bleeding, and direct injury to the larynx or rupture of the tracheobronchial tree. With experience,
these complications can be minimized.
The rigid bronchoscope must be sterilized after each use. The scope and ancillary equipment must be
mechanically cleaned off all blood and mucous debris before they are sent for sterilization. All glass and
metal components should be autoclaved, and the plastic caps should be wrapped separately and gas
sterilized.
FLEXIBLE BRONCHOSCOPY
Ideally, flexible bronchoscopy should be performed in a dedicated area of the hospital or outpatient
facility. Because intravenous sedation is routinely used, recovery areas are also needed. In the best
clinical scenario, such suites would allow clinicians to perform procedures with fluoroscopic or
computed tomography (CT) guidance and with the ability to administer general anesthesia. The
examination room must be large enough to store all equipment, supplies, and accessories. It is ideal to
have a storage area adjacent to the endoscopic suite. Special holding racks and storage cases should be
routinely used to minimize the risk of scope breakage.
TABLE 18.2 Flexible Fiberoptic Bronchoscopy

Advantages
Patient comfort
Segmental visualization
Segmental biopsy
Peripheral biopsy
Transbronchial needle aspiration
Bedside aspiration
Bronchoscopy on ventilator
Bypass distortion
Photography
Increased cancer diagnosis
Brachytherapy
Laser bronchoscopy
Disadvantages
Small channel
Breakdown
Sterilization
A portable cart supplied with a light source, bronchoscope, and accessories is a convenient way to
perform bedside bronchoscopy. It should be returned to the storage area for proper cleaning and
restocking.
Flexible bronchoscopy has many advantages over sole rigid bronchoscopy, as listed in Table 18.2.
Diagnostic material from peripheral as well as central lesions can be obtained with minimal risk. The
examination is usually performed under topical anesthesia and intravenous sedation, avoiding the risks of
general anesthesia. Retained secretions can be aspirated at the bedside in the ward or in the intensive care
unit. Patients receiving ventilator support can be examined without compromising the airway using a side-
arm adaptor. The scope can be passed through narrowed and distorted airways or beyond an obstructing
lesion. Flexible bronchoscopy is particularly valuable in assessing lobar and segmental airways to the
upper lobes. Still or video photography is easily performed to document findings (Fig. 18.5).
A new and persistent cough or a change in the cough pattern warrants a bronchoscopic examination
after careful exclusion of other causes. Furthermore, a wheeze, particularly one that is unilateral and fails
to clear with coughing, should be investigated. Maintaining a high index of suspicion, tracheal and major
airways lesions can be often diagnosed, even in the absence of radiologic findings.
FIGURE 18.5 Flexible bronchoscopy using a video-assisted technique.
Sputum can be obtained in a sterile fashion to assess for opportunistic infections, especially in the
immunocompromised patient. However, if the patient is suspected of having tuberculosis, induced sputum
specimens (using inhaled saline) should be examined before the bronchoscopy to avoid health care
workers to become contaminated. Endoscopic lobar and segmental saline lavage has proven to be of
benefit in postoperative patients unable to clear their secretions. Retained thick, tenacious mucous
secretions are easily suctioned at the bedside with minimal patient discomfort.
Although the most common cause of hemoptysis is chronic bronchitis, carcinoma is common in patients
with abnormal chest radiographs. According to Jackson1 and Poe2 and colleagues, in the presence of a
normal chest radiograph, malignancy should be seriously considered if the patient is older than 40 years
of age, has a significant smoking history, or has episodes of hemoptysis longer than 1 week in duration. In
addition to the most common lung cancer histotypes, hemoptysis associated with a wheeze or atelectasis
may also be caused by a bronchial carcinoid or an inflammatory bronchial stricture.
An abnormal chest radiograph suggesting carcinoma warrants a careful evaluation of the entire
tracheobronchial tree. The decision for bronchoscopy should always be based on clinical judgment, but
the physician should err on the side of performing an endoscopic evaluation to rule out a neoplasm. An
obstructing carcinoma may be the underlying cause of an unresolving pneumonia; an upper lobar infiltrate
should be viewed with particular suspicion. Bronchoscopy may also be used to assess for metastatic
tumors.
Bronchoscopy is indicated in the diagnosis and management of lung abscess. If conservative therapy
fails, bacteriologic sampling and placement of a pigtail catheter into the cavity via a guidewire represents
a promising approach.3 Furthermore, occasionally an obstructing neoplasm or foreign body is discovered.
The therapeutic value of bronchoscopy to remove inhaled gastric contents remains controversial.
However, a rapid and efficient bronchoscopy examination can support the diagnosis and may have
therapeutic benefit, particularly if particulate matter is retrieved.
After inhalation of smoke or caustic fumes, bronchoscopy is a safe and expeditious way of assessing
damage to the tracheobronchial mucosa. In these compromised patients, the airways frequently need
repeated bronchoscopy to debride necrotic mucosa and inspissated secretions. The inflammatory
response to this injury may progress for days, leading to delayed airway obstruction.
Patients with cystic fibrosis may also, on occasion, require aspiration of persistently thick and
tenacious secretions. However, routine bronchoscopy, once a mainstay of the care in such patients, has
been largely supplanted by the routine use of vigorous physiotherapy and mucolytic agents.
The role of bronchoscopic examination of a patient with a fever of unknown origin or a pulmonary
infiltrate after lung transplantation is widely accepted, as summarized by Higenbottam and colleagues.4
However, the need for routine surveillance biopsies in lung transplant recipients is still controversial.
According to Trulock,5 routine surveillance bronchoscopies with random biopsies should be performed 2
to 3 weeks, 6 to 8 weeks, 9 to 12 weeks, 6 months, and 1 year after transplantation and annually
thereafter. The most frequent unsuspected findings have been acute rejection and silent cytomegalovirus
pneumonia.
Early detection and treatment of these entities is thought to decrease the risk for chronic rejection,
according to Steinhoff and colleagues.6 Others, such as Stillwell and colleagues,7 maintain that in
asymptomatic patients, early stages of acute rejection or viral infection pose little risk of leading to more
serious conditions. However, despite advances in gene and immunologic monitoring techniques,
fiberoptic bronchoscopy remains the gold standard in the diagnosis of acute pulmonary allograft rejection
or infection after lung transplantation.8
Another indication for bronchoscopic assessment of the tracheobronchial tree is the suspicion of
airway trauma. Wheezing, hemoptysis, and the presence of subcutaneous or mediastinal emphysema are
the classic findings, but injury of the airway is often overshadowed by concomitant injuries such as aortic
rupture or myocardial contusion. Even when suspected, the endoscopic findings of a torn bronchus can be
remarkably subtle. Early diagnosis and repair of these injuries are of the utmost importance.
Transbronchoscopic bronchial biopsies, cytologic brushings, transbronchial needle aspiration
(TBNA), and bronchoalveolar lavage (BAL) are readily performed; the endoscopist should be familiar
with indications, techniques, and complications of each. Airway bleeding can be the most devastating
complication. Even severely ill and debilitated patients can undergo bronchoscopy safely if it is
performed in an appropriate facility by an experienced endoscopist.
Currently available standard flexible bronchoscopes range from 6.2 mm in outer diameter (3.2-mm
working channel to aspirate inspissated secretions and blood clots) to 2.7 mm in outer diameter (1.2-mm
working channel) for pediatric patients (Table 18.3). One of the most often used adult bronchoscopes has
an external diameter of 5.9 mm and a 2.2-mm working channel, allowing clear visualization and specimen
sampling of the entire tracheobronchial tree down to the fourth- or fifth-order bronchi (Fig. 18.6). A
forward field of view is 120 degrees; the angle of deflection is 180 degrees upward and 130 degrees
downward. A narrower instrument with an external diameter of 4.9 mm and an instrument channel of 2.2
mm easily passes through a bronchus narrowed by stricture or tumor, and its 180-degree upward
deflection facilitates examination of the often difficult to reach apical subsegment.
Video bronchoscopes provide a significantly larger image with higher resolution than is seen in
standard flexible bronchoscopes. However, these images can be viewed only with a video processor and
monitor. An assortment of different available bronchoscopes is listed in Table 18.3. These scopes are
fully immersible and most can be autoclaved. The expert endoscopist should have a variety of flexible
bronchoscopes available for diagnostic and therapeutic versatility (Fig. 18.7).
TABLE 18.3 Standard Viewing Fiberoptic Bronchoscope Specifications
Outer Diameter (mm) Instrument Channel (mm) Deflection (degrees) Field of View (degrees)
2.7 1.2 180/130 100
2.8 1.2 180/130 40
2.4 1.2 180/130 95
4.9 2.2 180/130 120
5.9 2.2 180/130 120
5.9 2.2 180/130 120
6.2 3.2 180/130 120
Video Fiberoptic Bronchoscopes
3.8 1.2 180/130 120
5.1 2.0 180/130 120
5.3 2.0 180/130 120
6.0 2.8 180/130 120
6.0 2.6 180/130 120
6.2 3.2 180/130 120
FIGURE 18.6 Flexible fiberoptic bronchoscope (Olympus BF-10, Melville, NY).
THE EXAMINATION
Anesthetic Considerations
Intravenous access is routinely available, and supplemental oxygen is usually provided through nasal
cannulas, as recommended by Prakash and Stubbs.9 Pulse oximetry, cuff blood pressure, and
electrocardiographic monitoring are routinely performed. Sedation should be administered to provide
patient comfort and cooperation. In several studies, however, 50% of the life-threatening complications
from bronchoscopy stemmed from hypoxemia, hypercapnia, and respiratory depression secondary to
oversedation. Therefore, the agents and their dosages must be individualized; their use may not be
necessary in every case.
FIGURE 18.7 Flexible fiberscopes viewed on end. From left to right: 4.9-mm bronchoscope with 2.2-mm channel; 5.7-mm
bronchoscope with 2.2-mm channel; 5.8-mm bronchoscope with 2.8-mm channel; and 6.3-mm bronchoscope with 3.2-mm
channel.
Preoperative opiates are sometimes given for their analgesic and antitussive properties. Meperidine
has an elimination half-life of 3.2 hours, but clearance is decreased in patients with renal or hepatic
failure or both. Like all opiates it can cause respiratory depression and hypotension. Naloxone, a specific
opioid antagonist, must be available whenever opioids are administered.
Intravenous benzodiazepines are often administered, providing anxiolysis and antegrade amnesia.
According to a bronchoscopy survey reported by Colt and colleagues,10 midazolam has become the
preferred agent since it is water-soluble, with a rapid onset, short duration of action, and an elimination
half-life of only 2 hours in normal subjects. Renal failure does not alter the distribution, elimination, or
clearance, but liver disease is associated with prolonged sedation. The recommended dose is 0.07 mg/kg.
Diazepam is not water-soluble and can cause significant, if only transient, phlebitis; its elimination half-
life is 24 to 57 hours in normal patients. Both agents should be used with caution, especially in elderly
patients and those with limited pulmonary reserve. Respiratory depression is a major side effect of both
benzodiazepines; the degree of respiratory depression is similar with both drugs. Flumazenil is a specific
benzodiazepine antagonist and should be available any time these agents are used. Because its elimination
half-life is only 1 hour, repeat doses or a continuous infusion may be necessary. Matot and Kramer11 have
reported that the alfentanil–propofol association is a reasonable alternative to meperidine–midazolam,
particularly in patients at risk or with known coronary artery disease (Table 18.4).
TABLE 18.4 Indications for Bronchoscopy

Diagnostic
Severe cough
Change in cough
Abnormal chest radiograph findings
Hemoptysis
Wheeze
Unresolved pneumonia
Abnormal sputum cytology
Diffuse lung disease
Opportunistic infection
Bacteriologic sampling
Metastatic malignancy
Smoke inhalation
Pediatric airway obstruction
Bronchoalveolar lavage
Upper esophageal cancer
Therapeutic
Atelectasis
Lung abscess
Foreign body
Stricture
Laser
Other Indications
Prolonged intubation
Difficult intubation
Bronchography
Gastric aspiration
Lobar gas sampling
Management of massive hemoptysis
Some physicians continue to premedicate patients with an antisialagogue, such as atropine or

glycopyrrolate, to reduce secretions and inhibit vasovagal responses, as documented by Williams and
colleagues.12 These medications also make topical anesthesia more effective. However, according to
Hasanoglu and colleagues,13 tachycardias and episodes of hypotension were more commonly observed
when atropine was administered. According to the survey reported by Colt and colleagues,10 only 62% of
respondents routinely used atropine as a premedication while far fewer used glycopyrrolate.
Topical anesthesia is preferred for fiberoptic bronchoscopy, but general anesthesia may be considered,
particularly for prolonged examinations required to identify carcinoma in situ in a patient with normal
chest radiography findings. Occasionally, general anesthesia is requested by extremely anxious patients.
The most commonly used agents for topical anesthesia are lidocaine (1% and 2%) and tetracaine
(0.5%, 1.0%, and 2.0%). Complications from topical anesthesia usually result from the administration of
excessive amounts, as documented by Credle,14 Suratt,15 and Pereira16 and their colleagues. If carefully
measured amounts are administered and the endoscopist remains at all times aware of the total milligram
dosage instilled, morbidity is usually minimized.
Lidocaine is a safe agent with short duration of action and a recommended dose of 0.2 to 0.3 mL of
1%/kg, albeit larger amounts have been administered without serious side effects. It is important to
remember that the extent of absorption and bioavailability depends on tissue vascularity and the technique
of application as well as the total dose administered, according to Mainland and colleagues.17 Lidocaine
should always be titrated slowly and patients must be monitored for mental status changes. The first sign
of toxicity is usually central nervous system excitation or seizure before cardiovascular collapse.
Tetracaine is another effective topical anesthetic, but side effects frequently occur when a dose of 80
mg is exceeded. The duration of action is prolonged and the first sign of toxicity may be sudden
cardiovascular collapse.
The association of benzocaine–tetracaine is a popular topical anesthetic agent with rapid onset of
action. This is why it is useful in rapid intubation and often administered in a propellant spray with a
tolerance dose delivered in only 2 seconds. Dosing is therefore difficult to regulate, and this agent should
be avoided when flexible bronchoscopy is being performed. Complications of all topical anesthetic
agents include methemoglobinemia, whereby patients become cyanotic owing to the oxidation of iron
from its normal reduced state, leaving it unavailable for oxygen binding and transport. Elderly, infant, and
anemic patients are particularly susceptible, as documented by Karim and coinvestigators.18 Intravenous
methylene blue (1 mg/kg) is the recommended initial definitive treatment. Rarely, exchange transfusion or
hemodialysis is necessary.
Several satisfactory methods are available to administer topical anesthesia. Using the nasotracheal
route, the nasopharynx is anesthetized initially using an atomized topical agent and the flexible
bronchoscope is then passed through the nares to a level just proximal to the false cords. With the larynx
in clear view, additional topical anesthetic is administered directly onto the vocal cords and into the
trachea. The bronchoscope is then passed through the glottis and additional topical anesthesia is instilled
down the tracheobronchial tree.
A second method of delivering topical anesthesia consists of initial spraying of the hypopharynx with
1% or 2% lidocaine using an atomizer. Then, 5 mL of 4% lidocaine is injected transtracheally through the
cricothyroid membrane using a short 21-gauge needle to minimize the risk for lacerating the posterior
wall of the trachea. Slight bleeding often occurs with this technique, so it should be avoided when a
patient is being examined for hemoptysis of unknown origin. Care is taken to confirm the position of the
needle in the tracheal lumen by aspirating air before injecting. It is possible to inject directly into the false
cords and precipitate laryngospasm. Anesthesia of the larynx is achieved as the patient coughs out the
medication. Supplemental 2% lidocaine is then instilled into the tracheobronchial tree while the flexible
bronchoscope is advanced. Because topical anesthetic agents inhibit bacterial growth, care should be
taken to minimize the amount aspirated into collection traps for microbiologic studies.
Flexible bronchoscopy is accomplished easily using general anesthesia. In the adult, a swivel adaptor
is attached to the endotracheal tube, and ventilation is maintained through the side arm of the adaptor. The
bronchoscope is passed through a tight-fitting plastic diaphragm on the adaptor. As large an endotracheal
tube as possible should be selected to minimize peak airway pressure and allow for adequate ventilation.
Most adult bronchoscopes can fit through at least a 7.5-mm endotracheal tube during general anesthesia.
In the sedated patient, the flexible fiberoptic bronchoscope can be inserted either through the nose or
the mouth into the hypopharynx. Although the nasal route may be more comfortable for the patient and
avoids possibility of the patient chewing on the instrument, this option does not permit easy withdrawal
and reinsertion for cleaning of the lens and clearing the channel of thick mucus. In addition, biopsy and
brushing cytology specimens must be withdrawn through the entire length of the channel, leading to a
potentially decreased yield of diagnostic material.
An alternative technique involves passing an uncuffed 8.0-mm endotracheal tube (overtube) via the
orotracheal route (Fig. 18.8). The patient breathes around and through this overtube. Airway access is
provided without repeated trauma to the larynx and subglottic region. The overtube allows rapid
withdrawal and reinsertion of the bronchoscope. Brushing and biopsy specimens are retrieved, leaving
the brush or biopsy forceps beyond the tip of the bronchoscope and avoiding loss of the specimen in the
working channel (Figs. 18.9 and 18.10). In addition, airway suctioning using a large-caliber catheter can
be performed through the overtube in the event of significant airway bleeding. Airflow resistance,
however, has been shown to increase significantly when a 5.8-mm bronchoscope is passed through an
endotracheal tube smaller than an 8.5-mm outer diameter. The use of a smaller endotracheal tube can lead
to hypercapnia and respiratory distress.
FIGURE 18.8 Flexible fiberoptic bronchoscope is inserted through an oral endotracheal tube.
FIGURE 18.9 Flexible fiberoptic bronchoscope with (from top to bottom) a 21-gauge transbronchial needle, a flexible cup
biopsy forceps, and a 7-mm nylon brush.
Supplemental oxygen, oximetry, and electrocardiographic monitoring are important because arterial
desaturation and increases in the heart rate and cardiac index are very frequently observed during the
procedure, according to Markou and colleagues.19
The Endoscopic Examination

The first phase of a diagnostic bronchoscopy is visualization of the larynx and the vocal cords.
Unsuspected leukoplakia, carcinoma in situ, and invasive carcinoma may be found. Vocal cord mobility
must be assessed. Recurrent laryngeal palsy secondary to carcinoma of the lung generally is considered a
sign of inoperability.
FIGURE 18.10 Bronchial brush is rapidly smeared onto a glass slide, which is immediately immersed in 90% ethanol to fix the
material for cytologic examination.
All lobar and segmental bronchi must be examined carefully and systematically because a second
lesion not visible on the chest radiograph is occasionally identified. The tracheobronchial tree remote
from the area in question is assessed first. In this way a complete examination can be performed and
samples from a different site, if taken, are less likely to be subject to cross-contamination.
After this part of the procedure has been performed, the bronchus leading to the known area of disease
is examined. The character of the secretions and the bronchial mucosa can be clues to the nature of the
underlying pathologic condition. Subtle mucosal abnormalities associated with carcinoma include
mucosal thickening, irregular bronchial folds or corrugation, and increased or irregular submucosal
vascularity. These findings may be associated with a loss of definition of the cartilaginous rings or
circular folds, bronchial stenosis, or extrinsic bronchial distortion. The extent and the exact location of
these endoscopic findings must be carefully observed when surgical intervention is anticipated.
Endobronchial Lesions
When mucosal changes are visualized, various sampling instruments like forceps, brushing, washing, or
transbronchial needles are available for cytohistologic assessment. Biopsies should be attempted, even
when the lesion is suspected to be a bronchial carcinoid, because lung-sparing resections can be
performed with minimal resection margins with this pathologic entity. The differential diagnosis of this
entity includes granulation tissue, polypoid squamous carcinoma, and endobronchial papilloma. Bleeding
is the most common complication and can usually be controlled with topical 1/100,000 epinephrine,
argon plasma coagulation (APC), or neodymium:yttrium-aluminum-garnet (Nd:YAG) laser photoablation.
Some entities, like renal metastases or carcinoids, are hypervascularized and more prone to bleeding, but
do not depict contraindications for bronchoscopic sampling. Identification of risk factors for bleeding and
the respective correction is necessary prior to bronchoscopy.
Biopsy specimens of segmental lesions beyond the field of vision are often obtained under
fluoroscopic control or other navigation techniques like endobronchial ultrasound (EBUS).20 Biopsy
through the flexible bronchoscope requires persistence and practice, especially when the lesion is
localized in the apical segments of the upper lobes. The accuracy of establishing the diagnosis of
carcinoma increases up to the number of three to four biopsies and does not significantly increase with
higher numbers. Many lesions have large necrotic areas, which do not provide diagnostic material if a
biopsy is performed. In those cases, sampling until mucosal bleeding is advised in order to raise the
diagnostic yield. After each biopsy, the forceps is placed in saline. Concentrated formalin solution is
added at the conclusion of the procedure to give a final dilution of 10%.
Forceps biopsies are the most often used sampling instruments in visible airway lesions. Many
different designs and sizes are available on the market. No comparative studies are available to clearly
demonstrate the advantages of one single kind of forceps and the choice of which one to use first is
dependent on the location and shape of the lesion. Through the invention of cryotechnology, sampling of
bigger lesions without squish artifacts is possible. Especially in case of flat, tangential lesions this
technology depicts a major improvement.
In the area of personalized therapy, with the need for sampling an adequate amount of tissue in order to
perform molecular marker assessment, other techniques like bronchial brushing, washing,21 or needle
aspiration22 are less frequently used in sampling endobronchial lesions.
Endobronchial mucosal changes may not be detected in peripheral masses. Under these circumstances,
fluoroscopic guidance and/or EBUS23 is essential to confirm the correct sampling position. Ideally, the
lesion is seen to move during fluoroscopy when it is sampled.
Peripheral Pulmonary Lesions

As with endobronchial lesions, many different biopsy instruments can be used to sample peripheral
lesions. In case of localized pulmonary pathologies, the use of navigation systems has to be warranted in
order to successfully hit the target. Modern navigation techniques such as EBUS, guide sheath, virtual
bronchoscopy (VB), and electromagnetic navigation have pushed the diagnostic yield notably in small
lesions. By this means, pulmonary nodules measuring 2 cm which where sampled with a prior reported
overall sensitivity of 33% by fluoroscopy-guided bronchoscopy can now be sampled with a pooled
diagnostic yield of 61%.10,14 Nonetheless, the conventional and most widely used guidance system
remains fluoroscopy. A careful assessment of the respective segmental bronchus leading to the pulmonary
lesion prior to the procedure is of particular importance when employing EBUS or fluoroscopic guidance.
After wedging the bronchoscope into the desired bronchus, the sampling instrument is being inserted and
advanced to the lesion. At this point, guidance via fluoroscopy helps the operator to guide the sampling
instrument toward the lesion. The sensitivity of the transbronchial approach to peripheral lesions varies
greatly, with all studies showing a strong correlation between size of the lesion and diagnostic yield of the
fluoroscopic-guided approach.
When it comes to diffuse lung diseases, such as sarcoidosis, the procedure can be performed without
means of a guidance system. Here again, the use of cryobiopsy seems to be particularly promising and
appeared to be safe and feasible in recent studies.24 Placement of the biopsy forceps near, but not at the
lung surface minimizes the risk of pneumothorax.
In the event of bleeding, the bronchoscope is left wedged in the segmental bronchus and suctioning is
employed. Irrigation with 1/100,000 epinephrine or iced water can be used if the bleeding does not
resolve spontaneously. Should the bleeding still continue, tamponading the segment bronchus or
instillation of fibrin might be necessary.
Five to seven transbronchial biopsy specimens have been found to provide the optimal diagnostic
yield. These samples should all be taken unilateral to avoid bilateral pneumothorax and help localize the
bleeding site in the event of significant hemoptysis. Coagulation studies and a platelet count should be
obtained preoperatively to identify patients at high risk for bleeding. Uremic patients are also known to be
at high risk for significant hemoptysis, and precautions must be taken.
Navigational Bronchoscopy
Owing to its low diagnostic yield, bronchoscopic sampling of small pulmonary nodules <2 cm was
previously not recommended by The American College of Chest Physicians.25 Due to the recent
development of innovative navigation techniques such as EBUS, guide sheath, VB, and electromagnetic
navigation bronchoscopy (ENB), this statement was revised, taking the higher diagnostic yield into
account.26
EBUS currently depicts the most practically used bronchoscopic navigation device in the diagnosis of
peripheral lung lesions. Consisting of a rotating piezoelectric crystal embedded in a flexible catheter, the
probe produces a 360-degree ultrasound image of the surrounding structures, providing real-time
confirmation of the correct position once the target lesion is reached. Aside from its utilization in the
assessment of peripheral lesions, it offers a detailed depiction of the airway wall with its different layers,
for example, in the diagnosis of carcinoma in situ. When approaching peripheral lung lesions, the
miniprobe is advanced into the target bronchus like a forceps. While advancing the miniprobe, a
characteristic “snowstorm like” whitish ultrasound image, representing air-filled alveolar tissue, can be
seen. Once a solid tumor is reached, the ultrasound image changes to a homogenous ultrasound image with
continuous hyperechoic margins.
When the target lesion is identified by EBUS, it is necessary to remove the ultrasonic probe in order to
introduce different biopsy instruments. This depicts a methodologic limitation of the EBUS-TBB
approach. The operator has mainly two options to overcome this constraint. First, EBUS can be used in
combination with a guide sheath. While removing the miniprobe, the guide sheath is left in place, offering
an advanced working channel for the biopsy instrument. Another EBUS guiding option depicts the
fluoroscopic registration of the miniprobe position once the target lesion is reached. By means of
fluoroscopic guidance, the biopsy instrument is thereafter advanced to the identical location. Shorter
duration and retrenchment are potential benefits of this approach at the expense of radiation burden.
Fluoroscopic registration of the miniprobe position seldom depicts an extra effort since fluoroscopic and
EBUS guidance are combined in order to reach the target lesion either way.
Other relatively novel guidance techniques are VB and ENB. VB originates from reconstructed helical
CT images and offers a three-dimensional (3D) rendering resembling the bronchoscopical investigation of
the lung. VB has no adverse effects except radiation exposure, but requires thin-section CT scans with a
slice thickness of 1.25 mm or less, depending on the system used. The hereby-constructed VB animation
enables the operator to examine the calculated pathways prior to the intervention. During the procedure,
VB images are synchronized with the bronchoscopic video in order to facilitate navigation. Especially in
conjunction with an ultrathin bronchoscope, with its ability to reach more distal airways where exact
navigation is getting more and more complicated, VB offers advantages.27
Compared with VB, ENB provides real-time navigation through its ability of mapping instruments
within an electromagnetic field. Besides providing navigation to peripheral lung lesions it also offers
guidance to mediastinal and hilar lymph nodes. As well as VBN, high-quality CT scans are required for
ENB in order to provide an adequate resolution for the creation of a 3D map of the airways. The guidance
system consists of four main components: a disposable working channel and guide catheter, a software
providing planning and navigation views of the lungs through merged CT images and hardware including
computer, monitors, and the electromagnetic location board. The location board emits low-frequency
electromagnetic waves creating an electromagnetic field that enables the 3D registration of a sensor in the
distal tip of a steerable navigation catheter. During the procedure the board is placed under the cranial
end of the mattress on the bronchoscopy table. The steerable guide catheter serves as an extended working
channel. Through its curved tip it can be steered by rotating the catheters handle.
The major disadvantage of ENB is the high costs accompanied by the procedure. A single use
locatable guide costs between US $700 and $1,000, when utilizing the SuperDimension system.
In recent years, the development of bronchoscopic navigation techniques has led to a distinct
improvement in the diagnosis of peripheral lung lesions without compromising safety. By this time,
bronchoscopy competes with the transthoracic approach to small lung lesions. While EBUS already
depicts a routinely used technique, VB and EMN are still rarely employed navigation tools. This is
mainly due to high costs involved and the concomitant technologic requirements.
FIGURE 18.11 Transbronchial needle for aspiration of mediastinal and hilar lymph nodes and masses.
Further increase of the diagnostic yield is possible by means of combining navigation techniques such
as EBUS with EMN or VB.28,29
Transbronchial Needle Aspiration

Since the mid-1980s, the technique of TBNA, championed by Wang,30 has found increasing favor in
sampling subcarinal and paratracheal lymph nodes and for examining widened spurs endoscopically.
Cytologic and histologic specimens are obtained by passing an ensheathed 21-gauge needle down the
working channel of the bronchoscope (Fig. 18.11). Failure to withdraw the needle into the protective
outer sheath has led to serious and costly repairs of flexible bronchoscopes, as documented by Mehta and
colleagues.31 Once the sheath is advanced beyond the tip of the scope, the 1.5-cm needle is advanced
beyond the sheath, through the wall of the trachea or bronchus, and into the mediastinal mass or suspicious
lymph nodes (Fig. 18.12). Obviously, in choosing the location to be sampled, knowledge of the location
of the major vessels adjacent to the airway is essential. The needle can be reinserted into the region in
question several times, applying gentle suction; suction must be avoided once the needle is completely
withdrawn. Different workup approaches of the aspirate are possible, depending mainly on the local
preferences of the cytopathologist. For example, 5 mL of saline can be flushed through the needle to
obtain a cytologic sample, which is immediately centrifuged; the resulting pellet is resuspended in 1 mL
of saline. The supernatant cell suspension is fixed in 95% ethanol and prepared with Papanicolaou stain.
Tissue fragments are fixed in Bouin solution and submitted for a cell block. Alternatively, the sample can
be crossed out directly on a slide by flushing air through the needle.
TBNA should be performed before brushing or lavaging to avoid contaminating the airway, which
could lead to an increased false-positive rate. Increased diagnostic accuracy is noted when TBNA is
performed with visible evidence of submucosal or peribronchial tumor.
Preoperative CT or MRI is imperative to define precisely the lesion in question as well as to assess
the proximity of major vessels (Fig. 18.13).
The invention of linear endobronchial ultrasonography has changed the practice of bronchoscopic
biopsy, in particular, the role of bronchoscopy for invasive mediastinal lymph node staging in lung cancer.
It allows for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and
depicts a real-time procedure. In contrast to conventional TBNA, the yield of EBUS-TBNA does not
seem to depend on the expertise of the bronchoscopist.32
The convex probe endobronchial ultrasound (CP-EBUS) bronchoscope has a 7.5-MHz convex
transducer at the tip, set at a 35-degree forward oblique angle. The angle of view is 80 degrees whereas
the direction of view is similar to the ultrasound probe. The EU-ME1 ultrasound processor (Olympus,
Tokyo, Japan) is equipped with a power Doppler mode as well as a color Doppler mode, leading to a
safer way of sampling. The outer diameter of the ultrasound tip is 6.9 mm which prohibits nasal insertion.
With a 2.2 mm working channel, dedicated 21- or 22-gauge needle can be used to perform EBUS-TBNA.
Having an exit at 20 degrees, the TBNA needle can be visualized through ultrasound and optics. Like the
conventional TBNA procedure, EBUS-TBNA can be performed on an outpatient basis under conscious
sedation. The use of a rigid bronchoscope facilitates the procedure through inhibition of the cough reflex
by general anesthesia and the fast and atraumatic extraction and reinsertion of the scope. Two monitors
are employed when performing EBUS-TBNA: one for the ultrasound image and one for the optic that is
located proximal to the ultrasound probe. Due to the invisibility of the ultrasound tip, careful attention
should be made when advancing the scope. In order to get an ultrasound image of the desired lymph node
station, the tip of the scope is flexed and gently attached onto the airway. Landmarks, provided by the
International Lymph Node Map, are used to identify the different lymph node stations. Lymph nodes with a
diameter above 1 cm in short axis, a round shape, and heterogeneous echogenicity and without the
presence of hila structures are suspicious for malignancy and should be sampled.
FIGURE 18.12 Transbronchial needle aspirate of subcarinal lymph nodes (A), a mass at the bifurcation of the left mainstem
bronchus (B), a nodal mass at the right tracheobronchial angle (C), and a central mass in the left upper lobe (D).
FIGURE 18.13 A: Photograph demonstrating bronchoscopic placement in the distal trachea of the ultrasound catheter through
the biopsy channel. The balloon is inflated to make contact with the entire surface of the trachea. Since the entire tracheal lumen
is occluded, ventilation is held until the examination can be completed. B: Photograph taken from an ultrasound examination of
the distal trachea demonstrating the right main pulmonary artery and both right and left paratracheal lymph nodes.
Before starting EBUS-TBNA, all lymph node stations should be assessed in a systematic way. When
sampling, TBNA should always be performed from N3 to N1 nodes in order to avoid contamination.
EBUS-TBNA offers a minimal invasive, precise, and safe evaluation of the mediastinum and the hilar
region. The reach covers the one of cervical mediastinoscopy plus hilar lymph nodes. With this, EBUS-
TBNA depicts an alternative to mediastinoscopy for mediastinal staging of NSCLC and offers a great
diagnostic yield in the diagnosis of lymphoma and sarcoidosis. A study by Annema et al. could show that
a lung cancer staging strategy combining EBUS and surgical staging compared with surgical staging alone
resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies.11
One of the main intraoperative complications of TBNA is mild airway bleeding. Mediastinal infection
depicts a rare complication of TBNA.
BRONCHOALVEOLAR LAVAGE
BAL is a useful technique to recover material from the terminal bronchiole and alveolar sacs. It depicts a
low-risk investigation and acquires diagnostic information with high value in certain interstitial lung
diseases (ILD). In the diagnosis of alveolar proteinosis, alveolar hemorrhage, bronchoalveolar carcinoma
and Langerhans cell histiocytosis, surgical lung biopsy can be avoided by this means in most cases.33 In
other ILDs, BAL offers additional information that must be interpreted in conjunction with clinical and
high-resolution CT findings. In general, fibrosing conditions are characterized by a neutrophilic and
eosinophilic BAL, whereas lymphocytosis accounts for granulomatous diseases. Determination of the
CD4/CD8 ratio may be helpful in some cases (e.g., sarcoidosis, hypersensitivity pneumonitis).34 In daily
clinical routine BAL also plays a role in the assessment of unspecific infiltration, infectious and rarely
malignant disease.35
BAL is performed by wedging the tip of the flexible bronchoscope into a sub-segmental bronchus and
then irrigating and aspirating the segment with 20- to 50-mL aliquots of sterile saline. The middle lobe
and lingual are preferred in diffuse lung diseases in order to attain a better recovery. A total volume of
100 to 300 mL of saline is instilled, and 40% to 60% of this volume is recovered as a specimen,
depending in part on the patience of the bronchoscopist. In patients who have loss of elastic recoil,
recovery of fluid is less, according to Helmers and Hunninghake,36 because the sub-segmental bronchiolar
walls collapse when suction is applied. In addition to microbiologic studies, lavage specimens have been
used to diagnose malignancies and to obtain inflammatory cells and pneumocytes for research studies, as
discussed by Kvale.37
BAL is a useful technique for obtaining microbiologic specimens, especially in immunosuppressed
patients. Fungal, bacterial, and viral culture specimens are easily acquired. In patients with acquired
immunodeficiency syndrome, the diagnosis of Pneumocystis carinii pneumonia also can be made with a
diagnostic yield exceeding 85%, according to Pisani and Wright.38
Potential side effects of BAL include bronchospasm, hypoxia, transient fever, and transient decline in
pulmonary function. Fever occurs typically few hours after bronchoscopy and resolves mostly within 24
hours. Major complications are rare and affect patients with severe lung or heart disease.39 There are no
additional absolute contraindications for BAL apart from those of bronchoscopy. BAL is not associated
with mortality and has a low complication rate (0 to 2,3%).13
COMPLICATIONS
Despite the relatively low risk, the benefits of bronchoscopy must be weighed against the potential for
complication in each patient. Credle and colleagues14 reported a complication rate of 0.08% and a
mortality rate of 0.01% in more than 24,000 flexible bronchoscopies. Premedication and topical
anesthesia were responsible for 11 of the 22 major complications. More dilute solutions of the topical
anesthetic agent provide a wider margin of safety. Intravenous diazepam counteracts the systemic effects
of excessive amounts of lidocaine and should be readily available. Elderly and debilitated patients should
receive minimal premedication, and topical anesthesia must be administered in carefully measured
amounts. Respiratory depression is a frequent complication of intravenous sedation in this patient
population.
Careful evaluation and preparation of the patient as well as adequate monitoring facilities are required
to minimize complications. Pulse oximetry, continuous electrocardiography monitoring, and intermittent
cuff blood pressure readings are all important parameters. Supplemental oxygen is given to minimize the
risk of hypoxemia. Respiratory depression has been documented in the recovery period. According to
Peacock and colleagues,40 topical anesthesia may be responsible for prolonged periods of respiratory
depression. Belen8 and Matsushima41 and their colleagues recommend that patients should not undergo
pulmonary function testing for at least 8 hours after bronchoscopy. General anesthesia may be indicated if
the patient has a history of intolerance to topical anesthetic agents or of difficult endoscopic examinations
under local anesthesia.
Massive bleeding is a recognized complication of bronchoscopy. Bleeding disorders must be
corrected by anticoagulant reversal or by the infusion of platelets either during or immediately before the
procedure. However, according to Herth and colleagues,39 aspirin does not increase the risk of bleeding
after transbronchial biopsies. There are no absolute contraindications for flexible bronchoscopy. A
brushing or biopsy should not be done unless the prothrombin time is >40% of normal and the platelet
count is >50,000/mL. Patients with uremia or pulmonary hypertension also bleed easily; brushings and
biopsies in these patients should be avoided. Topical epinephrine solution of 1/100,000 can be instilled
into the segmental bronchus before brushing to minimize bleeding or control established bleeding. In the
event of endobronchial hemorrhage, the scope should be wedged in the segmental bronchus to tamponade
the lumen, thereby allowing blood in the distal airway to clot. By applying suction, the distal airways are
occluded, leading to a faster and more distal clotting.
A pneumothorax can occur in up to 3% of patients undergoing a transbronchial lung biopsy. When lung
biopsies are performed for diffuse lung disease, fluoroscopic control might lower the risk for
pneumothorax. Patients may complain of sharp chest pain if the parietal pleura is irritated.
Bronchospasm is a potential complication in patients with known asthma, but it also may occur in
those with severe chronic obstructive lung disease. Severe asthmatics should be premedicated with
corticosteroids and bronchodilators. Laryngospasm is the direct consequence of inadequate topical
anesthesia; it can be avoided if the topical agent is placed precisely onto the vocal cords and into the
tracheobronchial tree.
Patients with hepatitis, human immunodeficiency virus, or suspected active tuberculosis can undergo
bronchoscopy if special care is taken by all personnel in the handling of the specimens and if all
instruments used are appropriately sterilized. Infections transmitted after instruments are properly cleaned
are uncommon. However, tuberculosis and gram-negative organisms have been transmitted by
inadequately cleaned flexible bronchoscopes.
Sepsis immediately following bronchoscopy is uncommon but fever is seen occasionally. Well-
designed prospective studies have documented an exceedingly low risk of bacteremia during and
following bronchoscopy. Nevertheless, BAL in patients with pneumonia can cause a sepsis-like clinical
picture, according to Plugin and Suter.42 Therefore, considering the risks, Dajani and colleagues24 report
that the American Heart Association recommends that patients with underlying valvular heart disease
receive prophylactic antibiotics before bronchoscopy to minimize the risk of bacterial endocarditis. This
recommendation also holds for patients with joint replacements.
Bronchoscopy should not be performed in a patient with bilateral vocal cord paralysis. The passage of
the bronchoscope through the glottis can lead to edema, causing life-threatening airway obstruction and
necessitating emergent intubation or tracheostomy. Patients with tracheal obstruction should be examined
cautiously; if the airway is severely compromised, biopsy or dilation of the tracheal lesion should be
avoided unless one is prepared to proceed directly to rigid bronchoscopy or definitive tracheal surgery.
CLEANING OF FLEXIBLE BRONCHOSCOPES

The care and cleaning of fiberoptic flexible bronchoscopes has become an issue of some concern. A
variety of gram-negative and fungal organisms and Mycobacterium tuberculosis have been recovered
from inadequately cleaned bronchoscopes, and some, including M. tuberculosis, have allegedly been
transmitted to patients through a contaminated bronchoscope, causing clinical infection, as reported by
Sammartino,43 Gubler,29 Nicolle,44 Frazer,27 and Agerton3 and their colleagues as well as by Prakash.45 In
some cases, the bronchoscope did not undergo adequate mechanical cleaning before being disinfected.
Vigorous manual cleaning of bronchoscopes, including running brushes down the instrument channel, is
essential, because Nicholson and colleagues46 have shown that without proper prior manual cleaning,
even immersion for 60 minutes in 2% glutaraldehyde will not eliminate M. tuberculosis from the
bronchoscope. Wheeler and colleagues47 identified a problem with inadequate cleaning of the suction
valve. In other cases, the automated disinfecting machines were faulty, according to Gubler29 and Frazer27
and their colleagues. Guidelines for cleaning fiberoptic bronchoscopes have been well established and
reported by Martin and Reichelderfer,48 but clinical practices vary widely among institutions.
SPECIAL CONSIDERATIONS
FOREIGN BODY RETRIEVAL

The suspicion of foreign body aspiration is an indication for bronchoscopy both to establish the diagnosis
and attempt removal. However, in using flexible bronchoscopy, the endoscopist must be absolutely certain
that a more complicated problem does not result from either losing the foreign body, impacting it distally
in the tracheobronchial tree, or causing airway bleeding from manipulation. In this regard, the rigid
bronchoscope remains the instrument of choice, allowing good exposure and airway control, especially in
removing foreign bodies from the airways of infants and children, according to Weissberg and Schwartz49
as well as Pasaoglu and colleagues.50 Grasping forceps, snares, baskets, and balloon-tipped catheters
have all been used to extract foreign bodies using flexible bronchoscopy, as summarized by Lan and
colleagues51 and Mehta and Rafanan.52 Although foreign bodies in adult patients can be retrieved with
various types of snares passed down the working channel of the fiberoptic bronchoscope, most foreign
bodies can be removed easily and quickly with a rigid bronchoscope, especially in the pediatric
population.
Inglis and Wagner53 reported the advantages of combining flexible and rigid bronchoscopy to improve
the detection and retrieval rate of foreign bodies, especially when fragments are lodged in the distal
airway or in the upper lobe bronchi (Fig. 18.14). Clearly endoscopists engaged in the art of foreign body
retrieval must be facile with both rigid and flexible bronchoscopy, according to Kelly and Marsh.54
FIGURE 18.14 Flexible bronchoscope with a foreign body basket retrieving a tooth, and a rigid bronchoscope with foreign body
forceps grasping peanut.
AUTOFLUORESCENCE BRONCHOSCOPY
In some centers, sputum cytology is used to screen patients at high risk for malignancy. Others believe that
surveillance bronchoscopy should be performed in these patients because it is much more successful in
establishing the diagnosis and can localize the pathology. Occasionally patients with suspicious or
positive cytologic findings are identified in the presence of a normal chest radiograph. In such cases, the
mouth, pharynx, larynx, and entire tracheobronchial tree must be examined carefully to identify the site of
the early carcinoma.
Autofluorescence bronchoscopy has been a particularly valuable aid in identifying the site and extent
of disease. Using a helium–cadmium laser or a filtered xenon lamp for illumination with blue light, in
vivo spectroscopy with an optical multichannel analyzer is performed during the bronchoscopic
examination. Areas of severe dysplasia and carcinoma can be recognized by their decrease in
autofluorescence intensity due to the thickening of the epithelial layer. By contrast, normal mucosa
appears predominantly in the short (green) wavelengths of the visible spectrum, as documented by Lam
and colleagues.55 Preferential horizontal diffusion of longer-wavelength fluorescent light from adjacent
normal submucosa causes the premalignant and malignant epithelium to appear red (Fig. 18.15).
Several fluorescence bronchoscopy systems are commercially available. The ultimate value of
fluorescence bronchoscopy, according to Weigel and coinvestigators,56 depends on the cost of the
equipment, its ease of use, and the future of screening bronchoscopy for the detection of early lung cancer,
including patients who have undergone a previous curative surgical procedure.
NARROW BAND IMAGING

Narrow band imaging (NBI) is a relatively novel technique that uses a narrow band filter instead of the
conventional RGB broadband filter in order to enhance the mucosal contrast, particularly the microvessel
structure. The optical absorption and scattering features of tissue are wavelength dependent with longer
wavelengths penetrating deeper into tissue. Thus the white light used in conventional bronchoscopy
produces an image of many different tissue layers that is bright but slightly blurred. In contrast, NBI only
employs a narrow spectrum of blue and green light with short wavelengths. The maximum absorption
wavelength of hemoglobin is around 415 nm and lies exactly within the wavelength range of NBI. This is
why NBI is able to greatly enhance microvessel structure. The better visualization of vessel anomalies in
bronchial mucosa leads to an improved detection of malignant lesions and severe mucosal dysplasia.36 In
the detection of early lung cancer it therefore depicts an alternative to autofluorescence bronchoscopy
with a comparatively higher specificity without significant loss in sensitivity.4
FIGURE 18.15 A: Photograph of a normal-appearing bronchial mucosa using a white light source. B: Photograph of the same
bronchial mucosa using a helium–cadmium laser light source to induce autofluorescence.
MASSIVE HEMOPTYSIS
Massive hemoptysis (600 mL in 24 hours) should be assessed with a rigid bronchoscope urgently but
under optimal conditions. Airway control with rapid and repeated suctioning is readily accomplished,
and a major bronchus can be packed with an epinephrine-soaked pledget or inflation with a Fogarty
balloon. Although massive hemoptysis can be assessed initially using a flexible bronchoscope through a
cuffed endotracheal tube, clots are not easily removed, and they often obscure visualization. The site of
massive hemoptysis must be localized, as described by Saw and colleagues,57 to prepare for possible
surgical excision, Nd:YAG laser photoablation, endobronchial tamponade, or bronchial artery
embolization.
With Nd:YAG laser photoablation, rigid bronchoscopes permit photoablation and rapid debridement
of an obstructing or bleeding lesion while simultaneously maintaining control of the airway and providing
a suction channel for the evacuation of clots and secretions. The rigid bronchoscope is necessary for the
placement of silicone endobronchial stents. However, self-expanding metal bronchial stents can be
deployed through a large endotracheal tube.
INTERVENTIONAL BRONCHOSCOPY
The past two decades have seen the advent of many endobronchial interventional procedures. These
include endobronchial electrocautery, Nd:YAG laser photoablation, cryoablation, photodynamic therapy
(using chemical tissue sensitizers, such as porphyrin compounds), the placement of endobronchial stents,
and the placement of radioactive brachytherapy sources in the form of seeds or catheters. These topics are
discussed elsewhere (see Chapter 113).
PEDIATRIC BRONCHOSCOPY
The bronchoscopic examination of infants and small children requires expertise and familiarity with all
available instrumentation, as emphasized by Wood.58 Examination of the infant airway using smaller Storz
rigid instruments with viewing telescopes is usually performed under general anesthesia (Fig. 18.16). A
3.0- or 3.5-mm sheath permits passage of the 2.7-mm optical telescope, which provides a good view of
the infant’s bronchi. A small suction catheter can be passed down the barrel. Secretions are readily
removed for microbiologic studies. Small biopsy and foreign body forceps can be manipulated through
this small channel with the viewing telescope in place. Muntz and colleagues59 have reported their
experience in performing transbronchial lung biopsies in the pediatric population through a rigid
bronchoscope.
Flexible fiberoptic bronchoscopy has become a practical tool in pediatrics with the development of a
bronchoscope with an external diameter of 3.5 mm and a channel of 1.2 mm. It has found favor in clearing
secretions as well as aiding in localizing and retrieving foreign bodies. Examination of infants may be
performed under sedation and topical anesthesia, provided the procedure is brief. Airway stenosis and
obstruction are contraindications to flexible instrumentation.
Complications related to pediatric bronchoscopy can be life threatening. A small bronchus may be
perforated with resultant pneumothorax or pneumomediastinum. Laryngospasm, subglottic edema, and
bronchospasm may all result from manipulation and may compromise the airway. Stridorous breathing
after the procedure may be an indication to humidify supplemental oxygen and to administer systemic
corticosteroids.
FIGURE 18.16 Infant rigid bronchoscope (Storz), 3.5-mm diameter with fiberoptic lighting. A: Components (from top to
bottom): forward-viewing endoscopic telescope (Hopkins); with detachable window plus side channels for connection to
anesthesia equipment, suctioning, and insertion of proximal light; proximal prismatic light carrier; and fiberoptic lighting cable. B:
The bronchoscope after assembly.
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SUGGESTED READINGS
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19
Ultrasound and Endoscopic Bronchoscopic
Ultrasound in the Evaluation of the Lungs,
Mediastinum, and Pleura
Basil Nasir ■ Moishe Liberman
The use of ultrasound is gaining popularity in medicine. The ultrasound has become an indispensable
component of the evaluation of patients in multiple medical specialties such as obstetrics, cardiology,
emergency medicine, and trauma.1 There are several reasons why this is, and it relates to the advantages
of ultrasonography, when compared to other imaging modalities:
1. Portability: With imaging modalities such as computed tomography (CT) and magnetic resonance
imaging (MRI), the patient needs to travel to a specialized location to be imaged. In the case of
ultrasound, the examination can be performed at the bedside or in the office. Although portable plain
films of the chest are routinely performed in all hospitals, this results in a substantially lower image
quality. The quality of the sonogram depends on multiple parameters such as operator skill, experience,
quality of the equipment, and technical patient-related aspects and is independent of location. One can
obtain images of excellent quality with a bedside exam. This is especially advantageous in patients who
are deemed too unstable for transport or patients in an intensive care setting. In the emergency
department, for example, ultrasound has become an elementary method of evaluating trauma victims,
especially if deemed unstable for CT scanning.
2. No radiation exposure.
3. Real time: The ability to perform real-time ultrasound is especially helpful during image-guided
procedures, such as thoracentesis or needle-biopsy technique. This is most pronounced when
performing fine-needle aspiration of mediastinal lymph nodes during endobronchial and
endoesophageal endoscopic ultrasound. The ability to identify the structure being biopsied, image it
accurately, and visualize the needle as it penetrates the structure adds a level of safety and accuracy not
obtained using non–real-time image-guided techniques.
4. Economic: In today’s cost-conscious health systems, the ability to cut cost at as many levels as possible
is of utmost importance. However, this point needs to be further clarified. The cost of obtaining a
portable ultrasound machine for surface ultrasonography is in excess of $10,000. However, once the
initial capital is spent, the additional cost of performing ultrasound is negligible, as no additional
equipment is needed and the maintenance cost for such machines is very low. This is slightly different
for endoscopic and endobronchial ultrasound because the maintenance costs are substantially higher.
There are several advantages that argue for the use of ultrasound in thoracic surgery; however, there
are some disadvantages associated with its use:
1. Operator dependent: This is one of the biggest barriers to the adoption of the ultrasound. Sonograms are
not as intuitive as CT images and require some degree of familiarity, training, and experience. In
addition, the strength of ultrasound lies in analyzing real-time images, which means that to get the most
out of ultrasound, the surgeon needs to be the one performing the scanning. Obviously, this may prove
impractical in a very busy practice. There is also the issue of competency with sonography and training.
Currently, there is no standardized means of training thoracic surgeons in the use of ultrasound or to
assess competency.
2. Poor resolution of images in certain body areas and body types.
3. Presence of artifact: Although this may seem to be a shortcoming of the ultrasound, the interplay of
artifact and the recognition of what is normal and what is abnormal can be very helpful in the
assessment of disease of the thoracic cavity. In fact, the recognition of pneumothorax on ultrasound is
heavily dependent on analyzing the change in artifact as opposed to visualizing a space, as is the case
with x-ray images.2
4. Poor performance in imaging hollow organs: The presence of air renders ultrasound very difficult, and
the imaging of hollow organs is extremely difficult with sonography. This fact alone makes the use of
ultrasound in thoracic disease counterintuitive given that the lungs are full of air. However, in the setting
of thoracic disease, the point of interest is usually devoid of air, and replaced with fluid or solid
material as is the case with pleural effusions and consolidated lung. It is this feature of thoracic disease
that makes ultrasound not only possible, but very suited for such circumstances.
SURFACE ULTRASOUND
The ability to successfully utilize ultrasound in the management of thoracic disease depends largely on
operator expertise. Therefore, it is crucial for surgeons to familiarize with the principles of ultrasound,
the sonographic appearance of normal chest anatomy as well as the equipment used to produce the
sonogram.
THE ULTRASOUND MACHINE

A wide variety of different ultrasound processors are available for use. Most modern ultrasound scanners
are multifunctional and can be used for more than one application with the ability to vary the settings to
suit different scenarios. Frequently, modern scanners will have different preadjusted settings to suit each
application that the operator can select from. This is a very convenient feature; however, it is still
beneficial to become familiar with the different parameters in order to be able to troubleshoot rare
circumstances where the preadjusted settings are not optimal. Regardless of which device is used, the
basic format and principles of ultrasound remain the same.
1. Mode of ultrasound: These include A-, B-, and M-modes. A-mode is of historical interest and is a one-
dimensional image generated by a single crystal that is of limited use. B-mode is the commonly
performed sonogram which is most frequently seen. The image is generated by displaying reflected
sound waves on a grayscale corresponding to its amplitude. B-mode forms the basic setting for thoracic
ultrasound and will be used almost exclusively by thoracic physicians. M-mode is used to record
moving structures over time. The M-mode is more commonly used in echocardiography, as opposed to
imaging of other organs within the thoracic cavity.
2. Probe selection: There are different types of probes, and each probe has specific characteristics that
make it more applicable for certain situations. The most common probes are shown in Figure 19.1. A
linear array probe has crystals arranged in parallel and generates a rectangular field of view. These
probes are usually used with higher-frequency settings and are well suited for superficial evaluation of
structures such as the chest wall. A curvilinear probe produces a divergent ultrasound beam that
produces a “pie-shaped” image. These are useful for deeper structures and are typically associated with
lower-frequency scanning. The smaller cardiac probe is similar to a curvilinear probe, but has a
smaller footprint and is particularly useful for scanning between ribs.
3. Frequency: The frequency of the ultrasound wave determines the resolution of the image as well as the
depth of penetration. Higher frequency results in better resolution, but sacrifices depth. Typical
frequency settings for thoracic ultrasound range from 3.5, 5, 7.5, to 10 MHz. The 7.5- or 10-MHz
settings are used for imaging of the chest wall where detailed resolution is needed as opposed to depth,
whereas 3.5-MHz settings are more suitable for detection of pleural effusion and pulmonary nodules.
4. Gain: As the image produced is dependent on the amount of ultrasound wave reflected back, there is
always some attenuation of the returned signal. The machine compensates for this by amplifying the
signal, and the degree of amplification is what is referred to as the gain. Changing the gain setting alters
the interface between black, white, and gray on the screen. It is used to vary the contrast between
different structures on the screen. This is adjusted manually. If set too low, there will be a decrease in
the image acquisition and some echoes will not be detected. If set too high, there will be an increase of
the amount of echoes detected and the development of artifactual noise.
NORMAL SONOGRAPHIC THORACIC ANATOMY

The chest wall, including the skin, subcutaneous tissue, and musculature, is easily identified as alternating
echogenic soft tissue layers. By using a high-frequency probe, one can discern the different layers of the
chest wall all the way down to the pleura (Fig. 19.2). Ultrasound examination of the chest is limited by
two major factors. The first is the presence of ribs. Ribs absorb the ultrasound beam resulting in acoustic
shadowing deeper to it. As a result, there is no visualization of structures beyond it. The second factor is
that aerated lung reflects ultrasound waves completely and, therefore, the appearance of a normal, aerated
lung shows a granular pattern. This, however, results in the classical appearance of the pleura as an
echogenic line. In a normal chest sonogram, the pleura appears as the most echogenic structure on B-mode
scans. When using a high-frequency probe, one can discern the parietal and visceral pleura separately.
The collective thickness of both should not exceed 2 mm. One of the most important structures to identify
is the diaphragm. The diaphragm appears as a thin, echogenic structure, which is usually oriented in a
direction that is more or less perpendicular to the screen (Fig. 19.3). This could also be confirmed by
identifying the liver or spleen caudally.
FIGURE 19.1 Ultrasound probes: (A) Cardiac or sector probe; (B) Linear probe; (C) Curvilinear probe.
FIGURE 19.2 Normal ultrasound: Image “A” is a surface sonogram of the chest wall taken with the linear probe set at a 10-
MHz frequency. The letter “M” denotes the chest wall musculature, seen as alternating layers of echogenic lines representing
the muscle fibers. The red arrow points to the echogenic pleural line, with a normal underlying line shadow. Image “B” is also a
normal ultrasound picture showing the horizontally oriented A lines. The red arrow refers to the pleural line. The blue arrows
refer to A line. Notice the equal intervals between all the lines, which is the hallmark of A lines. In image “B,” one can also note
the rib in cross-section, which appears as an oval, with the red arrow superimposed on it. The interface produced by the rib
reflects all the ultrasound waves, resulting in failure to image structures deep to it.
Due to the interface between the chest wall and the highly reflective air-containing lung, several
artifacts can be seen during pulmonary sonography3:
1. A lines: These are repetitive artifacts that are oriented horizontally on the screen. They represent a
reproduction of the echogenic pleural line. They are characteristically spread at distances equal to the
distance from the transducer to the pleural line, and hence occur at normal intervals. This is a normal
finding that indicates a normal lung surface.
2. B lines: These are vertically oriented artifact lines, also known as comet-tail artifacts, which start from
the pleural surface and run to the bottom of the screen. They are expected findings whenever there is an
air–fluid interface, as is the case with the lungs. They are also normal findings, but an excessive amount
of B lines is indicative of increased lung water content.
FIGURE 19.3 Ultrasound showing diaphragm: Sonogram taken using a curvilinear probe set at 3.3 MHz. There is a small
pleural effusion (PE), which enhances the visibility of the diaphragm (D).
Video 19.1 shows a real-time sonogram of a normal chest wall without pathology in both B- and M-
modes.
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Video 19.1 Pneumothorax.
PNEUMOTHORAX
Traditionally, the diagnosis of pneumothorax was made clinically and confirmed radiographically using
chest plain films or computed tomography (CT), with little utility of ultrasound. Ultrasound, however, has
a higher sensitivity for detecting pneumothorax when compared to plain films of the chest; however, their
specificity is comparable.4,5 Despite this, outside of trauma settings, ultrasound has not been routinely
adopted in the evaluation of a pneumothorax. The main reason for this is lack of expertise. From plain
films or CT images, one can visualize the pneumothorax, whereas with ultrasound, identification of a
pneumothorax is dependent on detecting the absence of typical artifact associated with visceral-to-
parietal pleural apposition. Without appropriate training or expertise, this can be difficult.
The sonographic signs of a pneumothorax include:
1. Absence of lung sliding (Video 19.2): During real-time sonography of the chest, the horizontal
movement of the lung (visceral pleura) relative to the chest wall (parietal pleura) can be readily seen.
This is termed the lung sliding sign. The absence of this sign has a sensitivity of greater than 95%.6 Just
as important, the detection of lung sliding is a very reliable sign against the presence of a pneumothorax
with a specificity of greater than 95% and a negative predictive value that approaches 100%.6
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2. Absence of B lines (Video 19.2): As described previously, B lines are artifacts that arise from the
presence of the lung immediately deep to the echogenic pleural line. Their absence would be indicative
of the absence of lung in that space and, therefore, the presence of a pneumothorax. Although one can
see a typical granular appearance deep to the pleura with or without a pneumothorax, it is the absence
of the B lines that differentiates lung from air. This sign is very reliable when ruling out pneumothorax
with a sensitivity and negative predictive value approaching 100%.7
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3. Lung point sign (Video 19.2): During partial collapse of the lung in a small- or moderate-sized
pneumothorax, the lung will be partially in contact with parietal pleura on the dependent portion.
Theoretically, if one scans immediately over the area where the lung separates from the parietal pleura,
one can visualize a normal appearance on one-half of the screen, and a sign of a pneumothorax (absence
of lung sliding or B lines) on the other half. This is termed the lung point sign. It is a useful sign when
present, but it is not seen in patients with a large pneumothorax.8
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4. M-mode: This is one scenario where M-mode scanning may be of use. The characteristic appearance of
normal subjects on M-mode is shown in Fig. 19.4. This is a typical appearance with a change from
horizontal lines to a granular appearance at the level of the pleural line, termed the “seashore
appearance.” In the presence of a pneumothorax, the seashore appearance is lost and, instead, replaced
with horizontal lines all the way to the bottom of the screen. This is termed the “barcode appearance.”
This is a very easy way to confirm the presence of a pneumothorax (Video 19.2).
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FIGURE 19.4 M-mode of pneumothorax: Image “A” shows an M-mode sonogram taken in a patient with no pneumothorax.
This is known as the seashore appearance. The echogenic pleural line is shown with the arrow. The lung below this line
demonstrates a normal granular pattern. Image “B” shows M-mode in a patient with a pneumothorax. The granular pattern
which is characteristic of the lung, is replaced by linear shadows giving the so-called barcode appearance.
PLEURAL EFFUSION
The utility of surface ultrasound in the diagnosis of pleural effusion is well known to thoracic physicians
and radiologists. In fact, there are multiple publications supporting the notion that ultrasound may be as
reliable, or perhaps better than plain films of the chest in detecting pleural effusion.9 Unlike plain films,
ultrasound can also provide qualitative data about the nature of the pleural effusion. Simple pleural fluid
appears as an anechoic or hypoechoic pocket surrounded by anatomic landmarks such as lung, diaphragm,
and chest wall without associated echoes or loculations.10 Such an effusion is depicted in Fig. 19.5. When
such a finding is noted, it can be expected that the fluid will be simple in nature, free flowing and likely a
transudate on chemical analysis.
Occasionally, and commonly in a thoracic surgical practice, there may be additional atypical
characteristics of the fluid. For example, the presence of loculations, which appear as fern-like structures,
can hint at multiple pockets of fluid that may not be drained by a single tube (Figs. 19.6 and 19.7). This is
especially true if the fluid is found in a nondependent portion of the chest cavity. The presence of
septations or swirling fern-like material within the pleural effusion is indicative of an exudate, and
possibly even an empyema.11
The value of ultrasound, however, lies in the ability to guide therapeutic aspects of pleural effusion
management. In a large, simple pleural effusion, whether the diagnosis is made by plain films or
ultrasound, then drainage is relatively uncomplicated, and may be achieved safely without the need for
image guidance. However, in complicated, multiloculated pleural effusions, ultrasound is of great use in
achieving success of drainage and reducing complications.12–14
FIGURE 19.5 Simple pleural effusion: Sonogram taken with a curvilinear probe set at 3.3 MHz. This shows a large simple
pleural effusion with no loculations. Atelectatic lung can be seen in the bottom part of the image.
FIGURE 19.6 Complex pleural effusion: This is a sonogram of a parapneumonic effusion taken with a curvilinear probe set at
3.3 MHz. The consolidated lower lobe can be seen with a heterogeneous appearance. The effusion is noted; it is a simple
effusion containing some debris as can be seen layering in the dependent aspect of the effusion.
MALIGNANT DISEASE OF THE CHEST

All patients with malignancy of the lungs, pleura, or mediastinum will require CT imaging as part of their
evaluation. In that setting, there is little to be gained by the addition of ultrasound, except in certain
instances. Occasionally, during the evaluation of a pleural effusion, there may be some subtle findings on
ultrasound that may suggest a malignant etiology. Findings such as pleural thickening greater than 1 cm,
pleural nodularity, and diaphragmatic thickening greater than 7 mm are highly suggestive of malignant
disease15 (Fig. 19.8).
FIGURE 19.7 Complex pleural effusion. This is a sonogram taken with 3.3-MHz setting of a loculated pleural effusion. The
fern-like loculation can be seen scattered throughout the effusion. Some of the pleural effusion has taken on a more solid
appearance (S) as can be seen on the bottom part of the screen.
FIGURE 19.8 Malignant pleural disease: This is a sonogram taken using a curvilinear probe set at 3.3 MHz in a patient with a
malignant pleural effusion. There is a moderately sized simple pleural effusion (PE). The diaphragm is marked with (D), and
there is a malignant-appearing deposit on the diaphragm marked with an asterisk (*).
Another important, albeit uncommon role for ultrasound is the ability to detect chest wall invasion in
patients with non–small cell lung cancer. Findings suggestive of chest wall invasion on ultrasound include
disruption of the parietal pleura, invasion of the ribs, or impairment of pleural movement with respiration.
Such findings are highly sensitive and specific for the evaluation of chest wall invasion by lung
tumors.15,16 In fact, ultrasound may be even more reliable than CT in evaluating for this particular finding,
as was documented in two prospective studies.16,17
ENDOBRONCHIAL ULTRASOUND
The initial staging for patients with suspected or biopsy-proven lung cancer involves CT and positron
emission tomography (PET).18 The accuracy of CT and PET scan, however, is suboptimal. The sensitivity
and specificity of CT in identifying mediastinal lymph node metastasis are 55% and 81%, respectively,
and those of PET are 77% and 86%, respectively.19 Therefore, confirmation with invasive mediastinal
staging is necessary in certain situations.
Since its advent in 1992, endobronchial ultrasound (EBUS) has been gaining popularity as an
acceptable mode of invasive mediastinal staging.20 During the initial years that EBUS was being used,
confirmation of negative results with mediastinoscopy was common practice. This practice is slowly
fading away as more data are becoming available that demonstrate equivalent, and in some cases,
superior results to mediastinoscopy.21–23 Table 19.1 shows a list of studies published in the last 10 years
documenting accuracy, negative predictive value, and sensitivity of EBUS in mediastinal staging of a
patient with lung cancer. In the vast majority of studies, EBUS yields results that are comparable to
mediastinoscopy. Although the role of mediastinoscopy is diminishing, there is still a role for
confirmatory staging procedures in certain situations, such as if no lymphocytes were obtained in the
EBUS specimen, or if the pretest probability of cancer involvement was high.
TABLE 19.1 Studies Reporting Sensitivity and/or Negative Predictive Value of Real-Time Endobronchial
Ultrasonography (EBUS) in the Mediastinal Staging of Confirmed or Highly Suspected Lung Cancer
Author, Year Study Design No. of Prevalence NPV Sensitivity Accuracy

Patients of N2
Disease, %
Cornwell et Retrospective 62 5 93 67 94
al., 201324
Herth et al., Prospective 97 10 98.9 89 NA
200825 observational
Herth et al., Prospective 100 21 96.3 92.3 NA
Hwangbo et Prospective 126 26 96.7 90 97.4
al., 200927 observational
Lee et al., Retrospective 102 30 96.9 93.8 97.9
200828
Liberman et Prospective 166 32 88 72 91
al., 201421 controlled
trial
Yasufuku et al., Prospective 153 35 91 81 93
201122 controlled
trial
Feller- Retrospective 131 35 89.7 85 NA
Kopman et
al., 200929
Petersen et al., Retrospective 157 43 90 85 NA
200930
Sanz-Santos et Retrospective 296 51 93.6 NA NA
al., 201231
Nakajima et Retrospective 438 52 90 97 98
al., 201332
Jhun et al., Retrospective 151 55 84.3 91.6 93.8
201233
Szlubowski et Retrospective 226 57 89 83.5 92.9
al., 200934
Bauwens et Retrospective 106 58 91 95 97
al., 200835
Joesph et al., Retrospective 131 58 90 92 NA
201336
Lee et al., Retrospective 73 62 94 95 97
201237
Cerfolio et al., Retrospective 72 63 79 57 83
201038
Navani et al., Retrospective 774 65 88 72 NA
201239
Kuo et al., Retrospective 43 65 85.7 80.6 91
201140
Hu et al., Retrospective 231 67+ 92 88 87
201341
Yasufuku et al., Prospective 105 67 89.5 94.6 96.3
Rintoul et al., Retrospective 109 71 60 91 92
200943
Cetinkaya et Retrospective 52 80 83 95 96
al., 201144
Ernst et al., Prospective 60 89 78 87 NA
200823 cross-over
Gu et al., Meta-analysis 1299 NA 93 NA NA
200945
Adams et al., Meta-analysis 782 NA NA 88 NA
200946
Abu-Hijleh et Retrospective 200 NA 75 87 91
al., 201347
Dong et al., Meta-analysis 1066 NA 93 90 96
201348
Whitson et al., Retrospective 120 NA 66 83 87
201349
In addition, EBUS has a role in the diagnostic evaluation of diseases other than lung cancer. The most
notable example is the evaluation of mediastinal lymphadenopathy where lymphoma is suspected. The
difficulty arises in the amount of tissue that is typically required to subtype lymphoma and the inability to
obtain specimens large enough for lymphoma analysis with needle techniques. Nonetheless, there has
been some data showing its utility in the assessment of suspected lymphoma; however, mediastinoscopy is
frequently needed.50–54 EBUS has also been shown to be useful in staging malignancy other than lung
cancer. For example, a recent publication showed that EBUS changed management in 12% of patients
with esophageal cancer.55
EQUIPMENT AND PREPARATION

There are two types of echoendoscopes for use during EBUS: radial EBUS and linear EBUS. They both
have different techniques and applications.
Radial EBUS
Radial EBUS mini-probes provide a circumferential view of the airway and lung parenchyma. Unlike
with endoesophageal ultrasound, there is no dedicated radial EBUS echoendoscope. Radial EBUS is
performed by passing a miniature, flexible ultrasound probe through the working channel of a standard
bronchoscope. The probe contains a rotating ultrasound which can generate a 360-degree image of the
surrounding structures. The probe also contains a balloon tip which allows for better contact with the
surrounding bronchial wall and generation of improved images. The probe is shown in Figure 19.9. The
probe is typically available in resolutions of between 20 and 30 MHz.
Linear EBUS
Linear EBUS, also known as convex-probe EBUS, is the most commonly used form of EBUS. Linear
EBUS differs from radial EBUS in a number of ways. The linear echobronchoscope consists of a fixed
array of transducers arranged in a curvilinear fashion. As a result, the field of vision is 60 degrees
parallel to the long axis of the scope, as opposed to a 360-degree image around the long axis of the scope
produced by radial EBUS. Moreover, the linear echobronchoscope is capable of utilizing color flow
Doppler imaging and real-time sonographic-guided fine-needle aspiration, contrary to radial EBUS,
where such tools are not used. Whereas radial EBUS is used to identify lesions in the lung parenchyma,
linear EBUS is reserved for evaluating central peribronchial structures, central tumors, mediastinal and
hilar lymph nodes. Linear echobronchoscopes provide a view in a plane that is parallel to the long axis of
the scope.
FIGURE 19.9 Radial ultrasound probe.

FIGURE 19.10 Linear endobronchial ultrasound probe.
Linear EBUS is performed with a dedicated scope that has both a video (white light) viewing
component and a 5-, 7.5-, 10-, or 12-MHz curved array transducer at the tip (Fig. 19.10). The video
component has a field of vision which is directed in a forward oblique direction at 35 degrees to the long
axis of the scope. This has to be taken into consideration when maneuvering the scope, for example, the
tip of the EBUS scope should be positioned more anteriorly when passing through the vocal cords to
correct for the forward-viewing phenomenon. The outer diameter of the scope is typically 6.2 to 6.9 mm.
There is a 2- to 2.2-mm working channel which is used for suction and the passage of a 25-, 22-, or 21-
gauge needle for biopsy under real-time ultrasonography. In addition, there is a balloon channel that is
positioned distal to the bronchoscope just proximal to the transducer. This is used to fill the balloon with
water or saline during real-time ultrasonography.
The scope is prepared by attaching a 20-mL syringe filled with water or saline and an arterial
stopcock to the balloon channel of the scope. Fluid is injected to evacuate any air within the channel.
Next, a disposable latex balloon is installed on the transducer, with care to ensure that the balloon
includes the outlet of the balloon channel. The balloon is tested to ensure that it inflates with saline and
that there are no air bubbles that would decrease image quality. The scope is now ready to be introduced
transorally or transnasally into the airway.
TECHNIQUE OF PERFORMING ENDOBRONCHIAL ULTRASOUND
The usual technique of performing endobronchial ultrasound is described here. The procedure can be
conducted under conscious sedation with intravenous benzodiazepine and opioid administration. In that
case, airway anesthesia is particularly important to minimize patient discomfort and coughing. We begin
the procedure by performing a regular fiberoptic bronchoscopy. The purpose of this is to visualize the
airway, assess for anatomical abnormalities, and provide adequate anesthesia of the airway. Airway
anesthesia is provided by injecting topical lidocaine over the vocal cords and airway mucosa. This is left
in the airway for approximately one minute before it is aspirated. Once bronchoscopy is performed and
the airway is appropriately prepared, endobronchial ultrasound can be commenced.
Radial EBUS
The purpose of radial EBUS is to be able to identify pulmonary nodules or masses within the lung
parenchyma and direct attempts at tissue acquisition with brushes, lavage, and fine-needle aspiration. As
such, in order to perform radial EBUS, one needs to localize the lesion to the bronchopulmonary segment
on the CT scan. A candidate lesion must also be close to an airway such that the probe may be passed into
or adjacent to it for identification. Radial EBUS can also be used to guide fiducial placement for
stereotactic body radiotherapy.
Once the proper bronchopulmonary segment is identified, the regular fiberoptic or video bronchoscope
is advanced into that segment as far as it can possibly go. Next, the radial miniature probe is passed
within a sheath carefully through the working channel and advanced into the airway where the lesion is
suspected. After the lesion is identified by means of a characteristic appearance (Fig. 19.11), the sheath is
fixed in place to the bronchoscope. A biopsy instrument, such as a forceps or brush can now be passed
through the sheath to obtain samples from the target lesion. It is important to know that biopsies performed
with radial EBUS are not real time, and therefore if the sheath is dislodged during withdrawing of the
probe or insertion of the biopsy instrument, the lesion will not be sampled. Intraprocedural fluoroscopy
can be used to provide some insurance about the stability of the sheath, but is not necessary for
performance of this procedure.
FIGURE 19.11 Radial ultrasound of intraparenchymal pulmonary nodule.
Linear EBUS
During the passage of the scope, one should take into consideration the fact that the tip of the scope is
distal and posterior to the visual field. For example, when the trachea is intubated, the tip of the scope is
distal and posterior when the vocal cords are in full view. Thus, slight forward flexion well above the
vocal cords will be needed and just the anterior commissure and the anterior part of the vocal cords will
be in view. Once the scope is in the trachea, it can be advanced directly to the area of interest or
systematic evaluation may be needed depending on the clinical situation. Gentle flexion of the tip of the
scope will bring the tip of the ultrasound probe in contact with the mucosa. The contact can be enhanced
by inflation of the balloon at the tip of the scope with normal saline. When in contact, the scope should be
rotated to identify vascular landmarks which together with anatomical landmarks will help in proper
classification of the mediastinal and hilar lymph nodes and other structures of interest. Color Doppler can
be used to further identify vascular structures. Ultrasound signs for malignant involvement of the lymph
nodes include size more than 1 cm in the short axis, round shape, distinct borders, heterogeneous
echogenicity, hypoechogenicity, presence of coagulation necrosis sign, and the lack of central hilar
structures.
When the biopsy target is identified, the needle can be placed in the working channel. Appropriate
handling of the biopsy needle is important in avoiding injury to the operators, patient, and the equipment.
The typical needle is a 21- or 22-gauge needle which is housed in a sheath with an outer diameter of 2
mm. The needle has a stylet inserted through it. With the target in view, real-time ultrasound-guided fine-
needle aspiration can be performed. The needle and sheath are passed through the working channel. It is
very important to ensure that the needle is completely encased by the sheath and locked such that
inadvertent protrusion of the needle during passage is avoided. This step is important to avoid damage to
the scope, and more importantly to the operators and the patient. The sheath is advanced through the
working channel until the tip is visualized in the top right-hand corner of the screen. The sheath is locked
in place just outside the field of vision to ensure that the needle will be deployed outside the scope and
avoid scope trauma. If the sheath is not advanced far enough, the needle will damage the scope when the
needle is unsheathed, and if it is advanced too far, then it will compromise the image quality. The sheath
is locked in place once the appropriate position is obtained. The probe is aligned with the target, and the
needle is jabbed into the target with a quick and smooth motion. The stylet is wiggled in and out a few
times to dislodge any possible cartilaginous tissue that might be caught in the needle. The stylet is either
pulled back or removed, and suction may or may not be used, depending on operator preference. The
needle is advanced back and forth into the target lesion to agitate the lesion and obtain tissue. Once
multiple passes have been made, the suction (if used) is released and the needle is withdrawn.
There are a number of ways to handle the specimen at that point, ranging from air-dried or alcohol-
fixed slides or placement directly into a cytologic preservation solution. The means of specimen handling
should be discussed with individual pathology departments.
FIGURE 19.12 The International Association of the Study of Lung Cancer (IASLC) lymph node map. (Reprinted from Rusch
VW, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map
in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4(5):568–577. Copyright ©
2009 International Association for the Study of Lung Cancer. With permission.)
Anatomic Landmarks for Invasive Mediastinal Staging

The most recent lymph node map published by the International Association of the Study of Lung Cancer
(IASLC) is the most widely accepted means of classifying hilar and mediastinal lymph nodes.56 The
lymph nodes are grouped into zones based on specific anatomic landmarks that are present on CT.
Although it may be difficult to completely apply the radiographic landmarks to endobronchial sonographic
anatomy, CT is used to guide accurate classification of lymph node stations and improve mediastinal
staging. A summary of the lymph node classification system is shown in Figures 19.12 and 19.13.
FIGURE 19.13 The IASLC lymph node map with descriptors based on anatomical landmarks depicted by CT. (Reprinted from
Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph
node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4(5):568–577.
Copyright © 2009 International Association for the Study of Lung Cancer. With permission.)
Hilar and Mediastinal Lymph Node Stations (Figs. 19.14 to 19.21)

FIGURE 19.14 Lower left paratracheal lymph (4L) and aortopulmonary window (5) lymph nodes as seen by EBUS. These
lymph nodes are identified by passing the scope into the left mainstem bronchus and retracting proximally into the trachea while
scanning against the left lateral wall. These lymph nodes are identified between the superior border of the pulmonary artery and
the lower border of the aorta. The pulmonary artery (PA) and aorta (AO) are marked on the image.
FIGURE 19.15 Right lower paratracheal lymph node (4R) as seen by EBUS. The superior vena cava in the longitudinal plane is
seen just distal from the ultrasound probe as an anechoic structure. This lymph node is identified by passing the scope into the
right mainstem bronchus and retracting proximally into the trachea while scanning against the right lateral or anterior wall of the
trachea. The azygos vein will be identified as a circular structure crossing the tracheobronchial angle on the right side just above
the right mainstem bronchus. By sonographic criteria, the 4R lymph node should be cephalad to the inferior border of the azygos
vein in order to be referred to as a station 4R lymph node for lung cancer staging. Any lymph node below that is a station 10R
lymph node. This distinction is very important as it differentiates between potentially resectable N1 disease and potentially
unresectable N2 disease in the case of metastases.
FIGURE 19.16 A: Subcarinal lymph nodes (7) as seen by EBUS. This lymph node is identified by passing the scope into either
mainstem bronchus and scanning medially and slightly anteriorly. Scanning in the posterior direction should identify the esophagus,
which can be distinguished from the subcarinal lymph node by the presence of mural layers. B: This is a hilar lymph node from
station 10L. This lymph node is identified by placing the scope in the left mainstem bronchus and scanning circumferentially. The
lymph node is usually identified medially. The pulmonary artery can be seen as an anechoic structure just distal to the lymph
node.
FIGURE 19.17 Right hilar lymph node (10R) as seen by EBUS. This lymph node is identified by placing the scope in the right
mainstem bronchus and scanning circumferentially. It is important to identify the azygos vein in order to differentiate this lymph
node from the right paratracheal lymph node.
FIGURE 19.18 A left interlobar lymph node (11L). This node is visualized by pressing the probe against the left secondary
carina, between the orifices of the left upper and lower lobe bronchi. A branch of the pulmonary artery is seen just distal and
inferior to the lymph node.
FIGURE 19.19 Right interlobar lymph node (11R) as seen by EBUS. This lymph node is visualized by pressing the scope
against the mucosa between the right upper lobe orifice and the bronchus intermedius (11s) or between the middle lobe bronchial
orifice and the remainder of the basilar segments (11i). The pulmonary artery is seen cephalad to the lymph node.
FIGURE 19.20 Left lobar lymph node (GG 12G –12L lymph node) as seen by EBUS. This lymph node is visualized by wedging
the scope within the adjacent lobar bronchus. In this image, a pulmonary mass (TUMEUR LSG) is identified distal to the lymph
node. The mass is separate from the lymph node by a shiny white line that is preserved between both lesions, indicating that this
is indeed a lymph node and not a peribronchial extension of the tumor.
FIGURE 19.21 Right lobar lymph node (12R) as seen by EBUS. This is visualized by wedging the scope within the right
segmental bronchi. The pulmonary arterial branches are seen distal to this lymph node as two anechoic structures. Due to the
inability to pass the scope far within the bronchus, there may be a portion of the probe that is not opposed against the mucosa,
resulting in decrease in the image quality, as can be seen on the right-hand side of the image. This is a commonly encountered
situation when attempting to visualize lobar lymph nodes due to the shortness of the lobar bronchi.
Mediastinal Cysts
Middle mediastinal cystic structures are not uncommonly encountered. They frequently present as
incidental findings on chest imaging with no symptoms. Occasionally, they may become symptomatic if
they compress adjacent structures or become infected. The management of these lesions is beyond the
scope of this chapter; however, we discuss the role of sonography in their evaluation. While CT may be
sufficient for evaluation in most cases, especially if an operative approach is considered, endobronchial,
or even endoesophageal sonography may provide information which may be helpful, especially in cases
where CT may not be able to differentiate between a mediastinal cyst or a mass. In this rare scenario,
endoscopic ultrasound may help by noting the echongenicity of the lesion in question. All bronchogenic
cysts, and a significant proportion of esophageal duplication and pericardal cysts can be visualized by
endobronchial ultrasound. Figure 19.22 shows an image of a simple bronchogenic cyst located in the right
paratracheal space. If the lesion has that classic appearance, then it can safely be labeled as a mediastinal
cyst and biopsy should not be performed. In this case, the physician may reliably consider this a
bronchogenic cyst and proceed with resection or observation depending on the clinical scenario. If the
echongenicity of the mass is higher than would be expected for a simple cyst, then a biopsy may be
entertained. We prefer to avoid needle biopsy of these lesions given the authors’ anecdotal experience
with increased incidence of infection of these cysts. Infected mediastinal cysts can convert an
asymptomatic problem to a symptomatic one, and will certainly complicate the management of these
otherwise benign lesions. Therefore, we typically reserve biopsy for lesions which can not be
distinguished from a malignancy clinically and radiographically.
FIGURE 19.22 Endobronchial ultrasound image of a right paratracheal bronchogenic cyst. This is a simple cyst without any
septations and the fluid does not appear complex. This was confirmed to be consistent with a simple bronchogenic cyst at the
time of resection.
INTRACAVITARY ULTRASOUND
The use of intraoperative ultrasound (IOUS) is well established in other disciplines, such as liver and
pancreatic surgery. The use of IOUS has not received as much attention in the field of thoracic surgery for
the same reasons that made surface ultrasound unpopular. One area were IOUS can be of benefit is in
localization of pulmonary nodules at the time of thoracoscopy. During the time when thoracotomy was the
main means of undertaking pulmonary resection, surgeons relied on palpation to identify pulmonary
nodules at risk of malignancy. With increasing use of thoracoscopy, the surgeon’s ability to palpate the
lung diminishes. This has been postulated to lead to high conversion rates to thoracotomy when looking
for small nodules. Conversion rates have been reported to be greater than 50%.57–59 Multiple means of
localizing nodules, including preoperative localization with wires, coils, or radioactive tracers has been
examined.57–60
Intracavitary ultrasound (VATS-US) has been examined in the literature as a means of localizing lung
nodules during thoracoscopy. Contrary to other means, this is a real-time method that does not rely on
preoperative preparatory procedures, such as placement of a localizing wire or injection of dye. The
technique relies on the passage of a long-tipped ultrasound probe dedicated for use in minimally invasive
surgery. These are the same probes used during laparoscopy by hepatobiliary surgeons. After port
placement, the lung is completely deflated, and thoracoscopy is performed. A sterile, intracavitary, 10-
mm VATS-US 5- to 10-MHz linear probe with a flexible angulating tip attached to an ultrasound
processor is introduced through one of the ports and used to examine the area of interest (Fig. 19.23).
Endoscopic articulation of the VATS-US probe often helps to identify nodules in more posterior or
inferior locations. Sterile sonographic jelly or water can be used to help localize nodules not easily
located with the initial ultrasound attempts. The nodules are localized by direct ultrasound visualization
of the nodule. An additional confirmatory sign is the presence of a hyperechoic shadow underneath the
nodule within the lung parenchyma (Figs. 19.24 and 19.25). After nodule localization, thoracoscopic
wedge resection can be performed.
FIGURE 19.23 Intracavitary ultrasound probe with a flexible angulating tip.
FIGURE 19.24 A: Small, 10-mm pulmonary nodule (arrow) located in the right lower lobe on preoperative computed
tomography image. B: Corresponding video-assisted thoracoscopic surgery ultrasound in vivo image of the nodule.
This technique has been shown to be a reliable means of identifying pulmonary nodules during
thoracoscopy.61 In a study by Khereba et al., 43 patients were enrolled with small nodules (range 2 to 20
mm, and average of 11 mm) and thoracoscopy was undertaken. Direct visualization, manual palpation,
and VATS-US were used to identify the nodules. VATS-US identified 93% of the nodules. More
importantly, the same study has shown that the conversion rate to thoracotomy can be decreased, and that
VATS-US prevented thoracotomy in 43% of cases. Multiple other studies have confirmed the feasibility of
this technique.62,63
FIGURE 19.25 A: Preoperative computed tomography image of small, irregular, left upper lobe ground-glass opacity with
solitary components (arrow). B: Corresponding video-assisted thoracoscopic surgery ultrasound in vivo image of the nodule.
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41. Hu Y, Puri V, Crabtree TD, et al. Attaining proficiency with endobronchial ultrasound-guided transbronchial needle aspiration. J Thorac
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Cancer 2005;50(3):347–354.
43. Rintoul RC, Tournoy KG, El Daly H, et al. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international
multi-centre experience. J Thorac Oncol 2009;4(1):44–48.
44. Cetinkaya E, Seyhan EC, Ozgul A, et al. Efficacy of convex probe endobronchial ultrasound (CP-EBUS) assisted transbronchial needle
aspiration for mediastinal staging in non-small cell lung cancer cases with mediastinal lymphadenopathy. Ann Thorac Cardiovasc Surg
2011;17(3):236–242.
45. Gu P, Zhao Y, Jiang L, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: A systematic
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46. Adams K, Shah PL, Edmonds L, et al. Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for
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20
Mediastinoscopy
Toni Lerut ■ Paul De Leyn
INTRODUCTION
It is generally accepted that Dr Dwight Harken, from the Brigham and Women’s Hospital in Boston, is to
be credited for the first description of the technique of mediastinoscopy in 1954.1
The technique he described was in fact inspired by the Daniels’s technique on biopsy of scalene lymph
nodes for the diagnosis of intrathoracic diseases described in 1949.2
In this procedure, after procaine infiltration of the skin, a horizontal supraclavicular incision was made
and the anterior scalene muscle and phrenic nerve were exposed by removal of the fat pad overlying this
muscle along with the contained lymph nodes. The sternocleidomastoid muscle was retracted medially,
and the superior mediastinum entered by blunt dissection (Fig. 20.1).
When a hard, fixed mass or difficult to enucleate nodes were encountered, a Jackson laryngoscope or
lighted retractor could be introduced, and a laryngeal biopsy forceps was used to obtain tissue under
direct vision.
The Harken technique, although considered extremely valuable to assess the superior mediastinum,
never gained wide acceptance. The method was considered technically difficult, demanding considerable
experience and not devoid of major complications.
Moreover, sometimes the procedure had to be done bilaterally.
FIGURE 20.1 Harken technique of mediastinoscopy.
Therefore, Radner3 recommended to biopsy the paratracheal lymph nodes through an incision in the
suprasternal notch.
It was however Dr Eric Carlens at the Karolinska Institute in Stockholm, who published in 1959
“Mediastinoscopy: a method for inspection and tissue biopsy” in Diseases of the Chest.4 The manuscript
highlighted the full significance and relevance of this technique in both diagnosis and staging of lung
cancer as well as of other malignancies.
Mediastinoscopy, as he described it (Fig. 20.2), was based on the principle that the shortest way to the
superior mediastinum is through an incision at the suprasternal notch. After dividing the soft tissues along
the midline down to the anterior wall a finger could be introduced for palpation and dissection can be
performed down to the carina.
A specially designed instrument resembling a children’s esophagoscope with a slit on the side was
then introduced and under direct vision tissue could be biopsied. In addition, haemostasis could be
secured under direct vision.
The description of the technique by Carlens basically hasn’t changed over the years and thoracic
surgeons are still familiar with it today.
FIGURE 20.2 Carlens technique of mediastinoscopy from original publication.
However, it is generally agreed that Dr Griff Pearson5 popularized mediastinoscopy as an essential

staging tool for lung cancer in North America and later on in Europe and the rest of the world.
As Dr Pearson stated, “…I met at the end of my training Dr Carlens during a visit to the Karolinska
Institute. Carlens had recently reported his experience with his innovative technique of mediastinoscopy,
and introduced me to the procedure and the instrumentation.
The authors reported their initial experience with this technique in 1963 and were satisfied that, with
experience, one could safely and regularly biopsy lymph nodes in the paratracheal and subcarinal areas.
Furthermore, it became apparent that mediastinoscopy could identify metastatic tumor in the superior
mediastinal lymph nodes which were not evident in plain chest films. We began to assess the value of this
procedure for the determination of operability in patients with apparently favorable and resectable
lesions…”5
By 1972 a much larger experience was reported by Dr Pearson and the Toronto group.6 They pointed
out that, with the introduction of mediastinoscopy as a staging tool, only patients with presumably
completely resectable non–small-cell cancer and proven ipsilateral N2 disease were to be operated upon.
This subset represented about 20% of all mediastinoscopy positive cases the other 80% being no longer
candidates for surgery.
In a subsequent landmark paper, Dr Pearson and his colleagues reported a 64% resectability rate and a
9% survival at 5 years in a favorable, selected subgroup of patients with N2 disease discovered at
mediastinoscopy.7
This poor resectability rate and the dismal long-term cure rate confirmed by other groups8 resulted in a
more generally accepted belief that all patients with N2 disease ought not to undergo resection.
The prognostic importance of the level and the extent of mediastinal lymph node involvement led to the
development of the internationally used lymph node maps named after Drs Naruke and Mountain-Dressler,
and underwent further refinement as a result of an IASLC international and multidisciplinary consensus
(Fig. 20.3).9
Two decades ago, two publications indicated that induction chemotherapy followed by lung resection
resulted in a significantly better survival than resection alone.10,11 A recent meta-analysis of 13
randomized clinical trials confirmed these data.12
As a result, it is now well accepted that the indication for induction therapy has to be based on
pathologic evidence of nodal disease and in which mediastinoscopy has been playing a pivotal role.
Although mediastinoscopy remains the clinical staging method with the highest sensitivity and
specificity for exclusion of mediastinal lymph node involvement, its role has been challenged by the
introduction of the PET/CT scan and the increasingly widespread use of noninvasive endoscopic staging
methods, such as EBUS, that is, transbronchial ultrasound-guided fine needle aspiration, and/or EUS, that
is, transesophageal ultrasound-guided fine needle aspiration.
In order to integrate the available imaging, endoscopic and surgical techniques in the lung cancer
staging process, the European Society of Thoracic Surgeons (ESTS) guidelines were published in 2007
along with an algorithm on preoperative mediastinal staging13 subsequently updated in 2014.14
In brief, the following recommendations were formulated:
a. Minimal requirements for mediastinal nodal staging
As a minimum requirement, the following nodal stations should be explored and biopsied:
1. Right and left lower paratracheal lymph nodes (stations 4R and 4L) and
2. Subcarinal lymph nodes (station 7).
If present, the right and left upper paratracheal stations 2R and 2L should also be biopsied. When
required to determine subsequent treatment strategy, lymph node stations 10R (below the azygos vein) and
10L (below the upper rim of left pulmonary artery) should be biopsied.
For left-sided tumors, stations 5 and 6 should be biopsied if crucial to change the treatment strategy.
The same applies to the lower mediastinal lymph nodes (stations 8 and 9). Biopsy of these stations could
be indicated in the event that extracapsular (nonresectable) nodal disease is expected from imaging
studies.
b. Algorithm for primary mediastinal staging
PET or PET–CT is indicated to stage the mediastinum and possible distant sites.
1. Direct surgery can be performed if all of the following three criteria apply: no suspect lymph nodes
detected by CT or PET, a tumor of ≤3 cm (Stage IA), and located in the periphery—that is, outer third
—of the lung.
2. In case of enlarged mediastinal lymph nodes on CT- or PET-positive lymph nodes, tissue confirmation
is indicated. In case of enlarged nodes, EBUS and EUS with FNA, when available, represent the first
choice for their minimal invasiveness and the high sensitivity of this combination to confirm mediastinal
nodal disease. If negative, mediastinoscopy is indicated. Needless to say, the combined use of
endoscopic staging and surgical staging results in the highest accuracy.
For a left upper lobe tumor, surgical staging of the aortopulmonary window nodes (if enlarged on CT
and/or PET–CT-positive) can be performed by anterior mediastinotomy, video-assisted thoracoscopic
surgery (VATS), or extended cervical mediastinoscopy if their involvement changes treatment strategy.
3. Staging by E(B)US/mediastinoscopy is indicated if at least one of following criteria applies: central
lesion, suspect N1 nodes, and, tumors >3 cm (mainly adenocarcinoma) with high FDG uptake
The choice between mediastinoscopy, with lymph node biopsy or removal, or endoscopic staging by
EBUS/EUS with FNA depends on the local availability of the technology and the necessary expertise to
adhere to minimal requirements for staging.
If mediastinal nodal staging by mediastinoscopy is negative, patients can undergo surgical treatment.
Likewise, surgery can be proposed after negative EBUS/EUS if the number of nodes explored and the
number of needle passes in each node meets the established requirements (see below).
TECHNIQUE OF MEDIASTINOSCOPY
Contraindications
Absolute contraindications for cervical mediastinoscopy are very rare.
• Contraindication for general anesthesia

• Extreme kyphosis
• Cutaneous tracheostomy (after laryngectomy)
Superior vena cava syndrome, previous sternotomy, and enlarged goiter do not preclude
mediastinoscopy as well as previous radiotherapy and mediastinoscopy. In the latter scenario, the
intervention can be much more challenging and time consuming due to intense fibrosis and adhesions.
FIGURE 20.3 IASLC modified Naruke Dressler map from original publication. (Reprinted from Rusch VW, Asamura H,
Watanabe H, et al. The IASLC lung cancer staging project. A proposal for a new international lymph node map in the seventh
edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4:568–577. Copyright © 2009 International Association
for the Study of Lung Cancer. With permission.)
Operative Technique
Under general anesthesia, the endotracheal tube is positioned at the left corner of the mouth (or, for the
left-handed surgeon, at the right corner) (Fig. 20.4).
The neck is somewhat kept in hyperextension by placing a roll behind the shoulders but avoiding
“floating” of the head. The patient is then draped in such a way that the anterior part of the chest is also
part of the operative field, in case an urgent median sternotomy should become necessary. The surgeon is
standing or sitting behind the patient’s head (Fig. 20.5).
The initial step is a 2 to 3 cm transverse incision placed at one fingerbreadth from the manubrium. The
pretracheal muscles are separated vertically in the midline to expose the anterior surface of the trachea
while the isthmus of the thyroid is retracted superiorly. The trachea is then exposed and the pretracheal
fascia incised, so that the dissection can be continued deep in the mediastinum.
The surgeon’s index finger is advanced along the pretracheal plane with the dorsum of the index finger
strictly adherent to the anterior trachea. At this point, the mediastinum is carefully palpated for the
presence of nodal disease (Fig. 20.6). This palpation is of extreme importance because pretracheal nodes
are more easily palpated than visualized (Fig. 20.7). Usually, the aortic arch can be felt to the patient’s
left and the innominate artery can be felt passing across the top of the operative field. Once this plane has
been developed down to the carina, the finger is withdrawn then the mediastinoscope is introduced and
advanced (Fig. 20.8). The plane in front of the mediastinoscope is developed with the use of blunt
dissection, using a metal suction device through the operative channel of the mediastinoscope. Safety is
maintained if the trachea or the main stem bronchi are kept in view at all times (Fig. 20.9). Getting away
from the airway is an invitation to vascular injury and must be avoided. Small bleeding vessels can be
coagulated; in order to do this, two different types of suction instruments can be used. One is made
entirely of steel and presents a standard electrocautery tip on the suction device outside the patient; the
other consists of a plastic sheet covering a metal stem with a cautery attachment and allows the use of a
cautery foot pedal.
FIGURE 20.4 Positioning of the head of the patient and of the orotracheal tube.
FIGURE 20.5 Overview of the positioning of the surgeon and scrub nurse and of the equipment.
FIGURE 20.6 Introduction of the index finger to explore the anterior surface of the trachea.
FIGURE 20.7 Palpating with index finger of the pretracheal nodes.
FIGURE 20.8 Conventional mediastinoscope. (From De Leyn P, Lerut T. Conventional mediastinoscopy. Multimedia Man
Cardiothorac Surg doi:10.1510/mmcts.2004.000158; Copyright © 2005 European Association for Cardiothoracic Surgery.
Reproduced with permission of MMCTS Editorial Office in the format Book via Copyright Clearance Center.)
FIGURE 20.9 A, B: Dissection toward the bifurcation and coagulation of small vessels over the anterior surface of the trachea.
(Part A from De Leyn P, Lerut T. Conventional mediastinoscopy. Multimedia Man Cardiothorac Surg
doi:10.1510/mmcts.2004.000158; Copyright © 2005 European Association for Cardiothoracic Surgery. Reproduced with
permission of MMCTS Editorial Office in the format Book via Copyright Clearance Center.)
One has to be very careful with coagulation at the left paratracheal groove due to the presence of the
left recurrent nerve (Fig. 20.10).
Before taking a biopsy from a lymph node, the node should be mobilized as much as possible to ensure
that the structure under view is a lymph node and not a major vessel. The dissection is easily performed
with a suction device. A recommended typical approach is to first identify the right and left main stem
bronchi, and then to systematically dissect the subcarinal space, the ipsilateral paratracheal space, and the
contralateral paratracheal space.
In case of doubt, the lymph node can be punctured with a long aspiration needle under negative suction
to ensure that the structure to be biopsied is not a vessel. However, with adequate mobilization and clear
identification of the anatomic landmark structures, such maneuver will rarely be necessary. Following
these tips, an inadvertent biopsy of the azygos vein or the pulmonary artery is extremely rare.
The lymph node is grasped by a biopsy forceps (Fig. 20.11). In case of resistance while exerting
traction, one has to be aware of the possible adherence of the node to an adjacent vessel, for example, the
azygos vein, the first branch of the pulmonary artery, or the innominate artery. A too forceful traction may
result in a vascular tear and major bleeding.
FIGURE 20.10 A, B: Visualization of the left recurrent nerve. (Part A from De Leyn P, Lerut T. Conventional
mediastinoscopy. Multimedia Man Cardiothorac Surg doi:10.1510/mmcts.2004.000158; Copyright © 2005 European
Association for Cardiothoracic Surgery. Reproduced with permission of MMCTS Editorial Office in the format Book via
Copyright Clearance Center.)
FIGURE 20.11 A, B: Visualizing and biopsying a subcarinal lymph node (station 7). (Part A from De Leyn P, Lerut T.
Conventional mediastinoscopy. Multimedia Man Cardiothorac Surg doi:10.1510/mmcts.2004.000158; Copyright © 2005
European Association for Cardiothoracic Surgery. Reproduced with permission of MMCTS Editorial Office in the format Book
via Copyright Clearance Center.)
Accessible Lymph Node Stations by Cervical Mediastinoscopy

Using cervical mediastinoscopy, the following nodal stations (according to the Mountain/Dressler
modification from the Naruke/American Thoracic Society-North American Lung Cancer Study Group
[ATS-LCSG] map) can be sampled: the highest mediastinal nodes (level 1), the left and right upper
paratracheal nodes (levels 2L and 2R), left and right lower paratracheal nodes (levels 4L and 4R), and,
the subcarinal nodes (level 7).
The posterior subcarinal nodes (level 3), paraesophageal nodes (level 8), inferior pulmonary ligament
nodes (level 9), subaortic nodes (level 5), and para-aortic nodes (level 6) cannot be biopsied using
standard cervical mediastinoscopy (Fig. 20.9).
Usually, the node stations along the trachea are the first to be biopsied whereas the subcarinal nodes
are biopsied last (Fig. 20.8). This order is followed because the subcarinal nodes, surrounded by intense
vascularization, more easily cause bleeding which may hamper the surgeon’s view.
CLOSURE
The strap muscles are approximated with one suture. Drainage of the mediastinal bed is usually not
required. A subcutaneous interrupted suture will obliterate the dead space. The skin is closed according
to surgeon’s preference.
Complications
Small bleedings from biopsy sites can be electrocoagulated. The most frequent cause of bleeding is
caused by damage to the branches of the bronchial arteries that run across the subcarinal region. If they
are damaged, applying some pressure temporarily using the suction device or by temporarily packing the
space for 5 to 10 minutes using resorbable hemostatic gauze pad will suffice to stop the bleeding.
Vascular clips can also be used.
Other vessels that may be injured are the azygos vein or the right upper lobe branch of the pulmonary
artery. Again, gauze packing may stop the bleeding. Accordingly, a long strip of large gauze packing
should always be available in the operating room. However, in some instances, packing may not solve an
uncontrollable hemorrhage, for example, from an injury of aorta or innominate artery. In such event, the
mediastinum is packed or the bleeding site is compressed with the surgeon’s finger, or the
mediastinoscope, and the decision is made whether thoracotomy or sternotomy will be performed. That
decision is based on the location of the bleeding and the location of the tumor if resection is indicated.
Right thoracotomy might be indicated when the bleeding is from the first branch of the right pulmonary
artery or from the azygos vein. In all other cases sternotomy offers the best chances to control the
bleeding.
Another structure at risk for injury is the left recurrent nerve. Vocal cord paralysis may result in
hoarseness and poor cough, thus increasing the risk for postoperative pulmonary infection.
Injury can be avoided by visualizing the nerve and being extremely cautious when taking biopsies at
the level of the left tracheobronchial angle, and the use of electrocautery should be avoided by all means
in this particular area. If a permanent lesion of the nerve is anticipated, thyroplasty to remediate
hoarseness and to avoid further pulmonary complications, for example, aspiration should be considered.
Injury to the trachea or main stem bronchus is possible, and can be managed by leaving a small drain
behind. Closure of the tear may be possible through the mediastinoscope.
Injury of the esophagus is possible when dissecting the subcarinal or left tracheobronchial space. Pain
and mediastinal emphysema in the immediate postoperative period should alert the surgeon if the injury
was not detected at the time of mediastinoscopy. If the tear is small and detected at the time of surgery,
simple drainage, nil by mouth and antibiotic treatment for a few days may represent effective measures. If
the injury to the esophagus is suspected in the immediate postoperative period, endoscopy or water-
soluble contrast study has to be performed to confirm diagnosis. A small contained leak can be treated
conservatively, but if there is a free leak into the mediastinum, prompt repair through a right thoracotomy
or VATS approach is the therapy of choice.
Complications are rare and usually not life-threatening. Unless additional or more extensive
procedures are scheduled at the same time and in the presence of permissible patient condition,
mediastinoscopy can be performed on an outpatient basis.15 In experienced hands, cervical
mediastinoscopy has no mortality and minimal morbidity. In a review of more than 20,000 cases,
complications did not exceed 2.5% and mortality was less than 0.5%, with only 0.1% to 0.5% of all
complications considered as major,16 with life-threatening bleeding being the most important one.
An analysis of a cohort of 4,000 consecutive mediastinoscopies from the authors’ own center revealed
no hospital mortality.17 Major bleeding requiring immediate intervention occurred in four patients. Injury
of the esophagus was seen in one patient in whom the mediastinum was drained through the
mediastinoscopy incision, and the fistula healed after a few days of conservative treatment. In one patient,
a tear of the left main stem bronchus was successfully repaired by endoscopic suturing through the
videomediastinoscope.
EXTENDED CERVICAL MEDIASTINOSCOPY

Left upper lobe tumors may metastasize to the subaortic (station 5) and para-aortic lymph nodes (station
6) (Figs. 20.12 and 20.13). These nodes cannot be biopsied through routine cervical mediastinoscopy. In
1965, Specht18 already described the technique of extended or “expanded” mediastinoscopy which was
later popularized by Ginsberg et al.19 This technique contemplated the exploration of the subaortic
(station 5) and para-aortic nodes (station 6) through the cervical incision. This technique is an alternative
to mediastinotomy performed in the anterior second interspace which is more commonly used to target
these nodal stations. The advantage of the extended mediastinoscopy is the saving of an additional
incision—a mediastinotomy—by biopsying all relevant nodal stations through one incision only. In this
procedure, the mediastinoscope is angled anterior and to the left, to allow the tip to pass over the aortic
arch and into the aortopulmonary window (Fig. 20.12). From the mediastinoscopy incision, a passage is
created by blunt dissection over the aortic arch, between the innominate artery and the left carotid artery,
either posteriorly or anteriorly to the left innominate vein. The mediastinoscope is then inserted obliquely
and its tip reaches the subaortic space where lymph nodes can be found in the fatty tissue (Fig. 20.13).
FIGURE 20.12 Introducing the mediastinoscope between the innominate vein over the aortic arch to the left of the innominate
artery.
FIGURE 20.13 Scheme of biopsy at station 5.
In experienced hands, the procedure yields a high accuracy and minimal morbidity.20 It is important to
state that this procedure is far less easy and therefore is less routinely performed compared with the
conventional mediastinoscopy.
ANTERIOR MEDIASTINOTOMY (CHAMBERLAIN PROCEDURE)

Left anterior mediastinotomy, also known as Chamberlain’s procedure (Fig. 20.14),21 can allow safe
access to level 5 lymph nodes located in the aortopulmonary window. In this procedure, a transverse
incision is made at the level of the second (or third rib) just lateral to the sternum. Care is taken not to
damage the internal mammary artery. The incision is carried down through the intercostal muscles, and an
examining finger can be passed in to palpate the level 5 and level 10 lymph nodes in the left hilum and
mediastinum. Dissection is carried out much in the same way as described previously for standard
mediastinoscopy. Extra care must be taken to identify and avoid injury to the left phrenic nerve as it
passes along the mediastinal pleura just anterior to the hilum.
REMEDIASTINOSCOPY
Palva et al. described the first remediastinoscopy and published a report on six remediastinoscopies in
their series of 1,188 (0.5%) mediastinoscopies.22
However, it is mainly in the past decade that repeat mediastinoscopy has gained further interest with
the most common indication being the assessment of objective tumor response and downstaging of locally
advanced lung cancer treated with induction therapy.23–25
Its rationale is based on the utmost importance of precise restaging of the mediastinum after induction
therapy for patients with involved mediastinal nodes (N2 or N3) since confirmation of downstaging of
mediastinal nodes is a very important prognostic factor in these patients.25 Although long-term survival
has been reported in patients with persistent N2 disease undergoing resection after induction therapy,
most of these patients will not benefit from surgery since resectability and long-term survival rates are
low.
While PET scan yields high accuracy in primary staging of the mediastinum, its accuracy in restaging
of the mediastinum after induction therapy is much reduced.
Reportedly, endoscopic techniques providing histology can be used in lieu of remediastinoscopy.
However, EBUS-TBNA is associated to a variable NPV, anywhere between 20% and 78%.26,27 These
results emphasize that a negative EBUS for restaging should be confirmed by the invasive surgical re-
exploration of the mediastinum.
FIGURE 20.14 Scheme of the Chamberlain procedure.

Accordingly, thoracic surgeons will be faced more and more frequently with the need to repeat the
mediastinoscopy. Several authors have shown that repeat mediastinoscopy is feasible with an accuracy of
85% and a sensitivity of 73%.28,29
However, remediastinoscopy is used only in very selected experienced centres and is not widely
adoptable due to severe fibrosis.30,31
The recent updated ESTS guidelines on preoperative staging recommend to first perform a EBUS/EUS
with FNA to assess tumor response after induction therapy, but emphasize that a negative EBUS for
restaging should be confirmed by an invasive surgical restaging.14
Given the lower accuracy of remediastinoscopy compared to that of mediastinoscopy for primary
staging the timing of mediastinoscopy is being debated (at baseline or restaging).
Technique
Positioning of the patient is not different from mediastinoscopy and the whole sternum is prepped to
anticipate the need for a sternotomy or hemiclamshell. The primary incision is reopened. Usually, the
isthmus or even the thyroid gland may be adherent to the trachea. Due to fibrotic adhesions, the
brachiocephalic trunk is adherent to the anterior surface of the trachea. Sharp dissection is performed to
find the anterior surface of the trachea.
Dissection is continued on the left side (Fig. 20.15) until the left tracheobronchial angle is visualized.
From this tunnel, blunt dissection to the right side is performed from below in a retrograde fashion. The
anterior surface of the trachea is freed from the adherent major vascular structures. Initially this is
performed with a dissection pledget. Once additional space is gained, this can be continued by finger
dissection. One has to do this carefully to avoid injury to the brachiocephalic artery. The pretracheal
space is then liberated and the scope can be returned in its normal position. Dense fibrosis and adhesions
render the thorough exploration of all nodal stations very difficult or even impossible. To reach the
subcarinal region, the pulmonary artery has to be pushed away. Adhesions can be divided with the
endoscopic shears. When there is a lot of precarinal fibrosis, it is best to dissect as far as possible on the
left main bronchus. From there the subcarinal space can be dissected and biopsied.
VIDEOMEDIASTINOSCOPY
Conventional equipment for cervical mediastinoscopy obliges surgeons to work in an uncomfortable
position. Only the operating surgeon has a “one eye” view through the instrument. Teaching as a result is
extremely difficult in particular because of the danger of damaging vital organs. When the trainee takes
over from the teacher the latter has no possibility to control or to guide the manoeuvres done by the
trainee. The development of videoscopic and video-assisted technology during recent years has opened
up new perspectives.
FIGURE 20.15 Remediastinoscopy: shown is the introduction of the scope directed toward the left anterolateral side of the
trachea. (From De Leyn P, Lerut T. Conventional mediastinoscopy. Multimedia Man Cardiothorac Surg
doi:10.1510/mmcts.2004.000158; Copyright © 2005 European Association for Cardiothoracic Surgery. Reproduced with
permission of MMCTS Editorial Office in the format Book via Copyright Clearance Center.)
The credit for bringing videomediastinoscopy to the international thoracic surgery community attention
goes to Lerut who presented the concept, developed in 1989 at the First International Symposium on
Thoracoscopic Surgery in San Antonio in January 1993 the proceeding of which were subsequently
published in The Annals of Thoracic Surgery.32 Here is the paragraph that describes the initial
experience and rational:
“…mediastinoscopy is a procedure that is rather difficult to teach to residents as the procedure has to be performed entirely through a
narrow tube. Together with the Storz Company (Tuttlingen, Germany), we recently developed a prototype of a mediastinoscope that can be
branched to the video camera and television monitor. The mediastinoscopy is performed with the same instruments as usual, but the entire
procedure can be followed on the television screen. This allows more people to observe the technical aspects of the procedure, obviously an
advantage in teaching how to perform it. Moreover, recording the procedure documents how and where biopsy specimens have been taken
(e.g., whether just a simple biopsy or complete excision of an entire particular lymph node was performed). This additional visual
information may become relevant in discussing problems of intranodular or extracapsular lymph node involvement resulting in better
understanding and standardization of how to perform and to evaluate mediastinoscopy. Besides video-assisted mediastinoscopy,
thoracoscopic exploration of the aortopulmonary window may become an alternative for the classic anterior mediastinotomy…”
Subsequently, the instrumentation of the videomediastinoscope was further developed and refined by
different authors and companies (Fig. 20.16).
FIGURE 20.16 A, B: Lerut mediastinoscope. (© KARL STORZ SE & Co. KG Germany)
FIGURE 20.17 Linder–Hürtgen modification. (© KARL STORZ SE & Co. KG Germany)
Today there are several models available, that is, the above described Lerut videomediastinoscope
(Fig. 20.17) and the Linder–Hürtgen modification (K Storz) (Fig. 20.18), the Linder–Dahan
mediastinoscope (Wolfe) (Fig. 20.18) being the most relevant ones.
FIGURE 20.18 Linder–Dahan mediastinoscope. (From Leschber G, Holinka G, Linder A. Video-assisted mediastinoscopic
lymphadenectomy (VAMLA)—a method for systematic mediastinal lymphnode dissection. Eur J Cardiothorac Surg
2003;24(2):192–195. Reproduced by permission of European Association for Cardiothoracic Surgery.)
FIGURE 20.19 Enhanced quality of image through magnification effect. (From De Leyn P, Lerut T. Videomediastinoscopy.
Multimedia Man Cardiothorac Surg doi:10.1510/mmcts.2004.000166. Copyright © 2005 European Association for
Cardiothoracic Surgery. Reproduced with permission of MMCTS Editorial Office in the format Book via Copyright Clearance
Center.)
The technique and approach of videomediastinoscopy is not different from that of conventional
mediastinoscopy (Video 20.1) Several authors have reported their experiences with the use of
videomediastinoscopy.33–38
Browser issues
Video 20.1 Technique of Videomediastinoscopy.
Complications rate is similar to the complication rate described after classic mediastinoscopy. Call et
al. reported in a series of 183 extensive videomediastinoscopic lymphadenectomies (VAMLA) a 3.2%
transient recurrent nerve paresis, 1% persistent recurrent nerve paralysis, 0.5% chylomediastinum,
0.5%pneumothorax, and 0.5% hematoma.35
Advantages
• Better imaging (Fig. 20.10)

The magnified image on the screen offers a much more detailed image (Fig. 20.19). Because of the
detailed imaging, a more accurate and extensive dissection is possible. As the anatomical landmarks
are more easily visualized, complications are possibly better prevented or, when they occur they can
more easily be controlled (see also Fig. 20.9, a picture taken with videomediastinoscopy)
• Bimanual preparation (Fig. 20.20)
Hurtgen et al.37 have shown that using bimanual dissection, complete lymph node dissection is feasible
through the videomediastinoscopy, the so-called video-assisted mediastinal lymph node dissection
(VAMLA). Sensitivity and negative predictive value is increased by performing
videomediastinoscopy.
• Teaching (Fig. 20.21)
A recent (39) paper showed that the learning curve of video-assisted mediastinoscopy is low as
compared to conventional mediastinoscopy. This study reported that after a short learning curve,
trainees were able to identify all stations, obtain adequate histological samples, and perform the
procedure without direct assistance in over 80% of the cases. No complications were reported.38
• Standardization
Mediastinoscopy is considered a key procedure for staging of lung cancer. However, there is a great
variation in the way the procedure is performed. Widespread international use of videotaped
mediastinoscopy may lead to better understanding and standardization of this procedure. Videotaping
of the surgical procedure may result in more accurate judgements during clinicopathological
discussions.
FIGURE 20.20 Bimanual dissection through the videomediastinoscope tube guided by the video-image. (From De Leyn P, Lerut
T. Videomediastinoscopy. Multimedia Man Cardiothorac Surg doi:10.1510/mmcts.2004.000166. Copyright © 2005 European
FIGURE 20.21 Teaching a resident through visualization of the perioperative field on the screen. (From De Leyn P, Lerut T.
Videomediastinoscopy. Multimedia Man Cardiothorac Surg doi:10.1510/mmcts.2004.000166. Copyright © 2005 European
CONCLUSION
Mediastinoscopy, despite the introduction of promising noninvasive staging tools, remains a “key player”
in the algorithm of staging of lung cancer and other primary or secondary chest malignancies as well.
Refinement of the technique, increasing experience, and in particular the introduction of
videomediastinoscopy have resulted in a number of interesting spin offs, for example, VAMLA, video-
assisted mediastinoscopic lymphadenectomy or TEMLA transcervical extended mediastinal
lymphadenectomy which will be described in the next chapter.
However, the main message resulting from these new developments in both noninvasive and invasive
staging of the mediastinum is that these developments have brought all involved specialties in dealing
with lung cancer closer to each other. This multidisciplinary approach in diagnosis and treatment of lung
cancer has been the most important step forward since the beginning of the second Millennium.
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21
Transcervical Mediastinal
Lymphadenectomy
Gunda Leschber
INDICATIONS
In patients with primary lung tumors it is necessary not only to take lymph node biopsies for staging, but
also to remove all mediastinal lymph nodes completely prior to the anatomical resection. This can be
done by transcervical mediastinal lymphadenectomy.
In 2002, Hürtgen et al.1 was the first to describe complete mediastinal lymphadenectomy by video-
mediastinoscopy for which he created a new term VAMLA, that is, video-assisted mediastinal
lymphadenectomy. Following extensive experience with (video-) mediastinoscopy, he sought to increase
the sensitivity of mediastinoscopy in lung cancer patients up to a level that was equivalent to an open
systematic lymphadenectomy. In his opinion, this depended largely on the amount of lymph node tissue
removed; thus, he developed the technique for complete en bloc resection of each nodal station including
adjacent fatty tissue. Upon inspection during subsequent thoracotomy, he found no residual lymph nodes in
the mediastinum. Hürtgen claimed, “VAMLA is particularly suited to identify minor N2 disease in patients
eligible for neoadjuvant therapy.”
We and other authors believe that VAMLA is particularly advantageous in candidates to VATS-
lobectomy as it facilitates the complete removal of lymph nodes especially in the subcarinal space (stat.
7).2–4
As the group of Witte et al.5 already in 2006 stated, complete removal of mediastinal lymph nodes
allows superior pre-operative staging as more tissue is available for pathologic examination. This is our
experience as well.
Current guidelines from ACCP6 and ESTS7 have cited the indication for invasive mediastinal staging
in patients with enlarged or metabolic active lymph nodes (PET positive) although they do not specify if
by VAMLA or conventional mediastinoscopy. The guidelines of the European Society of Thoracic
Surgeons support mediastinoscopy but have recommended performing VAMLA in clinical trials only as
there is not sufficient data to conclude that VAMLA is superior to other staging techniques.7
In the authors practice, we perform VAMLA on patients who are planned to undergo a VATS-
lobectomy. We achieve a more radical and faster lymphadenectomy in conjunction with a VATS-
lobectomy compared to a lymphadenectomy achieved by VATS alone.2 Others have published about the
same approach, with the same yield.3,4,8 Witte and colleagues9 found that VAMLA does not increase total
operating time when compared to systematic lymphadenectomy performed during VATS-lobectomy alone.
In their study they reported a median total operative time of 200 min (range 125 to 263 min) for the
combination of VAMLA and VATS-lobectomy in a two-step procedure compared to a median time of 202
min (range 135 to 275 min) for a single step VATS-lobectomy with subsequent lymphadenectomy. Kim
and colleagues8 reported 38.0 ± 12.3 min procedural time for VAMLA.
To note that in the study of Witte et al. the number of dissected mediastinal nodal stations was almost
twice as high in the VAMLA/VATS group (mean 6.45–9 stations) compared to the VATS group (mean
3.62–6 stations). The same difference was found for the mediastinal sample weight: VAMLA/VATS group
11.2 (range 2.7 to 21.4) g versus 5.5 (range 0.6 to 15) g for the VATS group.9
While in North America lymph node specimen removed by VAMLA are mainly examined by frozen
section immediately prior to curative resection, German and some other European thoracic surgeons often
send all lymph node tissue for permanent histopathology (personal communications). In our experience,
VATS-lobectomy is not impaired if performed within a few days of VAMLA, but an interval of more than
7 days makes dissection more difficult due to the formation of adhesions.1 It is important to have an
agreement with the pathologists to finalize pathology within 24 h after mediastinoscopy/VAMLA so one
can proceed to VATS-lobectomy 2 days after mediastinoscopy. Other authors, such as the group in Seoul,8
perform VAMLA just prior to VATS-lobectomy. Both approaches have benefits: a single step procedure
on one side, but the possibility to spare an unnecessary operation in case of extended N2 or N3 disease.
The operative costs of either approach have not been calculated yet.
As for the learning curve of VAMLA, it is similar to video-mediastinoscopy with the exception that
one has to become familiar with dissection of all mediastinal tissues as described below. One should be
careful in the beginning toward the most delicate tissues (pulmonary artery and vena cava) but the
advantage is self-control about the completeness in the subsequent VATS.
For a transcervical mediastinal lymphadenectomy via mediastinoscopy the same operative approach
(length of incision, instruments) is chosen as for mediastinoscopy (see Chapter 20).
FIGURE 21.1 Tip of the mediastinoscope with the camera looking at a 30-degree angle downward.
CONSIDERATIONS FOR TRANSCERVICAL MEDIASTINAL

LYMPHADENECTOMY (VAMLA)
1. It is advisable to use a video-mediastinoscope because the visibility of mediastinal structures on the
video screen is improved tremendously compared to direct vision through a conventional
mediastinoscope. Structures appear larger, in more detail and the assisting trainee can learn from each
procedure. It is a perfect teaching tool because all anatomical landmarks are gradually revealed during
the procedure and with the resection of each lymph node station, making for a great understanding of
mediastinal anatomy.
Furthermore, all members of the operating team can play a more active role in the procedure by
predicting and preparing for the next steps. In particular, once anesthesiologists will get familiar with
the procedure, they will be in a better position to predict the remaining operative time. As a result,
VAMLA will be characterized by shorter anesthetic time and a more rapid patient turnover.
FIGURE 21.2 A: Video screen with zoom function of mediastinoscope activated with part of the visual field missing; B: with
no zoom function showing the complete visual field of the camera with the arrow at 12 o’clock.
FIGURE 21.3 Tip of the mediastinoscope with the upper blade in form of an olive.
2. One has to be aware that the angle of the camera of the mediastinoscope is looking downward at an
angle of 30 degrees (Fig. 21.1). This means that anatomical structures lying ventrally are, in general,
less easily visualized during mediastinoscopy. It is important to remember that the pulmonary artery is
the major ventral structure which needs special attention during the whole procedure. Activation of the
zoom mode of the camera reduces the overall view of the operative field and can result in inadvertent
injuries. Therefore, it is important to maintain a broader view (the whole visual field of the camera on
the TV screen) and also maintain the proper orientation of the camera—imbedded arrow should be at
the 12 o’clock position (Fig. 21.2A,B).
Finally, keep in mind that the camera in the mediastinoscope is located below the olive of the upper
blade and if not careful, the upper blade can be pushed further into structures than appreciated in the
field of vision (Fig. 21.3).
FIGURE 21.4 Mediastinoscope closed (A) and with open blades (B).
3. Some surgeons prefer to use a mechanical camera holder for video-mediastinoscopy. The advantage is
a completely steady operative field once the camera holder is in a fixed position. Also, there is no need
for an assisting surgeon. However, this can be problematic particularly in more challenging cases or
with bleeding as the optic may be blurred by blood and needs immediate cleaning. In our experience,
mediastinal lymphadenectomy is best performed with an assisting surgeon who holds the scope. The
assistant must be familiar with the mediastinal anatomy and the steps of the procedure; a human is more
flexible in reacting in case of problems than a mechanical device.
4. In order to create a working space within the mediastinum it is advisable to use a mediastinoscope with
spreadable blades (Fig. 21.4). This permits the use of multiple, simultaneous instruments for bimanual
dissection of the different mediastinal structures. Additionally, nonspreadable scopes are too narrow to
allow angulation of instruments.
5. The use of instruments with curved tips (suction device) is beneficial as it allows better angulation
during the procedure and also follows the shape of the lymph node. Bipolar scissors with an insulated
shaft also help to reduce the risk of burn injuries to adjacent tissue, in particular the recurrent nerve.
The same instruments as for conventional mediastinoscopy are used in VAMLA (Fig. 21.5).
6. Prior to the procedure, a thorough evaluation of the CT scan and PET-CT should be performed to be
familiar with anatomical variations, thyroid nodules that may extend to the retrosternal space and to
identify the lymph nodes with metabolic activity. Lymph nodes with a high SUV are not necessarily
enlarged on conventional CT scans and on the other hand enlarged lymph nodes do not always show
PET activity.
7. In general, less bleeding occurs if lymph nodes are not disrupted but resected completely. The supplying
vessel can be isolated and clipped or cauterized. If there is any doubt about a potential vascular
structure it should be confirmed by needle aspiration before biopsy or resection.
FIGURE 21.5 Suction device with curved tip (A), tip of instruments used for mediastinoscopy: Babcock clamp, grasper, suction
(from above) (B).
TECHNIQUE: STEPS OF THE PROCEDURE

A transverse, cervical incision in the jugulum is created large enough to introduce a video-
mediastinoscope (2 to 3 cm). Dissection is carried down to the pretracheal fascia which is incised and
digitally elevated from the trachea. Enlarged mediastinal lymph nodes are sometimes already palpated
and can be partially dissected manually, particularly in the right paratracheal region.
It is worthwhile on the right side to identify the crossing of the brachiocephalic artery (innominate
artery) and start manual dissection of loose tissue from the lower border of the artery. This step prepares
for a more complete dissection of lymph nodes and surrounding fatty tissue from the right paratracheal
compartment. The brachiocephalic artery can be followed to the left to its origin from the aorta. Be aware
when palpating that arteriosclerotic plaques present in older patients may become loose if this maneuver
is not performed gently, thereby resulting in stroke or transient ischemic attack.
When inserting the mediastinoscope it is important to slip under the pretracheal fascia as this helps to
guide the scope along the plane of the trachea. The anterior tracheal surface with its cartilage rings is a
perfect landmark to maintain orientation, particularly in cases of confusing anatomy (Fig. 21.6).
By pushing the pre- and paratracheal tissues downward with the suction device, a working space is
slowly created allowing advancement of the scope. This maneuver is performed down to the bifurcation
of the trachea onto the main bronchi: the tracheobronchial angles. The right tracheobronchial angle is
more easily identified as it comes off at a sharper angle versus the left which runs more vertically. A
lymph node is often encountered on the right, just within this angle.
Once the right tracheobronchial angle is identified, the mediastinoscope is shifted back to the midline
in order to identify the main carina. Here, the pulmonary artery is crossing ventrally. By gentle dissection
—either with the suction device, a dissector, or the bipolar scissors—the artery can be lifted up from the
carina. The carina is pushed dorsally with the sucker exposing tethering attachments which are sharply or
bluntly transected (Fig. 21.7). Sometimes, there are small vessels within the attachments that need to be
coagulated or clipped, but no larger vessels are encountered in this area. Once, adhesions to both sides of
the midline are dissected free, a plane is created in which the mediastinoscope can be advanced and
achieve a good view into the subcarinal space. However, it is important to remember that the camera is
looking downward (dorsally) at an angle of 30 degrees and that most mediastinoscopes have a longer
upper blade. Inadvertent injuries to ventral structures—such as the pulmonary artery—may occur unless
caution is exercised. Gentle movements lower sheer forces to tissues and reduces the risk of injury
especially if adjacent structures are already freed.
FIGURE 21.6 Initial view while dissecting the trachea (adjacent fibrous tissue overlying the trachea with cartilage rings in
white).
FIGURE 21.7 Dissection of stat. 7 underneath the pulmonary artery, lymph nodes are pushed toward the left main bronchus
with the sucker while bipolar scissors dissect adhesions.
LYMPH NODE STATION 7

Lymph nodes from station 7 are situated immediately below the carina, often embedded in fatty tissue.
Dissection of these lymph nodes is made easier if the plane between pulmonary artery and carina has been
created (Fig. 21.8).
In most cases there is a bronchial artery arising from the left, crossing over the left mainstem bronchus
that supplies the subcarinal lymph nodes (less commonly the arterial supply arises from the right). The
vessel usually is clipped or transected after electrocoagulation.
Dissection starts directly at the level of the carina on the medial walls of both main bronchi (right and
left). The most cranial part of lymph node 7 is grasped with one hand and with the other hand dissection
started with the bipolar scissors or by blunt dissection. By pushing the lymph nodes medially or to the
opposite side, dissection of the bronchial walls is facilitated.
It is important to note that additional arterial supply to the lymph nodes also arises from bronchial
arteries which originate caudally. It is helpful to place a clip at the distal end of dissected tissue and
transect it with scissors. On the contrary, there is a risk to rip off these arteries if one pulls the lymph
nodes too much toward the mediastinoscope.
Clearing of the whole subcarinal space is facilitated if the pulmonary artery is gently lifted up with the
mediastinoscope to enlarge the working field. However, one must be very careful when moving a
mediastinoscope with open blades, it is better to always close the instrument before repositioning.
FIGURE 21.8 Multiple stat. 7 lymph nodes completely freed from carina, both main bronchi and pulmonary artery (clips set at
dissected bronchial artery).
An additional trick to have a good and large working space in the subcarinal area is to push dissected
tissue downward (caudally) instead of pulling it into the mediastinoscope (Fig. 21.9). Large tissue bulk
can easily obstruct the view or blur the optic of the scope. Sometimes it is necessary to remove part of the
lymph node packet to allow for better visualization of the subcarinal space.
When the lymph nodes are sufficiently freed from the bronchial wall on the left, the esophagus is easily
identified dorsally by its longitudinal fibers. Dissection of lymph nodes from the esophagus should be
performed with only sparse electrocautery as heat could lead to burn injuries of the esophageal wall.
Once the whole package is freed, it is removed en bloc, leaving the subcarinal compartment empty with
all structures clearly visible: both main bronchi as the lateral borders, pulmonary artery as the ventral
limitation and esophagus dorsally (Fig. 21.10).
FIGURE 21.9 Stat. 7 lymph nodes lifted up toward the pulmonary artery to dissect them from the esophagus.
FIGURE 21.10 Stat. 7 completely emptied from lymph node tissue with the esophagus visible dorsally, the pulmonary artery
ventrally, and both main bronchi as lateral borders. See clips applied to small vessels.
LYMPH NODE STATION 10 L
The mediastinoscope is now swung over to the lateral side of the left main bronchus (Fig. 21.11).
Dissection is carried down along the bronchial wall using the mediastinoscope and the sucker. The
mediastinoscope itself is advanced to the left, a maneuver that enlarges the operating field. If the
pulmonary artery has been freed as described before, the most distal lymph nodes encountered here are
already at the level of station 10 L (below the upper border of the pulmonary artery). When dissecting the
nodes off the fatty tissue, special care has to be taken to avoid tearing or heat application because the
recurrent laryngeal nerve is within close proximity and should not be harmed. The curved tip of the
suction device is particularly helpful in carving out lymph nodes located here. Lymph nodes may also be
grasped with one instrument and dissected from the surrounding tissues with another one (Figs. 21.12 and
21.13).
FIGURE 21.11 Left main bronchus before removal of lymph nodes stat. 10 L, ventrally the left pulmonary artery is crossing.
FIGURE 21.12 Dissection of lymph nodes stat. 10 L on the lateral border of the left main bronchus underneath the left
pulmonary artery.
FIGURE 21.13 Left main bronchus after removal of lymph nodes stat. 10 L.
FIGURE 21.14 Right tracheobronchial angle with right main bronchus and azygos vein, lymph node stat. 10 R underneath the
right pulmonary artery.
LYMPH NODE STATION 10 R

Next, the mediastinoscope is slightly withdrawn and moved over to the right side and dissection is
continued to free lymph node in station 10 R. By working along the lateral border of the right main
bronchus the origin of the right upper bronchus is soon encountered with lymph node tissue adjacent to it.
Ventrally, the right pulmonary artery is visible and cranially the azygos vein comes into view. Both
vessels should be treated gently. Dissection may be started from the upper lobe bronchus travelling
cranially or alternatively, the azygos vein can be used as a landmark to expose lymph nodes of station 10
R. Grasping the lymph node with the surrounding tissue with one hand and dissecting it from the described
structures is a safe method for complete removal.
When the lymph node tissue is completely removed, the entire inferior border of the azygos vein
should be exposed (Fig. 21.14).
In case of calcifications of lymph nodes in this location (i.e., posttuberculous) one should avoid
pulling excessively on the nodes as dense adhesions between the node and venous wall may result in
disruption of the azygos vein at its confluence with the superior vena cava. This complication can result in
massive bleeding and sometimes even needs thoracotomy to repair the injury.
LYMPH NODE STATION 4 R

The most challenging dissection of a complete mediastinal lymphadenectomy is the en bloc resection of
the paratracheal lymph nodes on the right. According to the new lymph node classification from 200910
the oncological midline has shifted to the left border of the trachea. This means that all lymph nodes from
the right side extending over to the trachea up to its left border are called lymph node station 4 R. Most
patients have a fair amount of fatty tissue in this area which contains embedded lymph nodes. Complete
removal eventually exposes the following structures: trachea as the medial/dorsal border, upper vena
cava as ventral border, and mediastinal pleura as the lateral limit. The lower (caudal) border consists of
the azygos vein, the upper (cranial) border is the crossing of the brachiocephalic artery (innominate
artery).
FIGURE 21.15 Upper border of azygos vein with pleura and lung shining through during removal of lymph nodes stat. 4 R.
There are two methods to dissect this compartment: either starting caudally at the level of the azygos
vein working upward or to start cranially at the level of the brachiocephalic artery and dissecting
downward. Both methods have advantages which are described below.
If one starts caudally with identification of the upper border of the azygos vein, this vessel is followed
to its confluence with the upper vena cava. All fatty tissue is then dissected from the veins exposing the
pleura with the right lung visible behind it (Fig. 21.15). The essential maneuver is to grasp the fatty tissue
at the superior border of the azygos vein and dissect with a sucker or the bipolar scissors to serially
divide all adhesions from the pleura. The pleura and the vena cava are followed upward, creating a large
bulk of fat containing the nodes. Again here visualization of dissection may be compromised by the
volume of tissue and partial removal of the lymph nodes packet may be required to avoid this trouble.
However, if lymph nodes are disrupted diffuse bleeding may occur. Eventually, the lower border of the
brachiocephalic artery is exposed. Medially, dissection off the trachea is easily performed.
FIGURE 21.16 Final view: Superior vena cava, pulmonary artery, pleura on the right side, and trachea after removal of lymph
nodes 4R.
Dissection may also be initiated at the lower border of the brachiocephalic artery. This allows the
lymph nodes and fatty tissue to be pushed downward away from the camera and mediastinoscope. In this
technique, it is more difficult to expose the upper vena cava, but the pleura is still easily exposed.
Moreover, trachea as the medial border allows good dissection.
A combination of both methods is often warranted to achieve a good result (Fig. 21.16).
LYMPH NODE STATION 4 L

Dissection of lymph nodes in the left paratracheal area (4 L) is always started at the level of the left
tracheobronchial angle. Here, above the upper limit of the pulmonary artery, lymph nodes are encountered
often also embedded in fatty tissue. Special attention has to be paid to the recurrent laryngeal nerve which
in general lies in proximity to the trachea. The nerve can be identified as a longitudinal structure of
approximately 1 mm in diameter. Occasionally, cardiac branches of the vagus nerve are also found which
derive from the recurrent laryngeal nerve and are much smaller in diameter. Nerve structures should be
preserved and electrocautery should be used sparingly when dissecting lymph nodes and fatty tissue in the
left paratracheal region. Blood supply to the nodes is diminutive so more liberal use of packing or
application of clips is preferred over electrocoagulation.
In general, fewer lymph nodes are encountered on the left side of the trachea than on the right. One has
to keep in mind that according to the new lymph node classification only nodes strictly lateral to the left
border of the trachea are classified as 4 L.
LYMPH NODE STATION 2 R+L
If enlarged or PET-positive lymph nodes are described in these positions, lymphadenectomy should be
performed. Generally, one should avoid removal of these lymph nodes which are rarely enlarged. They
are located above the crossing of the innominate vein (its lower border is the limit of this compartment).
Here, also on the right side, special attention is needed to avoid damage to the recurrent laryngeal nerve.
FINAL VIEW
Once the transcervical mediastinal lymphadenectomy is accomplished, a final inspection of the operating
field shows the anatomical landmarks very clearly: the trachea, both main bronchi, the origin of the right
upper lobe bronchus, the esophagus, azygos vein, and superior vena cava as well as the pleura on the right
side.
A complete mediastinal lymphadenectomy results in the harvest of large numbers of lymph nodes
imbedded in fatty tissue as shown in Figure 21.17.
FIGURE 21.17 Pathological specimen from transcervical mediastinal lymphadenectomy.

Hemostatic packing is not indicated. Also, there is no need for routine drain placement. If the pleura is
opened during dissection, it is sufficient to have anesthesia hold a Valsalva (the lung inflated) while
withdrawing the mediastinoscope. A routine chest radiograph is not necessary after VAMLA.
COMPLICATIONS
In our experience with more than 250 mediastinal lymphadenectomies (VAMLA), The authors have not
had any mortalities. This is consistent with the current literature. Morbidity continues to improve with
increased experience and most commonly includes recurrent nerve palsy or vascular lesions. Witte and
colleagues5 published their ample experience with 144 VAMLA between 2000 and 2004. They noted a
drop in the complication rate from 5.3% in the first half of the series to 2.6% in the second.5 When
compared to conventional mediastinoscopy the rate of complications is comparable, which can likely be
attributed to better visualization of mediastinal structures.11,12
The most common complication is temporary left recurrent laryngeal nerve palsy/dysphonia which
accounts for approximately 3.0%, but permanent palsy rates are much lower (1%).13 In his series, Turna
and colleagues4 mentioned 9% postoperative dysphonia but did not comment on the rate of permanent
nerve palsy.
RESULTS
In one of the largest series of VAMLA published to date, Call and colleagues13 demonstrated that VAMLA
detected a high rate of unsuspected N2 and N3 disease in patients presumed to be clinical N0 based on
workup. All patients had a complete preoperative staging including CT of the chest and upper abdomen,
PET scan, and bronchoscopy (but no EBUS/EUS), prior to undergoing VAMLA for pathological staging of
the mediastinum. Lung resection of NSCLC was planned in case of N0.
Among the 151 patients studied, 18% were found to have undetected N2 or N3 disease by VAMLA:
cN1 tumors (by CT or PET) accounted for 40.7%, cN0 and tumor >3 cm was 22.2%, and in cN0 and
tumors <3 cm was 6.4%. The authors concluded that except for the last group, invasive mediastinal
staging should be included in the staging algorithm for patients with lung cancer.
For small tumors, VAMLA was still recommended as a pre-resectional lymphadenectomy in
conjunction with VATS-lobectomy.
Kim and colleagues8 pointed out that the most difficult aspect of TNM-staging remains the nodal status
and that, VAMLA has enabled the minimally invasive approach to be equivalent to open lymphadenectomy
in terms of diagnostic accuracy and surgical radicality. They recommended VAMLA as a complement in
lung cancer patients in whom minimal invasive resection was planned.
In analyzing patients with left-sided tumors they compared VAMLA/VATS with lobectomy and
mediastinal lymphadenectomy by VATS alone with regard to resected lymph nodes and operative data.
The operative time for VATS was significantly lower in the VAMLA/VATS group, however if time for
VAMLA was added (it was done immediately prior to VATS), there was no difference between the two
groups. This reconfirmed earlier findings by Witte et al.9 also concerning the total number of lymph nodes
removed by each group. In the ample experience of Kim with 225 patients in the VAMLA/VATS group and
424 in the VATS group, the lymph node yield was 29.7 ± 10.8 versus 23.0 ± 8.6 respectively (P <0.001).
In the especially important lymph node stations 2, 4, and 7, the difference was most striking: 13.2 ± 6.9
versus 6.6 ± 4.5 (P <0.001). There were a higher number of patients upstaged from cN0 to pN2 or N3 in
the VAMLA/VATS group and also more patients downstaged from cN1 to pN0 in the VAMLA/VATS
group. This did not reach statistical significance. The authors concluded that complete mediastinal
lymphadenectomy in minimal invasive pulmonary resections is nicely complemented by VAMLA. The
added benefits of reduced time of one-lung ventilation for the VATS procedure and ease of procedure for
trainees were also appreciated.8 VAMLA is seen as an excellent teaching method and it allows
standardization of the procedure.2
In 2013, Turna and colleagues were the first to publish their data on long-term survival. They studied
433 patients with resected non–small cell lung cancer who had either undergone conventional
mediastinoscopy (n = 344) or VAMLA (n = 89) (79%:21%) prior to lung resection. All patients
underwent identical staging procedures (including PET-CT scan) and there was no statistical difference in
the patient’s clinical characteristics or in the distribution of clinical T stages. The choice of standard
mediastinoscopy or VAMLA was at the discretion of the surgeon. VAMLA discovered statistically more
N2/3 disease than standard mediastinoscopy (40.4 vs. 16.2, P <.001). These patients were excluded from
further surgery. The time interval between VAMLA/mediastinoscopy and pulmonary resection was less
than 30 days in 97.6% of cases. Survival rates in VAMLA patients were consistently better and
maintained with propensity matching for patients’ characteristics and clinical T-stage. Five-year survival
in VAMLA was superior at 86.5% versus 49.5% in standard mediastinoscopy.4 The authors have found
the same trend in our patients (nonpublished data).
TRANSCERVICAL EXTENDED MEDIASTINOSCOPIC LYMPHADENECTOMY

(TEMLA)
Another technique of transcervical mediastinal lymphadenectomy was developed by the group of
Zielinski in Poland in 2005.14 In addition to the approach by the route of mediastinoscopy, TEMLA uses a
sternal elevator and the thoracoscope additionally. This allows removal of nodes from stations 1, 2, and 4
bilaterally, 3, 7, and stations 5, 6 as well as station 8. A 5- to 6-cm cervical incision is necessary to
perform the extensive dissection of all vessels, to visualize both laryngeal nerves in length, thymic tissue
and to enter the aortopulmonary window. As with VAMLA, complete resection of all mediastinal tissue
(lymph nodes and fatty tissue) is achieved. An impressive number of lymph nodes are removed which is
comparable to the superradical bilateral mediastinal dissection described by Hata et al. in 1994.15
TEMLA is somewhat hurt by the lengthy operative time necessary for the meticulous dissection;
extending beyond 2 hours it is rendering some patients unfit for additional surgery.14 The sensitivity,
negative predictive value (NPV) and accuracy as well as specificity and positive predictive value (PPV)
do not differ between TEMLA and VAMLA, but both are better than conventional mediastinoscopy:
sensitivity 0.96, negative predictive value 0.98, accuracy 0.99, specificity 1 and PPV 1.13
Presently, the polish group remains the sole publishers of this technique; so, it seems debatable
whether it will find wide acceptance due to its invasiveness.16
REFERENCES
1. Hürtgen M, Friedel G, Toomes H, et al. Radical video-assisted mediastinoscopic lymphadenectomy (VAMLA)—technique and first
results. Eur J Cardiothorac Surg 2002;21(2):348–351.
2. Leschber G, Holinka G, Linder A. Video-assisted mediastinoscopic lymphadenectomy (VAMLA)—a method for systematic mediastinal
lymph node dissection. Eur J Cardiothorac Surg 2003;24(2):192–195.
3. Yoo DG, Kim YH, Kim DK, et al. Clinical feasibility and surgical benefits of video-assisted mediastinoscopic lymphadenectomy in the
treatment of resectable lung cancer. Eur J Cardiothorac Surg 2011;40(6):1483–1486.
4. Turna A, Demirkaya A, Ozkul S, et al. Video-assisted mediastinoscopic lymphadenectomy is associated with better survival than
mediastinoscopy in patients with resected non-small cell lung cancer. J Thorac Cardiovasc Surg 2013;146(4):774–780.
5. Witte B, Wolf M, Huertgen M, et al. Video-assisted mediastinoscopic surgery: clinical feasibility and accuracy of mediastinal lymph node
staging. Ann Thorac Surg 2006;82(5):1821–1827.
6. Detterbeck FC, Lewis SZ, Diekemper R, et al. Executive summary: diagnosis and management of lung cancer, 3rd ed: American
College of chest physicians evidence-based clinical practice guidelines. Chest 2013;143(suppl 5):7S–37S.
7. De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung
cancer. Eur J Cardiothorac Surg 2014;45(5):787–798.
8. Kim HJ, Kim YH, Choi SH, et al. Video-assisted mediastinoscopic lymphadenectomy combined with minimally invasive pulmonary
resection for left-sided lung cancer: feasibility and clinical impacts on surgical outcomes dagger. Eur J Cardiothorac Surg
2016;49(1):308–13.
9. Witte B, Messerschmidt A, Hillebrand H, et al. Combined videothoracoscopic and videomediastinoscopic approach improves radicality
of minimally invasive mediastinal lymphadenectomy for early stage lung carcinoma. Eur J Cardiothorac Surg 2009;35(2):343–347.
10. Sobin LH, Gospodarowicz MK, Wittekind C, et al. TNM Classification of Malignant Tumours. 7th ed. Chichester, West Sussex, UK;
Hoboken, NJ: Wiley-Blackwell; 2009. Available from http://site.ebrary.com/lib/yale/Doc?id=10342913.
11. Cho JH, Kim J, Kim K, et al. A comparative analysis of video-assisted mediastinoscopy and conventional mediastinoscopy. Ann Thorac
Surg 2011;92(3):1007–1011.
12. Leschber G, Sperling D, Klemm W, et al. Does video-mediastinoscopy improve the results of conventional mediastinoscopy? Eur J
Thorac Surg 2016;101(4):1326–1333.
14. Kuzdzal J, Zielinski M, Papla B, et al. Transcervical extended mediastinal lymphadenectomy—the new operative technique and early
results in lung cancer staging. Eur J Cardiothorac Surg. 2005;27(3):384–390; discussion 390.
15. Hata E, Miyamoto H, Tanaka M, et al. [The necessity of extended systemic dissection of the regional lymph node in radical operation
for lung cancer]. Kyobu Geka 1994;47(1):40–44.
16. Zielinski M, Szlubowski A, Kolodziej M, et al. Comparison of endobronchial ultrasound and/or endoesophageal ultrasound with
transcervical extended mediastinal lymphadenectomy for staging and restaging of non-small-cell lung cancer. J Thorac Oncol
2013;8(5):630–636.
22
Invasive Diagnostic Procedures
Michael Lanuti
INTRODUCTION
Invasive modalities are often implemented in the evaluation of thoracic diseases that span from benign to
malignant. Although diagnostic imaging with computed tomography, magnetic resonance imaging, and
positron emission tomography have greatly advanced over the decades, invasive procedures are
paramount in obtaining a diagnosis or staging thoracic neoplasms. Such modalities include
mediastinoscopy, anterior mediastinotomy (Chamberlain procedure), extended cervical mediastinoscopy,
scalene biopsy, thoracentesis, and diagnostic video-assisted thoracoscopy. In-depth discussion of
endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) will be covered elsewhere.
MEDIASTINOSCOPY
The gold standard for staging the mediastinum has traditionally been cervical mediastinoscopy; however,
EBUS is an alternative procedure that has gained increasing acceptance for mediastinal lymph node
staging. Mediastinoscopy was developed by Harken et al.1 in 1954 and then promulgated by Carlens in
1959 and later by Pearson in 1965.2 Carlens and Pearson recognized that mediastinoscopy was not only
for lung cancer staging but also for the diagnosis of lymphoma, metastatic disease from an extrathoracic
origin, infectious etiologies, and sarcoidosis. It is the modality upon which all comparisons of lymph
node accuracy are currently analyzed including the use of EBUS or EUS mediastinal lymph node
sampling. The mediastinoscopes used today are modifications of the original instruments, with distal
illumination, a beveled end, and a lateral slit for instrumentation (Fig. 22.1). The efficacy of
mediastinoscopy has been well established in the assessment of enlarged mediastinal lymph nodes with
100% specificity and 90% sensitivity. In patients with known or suspected lung cancer, the routine use
of mediastinoscopy can change the plan of care in up to 25% of patients. Large studies confirm false
negative rates from 5% to 8%.3,4 The false negative rate of mediastinoscopy may also be attributed to the
diligence of the surgeon dissecting and sampling the nodes. Ideally, five nodal stations (stations 2R, 4R,
7, 2L, and 4L) should be routinely examined (refer to Fig. 22.2), with a least one node sampled from each
station unless no nodal tissue is present after inspection. Video mediastinoscopy compared to
conventional mediastinoscopy appears to yield some improvement in sensitivity (92%) and false negative
rates (7%) by virtue of magnified optics and improved visualization.5,6
Routine mediastinoscopy remains somewhat controversial in that many lung cancer treatment centers
use the modality selectively. A national survey of 729 hospitals (31% teaching or university hospitals,
38% community cancer centers, 46% comprehensive community cancer centers) sponsored by the
American College of Surgeons identified more than 11,668 patients whose initial management included
surgical therapy for lung cancer.7 The mediastinum was evaluated preoperatively with mediastinoscopy in
only 27% of these surgical patients and only 26% underwent a staging PET. The underuse of invasive
mediastinal staging in both academic and community lung cancer care is sobering. Additionally
troublesome is that only 42% had lymph nodes sampled at any mediastinal level during surgery.
INDICATIONS AND CONTRAINDICATIONS

Mediastinoscopy should be performed in any patient harboring a suspicious lung nodule with enlarged
(>1 cm in short axis measured on CT) or fluorine-18–labeled deoxyglucose (FDG) avid mediastinal
lymph nodes (N2 or N3), those with peripheral tumors ≥3 cm, those with central tumors or superior
sulcus tumors, and T4 tumors requiring caval or tracheal resection. If pneumonectomy is being considered
as part of an oncologic treatment, invasive mediastinal staging is warranted. If patients are being
considered for pulmonary resection in the setting of synchronous solitary solid organ oligometastatic
disease, invasive mediastinal staging is highly recommended.8 T1 tumors with an aggressive histology
(i.e., large cell neuroendocrine, carcinosarcoma, small cell, or pleomorphic carcinomas) should also
undergo mediastinoscopy. Peripheral T1a-T1b lesions (tumors ≤3 cm) with PET-negative mediastinal
lymph nodes can be regarded as the one exception to the routine use of mediastinoscopy.9 This is not
universally accepted by all societies, where the National Comprehensive Cancer Network (NCCN)
recommends pathologic mediastinal lymph node evaluation in solid tumors ≥1 cm and purely nonsolid
tumors ≥3 cm.10 EBUS has emerged as the procedure of choice for lung cancer staging (endorsed by the
American College of Chest Physicians, and European Society of Thoracic Surgeons in 2013).11,12 EUS
mediastinal lymph node biopsy has been evaluated for lung cancer staging in combination with EBUS in
three prospective series (two of which were randomized).13–15 EUS mediastinal staging was
complimentary to EBUS in complete endosonographic staging of the mediastinum. The sensitivity of
combined sonographic staging was 68% to 94% with a negative predictive value of 91% to 93%,
which was better than EBUS or EUS alone. If EBUS- or EUS-directed biopsies are negative in a
pathologically enlarged or FDG-avid mediastinal lymph node, mediastinoscopy is still recommended.
FIGURE 22.1 The Carlens mediastinoscope. (© KARL STORZ SE & Co. KG Germany)
FIGURE 22.2 The Mountain-Dresler modification of the regional lymph node map originally proposed by the American
Thoracic Society. (Modified from Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest
1997;111:1718–1723c. Copyright © 1997 The American College of Chest Physicians. With permission.)
Mediastinoscopy does not have many strict contraindications except for perhaps inability to extend the
neck because of severe kyphosis or fused cervical vertebra. Relative contraindications to
mediastinoscopy include large thyroid goiter, severe atherosclerotic disease in the aortic arch, vertebral
arteries (vulnerability to ischemic events with neck extension), or the innominate artery which can
contribute to embolic stroke. End tracheal stoma after laryngectomy in association with neck radiation can
present anatomic difficulty with increased risk of cervical wound infection. Previous mediastinoscopy is
associated with fibrosis of the pretracheal tissue plane and makes redo mediastinoscopy challenging.
Despite this phenomenon, repeat mediastinoscopy is feasible and safe in most cases and can be carefully
used to restage the mediastinum after induction therapy.16 Particular care must be exercised in separating
the innominate artery from the trachea. Sharp dissection under direct vision is safer than the blunt
approach used in first-time mediastinoscopy. Many surgeons reserve EBUS directed biopsy for
preinduction mediastinal lymph node sampling in patients suspected of harboring locally advanced lung
cancer (stage IIIA) with positive N2 nodes. While mediastinoscopy is a useful diagnostic tool, its
implementation may not be warranted in conditions that place the patient at substantial risk for
catastrophic hemorrhage or other complications.
TECHNIQUE
Mediastinoscopy is an outpatient procedure that needs to be performed in a hospital setting to efficiently
manage the potential for hemorrhage. The patient is placed supine on the operating room table where the
head is placed at the top of the bed (Fig. 22.3). After establishing general endotracheal anesthesia the
neck is extended either with a thyroid bag or a roll under the shoulders. A pulse oximeter or radial artery
cannula can be used to monitor compression of the innominate artery (observation of a dampened wave
form) so as not to compromise blood flow to the right carotid artery for an extended period. Most
surgeons include the entire sternum in the operative field in the event that serious hemorrhage is
encountered and median sternotomy is necessary. In the event that a patient already has a previous median
sternotomy, a right or left anterior thoracotomy can be considered for exploration in the setting of acute
hemorrhage. Mediastinoscopy can be achieved with direct visualization through a standard scope (Fig.
22.1) or via a magnified view with a video mediastinoscope (Fig. 22.4). Video mediastinoscopy permits
both direct and monitor viewing and facilitates teaching since all participants in the operating theater can
observe. As previously mentioned, video mediastinoscopy has been shown to improve lymph node
sampling over conventional mediastinoscopy.5 Dissection is carried down through the incised platysma
muscle to the strap muscles (sternohyoid and sternothyroid). The thyroid isthmus is rarely divided.
Palpation of the trachea helps identify the soft tissue midline where the strap muscles (Fig. 22.5) can be
vertically separated to allow sharp entry into the pretracheal alveolar plane (Fig. 22.5A and B). There is
often an adipose layer in the midline. The anterior tracheal wall is visualized (Fig. 22.6C) and a tunnel
can be created by bluntly spreading with a meztenbaum scissors or by insertion of the index finger. Blunt
finger dissection caudally (Fig. 22.6) can often permit palpation of the innominate artery pulse which later
can be vulnerable to compression when using the mediastinoscope. Finger dissection is continued down
the trachea where the surgeon can appreciate tissue resistance and texture of mediastinal lymph nodes
(Fig. 22.7). It is essential to assess the area just above the sternal notch early in the dissection because
neck extension may elevate the innominate artery up into the base of the neck where it can be injured by
sharp dissection or cautery.
FIGURE 22.3 Position for mediastinoscopy with general anesthesia and endotracheal intubation. Shoulders are elevated and the
patient’s head at top of the table.
FIGURE 22.4 Video mediastinoscope with suction cautery. (© KARL STORZ SE & Co. KG Germany)
FIGURE 22.5 Mediastinoscopy: small cervical neck incision (A) just about the sternal notch. After division of platysma muscle,
strap muscles are exposed to identify the midline (B). Pretracheal fascia is sharply divided and raised to expose trachea (C).

FIGURE 22.6 Sagittal view (A) and coronal view (B) of finger dissection to develop the pretracheal plane. Digital palpation of
the innominate pulse (C) with additional caudal dissection towards carina (D). (Obtained from Mediastinoscopy and other
thoracic staging procedures. In Kaiser LR, Kron I, Spray T, eds. Mastery of Cardiothoracic Surgery. Philadelphia, PA:
Lippincott Williams & Wilkins; 2014:14–27.)
FIGURE 22.7 Oblique view of finger bluntly dissecting the pretracheal fascia to enter the node containing space. (Obtained
from Mediastinoscopy and other thoracic staging procedures. In: Kaiser LR, Kron I, Spray T. Mastery of Cardiothoracic
Surgery. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:14–27.)
The mediastinoscope can be inserted into the pretracheal tunnel where a suction-cautery dissector is
used to bluntly dissect this alveolar plane with occasional fibrous bands (Fig. 22.8). The instrument is
advanced only if it passes easily and there is a visible tunnel ahead. The surgeon can explore the entire
length of the trachea and both mainstem bronchi. The landscape is carefully surveyed to identify lymph
nodes in the various stations depicted in Figure 22.9. Nodes are identified by color and consistency.
Particular care is taken when retrieving specimens near the tracheobronchial angles because of the
proximity of the azygos vein and apical branch of the truncus anterior pulmonary artery on the right and
the recurrent laryngeal nerve on the left. The right main pulmonary artery is observed superior to the
carina and can be injured with cautery while achieving hemostasis from biopsies of subcarinal lymph
nodes. All dissection and lymph node biopsies should be in close proximity to airway. The blue-gray hue
of venous structures can sometimes be mistaken for an anthracotic node. If there is any doubt about the
solid or vascular nature of the tissue in question, aspiration is performed using a 20- or 22-gauge spinal
needle and 10- to 20-cc syringe (Fig. 22.10A). Target lymph nodes should be partially dissected (Fig.
22.10B) before any biopsy specimens are taken to reduce bleeding. Once sufficiently freed, the node is
grasped with a cupped biopsy forceps, and traction is applied under direct vision (Fig. 22.10C). If the
node cannot be extracted by gentle pulling and twisting, further dissection is carried out or an additional
instrument can be introduced down the scope to divide tethering attachments or stabilize the origin of the
lymph node to avoid traction injury to adjacent vasculature. The goal of standard mediastinoscopy is to
sample lymph nodes and not perform lymphadenectomy. When sampling lymph nodes for lung cancer, it is
important to sample multiple lymph node stations. Samples are routinely obtained from stations (2, 4, 7)
(Figs. 22.2 and 22.9). Of note, station 10 is a hilar node (N1) and by definition resides inside the pleural
envelope and cannot routinely be accessed with standard mediastinoscopy techniques. EBUS is the
modality of choice for accessing this nodal station. Sampling nodes contralateral to the primary tumor is
paramount to identify patients who harbor N3 disease (stage IIIB) where surgery has less of a curative
role. Labeling all specimens by numerical station is less subject to error and removes ambiguity from
pathology reports. This behavior should be aggressively embraced when training since it improves
communication (common language among all treating physicians) and provides more accurate data when
performing clinical research.
FIGURE 22.8 The mediastinoscope is passed into the pretracheal tunnel (A). Note the adjacent structures. Suction-cautery (B)
is used to further develop the pretracheal plane to expose carina and bilateral mainstem bronchi. (Obtained from
Mediastinoscopy and other thoracic staging procedures. In: Kaiser LR, Kron I, Spray T. Mastery of Cardiothoracic Surgery.
Philadelphia, PA: Lippincott Williams & Wilkins; 2014:14–27.)
FIGURE 22.9 Map depiction of regional lymph nodes according to accessibility by staging modality including mediastinoscopy,
endobronchial ultrasound (EBUS) and esophageal ultrasound (EUS). (Modified from Mountain CF, Dresler CM. Regional lymph
node classification for lung cancer staging. Chest 1997;111:1718–1723c. Copyright © 1997 The American College of Chest
Physicians. With permission.)
FIGURE 22.10 Tissue is identified and aspirated with a needle to ensure the absence of a vascular structure (A). An edge of
lymph node is dissected free (B) and biopsied with a cup forceps (C).
A few groups have developed videoscopic equipment and techniques for performing mediastinal
lymph node dissection. These techniques employ a double-bladed Dahan–Linder mediastinoscope, which
can be spread to open within the mediastinal field and allow greater visualization. The double-bladed
scope can be secured with a stabilizer, allowing two-handed dissection guided by the video image.
Video-assisted mediastinoscopic lymphadenectomy (VAMLA) allows for resection of the subcarinal,
right paratracheal, right tracheobronchial, and pretracheal lymph nodes as well as sampling of the left
paratracheal and tracheobronchial nodes.17 Data regarding VAMLA followed by confirmatory open
mediastinal resection for the staging of lung cancer demonstrates a sensitivity of 93% to 96% and a
specificity of 100%, with a false-negative rate of 0.9%.17,18 The complication rate in these series is 6%.
TABLE 22.1 Complications of Mediastinoscopy
Death < 0.2%
Major complications ≤ 1%
Major hemorrhage intraoperatively
Recurrent laryngeal nerve paralysis
Cerebrovascular accident
Esophageal perforation
Mediastinitis
Mediastinal hemorrhage postoperatively
Tracheobronchial injury
Phrenic nerve paralysis
Thoracic duct injury
Venous air embolism
Minor complications 2.5%
Pneumothorax
Recurrent laryngeal nerve palsy
Wound infection
Minor bleeding
Autonomic reflex bradycardia
COMPLICATIONS
The incidence of complications for mediastinoscopy across large series is extremely low (summarized in
Table 22.1). Although catastrophic hemorrhage can be observed during mediastinoscopy, most bleeding is
minor and can be controlled with application of surgicel (oxidized cellulose), transient packing, or partial
withdrawal of the scope to tamponade the mediastinum. Occasionally, hemoclips can be used in the face
of a visible small vessel particularly in the subcarinal area where bronchial arteries are prevalent.
Cautery should be not be used anywhere along the left paratracheal space to avoid thermal injury to the
recurrent laryngeal nerve. If significant bleeding occurs, the mediastinoscope is packed and left in place
for at least 10 minutes and gently removed. Preparation should be made to have blood available in the
operating theater along with additional instruments. If hemorrhage continues, packing is reinstituted, and
motions are commenced to perform median sternotomy or thoracotomy. Median sternotomy is the most
versatile incision and preferred for hemodynamic instability, or injury to innominate artery, aortic arch, or
right pulmonary artery. It also allows better access for cardiopulmonary bypass if necessary to control
hemorrhage from a major vessel. Performing pulmonary resection after control of major bleeding is a
disadvantage of median sternotomy. Right thoracotomy is often employed for the more common azygos
vein injury and for the less common superior vena caval injury. Large studies confirm low morbidity and
mortality as described in Table 22.2.3,4,19 The most underreported complication from mediastinoscopy is
left vocal cord palsy from recurrent nerve injury. This can be observed with traction injury from the scope
as well as thermal injury from cautery.20 Esophageal injury is extremely uncommon and can be
encountered in association with aggressive biopsy at the low left paratracheal or subcarinal space. This
injury may not be immediately recognized and the patient may present postoperatively with mediastinal
air, mediastinitis, or pleural effusion. Esophagram should be obtained and the injury should be managed
similar to other traumatic injuries to the esophagus. Pneumothorax can be observed when violating the
parietal pleura and is not often associated with a parenchymal injury. This can be managed
intraoperatively using a flexible rubber catheter that is brought out through the cervical wound. After the
mediastinoscope is removed, pleural air is evacuated during a valsalva maneuver as the tube is removed.
If there is a recognized lung parenchymal injury, tube thoracostomy must be implemented.
TABLE 22.2 Morbidity and Mortality Reported in Large Studies of Patients Undergoing Mediastinoscopy for Lung
Cancer
Study N No. With No. (%) With False- No. (%) of No. (%)
Lung Negative Results Complications Deaths
Cancer
Lemaire et al. 2,145 1,019 56 (5.5) 23 (1.07) 1 (0.05)
(2006)
Park et al. 3,391 NA NA 14 (0.04) 0
(2003)
Hammoud et 2,137 947 76 (8.0) 12 (0.06) 4 (0.2)
al. (1999)
Mediastinopleuroscopy
In mediastinopleuroscopy the pleural space is intentionally entered using a standard mediastinoscope. On
the right, the pleura is opened posterior to the innominate artery, whereas on the left, entry is gained
between the left common carotid and left subclavian arteries. In addition to pleural biopsy, fluid
sampling, and talc pleurodesis, small upper-lobe lung biopsies can be obtained.21 However, the risk of
seeding a clean mediastinum by transpleural biopsy of an upper-lobe cancer or infection must be
considered where CT guided needle biopsy may be a better option.
Extended Cervical Mediastinoscopy

Extended cervical mediastinoscopy is a modality that is implemented by few thoracic surgeons and
therefore is not routinely part of thoracic surgery education. It was designed to stage patients with left
upper lobe lung cancers in whom standard cervical mediastinoscopy results are negative. Ginsberg et
al.22 devised a method for access to the para-aortic (station 6) and aortopulmonary (station 5) lymph
nodes. The approach originates through a standard cervical incision where a tunnel is created over the
aortic arch, between the innominate artery and the left carotid artery (Fig. 22.11). The mediastinoscope is
inserted obliquely to reach the subaortic space. The distinction between subaortic and para-aortic space
is difficult and frequently limited by the bony chest wall. In addition to potential injury to the innominate
and carotid artery, injury can be observed with the left main pulmonary artery, left recurrent laryngeal
nerve, and left phrenic nerve. Alternatively, these nodal stations can be accessed by anterior
mediastinotomy or VATS with improved visualization.
ANTERIOR MEDIASTINOTOMY OR ANTERIOR MEDIASTINOSCOPY

This procedure was described in 1966 by McNeill and Chamberlain and is often employed in lieu of
extended cervical mediastinoscopy for lung cancer staging. It is an outpatient procedure that can target
enlarged prevascular (station 6) or aortopulmonary (station 5) lymph nodes in the setting of lung cancer or
anterior mediastinal masses that require a diagnosis. Lymph nodes in the aortopulmonary window
primarily receive lymphatic drainage from the left upper lobe and are classified as N2 nodes. Of note, the
left upper lobe drains not only to the adjacent subaortic and anterior mediastinal stations, but also to the
ipsilateral paratracheal lymph nodes. Anterior mediastinotomy can also be used on the right and offers
access to the upper hilum, lung, and pleura on both sides. In addition to nodal staging, this modality
allows assessment of invasion of the mediastinum, pulmonary vessels, and phrenic nerve. When
mediastinotomy is indicated by CT findings, it is usually preceded by mediastinoscopy in the setting of
lung cancer staging.
FIGURE 22.11 Extended cervical mediastinoscopy: Tunnel over the aortic arch is created (A) to reach the aortopulmonary
window with the standard mediastinoscope (B). (Obtained from Mediastinoscopy and other thoracic staging procedures. In:
Kaiser LR, Kron I, Spray T. Mastery of Cardiothoracic Surgery. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:14–
27.)
CONTRAINDICATIONS
Prior sternotomy is not a contraindication but warrants caution since the endothoracic fascia has usually
been opened on the left and sometimes on the right particularly for cardiac revascularization procedures.
The procedure should generally not be performed, however, in the presence of a patent left internal
mammary artery bypass graft. In order to protect the graft in the event of repeat sternotomy, many cardiac
surgeons drape it laterally, often opening the pleura to do so. This places the artery anterior to the lung
hilum, essentially along the course of the phrenic nerve, and subject to injury. Other structures that can be
injured include the vagus nerve, the intercostal artery and vein, the superior pulmonary vein, the main
pulmonary artery, and the aorta.
TECHNIQUE
The procedure requires general anesthesia and a single lumen endotracheal tube. It can be performed
through a 5 cm transverse incision at the left sternal border over the second or third interspace.23 The
fibers of the pectoralis muscle are split to expose the cartilage. Although the original description
recommends excision of the second costal cartilage (Fig. 22.12), this can be obviated with the use of a
mediastinoscope (Fig. 22.13). The mediastinum is entered after incising the endothoracic fascia. The
internal mammary artery and vein may be ligated if necessary but can often be retracted and preserved.
Although an extrapleural plane can be developed to access station 5 or 6, this is not always feasible.
Finger dissection can be implemented to loosen areolar tissue; however, the mediastinoscope improves
visualization inward until the aorta, pulmonary artery, and intervening space are noted. This area is
assessed for fixation, invasion, and adenopathy. The vagus and phrenic nerves can sometimes be
identified along the aortic arch and the location of the recurrent laryngeal branch thereby inferred. When
sampling a mediastinal mass suspicious of a thymic neoplasm, entering the pleural space can be a risk for
pleural dissemination of disease and should be avoided if possible. The mediastinotomy site is often
excised (full thickness) during definitive surgical management of thymic neoplasms to reduce the
incidence of local tumor recurrence by virtue of tumor cell implantation at the time of mediastinotomy.
When mediastinotomy is done in conjunction with cervical mediastinoscopy, the neck incision is left open
to allow bidirectional palpation of the aortopulmonary region (Fig. 22.14). During palpation the surgeon
formulates a tactile map of normal and abnormal structures and can begin freeing enlarged nodes. A
mediastinoscope is also useful for improved lighting when performing biopsy with a cup forceps. If the
pleural cavity is entered, one can aspirate the pneumothorax using a flexible rubber catheter that is
brought out through the wound edge. After wound closure, pleural air is evacuated during a valsalva
maneuver (inflate lung to 25 to 30 cm H2O as the tube is removed).
FIGURE 22.12 Anterior mediastinotomy: Transverse incision over the second costal cartilage (A). Cartilage is removed (B)
exposing endothoracic fascia then mediastinal pleura and internal mammary artery and vein. (C) View of enlarged subaortic
lymph nodes (station 5). (Obtained from Shield’s chapter 18.)
FIGURE 22.13 Anterior mediastinoscopy: Mediastinoscope is placed through a parasternal incision in the 2nd intercostal space
allowing access to aortopulmonary lymph nodes. (Reprinted from Pearson FG, Cooper JD, Deslauriers J, et al. Thoracic
Surgery. 2nd ed. New York: Churchill Livingstone; 2002:100. Copyright © 2002 Elsevier. With permission.)
COMPLICATIONS
Potential pitfalls here are inadvertent biopsy of the left main pulmonary artery or aortic arch or injury to
phrenic or recurrent laryngeal nerve. Complication rates of 6.8% with no mortality were reported for
anterior mediastinotomy in a retrospective series of 151 patients.24 Chylothorax after mediastinotomy is
rare, but has been reported. Adequate visualization is mandatory and if it cannot be achieved,
thoracoscopy can be added through additional port incisions while intermittent ventilation is employed.
SCALENE BIOPSY
Scalene lymph node biopsy is an open procedure for sampling enlarged nodes or an apical mass
extending into the scalene triangle. Scalene fat-pad excision denotes resection of all the node-bearing
areolar tissue in this region. This modality is infrequently implemented in the contemporary era due to the
advent of ultrasound-guided core needle biopsy.
FIGURE 22.14 Bi-directional digital palpation of the aortopulmonary region at the time of combined cervical and left anterior
mediastinotomy. (Obtained from Mediastinoscopy and Other Thoracic Staging Procedures. In: Kaiser LR, Kron I, Spray T.
Mastery of Cardiothoracic Surgery. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:14–27.)
INDICATIONS
Prior to the widespread adoption of CT and PET, scalene fat-pad biopsy reportedly yielded positive
nodes between 3.5%25 and 20%.26 With the advent of CT/PET imaging and ultrasound-guided fine-needle
aspiration (FNA), scalene-node biopsy for lung cancer staging is used primarily when imaging studies
suggest nodal involvement, but FNA is nondiagnostic. Surgical scalene-node biopsy is also useful in
diagnosing lymphoma if nodes are palpable. Although sarcoidosis can be diagnosed by mediastinoscopy
in 98% to 100% of cases, the diagnostic yield of blind scalene-node biopsy is sufficiently high that the
procedure may be substituted for mediastinoscopy when the diagnosis is elusive by bronchoscopy and
clinical evidence and general anesthesia must be avoided. Palpable scalene nodes can often be aspirated
in the office or clinic (see Fig. 22.15D).
CONTRAINDICATIONS
Although there are no absolute contraindications to scalene-node biopsy, poor healing, malignant wound
seeding, and chylous fistulas can occur in cases of bulky adenopathy and extranodal tumor infiltration
with or without prior cervical radiation. Open biopsy should generally be avoided in this setting in favor
of needle biopsy.
TECHNIQUE
Fat-pad excision is described in order to highlight the anatomy but is rarely necessary. In the presence of
enlarged nodes, abnormal tissue can be sampled by standard methods (i.e., incisional or excisional lymph
node biopsy) under local anesthesia. The neck is extended and the head turned to the contralateral side. A
4-cm incision centered between the heads of the sternocleidomastoid muscle and about 2 cm above the
clavicle (Fig. 22.15A) is deepened through the platysma. The muscle heads are retracted in opposite
directions, or the entire muscle is retracted medially. The omohyoid is retracted upward. The boundaries
of the scalene triangle are the jugular vein medially, the subclavian vein inferiorly, and the omohyoid
muscle superolaterally (Fig. 22.15B). The anterior scalene muscle, with the phrenic nerve coursing along
its surface, constitutes the deep margin of dissection. The fat pad is dissected from these structures (Fig.
22.15C) from below upward. Visible lymphatic channels are clipped or ligated. The transverse cervical
artery, arising from the subclavian and entering the fat pad inferiorly, may require ligation. On the left, the
thoracic duct can often be identified near its entry into the superior aspect of the subclavian vein. If
injured, it must be meticulously ligated. When scalene biopsy is performed along with mediastinoscopy,
the mediastinoscopy incision is extended 1 or 2 cm to the appropriate side, and a skin flap is developed.
The scalene triangle can then be reached posterior to the sternal head of the sternocleidomastoid muscle
by retracting the muscle anteriorly or transecting it at its insertion.
FIGURE 22.15 Scalene biopsy. A: Skin incision over the sternocleidomastoid muscle. B: Anatomy of the scalene triangle. C:
Resection of the fat pad, exposing the anterior scalene muscle and phrenic nerve. D: Alternative: percutaneous needle aspiration
of enlarged lymph node.
COMPLICATIONS
Mortality for this procedure is negligible. Injury to the major vessels should be rare. The jugular can be
repaired easily, but a subclavian injury may require proximal and distal control requiring clavicular
resection. Phrenic nerve injury is prevented by avoiding cautery deep to the fat pad. Chylous fistula can
be a troublesome problem and usually originates from a raw nodal surface following incisional biopsy
rather than from injury to a major lymphatic channel. Pneumothorax may result from violation of the
pleural cupola or, less likely, puncture of the lung. Venous air embolism can occur, as in any cervical
procedure.
THORACENTESIS
The pleural cavity is subject to production and elimination of >1 L pleural fluid daily.27 Disruption of this
balance can cause pleural fluid accumulation invoking multiple possible etiologies. Diagnostic
thoracentesis (up to 100 mL of fluid) is performed when the etiology of an effusion is unknown. The goal
of therapeutic thoracentesis is the removal of enough fluid to relieve symptoms, treat infection, or allow
better radiographic assessment of the lung. Drainage of larger amounts may be associated with a higher
rate of complications, but data suggest that only 0.5% of patients who undergo aspiration of more than
1,000 mL develop re-expansion pulmonary edema.28 About 250 mL is usually necessary to visualize an
effusion on upright chest radiograph as costophrenic blunting. A lateral decubitus film is useful in
determining whether the fluid is free-flowing. Chest CT and ultrasonography have increased the
sensitivity and accuracy of the diagnosis of pleural effusions. Radiologic and physical findings determine
the site of needle aspiration. On clinical exam, the best site for thoracentesis is usually two finger
breadths below the superior aspect of percussion dullness. Small effusions can be aspirated under
ultrasound guidance. CT scan is additionally useful in managing complex loculated effusions.

Thoracentesis should be performed for diagnostic or therapeutic evaluation of pleural effusions when the
etiology is unknown. Malignant pleural effusions can be repeatedly drained with thoracenteses; however,
one should consider more definitive treatment with pleurodesis (if the lung is not entrapped in a fibrous
peel) or an indwelling pleural catheter. The only absolute contraindication to thoracentesis is a severe
bleeding diathesis. Pleural fluid sampling can be performed safely in the presence of mild coagulation
abnormalities.29 No increased risk for hemorrhage was seen if the coagulation studies were not more than
twice normal. Although a low platelet count did not increase the risk, a creatinine above 6 mg/dL was
associated with a greater drop in hemoglobin when compared to patients with normal creatinine.
TECHNIQUE
The patient is generally placed in a sitting position, leaning forward onto an elevated stand to support the
arms. Debilitated and bedridden patients are often placed in a lateral decubitus position with the side of
the effusion down. Although aspiration of pleural fluid sample can be performed using only a needle and
syringe, most thoracenteses are currently done using a kit containing local anesthetic, drapes, needles and
syringes, a drainage catheter, and vacuum containers for fluid drainage (therapeutic thoracentesis). The
needle can be fitted at the outset with a three-way stopcock, thus permitting multiple fillings of the syringe
without exposing the needle to air. The chest is first percussed for dullness to determine the level of the
effusion. After the instillation of a local anesthetic in the skin and subcutaneous tissue, an 18- or 21-gauge
needle is introduced just above the superior border of the rib to avoid the intercostal vessels and nerve
(Fig. 22.16) and passed into the parietal pleura. The needle is then introduced into the effusion and a
sample is aspirated. A catheter may also be introduced using a wire and Seldinger technique. In most
cases, the needle is introduced posteriorly several inches lateral to the spine. If air but no fluid is
aspirated, the entry site may be too high and a lower intercostal space should be tried. If neither air nor
fluid is found, the site may be too low, the chest wall too thick for the needle, or the fluid too viscous.
These problems can be remedied by moving to a different site, using a longer needle, or using a larger-
bore needle. If the thoracentesis remains unsuccessful, repeat imaging or access under ultrasound
guidance is indicated.
FIGURE 22.16 Standard upright position for thoracentesis (A), where needle aspiration is performed just above the superior
border of the palpated rib (B).
Fluid characteristics such as appearance and odor may provide diagnostic clues. Empyema or
anaerobic infection is marked by purulent fluid with a foul odor whereas an odorless thin milky
appearance may suggest chylous effusion. Sanguineous or serosanguineous fluid suggests malignancy,
tuberculosis, or trauma. Pleural fluid can be assayed for chemistry, cell count and differential, cytology if
malignancy is suspected, and cultures to rule out infection. Chemical analysis includes measurement of
pH, specific gravity, glucose, total protein, lactic dehydrogenase, triglycerides and sometimes amylase.
The concentration of total protein and lactate dehydrogenase (LDH) in pleural fluid is directly related to
their level in the plasma. A blood sample is needed at the time of the thoracentesis to determine the
relative serum and pleural fluid concentrations. A primary concern is whether the process is an exudate or
a transudate. Infection and neoplasm are the major causes of exudative effusions.
COMPLICATIONS
Pneumothorax is the most frequent complication of thoracentesis. In a report of 9,320 inpatient
thoracentesis at a single institution over 12 years, postprocedure pneumothorax was identified in <1%.30
In this series, iatrogenic pneumothorax was significantly associated with removal of >1500 mL fluid (p <
0.0001), unilateral procedures (p = 0.001) and more than one needle pass through the skin (p = 0.001).
Ultrasound guidance has been shown to decrease the incidence of pneumothorax, with a rate of 2.5%
reported in a series of 605 patients.28 Bleeding from injury to an intercostal vessel is uncommon but tends
to occur more often in elderly patients whose intercostal arteries may be tortuous.31 Vasovagal-mediated
bradycardia and hypotension can also occur. Rare complications include bleeding from injury to an upper
abdominal organ (liver or spleen), tumor implantation of the needle tract, and introduction of infection
into the pleural space. Re-expansion pulmonary edema is an uncommon but potentially serious problem
after therapeutic thoracentesis or rapid expansion of a lung collapsed due to pneumothorax. Re-expansion
of the lung, resulting in the upregulation of xanthine oxidase—with subsequent free radical damage and
apoptosis of endothelial and type II alveolar cells—has been implicated in the development of edema.32,33
Re-expansion pulmonary edema tends to occur with large effusions that have been present for several
days to months. Suggested preventive measures include minimizing negative intrapleural pressure during
thoracentesis, limiting the volume of fluid removed per procedure, and terminating the procedure if
excessive cough or chest pain develops. There is, however, no consensus with respect to the amount of
fluid that can be drained safely. It has been suggested that withdrawal be limited to 1 to 1.5 L unless
pleural pressures are measured,34 but other reports found no upper limit to fluid volume.35 In practice,
careful clinical observation of the patient and a low threshold to terminate the procedure are indicated.
VIDEO-ASSISTED THORACOSCOPY FOR DIAGNOSIS

Video-assisted thoracoscopic surgery (VATS) is a diagnostic tool for pleural diseases, interstitial lung
disease, solitary pulmonary nodules, and has become a necessary skill in a thoracic surgeon’s
armamentarium. VATS plays a significant role in the diagnosis and management of lung cancer including
assessment of T-stage for locally advanced tumors and sampling difficult to reach, suspicious,
intrathoracic lymph nodes. Although the birth of thoracoscopy is generally credited to Hans Christian
Jacobeus, a Swedish internist of the early 20th century, Hoksch et al.,36 suggest that this technique may
have existed even half a century earlier. Much of the early use of thoracoscopy was for the diagnosis of
intrathoracic diseases. The modality became more established in clinical practice with the advent of high-
resolution video-endoscopic systems in the 1980s and evolving techniques of selective single-lung
ventilation. The fusion of these newer elements greatly enhanced the application of the old technique of
thoracoscopy in the routine management of chest disease, evolving into the modern use of VATS today.
TECHNIQUE
VATS is traditionally performed under general anesthesia with selective one-lung ventilation using a
double lumen endotracheal tube or a bronchial blocker. Awake video-assisted thoracic surgery under
local anesthesia is an alternative that has been reported by some investigators,37 but not widely adopted.
In young children for whom no suitably sized double-lumen endotracheal tube is available, a small single-
lumen tube is often directed into the contralateral mainstem bronchus. After successful fiber optic
placement of a double lumen endotracheal tube, the patient is placed in the maximally flexed lateral
decubitus position tilted slightly backward to prevent the hip from obstructing downward movement of the
thoracoscope (Fig. 22.17). The positions of the surgeon and assistant depend on the site of pathology as
suggested by preoperative imaging. The television monitors are positioned to allow the surgeon and
assistant to look straight ahead when operating. Five- or 10-mm thoracoscopes are used with a 0- or 30-
degree lens and a three-chip CCD video camera. Thoracoscopes and instruments of smaller diameters
(i.e., needlescopic instruments 2 mm diameter) have also been successfully implemented in diagnostic
procedures.38 The camera port is placed at the eighth or ninth interspace along the posterior axillary line
(avoiding the apex of the heart on the left). The posterior port is placed where the lower lobe edge
touches the diaphragm (in line with the scapular tip; see Fig. 22.18). Once intrapleural visualization is
achieved, the hilum and major fissure should be identified. Nerve blocks can be considered at this time
using 0.25% to 0.5% bupivacaine under direct thoracoscopic guidance. A third axillary port site should
be placed to triangulate over the target lesion. There should be little hesitation to widen any single port
site to improve digital palpation of an indeterminate nodule (Fig. 22.19). There are many variations of
thoracoscopic instruments that can be implemented, but a standard sponge holding forceps provides
atraumatic retraction of the lung or retrieval of blood or debris during decortication procedures.
Pulmonary biopsies are taken using standard thoracoscopic linear staplers. An alternative technique to
removing a suspicious nodule is the enucleative precision cautery technique first described by Perelman
and later advocated by Cooper et al.39 At the end of the procedure, most surgeons leave a single chest
tube (20 to 28 Fr) overnight. Some authors advocate even sooner removal of the chest tube depending on
what diagnostic procedure is employed.
FIGURE 22.17 Proper positioning for VATS (maximally flexed and tilted slightly backward to prevent the hip from obstructing
downward movement of the thoracoscope).
FIGURE 22.18 Standard port placement for VATS.
A related but totally different technique is pleuroscopy (sometimes referred to as “medical

pleuroscopy,” which can be performed using a sterile fiberoptic bronchoscope. The sterile bronchoscope
is usually inserted under local anesthesia through a chest drain tract into the pleural cavity or through a
small chest incision. The scope can be placed through a truncated chest tube, which can then guide the tip
of the endoscope to the area of interest. The application of this technique is limited and should be
reserved for the occasional frail or debilitated patient who cannot tolerate a general anesthesia, but for
whom an accurate tissue diagnosis (usually a pleural biopsy) is required.
FIGURE 22.19 Three port VATS with single digit palpation of a solitary lung nodule.
VATS IN PLEURAL DISEASE

Diagnosing Pleural Effusions
If conventional methods such as thoracentesis or percutaneous pleural biopsy are nondiagnostic for the
evaluation of a symptomatic pleural effusion, VATS can provide additional assessment of the pleural
cavity. A precise histologic diagnosis is rarely indicated for a transudative effusion; however, an
exudative effusion calls for further investigation to exclude malignancy, collagen vascular disease, and
tuberculosis, among others. The diagnostic effectiveness of VATS in pleural disease is perhaps even
greater than exploratory thoracotomy, given the superior ability of VATS to visualize the entire lateral
chest wall. VATS allows for all of the pleural surfaces (including the mediastinal, diaphragmatic, and
visceral pleura) to be fully visualized and accessible for biopsy. This can sometimes be achieved with
less than three traditional port sites. For the one-port technique, the biopsy forceps can be inserted
alongside the video thoracoscope through the same port to reach the target lesion. In patients coming to an
operation with a chest drain already in situ, the drain site wound can be used as the single port, avoiding
extra incisions. Representative parietal pleural biopsies can be undertaken with endoscopic biopsy
forceps inserted through the instrument ports. If malignant mesothelioma is on the differential diagnosis,
pleural fluid alone has a diagnostic yield of 4% to 20%, and so full thickness pleural biopsies should be
obtained to confirm extension of disease into intercostal muscle. If the etiology of the pleural effusion is
determined to be malignant, one can elect to apply chemical pleurodesis by talc insufflation. The
literature on the efficacy of diagnostic VATS is voluminous and consistently reports positive diagnosis
rates for indeterminate pleural effusions in 95% to 100% of cases. A 1991 meta-analysis40 by Menzies
and Charbonneau of 1,500 cases of indeterminate pleural effusions worldwide confirmed that VATS
provided 90% diagnostic accuracy with only 3% morbidity. The use of VATS enables the surgeon to
diagnose less common causes of indeterminate pleural effusions including the location and repair of
sources of persistent airleak, chylothorax, or pleuroperitoneal fistulas associated with peritoneal dialysis
or diaphragm injuries.
Diagnosing Pleural Space Infection
Empyema usually develops from superinfection of a parapneumonic effusion that is often associated with
pneumonia. This process follows a well-described sequence, classically progressing through exudative,
fibrinopurulent, and then organized phases. As an alternative to fibrinoytic therapy for pleural space
infection,41 VATS can be used to therapeutically break down loculations in the fibrinopurulent phase and
achieve decortication yielding larger tissue amounts for microbiology analysis. If mycobacterial disease
is on the differential diagnosis, VATS can be implemented for tissue biopsy of the pleura to improve the
microbiologic yield since mycobacterial species are notoriously difficult to culture from pleural fluid.
For diagnostic purposes, aspirated pleural fluid and exudative peel from the parietal or visceral pleural
surfaces are also submitted for microbiology and pathologic studies. In areas where tuberculosis is still
endemic, microbiology studies to exclude acid-fast bacilli are also mandatory.
Diagnosing Interstitial Lung Disease

Pulmonary infiltrates on radiographic imaging are common and can present a diagnostic challenge given
the wide variety of possible etiologies with a similar radiologic appearance. Although a diagnosis may
be inferred in the appropriate clinical context, occasions arise when tissue is necessary to confirm a
diagnosis and significantly influence treatment. These diagnoses may include hypersensitivity
pneumonitis, diffuse alveolar damage, nonspecific interstitial pneumonitis, usual interstitial pneumonitis,
pneumonia, and others. Percutaneous or bronchoscopic biopsy techniques are of limited value in this
group of patients owing to the small size of the specimens generally obtained. VATS has replaced the
traditional open-lung biopsy as a diagnostic tool for obtaining larger quantities of tissue for improved
pathologic yield. Open lung biopsy through a limited thoracotomy is still considered in patients who
cannot tolerate one-lung ventilation. These patients are often critically ill on mechanical ventilation with
high oxygen requirements and increased airway pressures where exchange from a single lumen to a
double lumen endotracheal tube may be hazardous and not warranted. VATS has increased appeal due to
reduced postoperative morbidity and pain to the patient. It has also been shown in numerous studies that
the size and quality of the biopsy from VATS is not inferior to that obtained by the open procedure and that
the diagnostic accuracy is extremely high with a low complication rate, shorter hospital stay, and reduced
chest tube duration.42,43
The same basic three-port technique described previously is placed to triangulate the site of suspected
maximal pathology as suggested by preoperative imaging. If all other factors are equal in bilateral
disease, a right-sided approach is preferred because the extra fissure and lobe edges improve the
technical feasibility of lung sampling at a lung edge. Wedge excision biopsy is the standard using linear
thoracoscopic staplers where lung thickness may require a thick tissue staple load. Should wound
protection be required in cases of suspected malignancy, a specimen can be delivered inside an endocatch
plastic bag. The number of biopsy specimens is dependent on the surgeon’s preference; however,
published single center series suggest that taking a second biopsy specimen does not necessarily yield a
different result from the first.44
Surgeons should be acutely aware that lung biopsy in patients who harbor acute or chronic interstitial
lung disease can be associated with significant operative risk. In a historical series of 80 such patients
undergoing open-lung biopsy, Warner et al.45 reported a positive diagnosis in only 66% (53/80), and the
results altered management in only 70%. On the other hand, 19% (15/80) of those patients suffered
biopsy-related complications, and only 24 survived to be discharged from hospital. In a more
contemporary series of diagnostic VATS lung biopsy in 32 patients with a nonspecific diagnosis of
interstitial lung disease, 30-day mortality was 0% (90-day mortality 5%) but the complication rate was
66%.46 Clinical judgment is therefore critical in selecting patients of this category for a surgical
procedure.
VATS AND SOLITARY PULMONARY NODULES

Solitary pulmonary nodules “coin lesions” are defined as a single intrapulmonary mass lesion that
measures ≤3 cm in diameter. The prevalence of pulmonary nodules has greatly increased with amplified
utilization of chest CT for pulmonary symptoms and the adoption of low-dose CT chest for lung cancer
screening spawned by the National Lung Cancer Screening Trial.47 Radiologic findings in a clinical
context have limited use in diagnosis. Enlarging solitary pulmonary nodules are regarded as neoplastic
until proven otherwise. PET avid pulmonary nodules often prompt the need for a tissue diagnosis.
Although one can consider CT-guided fine needle aspiration as a diagnostic modality, a negative biopsy
rarely definitively excludes malignancy. VATS offers an accurate tissue diagnosis in virtually all cases but
also allows staging of a primary lung cancer if confirmed on frozen section. VATS can also be used as a
therapeutic modality where curative pulmonary resection can be performed at the same time as diagnostic
VATS.
Many studies have confirmed the diagnostic accuracy of VATS for lung nodules to be consistently in
the vicinity of 95%. Besides giving high diagnostic accuracy, the use of VATS for biopsy of solitary lung
nodules has been associated with remarkably low morbidity.48 The technique is standard with three ports
arranged in a triangular pattern aimed at the target lesion as determined by preoperative CT chest. Not all
lesions can be directly visualized on the visceral pleural surface, so digital palpation is an essential step
in almost all cases. The part of the lung explored can be brought up to the fingertip for palpation using
sponge-holding forceps. It may often be necessary to release any pleural adhesions and the pulmonary
ligament to mobilize the entire lung for thorough palpation.
Solid pulmonary nodules <1 cm in diameter or >10 mm from the pleural surface can elude all attempts
at localization intraoperatively. Ground glass opacities are particularly difficult to palpate during VATS.
Should such a situation be suspected from the preoperative CT appearance, the surgeon is advised to have
the lesion marked preoperatively by means of a number of localization techniques, including navigation
bronchoscopy-guided methylene blue injection,49 CT-guided radio-isotope injection,50 fiducial marker
insertion,51 or hook wire insertion.52 Another alternative for lung nodule localization is intraoperative
VATS endosonography. In a single institution series of 46 patients, lung nodules in 20 (43%) cases were
not detected by conventional means and successfully identified with intraoperative ultrasound thus
avoiding thoracotomy for diagnosis in those patients.53 In some instances, a deep-seated lesion may not be
amenable to simple wedge excision where anatomic segmentectomy or lobectomy may be necessary.
Specimen retrieval should always include the use of an endocatch bag to protect port sites from potential
tumor seeding.
VATS AND LUNG CANCER STAGING

Modern lung cancer staging modalities include diagnostic quality CT chest, attenuation correction CT-
PET, mediastinoscopy, endobronchial and/or endoscopic ultrasound biopsy of mediastinal lymph nodes,
MRI brain, thoracoscopy, and thoracotomy. In an effort to avoid a futile thoracotomy or a noncurative
pulmonary resection, VATS offers direct visualization of the pleura and can be used to rule out occult
pleural metastases prior to pulmonary resection. It can also be used to better assess the T-status of the
lung tumor (i.e., chest wall, mediastinal, or pericardial invasion) or permit ipsilateral mediastinal or hilar
lymph node sampling. Evidence supporting the usefulness of VATS in detecting pleural metastases dates
back to 1996, where prethoracotomy lung cancer staging with VATS identified 2/39 (5%) patients
rendered inoperable as a result the VATs findings.54 If chest wall invasion is noted, VATS can guide the
level of the thoracotomy further defining the margins of chest wall resection en bloc with tumor.
CONTRAINDICATIONS AND COMPLICATIONS

Contraindications to diagnostic VATS include the inability to tolerate one-lung ventilation or pleural
symphysis by virtue of previous mechanical/chemical pleurodesis or an inflammatory process. Life-
threatening intraoperative complications of diagnostic VATS are very uncommon and overall hospital
mortality (0.5% to 3.6%) and conversion rates (2% to 13%) are low. One of the feared complications of
VATS is vascular injury that cannot be controlled before the need of transfusion or resuscitation. This can
be mitigated by good port placement and meticulous technique. The surgeon should be prepared to
tamponade bleeding with a 5 to 10 mm endo-peanut or sponge stick. Usually, conversion is best achieved
by extending the anterior utility incision to an anterior thoracotomy, as opposed to a separate
posterolateral thoracotomy. It is important to note that most bleeding can be controlled with a direct
pressure technique where conversion can be performed in a nonemergent manner. The surgeon should also
communicate with their anesthesiologists to prepare for blood loss and have cross matched blood in the
room upon identification of a major vascular injury. Another important pitfall is the application of
excessive torque to the thoracoscopic port sites which can be associated with intercostal nerve injury,
resulting in significant and prolonged postoperative pain.
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2003;126(3):726–731.
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Thorac Surg 2006;82(6):2004–2009. doi: 10.1016/j.athoracsur.2006.06.031.
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32. Jackson RM, Veal CF, Alexander CB, et al. Re-expansion pulmonary edema. A potential role for free radicals in its pathogenesis. Am
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33. Saito S, Ogawa J, Minamiya Y. Pulmonary reexpansion causes xanthine oxidase-induced apoptosis in rat lung. Am J Physiol Lung Cell
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34. Light RW, Jenkinson SG, Minh VD, et al. Observations on pleural fluid pressures as fluid is withdrawn during thoracentesis. Am Rev
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35. Feller-Kopman D, Berkowitz D, Boiselle P, et al. Large-volume thoracentesis and the risk of reexpansion pulmonary edema. Ann
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36. Hoksch B, Birken-Bertsch H, Muller JM. Thoracoscopy before Jacobaeus. Ann Thorac Surg 2002;74(4):1288–1290.
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41. Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J
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43. Fibla JJ, Molins L, Blanco A, et al. Video-assisted thoracoscopic lung biopsy in the diagnosis of interstitial lung disease: a prospective,
multi-center study in 224 patients. Arch Bronconeumol 2012;48(3):81–85.
44. Flint A, Martinez FJ, Young ML, et al. Influence of sample number and biopsy site on the histologic diagnosis of diffuse lung disease.
Ann Thorac Surg 1995;60(6):1605–1607; discussion 7–8.
45. Warner DO, Warner MA, Divertie MB. Open lung biopsy in patients with diffuse pulmonary infiltrates and acute respiratory failure. Am
Rev Respir Dis. 1988;137(1):90–94.
46. Luo Q, Han Q, Chen X, et al. The diagnosis efficacy and safety of video-assisted thoracoscopy surgery (VATS) in undefined interstitial
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47. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose
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48. Hazelrigg SR, Magee MJ, Cetindag IB. Video-assisted thoracic surgery for diagnosis of the solitary lung nodule. Chest Surg Clin N Am
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49. Krimsky WS, Minnich DJ, Cattaneo SM, et al. Thoracoscopic detection of occult indeterminate pulmonary nodules using bronchoscopic
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50. Grogan EL, Stukenborg GJ, Nagji AS, et al. Radiotracer-guided thoracoscopic resection is a cost-effective technique for the evaluation
of subcentimeter pulmonary nodules. Ann Thorac Surg 2008;86(3):934–940; discussion 934–940.
51. Sancheti MS, Lee R, Ahmed SU, et al. Percutaneous fiducial localization for thoracoscopic wedge resection of small pulmonary
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52. Seo JM, Lee HY, Kim HK, et al. Factors determining successful computed tomography-guided localization of lung nodules. J Thorac
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53. Khereba M, Ferraro P, Duranceau A, et al. Thoracoscopic localization of intraparenchymal pulmonary nodules using direct intracavitary
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54. Yim AP. Routine video-assisted thoracoscopy prior to thoracotomy. Chest 1996;109(4):1099–1100.
Section
VI
PREOPERATIVE ASSESSMENT OF THE

THORACIC SURGICAL PATIENT
23
General Risk Assessment of Patients for
Thoracic Surgical Procedures
Alessandro Brunelli ■ Cecilia Pompili ■ Michele Salati
INTRODUCTION
Surgical risk is an elusive concept that is difficult to define properly. The patient, their family, the
surgeon, the hospital administrator, and the payers may all have a different perception of surgical risk.
They usually weigh the success of an operation using different scales and metrics. Surgeons are mostly
focused on objective and immediately measurable endpoints, typically length of stay, mortality, and
morbidity. Patients and their carers are generally more concerned about their residual function and quality
of life. One of their most frequent questions during preoperative consultation is “would I be able to
resume my current daily lifestyle?”
Currently, there is no valid risk model or predictive equation that can reliably estimate the decline in
physical or emotional components of quality of life after lung resection for cancer. Yet, permanent
disability and loss of independence remain the main concerns of surgical candidates, even more than
immediate mortality or complications.1 These concepts are far more difficult to estimate and risk-stratify
compared to objective outcomes such as mortality since they involve a high degree of subjectivity and
because objective factors traditionally used to estimate mortality or morbidity have failed to show an
association with physical or mental domains of quality of life.2
PATIENT PERCEPTION OF SURGICAL RISK: THE IMPORTANCE OF

RESIDUAL QUALITY OF LIFE IN THE SHARED DECISION-MAKING
PROCESS
The perception of health status remains the most important aspect that influences the decision of the
patient to proceed to surgery. This decision is driven most of all by the tradeoff between probability of
cancer cure and residual quality of life.3 Unfortunately, quality of life is difficult to predict based on
objective factors and as such the counseling physician has insufficient evidence to properly inform the
patient in this regard. This information is most important, as it appears critical in determining the patient’s
attitude in the shared decision about proceeding to surgery.4
Shared decision making (SDM) is a concept suited to situations where patients are given two or more
medically reasonable options with no professional consensus. In order to develop SDM guidelines or
integrate this concept into the existing decisional algorithms, the last two decades have witnessed an
increasing number of trials investigating the overall lack of concordance between physician and patient
perceptions of the decisional context in many clinical areas including lung cancer management.5 The
majority of these trials have shown that concerns and treatments strategies were insufficiently discussed
between the patients and physicians.
In the attempt to potentially increase communication, patient engagement, and documentation of
consent, several computerized interactive methods with outcome probabilities tailored to individual
patients have been proposed. Online tools for treatment decision making have resulted in a positive
influence on clinician’s decisions and have already been developed for advanced stage NSCLC.6 The
General Medical Council in UK has introduced a document focusing on the central role of an SDM
process, empowering the patient to take responsibility for aspects of their care and work together with the
doctor to make the most appropriate treatment decision tailored to their need (http://www.gmc-
uk.org/guidance/ethical_guidance/consent_guidance_index.asp). Similarly, the Institute of Medicine
(IOM) identified the process of engaging patients and supporting patient decision making as an essential
component of care.7 Patient involvement in decision making is particularly important when considering
treatment goals, such as choosing a less aggressive (and potentially less efficacious) treatment to provide
increased quality of life. In fact, the role of quality of life in this patient-centered type of care is twofold:
first of all, patients need to have a complete information about their residual quality of life after
pulmonary resection in order to undertake the best decision for their cancer treatment. Secondly, they need
to gain understanding on whether and how this shared decision will eventually improve the postoperative
quality of life. Further studies are needed to address this issue.
SDM is a multifactorial process, which still needs to be deeply investigated. The core value of SDM
remains its contribution to facilitate patient knowledge about their treatment trajectory, with the ultimate
aim to improve patient adherence and satisfaction with treatment. In recent years, however, this strategy
has been promoted also as a tool to reduce health care overtreatment and costs.8 Interestingly, a recent
Cochrane review showed that 20% of patients who participate in SDM chose less invasive surgical
options and more conservative treatment compared to patients who did not use decision aids.9 However,
in this review, only the minority of studies demonstrated the cost-saving effect of implementing SDM in
clinical care.
Lung cancer patients are usually risk-averse until they are faced with the prospect of cancer
progression and lack of alternatives for cure. When this information is factored into the decision-making
equation, they are usually willing to accept extremely high risks of postoperative complications and
surgery-related death.1 On the other hand, patients are increasingly aware and conscious about the risks of
a permanent and long-lasting disability: the interference of cancer treatment in their daily lifestyle is one
of the most important treatment outcomes for the patient. Therefore, information about residual quality of
life after surgical treatment becomes mandatory, particularly in the presence of different treatment options.
The growing numbers of elderly patients diagnosed with lung cancer and the increasing utilization of
lung cancer screening are progressively changing the case mix of patients involved in the surgical
decision-making process. The explanation of surgical risk needs to be tailored by a full comprehension of
the cognitive abilities of older patients. Compared to younger patients, the elderly tend to cope with
cancer-diagnosis–related stress with religious support and to weigh their health-related quality of life
heavier in their decision-making process.
Salati and colleagues10 showed that although the elderly population of lung resection candidates
presented with poorer performance scores and performed worse during the exercise test, subjectively
suggesting a poorer physical status, they nevertheless had higher preoperative mental composite scores on
a QoL questionnaire compared to younger patients. It appears that although the elderly are conscious of
their poorer physical conditions, they are also more prepared to be sick and to face the challenge of
cancer and a cancer operation (Fig. 23.1, modified from Fig. 23.3).
FIGURE 23.1 Radar chart showing preoperative SF36v2 quality of life domains of elderly patients versus younger patients. (*),
significant differences between the two groups (p <0.05). PF, physical functioning; RP, role limitation due to physical problems;
BP, body pain; GH, general health perception; VT, energy and vitality; SF, social functioning; RE, role limitation due to emotional
problems; MH, mental health; PCS, physical component summary; MCS, mental component summary. (From Salati M, Brunelli
A, Xiume F, et al. Quality of life in the elderly after major lung resection for lung cancer. Interact Cardiovasc Thorac Surg
Furthermore, with the shift of health care to increasingly empower patients in medical decisions, the
burden imposed on patients to understand health-related information in order to make fully informed
choices needs to be fully investigated. The other aspect that needs to be investigated is SDM in patients
disadvantaged by poverty, lack of education, or linguistic barriers as they are likely to make decisions
without a real comprehension of risks and benefits. A recent review11 studied the ability to understand and
use numerical information, and its relation to cognition, health behaviors, and medical outcomes. The
authors found that many people lack basic numerical skills that are essential to maintain their health and
make informed medical decisions: “Low numeracy distorts perceptions of risks and benefits of screening,
reduces medication compliance, impedes access to treatments, and impairs risk communication.”
Transfer of information increases patient responsibilities, a fact that in many individuals can
emotionally impair the decision making process. The tradeoff between costs and benefits of informing a
patient needs to be taken into consideration in the SDM. One of such costs is cognitive overload. Too
much information is likely to lead to worse decision especially when emotionally overwhelmed like in
cancer patients. The most appropriate contents and form of shared information should be tailored to the
patient emotional and cognitive statuses by assuming responsibility of patient care in a paternalistic
manner.12
It has been suggested that patient participation in SDM may increase the quality of life after the
treatment. For instance, in breast reconstruction surgery, patients who adopted a more active role, whether
using an informed or shared approach, had higher general patient satisfaction and physical component
summary scores when compared with patients whose decision making was paternalistic.13
However, there are no sufficient data to confirm this theory. Recently, results from the NELSON
screening trials showed that QoL during screening was not worse among subjects that did or did not make
an informed decision to participate in a lung cancer CT screening.14
FIGURE 23.2 American College of Chest Physicians Cardiologic algorithm to stratify the risk of lung resection candidates.
(Reprinted from Brunelli A, Kim AW, Berger KI, et al. Physiologic evaluation of the patient with lung cancer being considered
for resectional surgery: Diagnosis and management of lung cancer, 3rd ed: American College of chest physicians evidence-based
clinical practice guidelines. Chest 2013;143(5 Suppl):e166S–e190S. Copyright © 2013 The American College of Chest
Physicians. With permission.)
SURGEON PERCEPTION: THE OBJECTIVE EVALUATION OF SURGICAL

RISK
CARDIAC RISK EVALUATION

The risk of major cardiac events (i.e., ventricular fibrillation, pulmonary edema, complete heart block,
cardiac arrest, or cardiac death during admission) after major anatomic lung resection is approximately
3%.15,16 This is partly explained by the fact many lung cancer surgical candidates have an underlying
cardiovascular comorbidity due to cigarette smoking, which increases their risk of perioperative
cardiovascular complications. In fact, a recent study using data from the Surveillance, Epidemiology, and
End Results-Medicare data on patients undergoing lung cancer resection within 1 year after coronary
stenting showed a higher rate of major cardiovascular events (9.3% vs. 7.7%, p <0.0001) and mortality
(4.9% vs. 4.6%, p <0.0001) in stented patients compared to nonstented ones.16
Overall, the available literature specific to cardiac risk and lung cancer surgery is scant. Therefore,
most of what can currently be recommended must be extrapolated from abdominal or vascular
surgery.15,18 There are currently two published guidelines on cardiac risk evaluation and treatment for
lung resection candidates by the ERS-ESTS joint task force and the American College of Chest
Physicians (ACCP), respectively.19,20 These two guidelines are very similar and mostly based on the
ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac
surgery.18 Briefly, both guidelines recommend the preliminary use of a scoring system to estimate the risk
of major cardiac events. The ERS-ESTS guidelines suggested using the RCRI originally published in
1999 by Lee et al.15 whereas the most updated ACCP guidelines recommended the use of the recalibrated
version of the RCRI, the so-called Thoracic RCRI (ThRCRI) (Fig. 23.2).
The RCRI is a 4-class 6-factors cardiac risk score including history of coronary artery disease,
cerebrovascular disease, insulin-dependent diabetes, congestive heart failure, serum creatinine level
greater than 2 mg/dL, and high-risk surgery. All factors are equally weighed and 1 point is assigned for
their presence. Although RCRI has been indicated as the preferable cardiac risk score by the American
Heart Association/American College of Cardiology,18 by the European Society of Cardiology/European
Society of Anesthesiology guidelines,21 and by the joint ERS-ESTS task force on fitness for radical
treatment of lung cancer patients,19 this score was originally developed from a generic surgical
population including only a small group of thoracic patients. Most recently, Brunelli et al.16 recalibrated
the RCRI in a large population of candidates for major anatomic lung resection to obtain a more specific
tool in the thoracic surgical patient. This resulted in a simplified weighed score, in which only four of the
original six factors were shown to be reliably associated with major cardiac morbidity with different
weights (history of coronary artery disease, 1.5 points; cerebrovascular disease 1.5 points; serum
creatinine level greater than 2 mg/dL, 1 point; and pneumonectomy, 1.5 points). The resulting aggregate
score, ranging from 0 to 5.5 points and named the ThRCRI, was found to be more accurate than the
traditional one in the thoracic population (c index 0.72 vs. 0.61, p = 0.004). Patients in class D (score
>2.5) have a risk of major cardiac events of 23% vs. 1.5% of those in class A (score 0) (Fig. 23.3).
FIGURE 23.3 Stratification of postoperative major cardiac events by the Revised Cardiac Risk Index and the Thoracic Revised
Cardiac Risk Index.
The ThRCRI was subsequently validated by a number of studies.16,22 Most recently, the score was
tested and validated in a large population from the STS database.23 In more than 26,000 patients
undergoing pulmonary anatomic resection, the incidence of major cardiovascular complications was
4.3%. ThRCRI scores in patients without major cardiovascular complications was half that of patients
with complications (0.6 vs. 1.1, p <0.0001). Score categories yielded incremental risks of major
cardiovascular complications (A: 2.9%; B: 5.8%; C: 11.9%; D: 11.1%; p <0.0001).
For patients whose exercise capacity is limited, those with a ThRCRI >1.5 or those with known or
newly suspected cardiac disease, noninvasive cardiac evaluation is recommended as per AHA/ACC
guidelines18 to identify the relatively small proportion of patients needing more aggressive interventions
to control heart failure or arrhythmias or to treat underlying myocardial ischemia. Appropriately
aggressive cardiac interventions should be instituted prior to surgery only in patients who would need
them irrespective of the planned surgery. In fact, a detailed evaluation for coronary heart disease is not
recommended in patients who have an acceptable exercise tolerance,18,24,25 and in those with a Revised
Cardiac Risk Index (RCRI) <2.15 Furthermore, prophylactic coronary revascularization prior to surgery in
patients who otherwise do not need such a procedure does not appear to reduce perioperative risk.26
Similarly, the start of a new therapy such as beta-blockers to prevent ischemic risk also appears
questionable. Data from the POISE study group have shown that although commonly used regimens of
perioperative beta-blockers are able to reduce the risk of cardiovascular death and nonfatal myocardial
ischemia (HR 0.84), they can actually increase the risk of stroke (HR 2.17) and overall mortality (HR
1.33).27 Therefore, the new institution of a beta-blocker therapy is not recommended in those ischemic
heart disease patients, that are not already taking them.
Finally, cardiopulmonary exercise test (CPET) has been proven to be a useful tool to detect both
exercise-induced myocardial ischemia with a diagnostic accuracy similar to single-photon emission
computed tomographic myocardial perfusion study28,29 and even superior to ECG stress testing.30 For this
reason, CPET should, in our opinion, be proposed as a noninvasive test to detect and quantify myocardial
perfusion defects in patients at increased risk for coronary artery disease.
COMORBIDITY SCORING SYSTEMS

Scoring systems are often used in our specialty to predict the probability of selected outcomes in groups
of patients, thus enabling risk stratification. The main limitation is the lack of accuracy on an individual
patient basis. Scoring systems may be accurate in estimating the mortality rate in a certain group of
patients but they fail in identifying which of the patient will exactly die after the operation. Therefore, they
cannot be used as a selection tool for surgery, but only for estimating the risk of morbidity and mortality,
which can be informative during preoperative counseling. Several comorbidity scores have been used in
our specialty. The following are the most studied and frequently used.
Charlson Comorbidity Index

The Charlson Comorbidity Index (CCI) is a score that quantifies the risk of mortality in relation to the
multiple pathological conditions of a patient. It was originally derived in 1987 by Charlson and
colleagues.31 They examined the impact of several baseline comorbidities on the mortality rate of 559
medical patients during their first year after the admission. Seventeen conditions were found to correlate
with mortality. Each of these were weighted according to their independent contribution to the risk of
death (expressed as a single numeric value). The sum of the individual pathological condition values
indicated the CCI of a patient. In the original population, the mortality risk progression related to the CCI
was CCI = 0 – risk = 8%, CCI = 1 – risk = 25%, CCI = 2 – risk = 48%, CCI > 3 – risk = 59%. Since its
publication, the CCI has been widely used for the stratification of risk, and for measuring the burden of
comorbidities on many groups of patients in the medical, surgical, and intensive care fields.
In 2003, the CCI was applied in thoracic surgery for the first time by Birim et al.32 to assess the risk of
early morbidity after lung resection on a retrospective series of 205 patients following a major lung
resection (only four wedge resections, 25% pneumonectomies). Several baseline characteristics,
including the CCI, were evaluated in the uni- and multivariable analysis for the purpose of identifying
factors associated with the development of major complications (defined as potential life-threatening
postsurgical conditions). For the 15.6% of patients experiencing major complications, the only predictor
was represented by a CCI of grade 3 to 4.
The same authors have also used the CCI for predicting late outcome in 433 patients undergoing lung
resection (lobectomy 66%, pneumonectomy 30%, wedge 4%) with curative intent for primary lung cancer
(stage IA and IB in 90% of cases).33 The CCI and several preoperative and operative factors were
analyzed for verifying the association with long-term survival and disease-free survival. The results
showed that the CCI predicted both long-term and disease-free survival in association with age, type of
resection, and stage of disease. Moreover, a CCI of 1 to 2 points increased the risk of mortality by 1.4
fold whilst a CCI >3 by 2.2 fold. In the same year, these results were corroborated by a retrospective
study of Moro-Sibilot et al.34 on 588 patients with pathological stage I NSCLC following to lung
resection (lobectomy 84.2%, pneumonectomy 9%, segmentectomy 6.8%). They found that a CCI score >2
was associated with a reduction of the overall 5-year survival, with a hazard ratio of 1.81. Two years
later, Wang obtained the same association in a population of 426 stage I primary lung cancer patients
(lobectomy–bilobectomy 91%, pneumonectomy 3%, wedge-segmentectomy 6%).35 Again a CCI >2 was
predictive of a poorer long-term survival (hazard ratio 1.7), in association with age >65 years and stage
IB disease.
Physiological and Operative Severity Score for the Enumeration of Mortality and
Morbidity (POSSUM)
The physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM)
was originally proposed by Copeland et al.36 in the early 90s as a scoring system for auditing the quality
of care in general surgery. Obtained as the sum of a Physiological Score (evaluating 12 baseline
characteristics of the patient) and an Operative Severity Score (evaluating six operative factors), the
POSSUM indicated a proportionally higher risk of morbidity and mortality associated with higher
cumulative score values.
FIGURE 23.4 Incidence of complications according to EVAD score and type of complications. (From Ferguson MK, Durkin
AE. A comparison of three scoring systems for predicting complications after major lung resection. Eur J Cardiothorac Surg
In 1999, Brunelli et al.37 validated the use of POSSUM in thoracic surgery, applying it to 250 lung
resection candidates (36 wedge resections, 160 lobectomies, and 54 pneumonectomies). The POSSUM
score did predict surgical outcomes, without significant differences between observed and predicted
morbidity. Moreover, by adjusting the POSSUM score with other preoperative factors, it was possible to
develop a corrected model that showed a perfect agreement between observed and predicted morbidity
(seven complications predicted and seven complications observed) in the deciles of probable
complication from 0.7 to 1.0 (classes of patients at higher risk of complications). These authors also used
the POSSUM score for evaluating performance in two different time periods (1992 to 1994, 362 patients
treated vs. 1995 to 1997, 439 patents treated).38 The POSSUM-predicted morbidity during the first 3
years was significantly lower than the observed one (predicted morbidity 24.3% vs. observed morbidity
19.6%, p = 0.01), suggesting that clinical performance could be improved. Performance was improved
during the late 3 years, when the predicted and observed morbidities did not differ (predicted morbidity
19.1% vs. observed morbidity 20.5%, p = 0.8), demonstrating the applicability of the POSSUM score as
a tool of internal audit in thoracic surgery.
EVAD Score
In 2003, Ferguson and Durkin39 proposed a new index for predicting the risk of complications and death
after major lung resection. The score was derived on an initial population of 400 patients that had a major
lung resection at a single center during a 15-year time span. Three largely available preoperative
parameters (patient’s age, FEV1%, and DLCO%) were used for creating weighted single scores, which
were then combined to obtain an EVAD score, which is the acronym of expiratory volume, age, and
diffusion. The EVAD was tested for correlation with several postoperative outcomes (pulmonary
complications, cardiovascular complications, cardiopulmonary complications, infectious complications,
other complications, nonfatal complications, death, and any complication) in a different population of
patients undergoing major lung resection in the same center between 1996 and 2001. This scoring system
was able to predict an incremental risk of complications in all categories except infectious complications
and death (Fig. 23.4). The EVAD score was also compared to others risk scores (POSSUM and
cardiopulmonary risk index), and EVAD was better at quantifying the risk of almost all of the above-
mentioned complication categories.
The limits of the EVAD, represented by the absence of a unique threshold able to discriminate patients
with high risk from the ones at low risk and an only moderate discrimination ability (as testified by a c-
index <0.8).
Thoracoscore
Based on the data collected within the French Society of Thoracic and Cardiovascular Surgery database
(Epithor), the Thoracoscore is a risk index for predicting the in-hospital mortality after various thoracic
surgery procedures (lobectomy: 24.1%, pneumonectomy: 6%, wedge: 43.4%, mediastinoscopy or other
mediastinal surgery: 26.1%).40 It was derived from the analysis of 10,122 patients (mortality rate: 2.1%),
and its effectiveness was tested on a second group of 5,061 patients (mortality rate: 2.4%). Multivariable
analysis identified several factors associated with mortality and included in the model for the prediction
of in-hospital death: age, sex, dyspnea score, American Society of Anesthesiologists score, performance
status classification, priority of surgery, diagnosis group, procedure class, and comorbidity score. The
odds ratios of each of these 9 factors were utilized in the prediction of mortality risk. The model was able
to reliably assess the risk of in-hospital death (c-index 0.85) and the correlation between the expected and
observed mortality was very high (correlation rate 0.99) in all the risk classes analyzed.
After this first study published in 2006, other papers have attempted to validate the Thoracoscore in
different settings, obtaining nonunivocal results about its ability to predict the mortality risk in thoracic
surgery patients. A study by Chamogeorgakis and colleagues verified the association between a modified
version of the Thoracoscore and early and mid-term mortality in a population of 1,675 thoracic surgery
patients.41 Most of the patients had undergone a lung resection (37%) or other surgical procedure on the
mediastinum (32%), although procedures on pleura and pericardium (16%), esophagus and chest wall
(10%) were also included. The overall early mortality was 3.2% and the 2-year mortality was 21.4%.
The modified version of the Thoracoscore excluded the dyspnea score (a parameter not available in this
retrospective cohort), nevertheless, the adapted Thoracoscore was an independent factor associated with
both in-hospital (OR 1.2, p <0.001) and 2-years mortality rates (OR 1.12, p <0.001). The ability of the
new model to predict early outcome was excellent (C statistic 0.84). The same authors reinforced their
previous results in a second study, where the modified Thoracoscore was applied to predict the
postoperative mortality in a different group of patients.42 One-hundred fifty-five patients were
prospectively enrolled in this study with a considerable case mix (21% wedge pulmonary resections,
21% chest wall and pleural procedures, 15% pulmonary lobectomies, 14% neck and mediastinal
procedures, 8% minor cardiac procedures, 6.5% tumor biopsies, 5% tracheal procedures, 4%
pneumonectomies, 3% chest trauma, 2% esophageal procedures) and an in-hospital mortality of 5.2%.
Again, the ability of predicting mortality by the Thoracoscore was high, with a predicted mortality of
4.9% and a C statistics of 0.96.
On the other hand, two different studies highlighted the limitations of the Thoracoscore when applied
to specific subgroups of patients. In 2012, Bradley et al.43 verified the association between Thoracoscore
and postoperative complications and mortality in a prospective cohort of 703 surgical patients from a
single center. The authors examined only patients after lung resections surgery (lobectomies 55%, wedge
resections 22%, pneumonectomies 10%, sleeve resections 3%, explorations 4%) and most of the
operations (91%) were performed for primary lung cancer. The pulmonary morbidity rate was 16% and
the postoperative mortality rate was 2%. The Thoracoscore was not associated with mortality (p = 0.11)
but did associate with the development of pulmonary complications (p = 0.002). Nevertheless, the ability
of the Thoracoscore to predict mortality and morbidity was low, with an area under the ROC curve of
0.68 and 0.64, respectively.
A second study by Qadri44 revealed an underperformance of the Thoracoscore in predicting the early
mortality in a group of 243 patients following pneumonectomy for lung cancer in a single center, during a
period of 10 years. The overall mortality rate was 4.5% with a decreasing trend in the last 5-year cohort
(1998 to 2002 mortality = 5%, 2003 to 2008 mortality = 3.8%), while the predicted mortality based on
the Thoracoscore was 8%. Moreover, dividing the entire population into four risk groups based on
increasing Thoracoscore value (low risk: Thoracoscore 0 to 3, moderate: 3.1 to 5, high: 5.1 to 8, very
high: >8), identified an overestimation of the risk in the lower groups and an underestimation in the higher
ones.
Finally, in 2011, Bernard developed a refined risk model to predict in-hospital mortality after lung
resection again based on data derived from Epithor, the French Thoracic Surgery Database also used to
develop the Thoracoscore.45 In contrast to the previous analysis of Falcoz et al.,40 this group included
only patients undergoing lobectomy (73%), pneumonectomy (17%), and limited pulmonary resection
(10%) for lung cancer. The overall mortality rate for these 690 patients, out of the total 18,049, was
3.8%: 3% for lobectomies, 7.7% for pneumonectomy, and 2.4% for limited resections. The multivariable
analysis included several preoperative baseline characteristics, patient comorbidities, and type of
resection performed, and identified the following parameters as significantly associated with in-hospital
death: age, sex, ASA score, performance status, FEV, BMI, side, lobectomy, pneumonectomy, extended
resection, stage III disease, stage IV disease, and comorbidities. The authors developed two bias-
corrected risk models; model one using the comorbidity parameter as a specific condition affecting the
outcome and model 2 using the comorbidity parameter as the sum of the pathological conditions
(independently from the type). Both risk models performed well in predicting the in-hospital mortality,
with an area under the ROC curve of 0.784 for model one and 0.78 for model two (Fig. 23.5). The results
were internally validated using a bootstrap technique rather than testing the model on a different group of
patients. Despite the reliability of both the risk models, the authors favored using the second one as it
seemed more cost-effective.
ESOS
In 2005, Berrisford and colleagues,46 on behalf of the Audit and guidelines committee of the European
Society of Thoracic Surgeons and the European Association of Cardiothoracic Surgeons, developed a
model to predict the in-hospital mortality in patients undergoing their first lung resection. The analysis
was conducted on data from 3,426 patients (wedge/segmentectomies 26%, lobectomies 59%,
pneumonectomies 14%, lung volume reduction surgery 1%) collected in a European database gathered
from 27 Thoracic Surgery Units from 14 different countries. The overall mortality rate was 1.9% (66
patients), and the highest rate was observed in the pneumonectomy group (4%). A logistic regression
analysis was performed using 60% of the entire population, in order to identify the baseline
characteristics associated with in-hospital mortality, and to build a model to be tested on the remaining
40% of patients. The model to predict the in-hospital death was based on age, dyspnea score, American
Society of Anesthesiologists score and type of resection. The initial model revealed an underestimation of
mortality for patients at medium risk and overestimation for patients at high risk, and thus the analysis was
refined to develop a second model. This was developed using only lung cancer patients (85% of the
initial cohort) and was called European Society Objective Score (ESOS). The ESOS was a risk model
based on age and ppoFEV1 and was able to predict in-hospital death with high concordance between
predicted and observed mortality for all the risk classes within the testing group of patients (Fig. 23.6).
FIGURE 23.5 Calibration plot of observed versus predicted in-hospital mortality after lung cancer surgery for the two models
developed from the Epithor. (Reproduced with permission from Bernard A, Rivera C, Pages PB, et al. Risk model of in-hospital
mortality after pulmonary resection for cancer: a national database of the French Society of Thoracic and Cardiovascular
Surgery (Epithor). J Thorac Cardiovasc Surg 2011;141(2):449–458. Copyright © 2011 The American Association for Thoracic
Surgery. With permission.)
FIGURE 23.6 Cumulative observed mortality versus ESOS predicted mortality with cases ordered by increasing predicted risk.
(From Berrisford R, Brunelli A, Rocco G, et al. The European Thoracic Surgery Database project: modelling the risk of in-
hospital death following lung resection. Eur J Cardiothorac Surg 2005;28:306–311. Reproduced by permission of European
Association for Cardiothoracic Surgery.)
Three years later, Brunelli et al.47 on behalf of the ESTS Audit and Clinical Excellence Committee,
published a paper where ESOS was used to evaluate the performance of three different European
Thoracic Surgery Units. Six-hundred ninety-five patients (578 lobectomies and 117 pneumonectomies)
after major lung resections for lung cancer were retrospectively analyzed (Unit A: 264 patients, Unit B:
262 patients, and Unit C:169 patients). The Units showed different unadjusted mortality rates: 2.3% for
Unit A, 2.6% for Unit B, and 4.1% for Unit C, but the authors demonstrated that the ESOS-predicted
mortality rate was in line with the observed one, confirming the reliability of ESOS in predicting in-
hospital mortality. Moreover, they showed that all of the Units performed in line with the ESOS expected
outcomes, despite the difference initially noted in the observed mortality rates, thereby suggesting that risk
factors, and thus mortality, differed among the patient populations seen at the different thoracic surgical
units.
SURGEON PERCEPTION OF SURGICAL RISK: THE DELICATE BALANCE

BETWEEN INSTINCT AND LOGIC
In addition to using objective measures and tests, surgeons strongly rely on their “gestalt” to assess the
risk of an individual patient. However, physician estimates of risk are not consistently accurate or are
poorly reproducible.47–50 In general, surgeons tend to overestimate the risk of complications in healthy
patients and underestimate risks in sicker ones. They also tend to use objective findings and results from
preoperative tests selectively and inconsistently. Surgeons often rely on their clinical reasoning skills to
make care decisions when faced with complex and uncertain information. Clinical reasoning skills are
influenced by experience, exposure, internal biases, and most of all the surgeon’s clinical gestalt.
Clinical gestalt or snap judgment is the theory that physicians actively organize clinical perceptions
into logical constructs.51 It is the ability of pattern recognition, which allows clinical decisions to be
taken even in the absence of complete information or in the presence of a large amount of complex or
conflicting data (i.e., objective parameters). In essence, clinical gestalt is a heuristic process to problem-
solving that uses mental shortcuts to ease the cognitive load of clinical decision making.52 At present, the
literature suggests that experience is capable of positively influencing the decision-making accuracy and it
has been shown that experienced clinicians do have better pattern recognition skills.52
In a recent investigation, Ferguson et al.53 found that experienced practicing surgeons were more
accurate than trainees in estimating the surgical risk of thoracic patients. In his book “Blink,” Malcolm
Gladwell describes the ability to make snap judgments about complex problems relying on instinct and
rapid pattern recognition.54 Our unconscious is able to find patterns in situations and behaviors based on
very narrow slices of experience, the so-called “thin-slicing.” In a recent study, Dijksterhuis et al.55
showed that it is not always advantageous to engage in thorough conscious deliberation before making a
choice or taking a decision. Interestingly, simple choices produced better results after conscious thought;
however, choices in complex matters (when many different variables needed to be taken into
consideration) were better when left to unconscious thought. This hypothesis was supported in a study of
consumer choice where purchases of complex products were viewed more favorably when decisions
were made in the absence of attentive deliberation. This concept is not new and was originally proposed
by Sigmund Freud. He found considering all pros and cons advantageous when making a decision of
minor importance but in vital and more complex matters he was convinced that the decision should come
from the unconscious.
Patient selection for operation and estimation of surgical risk are complex processes, where multiple
factors both objective and subjective need to be taken into account. Information and understanding,
instinct and logic need to be carefully balanced by using the right combination of conscious and
unconscious analysis for each patient.
Experience and knowledge (information) are able to improve our snap judgment ability. This was
demonstrated in a recent study where experts and nonexperts were asked to predict the results of soccer
matches after conscious or unconscious thought. Experts who thought unconsciously outperformed all
other participants, and were better at applying diagnostic information than experts who thought
consciously.56 However, one must be careful as gestalt is biased by many possible errors in both
empirical and rational aspects, regardless the level of experience or capability. The use of statistical risk
analyses and risk predictive modeling is able to increase the level of knowledge, which in turn will allow
one to perform a more accurate and less biased rapid cognition analysis on an individual patient.
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24
Pulmonary Physiologic Assessment of
Operative Risk
Diego Avella Patino ■ Mark K. Ferguson
Complications occur frequently after major thoracic surgery. Their development is related to a variety of
factors, including the type of operation performed, the approach to the operation, and the underlying
condition of the patient. The occurrence of pulmonary complications is associated with prolonged
hospitalization, a higher cost of hospital care, and an increase in operative mortality. Every effort should
be made to reduce the incidence of such complications and to manage them expeditiously when they
occur.
The ability to predict which patients are at higher risk for postoperative complications enables
physicians and other caregivers to select appropriate patients for major surgery and to discuss relative
risks with patients so that informed consent about a planned operation can be obtained. Risk stratification
helps identify patients who might benefit from preoperative cardiopulmonary rehabilitation in an effort to
reduce the incidence of complications, and may direct patients to physicians or medical centers better
able to manage higher-risk operations. Risk stratification also permits assignment of additional resources
to the postoperative care of those patients deemed to be at increased risk for pulmonary complications.
The development of pulmonary complications—as well as the risk for operative mortality after
pulmonary, esophageal, and upper abdominal operations—has been shown to be associated with the
preoperative pulmonary status of the patient. Ensuring that an appropriate pulmonary physiologic
assessment of patients has been performed before the operation is the responsibility of the treating
surgeon. Historically, surgeons have been among the leaders in developing criteria for risk stratification
based on pulmonary physiologic status. These efforts have led to algorithms that help treating physicians
quantify the relative risk for complications based on a few important tests. However, numbers alone
should not be used to make recommendations for individual patients; clinical judgment remains the most
important factor in successful surgical care.
EFFECTS OF SURGERY ON PULMONARY FUNCTION

The type of operation and the incision used to perform an operation have varying deleterious effects on
pulmonary function that have been well described with regard to the extent of functional decrement and
the time course of recovery. Functional residual capacity (FRC) has been recognized for decades as the
single most important lung volume component associated with the development of pulmonary
complications after most types of operations. FRC is the lung volume that exists at the end of normal
expiration; its components are the expiratory reserve volume and the residual volume (RV) (Fig. 24.1). A
number of factors are associated with a postoperative decrease in FRC, including general anesthesia,
conditions that increase intra-abdominal pressure (such as obesity, ascites, and the supine position), and,
most important, the type and location of incisions used for an operation.1–3
Knowledge of the interaction of FRC with the closing volume (CV) of the lung is key in understanding
postoperative pulmonary complications. The CV is the volume of the lung at which airflow from
dependent parts of the lung stops during expiration owing to airway closure. Factors that promote an
increase in CV include advancing age, tobacco use, fluid overload, bronchospasm, and the presence of
airway secretions. Under normal circumstances, FRC is about 50% and CV is about 30% of total lung
capacity (TLC). A reduction in FRC or an increase in CV results in premature airway closure and
atelectasis.4,5 The resulting ventilation/perfusion mismatch causes hypoxia, and trapping of secretions
contributes to pneumonitis, both of which may contribute to the development of respiratory insufficiency.3
FIGURE 24.1 Lung volume measurements and their interrelationships. TLC, total lung capacity; VC, vital capacity; RV, residual
volume; IC, inspiratory capacity; FRC, functional residual capacity; IRV, inspiratory reserve volume; TV, tidal volume; ERV,
expiratory reserve volume; RV, residual volume.
FRC is reduced by 10% to 15% after lower abdominal operations, 30% following upper abdominal
operations, and 35% with thoracotomies. No consistent changes in FRC occur after operations that do not
involve the abdomen or thorax. The reduction of FRC after abdominal surgery is attributed to both
dysfunction of abdominal wall musculature and impaired diaphragmatic function. Upper abdominal
incisions cause a substantial decrease in the function of both the diaphragm and lungs.6 Open operations
cause greater perturbations in lung function than do laparoscopic operations,7–9 although adverse effects
after laparoscopic operations are nevertheless substantial.10 Maximum diaphragmatic pressure decreases
after laparoscopic upper abdominal procedures by >50% during the first 6 hours after surgery, with
partial recovery evident by 24 hours.11,12 Laparoscopic lower abdominal procedures cause minimal
reductions in diaphragmatic activity and lung function compared with those evident after upper abdominal
laparoscopy, demonstrating that even minimally invasive procedures cause diaphragmatic and ventilatory
dysfunction that is dependent on the location of the operation.12,13
Postoperative pain does not appear to be an adequate explanation for these changes, which develop
despite adequate postoperative analgesia.14 Instead, it has been suggested that reflexes inhibit phrenic
nerve output.15 Extradural block has been shown to improve postoperative diaphragmatic function after
upper abdominal surgery, supporting the contention that interruption of afferents that inhibit diaphragm
activity may result in improved outcomes.16,17
The performance of a sternotomy has deleterious effects on chest wall mechanics and postoperative
pulmonary function similar to those following laparotomy, possibly leading to pulmonary
complications.18–21 A partial sternotomy appears to have no important benefit over a fully sternotomy in
terms of immediate postoperative lung function.18 A restrictive pattern develops in the early postoperative
period that is manifested by a decrease in FRC and impaired inspiratory and expiratory pressures.22
Respiratory pressures return to normal 6 weeks postoperatively, but FRC and other ventilatory
parameters remain decreased. A restrictive ventilatory defect appears in the early postoperative period
after median sternotomy owing to reduced and uncoordinated rib cage expansion; this is no longer evident
3 months postoperatively.23 Harvesting an internal mammary artery graft for coronary revascularization
impairs chest wall mechanics more than when saphenous vein grafts are used.24 Overall, reports suggest
that structural alterations in chest wall mechanics and decreased blood flow to intercostal muscles are
responsible for restrictive ventilatory changes after sternotomy that may be related to the development of
pulmonary complications.
FIGURE 24.2 Changes in forced vital capacity (FVC) and in the forced expiratory volume in 1 second (FEV1) during the first 3
months after thoracotomy. (Data from references 25, 26, and 27.)
FIGURE 24.3 Permanent changes in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing
capacity of the lung for carbon monoxide (DLCO) after various types of lung resection. (Data from references 32–42, 44, and
45.)
Thoracotomy is the operative approach associated with the highest potential risk for postoperative
pulmonary complications, owing to restricted chest wall motion, impaired diaphragm activity, and
possible loss of pulmonary parenchyma. The development of diaphragmatic dysfunction after thoracotomy
resembles the dysfunction that accompanies upper abdominal operations.25 Epidural analgesia does not
reverse diaphragmatic dysfunction after thoracotomy, a situation analogous to upper abdominal surgery.25
A thoracotomy incision transiently reduces most ventilatory parameters postoperatively, with a
precipitous drop occurring by the first postoperative day (Fig. 24.2). At the end of the second
postoperative week, some recovery occurs, but there is continued slow improvement for almost 3 months
after surgery.
Thoracoscopic operations cause a somewhat smaller decrement in pulmonary function during the
immediate postoperative period,26,27–29 that may be protective in reducing postoperative complications
compared to open thoracotomy.30 The advantage persists for the first postoperative week, after which
both open thoracotomy and thoracoscopic approaches to major lung resection appear to have similar
outcomes. A multitude of authors point out that major lung resection permanently reduces spirometric
values and diffusing capacity by varying degrees, depending on the amount of lung that is resected. The
lobe that is resected also has an impact on postoperative lung function.31 When measured 6 months to 1
year postoperatively, segmental or wedge resections reduce lung function by <10%, lobectomy or
bilobectomy results in decreases of 5% to 15%, and pneumonectomy reduces values by 20% to 40% (Fig.
24.3).32–52
PREDICTIVE FACTORS FOR PULMONARY MORBIDITY AND MORTALITY

AFTER MAJOR LUNG RESECTION
Many tests have been used to identify factors associated with postoperative pulmonary morbidity after
major lung resections (Table 24.1). As a result, a number of algorithms have been developed for the
preoperative assessment of such patients.
TABLE 24.1 Cardiopulmonary Function Tests Used in the Preoperative Assessment

of Thoracic Surgery Patients
Test Lung Airway Gas Muscle Cardiac Effort and
Capacity Resistance Exchange Strength Output Motivation
FVC •
FEV1 • •
FEV1/FVC •
MVV • • • •
Stair climb or shuttle • • • • •
walk
DLCO •
Peak VO2 • • • • •
LUNG VOLUME MEASUREMENTS

The measurement of lung volumes, including TLC and RV, is useful in the evaluation of the lung resection
candidate. Vital capacity (VC) is decreased when TLC is reduced by restrictive processes, when RV is
increased owing to air trapping in obstructive disease, or by a combination of these factors (Fig. 24.4).
Recognition of which elements contribute to a decreased VC may help in assessing the preoperative
patient. It is not possible to make this distinction without measurement of RV, which cannot be obtained by
routine spirometry but requires helium equilibration, nitrogen washout, or body plethysmography
techniques.
Restrictive physiology causes reductions in VC as well as TLC, RV, and FRC. It is evident with
pulmonary fibrosis, sarcoidosis, muscular weakness and disease, chest wall deformities, large acquired
diaphragmatic hernias, and trapped lung in the setting of extensive pleural fibrosis. In the case of a
trapped lung, surgery that includes a pulmonary decortication may help resolve the restrictive physiology,
resulting in improved pulmonary dynamics postoperatively. Similar effects are produced by surgical
correction of a large diaphragmatic hernia. None of the other conditions that cause a restrictive
physiology are improved by thoracic surgery, highlighting the possible risk to these patients from major
thoracic surgical procedures.
FIGURE 24.4 Relative changes in lung volumes associated with lung diseases. See Figure 24.1 for definitions.
Obstructive physiology causes reductions in VC, but there are associated increases in TLC, RV, and
FRC. It is present in emphysema, chronic bronchitis, and asthma. The use of bronchodilators and, in
severe cases, inhaled or systemic steroids can dramatically improve obstructive physiology in patients
with reactive airways disease, making thoracic surgery much safer. In highly selected patients with
heterogeneous emphysema, resection of the most affected regions of the lung can result in an increase in
VC. In most other instances, the abnormal measurements are relatively fixed, and major lung surgery
further reduces VC.
SPIROMETRY
The relationship between VC and mortality in the general population was identified in the mid-1800s. By
the middle of the 20th century, a variety of lung volume measurements were being used in the physiologic
assessment of candidates for lung resection. The utility of measuring forced expiratory volume in the first
second (FEV1) and its correlation with obstructive ventilatory abnormalities was demonstrated in the
early 1950s.53 Subsequently, mortality and respiratory insufficiency were more clearly correlated to
reduction of FVC and FEV1.54
FEV1 was first identified in 1973 to be a predictor of which patients would not tolerate major lung
resection.55 Others subsequently described patients with a substantially reduced FEV1 as being at
increased.56 The general guidelines of FEV1 of <2.0 L and MVV <50% of predicted as indicative of a
potential increased risk for major lung surgery were supported in a 1975 report suggesting that additional
physiologic studies be obtained in these patients.57 During the 1960s and 1970s, the use of timed
measurements of expiratory volumes thus became standard in the evaluation of candidates for lung
resection.
PREDICTED POSTOPERATIVE FUNCTION

Pulmonary scintigraphy was initially developed in the 1950s to study the regional distribution of lung
ventilation and was first utilized in estimating postoperative function, particularly in patients undergoing
pneumonectomy, in the early 1970s.57–59 The percentage of function attributed to the lung not being
resected was multiplied by the preoperative measured value of lung function to achieve a predicted
postoperative value for lung function (Fig. 24.5). A technique was subsequently developed for using lung
scintigraphy to estimate postoperative function in patients undergoing lobectomy: the expected loss of
function was calculated by multiplying the preoperative FEV1 by the percentage of function in the affected
lung and by the percentage of segments of that lung that were to be resected.32
FIGURE 24.5 Quantitative perfusion scan (anterior view) of a patient with a proximal right-upper-lobe lung cancer. Distribution
of radiotracer is indicated according to upper and lower lung zones.
The superiority of perfusion over either ventilation alone or a combination of ventilation and perfusion
for estimating postoperative lung function was demonstrated in 1980.60 The percentage of perfusion to the
lung that would remain postoperatively was multiplied by the preoperative spirometric value to yield the
predicted postoperative value. The correlation between calculated and actual measurements of
postoperative lung function was high, and the error rate was <10% (Fig. 24.6). This accuracy has
subsequently been confirmed by many other authors.61,62
Pulmonary scintigraphy as a means for estimating postoperative pulmonary function yielded suggested
cutoff values for operability that differed among investigators. Various authors suggested that a
postoperative predicted FEV1 of <800 or 1,000 mL precluded resection.57,58 Despite the lack of
conclusive evidence supporting this guideline, a postoperative predicted FEV1 of 800 mL to 1 L is still
used by some surgeons as a cutoff for distinguishing between normal-risk and high-risk candidates for
major lung resection. More accurate predictive algorithms are described below.
The calculation of postoperative lung function using simple equations rather than physiologic tests was
originally introduced in 1975.63 Initially, all functional and nonfunctional lung segments were utilized in
the calculation of predicted postoperative (ppo) FEV1 and the correlation between the predicted and
actual FEV1 was high.60 Using this technique, an increase in postoperative morbidity was demonstrated in
patients with a predicted postoperative FEV1 of <900 to 1,000 mL.64,65 A number of studies have
confirmed the good correlation between predicted postoperative and measured postoperative FEV1 and
FVC in patients undergoing major lung resection.35,39,66,67 However, postoperative predicted values after
resection can underestimate or overestimate FEV1 by as much as 250 mL. Part of the explanation for the
discrepancy between predicted and measured values in some studies might have been the inclusion of
nonfunctioning segments in the estimation of postoperative function.68
Improved techniques for calculating predicted postoperative spirometric values use the number of
functioning segments as the denominator and the number of functioning segments remaining after resection
as the numerator for purposes of calculating predicted postoperative values.69 In this way, segments that
are nonfunctional (owing to obstruction by a proximal cancer or consolidation or destruction due to an
inflammatory process) are not included in the following calculation:
Postop = Preop × (Postop segments/Preop segments)
where Postop, the postoperative lung function value; Preop, the preoperative lung function value; Postop
segments, the number of segments remaining after resection; and Preop segments, the number of
functioning segments present prior to the operation. This calculation technique is better than using all lung
segments in estimating postoperative function.70
The use of quantitative computed tomography (CT) in estimating relative lung function as a means for
calculating predicted postoperative function is similar to lung perfusion scintigraphy and segmental
percentage loss in the accuracy of predicting postoperative function.70,71–73 As this technique improves, it
may yield better accuracy in predicting postoperative lung function than either the segmental counting
technique or lung perfusion scintigraphy. Currently, quantitative CT or scintigraphic assessment of
perfusion is similar to anatomic techniques for estimating postoperative function after segmentectomy or
lobectomy, whereas anatomic techniques are not as accurate for estimating postoperative function after
pneumonectomy. There are some clinical situations in which previous lung procedures or centrally
located malignant disease may alter ventilation and/or perfusion to the target lung. In these situations, a
quantitative ventilation–perfusion (VQ) scan may provide more accurate estimates of postoperative lung
function than other techniques.74
FIGURE 24.6 Comparison of calculated and measured postoperative FEV1 for patients after lobectomy (left) and
pneumonectomy (right). The solid lines were calculated by linear regression and the dashed lines represent the lines of identity.
(Data from references 35,60,66,70.)
SPIROMETRY EXPRESSED AS A PERCENTAGE OF PREDICTED NORMAL

VALUES
The disadvantage of using absolute rather than relative values for predicting risk is easily illustrated: a
postoperative FEV1 of 800 mL represents 48% of the predicted normal for a short, elderly woman but
only 21% of the predicted normal for a tall, middle-aged man. Significant increases in pulmonary
complications and mortality after major lung resections have been associated with a low preoperative
FEV1 but are more closely related to a reduced predicted postoperative (ppo) FEV1.75–78 A ppoFEV1
<60% has been associated with an increase in the incidence of pulmonary complications after lung
resection.76,77,79,80 In patients with ppoFEV1 <30%, the incidence of respiratory complications may be as
high as 41%.80 Observational studies indicate that for each 10-point decrease in ppoFEV1% there is a
10% to 30% increased risk of having pulmonary and cardiovascular complications, respectively, after
major lung resection.77 Furthermore, a decreasing ppoFEV1% is associated with increased risk of
intensive care unit readmission and prolonged hospitalizations.77,81
Care must be taken in using spirometric values as a means for selecting patients at the lower limits of
lung function for major lung resection. In patients with moderate to severe chronic obstructive pulmonary
disease (COPD), a low FEV1 might not accurately predict the risk of postoperative complications.
Resection of parenchyma affected by COPD is associated in some patients with an improvement in
respiratory mechanics, having a beneficial effect that is evident immediately after surgery.82–85 The extent
of planned resection as well as the surgical approach (open vs. minimally invasive) also have to be
considered as part of the preoperative interpretation of pulmonary function and risk assessment.86 Several
studies have demonstrated low morbidity (15% to 25%) and low mortality (1% to 5%) in patients with
preoperative FEV1 ranging from 26% to 45%.83,85 Acceptable outcomes after lung resection with
predicted postoperative FEV1 <30% have been demonstrated.87
Most of the studies evaluating the impact of pulmonary function in postoperative outcomes have been
done in patients undergoing lung resections via thoracotomy. The overall physiologic impact of lung
resection via a thoracoscopic approach is less severe than for open resection. In a retrospective study
comparing thoracoscopic to open lobectomy, preoperative FEV1 was an independent predictor of
morbidity in thoracotomy patients but not in thoracoscopy patients.78 In contrast, ppoFEV1 was identified
as being predictive of respiratory complications after major lung resection regardless of the approach
used for resection,88 suggesting that this predicted postoperative value is a useful means for estimating
risk for lung resection patients undergoing either thoracotomy or thoracoscopy.
Selected patients with more severe obstructive lung disease—as defined by worse FEV1 or lower
FEV1/FVC ratio—experience less percentage loss of lung function as measured by spirometry than do
patients with normal lung function (Fig. 24.7).48,89–91 A substantial proportion of these patients, likely
those with heterogeneous disease who undergo resection of the most diseased portions of their lungs,
experience improvement in measured lung function and respiratory symptoms postoperatively. The use of
absolute limits for determining which patients should be excluded from consideration for major lung
resection should be tempered by the relative inaccuracy of predicting postoperative function in higher-
risk patients.
DIFFUSING CAPACITY OF THE LUNG

The most important factors determining the diffusing capacity of the lung for carbon monoxide (DLCO;
also referred to as transfer factor, or TLCO) are the volume or surface area of the pulmonary capillary
bed. Loss of alveoli resulting in a reduced DLCO is most commonly seen in emphysema, but other factors
that obliterate capillaries—such as vasculitis, embolic disease, and interstitial inflammatory diseases—
may also decrease diffusing capacity. Processes that reduce gas entry, such as filling of alveoli and
ventilation maldistributions, also result in a reduced DLCO. Low hemoglobin may cause a decrease in gas
uptake, whereas congestive heart failure with an associated increase in hemoglobin or polycythemia may
cause an increase in gas uptake; these factors can theoretically influence DLCO, but they are often
corrected in calculating the DLCO. Many patients with lung cancer have a decreased DLCO out of
proportion to their degree of emphysema based on spirometric studies, suggesting the presence of
subclinical emphysematous changes not detectable by routine spirometry.92
FIGURE 24.7 Predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1) values (dashed line) relative to
those observed (solid line) at 3 months. (Reprinted from Brunelli A, Refai M, Salati M, et al. Predicted versus observed FEV1
and DLCO after major lung resection: A prospective evaluation at different postoperative periods. Ann Thorac Surg
2007;83:1134–1139. Copyright © 2007 The Society of Thoracic Surgeons. With permission.)
Preoperative assessment of lung function should include measurement of both spirometric values and
DLCO. These parameters characterize the function of two separate compartments of the respiratory
apparatus. Alterations in spirometry represent lung volume and airflow limitations, whereas DLCO
describes the function of the alveolar-capillary membrane. The correlation between spirometric values
and DLCO is relatively poor; assuming that patients with normal spirometry will also have a normal DLCO
is erroneous (Fig. 24.8). More than 40% of surgical patients with FEV1 >80% have a DLCO <80% and in
some patients with normal spirometry, the DLCO is <40% predicted.93 Analyses have demonstrated that
spirometry and DLCO are independent predictors of outcomes after major lung resection.94
Substantial decreases in DLCO occur after lung resection95–98 averaging 20% for wedge resection,
30% for lobectomy, and 41% for pneumonectomy. The recommendation for the routine assessment of
DLCO in patients who are candidates for major lung resection was initially published in 1963.99 In
general, diffusing capacity does not decrease chronically after pneumonectomy to the same extent that
spirometric values do, and patients appear to tolerate exercise better than would be expected. This might
be due to the normal ability to recruit DLCO during exercise that is preserved even after
pneumonectomy.100
FIGURE 24.8 The correlation between DLCO and FEV1 (left panel) and FEV1/FVC (right panel) ratio, illustrating poor
correlation between DLCO and spirometric measurements.
An important relationship between low diffusing capacity and operative mortality after major lung
resection was initially documented in 1970.101 This was confirmed in later studies in which each 10-point
decrease in DLCO was associated with a 20% to 35% increase in the risk of mortality.77,102 DLCO also
was identified as an independent predictor of postoperative pulmonary complications after major lung
resection, and it was suggested that a preoperative DLCO of <60% of predicted is an indicator of high risk
for postoperative complications.103,104
Using the predicted postoperative DLCO (ppoDLCO) expressed as a percentage of normal increases the
accuracy of estimating the risk of postoperative respiratory complications and mortality.105 As with
ppoFEV1, the risk of postoperative complications increases 10% to 20% for each 10-point decrease in
DLCO (Fig. 24.9).77,81
A low diffusing capacity has been shown to predict not only postoperative complications but also the
likelihood of long-term oxygen use and readmission for respiratory problems during the first year after
major lung resection.106 A low DLCO has historically been associated with a decrease in long-term
survival in patients with emphysema.107 A recent large retrospective analysis demonstrated that predicted
postoperative (ppo) lung function, measured by both ppoDLCO and ppoFEV1 were significant independent
predictors of all-cause mortality in patients undergoing major lung resections (Figs. 24.10 and 24.11).108
FIGURE 24.9 The relationship between diffusing capacity, age, and mortality after major lung resection. (Data from reference
53.)
Use of DLCO cutoff values to eliminate patients from consideration for major lung resection should be
carefully considered in the light of both short- and long-term pulmonary function. Postoperative predicted
values for DLCO are 12% lower than expected 1 week after lobectomy but are 10% higher than expected
at the 3-month postoperative interval. After pneumonectomy, predicted postoperative values are relatively
accurate in the immediate postoperative period but underestimate true DLCO at the 3-month period by
17%.48 Lung resection results in distention of remaining alveoli, leading to recruitment of capillary
surface area and blood volume, which results in an increase of diffusing capacity.109 The accuracy of
predicting postoperative DLCO is also influenced by the degree of underlying lung disease. In patients
with poorer initial lung function, estimates of postoperative DLCO are relatively accurate, whereas in
patients with relatively normal lung function, postoperative DLCO is often underestimated (Fig. 24.12).48
This is the inverse of the relationship of predicted to actual postoperative spirometry.
FIGURE 24.10 The association of ppoFEV1% and survival. (Reproduced from Ferguson MK, Watson S, Johnson E, et al.
Predicted postoperative lung function is associated with all-cause long-term mortality after major lung resection for cancer. Eur J
Cardiothorac Surg 2014;45:660–664, with permission.)
FIGURE 24.11 The association of ppoDLCO% and survival. (From Ferguson MK, Watson S, Johnson E, et al. Predicted
postoperative lung function is associated with all-cause long-term mortality after major lung resection for cancer. Eur J
Cardiothorac Surg 2014;45:660–664. Reproduced by permission of European Association for Cardiothoracic Surgery.)
FIGURE 24.12 Predicted postoperative (ppo) diffusing capacity (DLCO) values (dashed line) relative to the observed ones
(solid line) at 3 months. (Reprinted from Brunelli A, Refai M, Salati M, et al. Predicted versus observed FEV1 and DLCO after
major lung resection: A prospective evaluation at different postoperative periods. Ann Thorac Surg 2007;83:1134–1139.
Copyright © 2007 The Society of Thoracic Surgeons. With permission.)
FIGURE 24.13 Incidence of complications after lung resection related to DLCO and chronic obstructive pulmonary disease
(COPD) category. (Data from Ferguson MK, Gaissert HA, Grab JD, et al. Pulmonary complications after lung resection in the
absence of chronic obstructive pulmonary disease: The predictive role of diffusing capacity. J Thoracic Cardiovasc Surg
2009;138:1297–1302.)
Recent evidence indicates that, even in patients without important airflow limitation as measured by
FEV1%, ppoDLCO is an important independent predictor of cardiopulmonary complications.93,102 In
patients without COPD (defined as FEV1/FVC ratio <0.7), DLCO is an important determinant of
postoperative pulmonary complications.81 Indeed, in this group of patients, DLCO impairment is a stronger
predictor of pulmonary complications than it is in patients who have COPD (Fig. 24.13).102 Thus,
measurement of DLCO in all lung resection candidates is recommended.
Patients who are candidates for major lung resection for cancer are increasingly likely to undergo
induction chemotherapy prior to surgery. Recent evidence suggests that induction therapy in lung cancer
patients can result in a 15% to 20% reduction in DLCO in a setting in which spirometric values are
maintained.50,110–112 It is thought that the effect on DLCO may be a result of radiation or chemotherapy-
induced pneumonitis, limiting gas diffusion across the pulmonary alveolar-capillary membrane. Reversal
of this process usually requires sufficient time for the underlying inflammation to subside, helping to
restore the diffusing abilities of the membrane.
EXERCISE CAPACITY AND OXYGEN CONSUMPTION

Decreased exercise capacity after major lung resection was recognized in the 1940s and 1950s.97,113–116
The degree of dysfunction was correlated with advanced patient age, reduced MVV, and increased RV.
Reduced exercise capacity was also associated with the degree of pulmonary arterial hypertension that
developed during exercise. The etiology of decreased exercise tolerance after major lung resection is
multifactorial. As the amount of resected lung increases, the lung becomes stiffer, and elastic recoil
pressure similarly rises. The work of breathing thus increases, requiring shunting of blood from working
extremity muscles to muscles doing the work of breathing.117 Maximum effort tolerance decreases, which
is associated with an increase in pulmonary artery pressure and pulmonary vascular resistance during
exercise compared with preoperative values.36 Similarly, peripheral vascular resistance and peripheral
arterial blood pressure increase during exercise, changes that are associated with a decrease in cardiac
output and stroke volume. Arterial oxygen saturation decreases during exercise, possibly owing to a
lower diffusing capacity.100,118 These changes are most pronounced after pneumonectomy, but
proportionally smaller changes are evident after lobectomy.41,43,119 Interestingly, ventilatory impairment
does not limit exercise tolerance in most situations.40 Exercise training in patients who have undergone
major lung resection results in an increase in maximum oxygen consumption, endurance, and peripheral
oxygen extraction.120 However, in comparison to normal people who undergo exercise training, no
increase in cardiac and stroke indexes occur.
The rationale for preoperative cardiopulmonary exercise testing (CPET) is to identify patients who are
close to the margin of cardiopulmonary function so that the risks of surgery and the status of postoperative
exercise tolerance can be predicted. It allows a formal evaluation of the cardiopulmonary reserve needed
to survive the stress of surgery and its potential complications. Patients with ppoFEV1 >60% or ppoDLCO
>60% are considered to be at low risk for major lung resection including pneumonectomy.84,121 When
either ppoFEV1 or ppoDLCO is less than 60% it is recommended that patients undergo an evaluation of
their exercise capacity. Exercise testing quantifies what many believe to be the best determinant of
functional capacity: oxygen consumption during maximum exercise, or peak VO2. The potential advantage
of exercise testing over conventional tests, such as spirometry and measurement of diffusing capacity, is
that most components that determine performance are evaluated, including ventilatory function, gas
exchange, cardiac function, cardiopulmonary conditioning, and effort. The disadvantages of exercise
testing include the need for costly resources to perform the technically demanding versions of the test, and
the need for considerable patient effort and cooperation in order to achieve reliable results.
One form of exercise testing that was introduced early in clinical practice was verification that
patients were able to complete a fixed exercise challenge to enable them to qualify for major lung
resection. Tasks included such things as ascending a specified number of steps or flights of stairs and
walking for 6 minutes to enable measurement of the distance covered. These types of evaluation are
currently used frequently and are clinically valuable.122–125 They enable some quantitation of effort and
correlate well with laboratory-based assessments (Fig. 24.14), but do not permit assessment of the
underlying cause for an inadequate performance.126
FIGURE 24.14 Relationship between stair climb altitude and measured oxygen consumption (peak VO2). (Reproduced from
Brunelli A, Xiumé F, Refai M, et al. Peak oxygen consumption measured during the stair-climbing test in lung resection
candidates. Respiration 2010;80:207–211.)
TABLE 24.2 Incidence of Postoperative Cardiopulmonary Complications Categorized

According to Peak Oxygen Consumption During Exercise (Peak VO2)
Author Year Patients Low Peak VO2 Normal Peak VO2 p Value
Epstein88 1993 42 8/14 10/28 0.19
Walsh89 1994 25 7/20 3/5 0.18
Bolliger90 1995 80 8/17 8/63 0.002
Pate91 1996 9 2/4 0/3 0.25
Wang92 1999 40 5/12 8/28 0.42
Wang66 2000 57 11/15 8/42 <0.001
Brutsche93 2000 125 11/17 20/108 <0.001
Bayram94 2007 55 11/28 0/27 <0.001
Low peak VO2: <15 mL/kg/min; Normal peak VO2: >15 mL/kg/min.
The most reliable technique for exercise testing involves the assessment of maximum oxygen
consumption during maximum exercise (peak VO2).127,128 This requires measurement of oxygen uptake,
carbon dioxide output, minute ventilation, blood pressure, electrocardiogram, and pulse oximetry. Patients
undergo symptom-limited incremental exercise on a cycle ergometer or on a treadmill. The use of
maximal exercise testing was introduced clinically in the mid-1980s and numerous published reports in
the subsequent two decades generally support the initial favorable impression of its utility in predicting
operative morbidity and mortality after major lung resection (Table 24.2).105,129–136
The American College of Chest Physicians (ACCP) and the European Respiratory Society
(ERS)/European Society of Thoracic Surgeons (ESTS) guidelines support the concept that a peak VO2
<10 mL/kg/min characterizes a patient as being extremely high risk for major lung resection, whereas a
peak VO2 >20 mL/kg/min is generally considered to be indicative of a patient with a low risk for
complications.121,137 The zone between the two values is intermediate in terms of associated risk. Some
studies that analyzed the potential utility of maximal exercise testing have demonstrated an important
difference in the incidences of postoperative cardiopulmonary complications and mortality comparing
patients with a low peak VO2 (<15 mL/kg/min) and those with a higher peak VO2 (>15
mL/kg/min).105,127,131,138 In prospective studies, peak VO2 was identified as an independent predictor of
postoperative complications after major lung resection.121,134
Predicted postoperative peak VO2 and peak VO2 expressed as a percentage of predicted have been
suggested as effective parameters for risk stratification for major lung resection.127 A peak VO2 of <50%
to 60% of predicted is associated with an increased risk for complications and mortality127,131,138,139 and
<35% predicted is generally accepted as a contraindication for major anatomic lung resections.136 In
general, a peak VO2 >20 mL/kg/min or >75% predicted are considered as indicating the patient to be at
normal risk for any type of major anatomic lung resection including pneumonectomy.135,140,141 There is
also agreement on the substantially increased mortality in patients with a peak VO2 <10 mL/kg/min or
<35% predicted.140,141 The probability of complications after surgery in patients with a peak VO2 <40%
predicted is near 90%.138
In addition to the high-technology CPET described earlier, so-called “low-tech” fixed exercise
challenges are frequently used clinically to enable physicians to assess candidates for major lung
resection. Typical tasks included such things as stair climbing, the 6-minute walk test, and the shuttle-
walk test. Walking between 20 (400 m) and 25 (450 m) shuttles correlated with a peak VO2 >15
mL/kg/min.142,143 Climbing stairs for 22 m or more was also strongly correlated to a peak VO2 >15
mL/kg/min.137 In contrast, patients who climbed less than 12 m and underwent major lung resections had
significantly greater overall costs, rates of cardiopulmonary complications, and mortality after major lung
resections.124
Comorbidities such as neuromuscular disorders, peripheral vascular disease, amputation, arthritis, and
morbid obesity limit the utilization of CPET in preoperative evaluation. This group of patients has a
higher mortality in comparison to the patients that were able to perform the test.122
BLOOD GASES
Although many sources cite suggested values for pO2 and pCO2 that are intended to discriminate between
normal-risk and high-risk populations of patients for lung resection, the origin of these values is obscure.
Early in the history of routine lung resection, some authors either made no mention of blood gas
measurements or stated that they were of little value in assessing operative risk.54,56,144–150
Hypercapnia, defined as a pCO2 of >45 mm Hg, is normally a result of alveolar hypoventilation. Most
patients with hypercapnia have a severely reduced FEV1 and are at increased risk for death and severe
complications after major lung resection. As a result, the identification of hypercapnia in such individuals
is confirmatory and does not add additional information regarding operative risk. Many studies have been
unable to demonstrate a significant relationship between elevated pCO2 and the risk for respiratory
complications or mortality after major lung resection.57,65,75,101,103,151 This finding must be tempered by the
fact that, in most of these reports, patients were initially selected as candidates for operation based on
preoperative blood gas analyses. Hypercapnia to levels of 45 to 55 mm Hg did not affect outcomes after
lung volume reduction surgery,152 whereas an increased pCO2 in another study was associated with
unacceptable outcomes after lung volume reduction surgery.153
The situation regarding arterial oxygen levels is equally uncertain. In early studies, the combination of
pulmonary hypertension and arterial hypoxemia (pO2 <45 mm Hg) defined patients as being inoperable.57
Subsequent studies failed to demonstrate a relationship between relative hypoxemia (pO2 <65 mm Hg)
and operative mortality after thoracotomy for lung cancer75 or between a pO2 <75 mm Hg and major
morbidity after pneumonectomy.151 Some authors propose that arterial hypoxemia (pO2 <50 to 60 mm Hg)
is a contraindication to lung resection.113 However, only a modest difference was identified between pO2
values in patients with and without pulmonary complications after major pulmonary surgery.134 In one
report, hypoxia to levels of 45 to 55 mm Hg did not have a significant effect on complications after lung
volume reduction surgery,152 whereas others suggest that a decreased pO2 is related to unacceptable
outcomes after lung volume reduction surgery.153
Healthy individuals typically increase their arterial oxygen saturation during exercise. Arterial oxygen
desaturation to <85% during exercise is found in about half of patients with COPD undergoing low-tech
exercise testing, and is more pronounced during walking than cycling exercise.154 Desaturation >4%
during stair climbing exercise is another marker of increased surgical risk, and is a better predictor of
outcomes than saturations decreasing below 90%.155
Substantially increased pCO2 or reduced pO2 is likely to contribute to increased morbidity and
mortality after major lung resection. Because of existing clinical referral and patient selection processes,
however, the exact parameters permitting safe surgery may never be established.
PULMONARY HEMODYNAMICS
An increase in pulmonary artery pressure and pulmonary vascular resistance was recognized early in the
history of major lung resection as a normal response to surgery.97,116,156–158 Subsequent work quantified
the changes, demonstrating an increase in pulmonary artery pressure of nearly 10% and an increase in
pulmonary vascular resistance of almost 35% during exercise after major lung resection, changes that
were associated with decreased exercise capacity but were clinically well tolerated.36 However, the
magnitude of these alterations exposes patients with pre-existing severe underlying lung disease to the
risk for serious adverse consequences of major lung resection. The attendant long-term disability and high
rate of mortality associated with such changes prompted the development of preoperative assessment of
pulmonary vascular status before lung resection. For decades, pulmonary vascular compliance was
assessed before pneumonectomy by measuring pulmonary artery pressure at rest and during exercise with
unilateral pulmonary artery occlusion using a balloon.159 Intraoperative assessment of pulmonary artery
pressure during unilateral pulmonary artery occlusion was also used routinely by many surgeons before
proceeding with pneumonectomy.148,160 Assessment of pulmonary vascular compliance also has been
accomplished using a balloon flotation catheter. Recently, continuous-wave Doppler echocardiography
measurement of pulmonary arterial pressure is utilized as a reliable surrogate of pulmonary arterial
pressures.161,162 Pulmonary hypertension after pneumonectomy for cancer is associated with a high risk
for a suboptimal clinical outcome.163
Abnormally elevated pulmonary vascular resistance or pulmonary artery pressure at rest, during
exercise, or with unilateral pulmonary artery occlusion has been associated with a high rate of operative
mortality after major lung resection.148,160,164,165 Abnormalities such as dilated pulmonary arteries,
suggesting the presence of pulmonary hypertension, are often evident on preoperative CT of the lung
resection candidate. The use of invasive evaluations of pulmonary hemodynamics has been almost
entirely supplanted by assessment of diffusing capacity and peak VO2. In fact, assessment of more global
parameters, such as diffusing capacity, may be superior to measurement of pulmonary hemodynamics in
predicting complications after major lung resection.166 Abnormal pulmonary hemodynamics in patients
undergoing major lung resection is usually a result of severe underlying lung disease rather than
abnormalities of the pulmonary artery or its main branches. As a result, most patients with underlying lung
disease severe enough to compromise pulmonary hemodynamics exhibit substantial abnormalities of
spirometry, diffusing capacity, and peak VO2. In the few patients in whom a primary cause of abnormal
pulmonary hemodynamics is thought to exist, echocardiography or right heart catheterization is indicated.
The presence of substantial pulmonary hypertension is a strong contraindication to major lung resection.
RISK SCORING
The overall risk for morbidity after pulmonary resection is relatively high. A large number of predictive
risk factors for major lung resection have been identified. These factors have stimulated research into risk
assessment algorithms that would permit the preoperative calculation of the risk for complications in
individual patients. Identification of such risks would help stratify patients into risk levels as an aid in
appropriate selection of patients for lung resection. Patients determined to be at increased risk may
benefit from preoperative cardiopulmonary rehabilitation, possibly reducing the incidence of
complications. Identification of increased risk may permit use of increased resources for postoperative
care. Risk stratification also makes possible comparison of outcomes among surgeons and among
institutions for quality assurance purposes.
FIGURE 24.15 Incidence of complications after major lung resection according to risk and complication categories for the
EVAD system. (Based on preoperative spirometry, diffusing capacity, and age; see text for details.) (Data from reference 170.)
Multiple predictive models have been developed with the aim of establishing which patients have an
increased risk of major morbidity or mortality after major lung resection. The early studies from the
Veterans Affairs National System Quality Improvement Program (VA NSQIP),126 the European Society
Subjective Score (ESSS.01) and the European Society Objective Score (ESOS.01)167 incorporated
several demographic and clinical variables but pulmonary function data were missing in a large
percentage of the patients.
The British Thoracic Society recommended measurement of FEV1 and DLCO for assessment of
respiratory morbidity in all patients.168 An analysis of more than 18,000 patients from the Society of
Thoracic Surgeons (STS) database who underwent lung resection developed a model for predicting
adverse outcomes after major lung resection, but due to the absence of DLCO data in almost 40% of
patients this variable was not included.169
Pulmonary complications occurring after major lung resection have been shown to be strongly related
to spirometry, patient age, and diffusing capacity. These were combined into the Expiratory Volume, Age,
Diffusing Capacity (EVAD) scoring system, which has been shown to predict pulmonary complications
more accurately than the Cardiopulmonary Risk Index (CPRI) and the Physiological and Operative
Severity Score for Enumeration of Mortality and Morbidity (POSSUM)170 (Fig. 24.15). EVAD, combined
with the Charlson comorbidity score, correlates well with physician estimates of postoperative
complications.171,172
Another prediction model used a history of preoperative chemotherapy and DLCO decrement to stratify
the risk of pulmonary complications into three different categories.173 This model has an average
predictive capacity and it is a simple and practical score model, but has not been validated by other
studies.
RISK ASSESSMENT ALGORITHMS

Two major efforts have resulted in comprehensive risk assessment algorithms that focus on evaluation of
lung function prior to major lung resection. The ERS and the European Society of Thoracic Surgery
(ERS/ESTS) developed clinical guidelines in 2009 and the ACCP completed a similar effort in
2010.140,141 Both emphasize the importance of an initial assessment of cardiac risk and intervention
according to the recommendations of the American College of Cardiology and the American Heart
Association (ACC/AHA) prior to assessment of lung function. Once the patient is determined to be at low
risk from a cardiac perspective, a pulmonary function evaluation is performed. Pulmonary function tests
and CPET are included in both algorithms. The European guidelines utilize preoperative PFT values
whereas the ACCP guidelines consider predicted postoperative values. The European guidelines
recommend CPET for all the patients with a preoperative FEV1 or DLCO <80%. The ACCP guidelines
include a stair climbing or shuttle walk for patients with a ppoFEV1 or ppoDLCO between 30% and 60%
of predicted. An algorithm for use in predicting risk in lung resection patients after ascertaining their
cardiovascular status is modeled after these two sets of guidelines (Fig. 24.16).
A case control study on 670 matched patients before and after the implementation of the ERS/ESTS
guidelines in 2009 concluded that morbidity and 30-day mortality rate has decreased but did not reach
statistical significance.174 One of the reasons may be incomplete evaluation of patients according to
published guidelines. In a survey of European surgeons published in 2009, only 36% routinely measured
DLCO despite the fact that 74% considered DLCO to be an important predictor of outcomes.175
FIGURE 24.16 Suggested algorithm for evaluating patients for their suitability for major lung resection (ppoFEV1%: predicted
postoperative FEV1 expressed as a percent of normal; ppoDLCO%, predicted postoperative diffusing capacity expressed as a
percent of normal; CPET, high tech cardiopulmonary exercise test; peak VO2: VO2 in mL/kg/min). (Adapted from Brunelli A,
Kim AW, Berger KI, et al. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery:
diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice
guidelines. Chest. 2013;143(5 Suppl):e166S–e190S. Copyright © 2013 The American College of Chest Physicians. With
permission.)
ASSESSMENT OF RISK FOR OTHER PROCEDURES

The alterations in diaphragm function and resultant short-term perturbations in pulmonary function that
occur after major thoracic or upper abdominal surgery are summarized earlier in this chapter. Despite the
extensive number of data that have been generated regarding this topic, risk factors for thoracic surgical
procedures other than standard lung resections have not been well defined. Similarly, risk factors for
abdominal surgical procedures related to pulmonary complications remain unidentified. In prospective
studies, neither hypercarbia nor reduced spirometry values were predictive of an increased risk for
pulmonary complications after nonpulmonary thoracic surgery.176–178 With two exceptions, the
appropriate preoperative physiologic evaluation for the general thoracic surgical patient has not been
determined. Those exceptions are the evaluation of the lung resection candidate as outlined earlier in this
chapter and possibly candidates for esophagectomy.
The physiologic evaluation of candidates for esophagectomy has been explored in some detail. The
impetus to evaluate esophagectomy patients lies in the high rate of postoperative pulmonary complications
associated with this operation. Based on retrospective studies, the physiologic predictors of an increased
risk for pulmonary complications after esophagectomy are advanced age and reduced FEV1. Patients with
pulmonary complications have been shown to have an FEV1 substantially less than those without such
complications (88% compared with 99%).179 A retrospective review of patients who underwent
esophagectomy determined that patient age, FEV1, DLCO, performance status (Zubrod/ECOG), serum
creatinine, current cigarette use, and transthoracic resection were independent predictors of major
pulmonary complications.180 The operative mortality was 10-fold increased in the patients who
developed pulmonary complications. These findings have been validated in a larger contemporary single
institution study (Fig. 24.17).181 There is also evidence that measurement of oxygen consumption during
exercise may help predict complications, but this technique requires further scrutiny.28 A retrospective
analysis of patients in the National Cancer Database (NCD) who underwent esophagectomy found that
male sex and COPD were predictors of operative mortality. For 30-day mortality, smoking within 1 year
before surgery and weight loss of more than 10% within 6 months of surgery had ORs of 2.3 and 2.1,
respectively.
CONCLUSIONS
Assessment of pulmonary physiology is invaluable in estimating perioperative risk in patients undergoing
major lung resection or esophagectomy. The identification of increased risk may permit mitigation of
clinical factors through cardiopulmonary rehabilitation, facilitates informed discussions with patients and
families, may alter surgical recommendations or approaches, and provides the opportunity to increase
perioperative resources to successfully manage such patients. There are well-accepted algorithms for
routine preoperative pulmonary evaluation prior to lung resection, although implementation of such
algorithms is slow. Additional research into predictive pulmonary testing for other procedures is
warranted.
FIGURE 24.17 Incidence of pulmonary complications after esophagectomy according to risk score. (From Reinersman J, Allen
MS, Deschamps C, et al. External validation of the Ferguson pulmonary risk score for predicting major pulmonary complications
after oesophagectomy. Eur J Cardiothorac Surg 2015;49(1):333–338, with permission.)
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Section
VII
PREOPERATIVE AND ANESTHETIC

MANAGEMENT OF THE GENERAL
THORACIC SURGICAL PATIENT
25
Preoperative Preparation of the General
Thoracic Surgical Patient
Traves D. Crabtree ■ Seth B. Krantz
INTRODUCTION
Patients undergoing thoracic surgery face a host of unique factors that affect their recovery and the
surgeon’s ability to provide excellent outcomes. This includes the presence of the bony thorax, requiring
either a rib spreading thoracotomy or, with VATS, several intercostal incisions that frequently place some
degree of force on the intercostal bundles. Physiologic consequences of pulmonary resection, nutritional
consequences of esophageal surgery, and the frequent comorbidities attributable to smoking are present in
many of the patients needing a thoracic operation. Understanding these challenges, and preparing the
patient preoperatively, should be expected to improve outcomes for thoracic surgical patients.
Preoperative “preparation,” while related to, is not synonymous with preoperative assessment. Proper
assessment of these patients is discussed in significant detail elsewhere but involves evaluation of
pulmonary function, cardiac risk stratification and modification, and assessment of performance status and
nutrition. The patients deemed high risk, especially those with limited lung function, are often denied
surgery altogether, or undergo surgery knowing they are at increased risk for postoperative morbidity and
mortality. Such assessment and risk stratification is crucial in order to facilitate appropriate patient
selection and help ensure better outcomes for patients. There is increasing focus, however, on
modification of these risk factors both before and after surgery, and a renewed focus on interventions that
can be taken prior to surgery in order to improve the likelihood of positive results for patients. These
strategies include preoperative pulmonary rehabilitation, smoking cessation, and treatment of nutritional
deficiencies, among others. This chapter will first highlight the general risks of thoracic surgery and
associated risk factors, provide a brief review of assessment tools, and finally, present an expanded focus
on preoperative interventions meant to prepare the patient for a thoracic surgical operation.
PREOPERATIVE RISK ASSESSMENT

Appropriate assessment of the patient’s ability to tolerate surgery is critical to proper preparation of the
patient for surgery. Many of the interventions discussed later in this chapter, for example, pulmonary
rehabilitation and nutritional supplementation, may not benefit every patient, and thus stratifying who is at
higher risk for complications and may benefit from preoperative interventions is critical. Most patients
undergoing a thoracic operation should have formal pulmonary function tests. This involves volume loop
spirometry to evaluate for any obstructive or restrictive deficits, problems with gas exchange, and should
include a resting arterial blood gas.1
Patients with a preoperative FEV1 less than 60% are at increased risk of adverse outcomes such as
pneumonia, tracheostomy, prolonged air leak and chest tube, and bronchopleural fistula.1 Patients whose
lung function is borderline for resection should undergo quantitative ventilation perfusion scanning and
the CT scan should be carefully reviewed to determine not only which lobe, but which anatomic segments
are involved. This gives a more accurate estimate of the contribution the planned resection area provides
to current lung function, and thus what their postoperative function will be. Perhaps underutilized in the
current era, a sensitive measure of cardiopulmonary risk is formal assessment cardiopulmonary exercise
testing with measurement of the maximum uptake of oxygen with exercise (VO2 max). Values less than 10
mL/kg/min place the patient at very high risk for postoperative complications and are generally
considered to be contraindication to resection. VO2 max greater than 15 mL/kg/min predicts standard risk,
and those patients in between are at intermediate risk for postoperative complications.
History and physical examination should include a thorough evaluation for any coexisting
cardiovascular disease given the strong smoking history in most thoracic surgical patients. Patients who
complain of dyspnea and fatigue, especially those who have relatively normal pulmonary function, should
be evaluated for coronary artery disease and/or congestive heart failure, usually with a pharmacologic
stress test, echocardiogram, and potentially cardiac catheterization in those patients whose noninvasive
testing suggests reversible ischemia.
Malnutrition is a risk factor for increased perioperative complications, and is especially important in
patients with COPD, who are frequently catabolic due to their increased work of breathing, in cancer
patients in general, and in esophageal cancer patients in particular due to dysphagia. Perioperative weight
loss greater than 10% is associated with decreased long-term survival after esophagectomy. As discussed
in greater detail below, patients with significant malnutrition should be considered for nutritional
supplementation.2
PULMONARY RESECTION
As expected, the risk of adverse outcomes for pulmonary resection is directly related to the amount of
lung being resected and the amount of underlying lung disease. The primary causes of major morbidity
after pulmonary resection are pneumonia, prolonged air leak and prolonged chest tube requirement,
respiratory failure and need for tracheostomy, and bronchopleural fistula. Reducing this risk involves
either (1) resecting less lung, which may sacrifice the oncologic benefit, or (2) improving the patient’s
ability to tolerate resection. The primary means of improving the patient’s suitability for resection involve
reducing ongoing damage through smoking cessation and by enrolling in formal pulmonary rehabilitation.
PULMONARY REHABILITATION
Pulmonary rehabilitation generally refers to a formal program designed to improve pulmonary functional
status and exercise capacity. The American Thoracic Society and European Respiratory Society have
published joint guidelines on exercise and pulmonary rehabilitation in patients with COPD and chronic
lung disease with an excellent summary of the available data on pulmonary rehabilitation for a range of
conditions.3 Some of the best evidence demonstrating improvement in functional outcomes comes from the
National Emphysema Treatment Trial (NETT).4 In that trial, COPD patients with markedly decreased lung
function (mean FEV1 26%), were randomized either to lung volume reduction surgery (LVRS) with best
medical care, or best medical care alone. Prior to randomization, all patients were assigned to a formal
pulmonary rehabilitation program, and completion and adherence to that program was required in order to
undergo randomization and treatment in the trial. Rehabilitation focused not only on physical improvement
in exercise capacity and pulmonary function, but on psychological wellness and nutritional assessment
and optimization. The program was intensive, involving 16 to 20 sessions over 6 to 10 weeks with the
exercise program consisting of endurance exercises, flexibility, and strength training. Overall, there was a
significant improvement in exercise capacity and quality of life, despite no significant change in measured
pulmonary function tests. Importantly, more than 50% of the patients had a clinically significant
improvement in exercise capacity and dyspnea as rated by their clinicians.5 Most notably, patients without
any prior pulmonary rehabilitation showed the largest gains, a population likely very similar to those
newly referred for pulmonary resection for cancer. Several other studies have demonstrated a similar
improvement in functional outcomes, along with improvement in pulmonary function tests in patients with
COPD who enroll in pulmonary rehabilitation.6–8 Unfortunately, these studies were in the general COPD
patient population and not in patients undergoing pulmonary resection. While they demonstrate
improvement in lung function from pulmonary rehabilitation, their applicability to improvement in
perioperative outcomes is limited.
The increased operative risk associated with poor lung function is not specific to general thoracic
surgery, and one of the largest studies looking at preoperative pulmonary function and rehabilitation and
its effect on outcomes was done in patients undergoing coronary artery bypass grafting.9 Patients referred
for CABG who were deemed to be high risk for pulmonary complications (based on history such as
diabetes and smoking, in combination with PFTs) were randomized to a pulmonary rehabilitation plan
focused specifically on improving inspiratory muscle strength (inspiratory muscle therapy, IMT) or usual
care. They looked at 299 patients and found a significant reduction in overall pulmonary complications,
pneumonias, and hospital length of stay in patients in the IMT group.9 The overall reduction in
complications was nearly 20%, with an absolute pneumonia reduction rate of 10%. The numbers needed
to treat to reduce a single postoperative pulmonary complication and a single postoperative pneumonia
were six and ten, respectively. Only those patients with a documented improvement in their IMT actually
showed a reduced complication rate. Patients who underwent preoperative rehabilitation also showed a
decreased length of stay relative to the usual care group. With respect to any delay in surgery due to the
length of the rehabilitation program, a concern in several of the studies of lung cancer patients discussed
below, it is important to note that with a minimum of 2 weeks of rehabilitation, there was no significant
difference in time awaiting surgery between the pulmonary rehabilitation group and the group who
received usual care.
The impact of preoperative pulmonary rehabilitation on patients undergoing pulmonary resection
comes primarily from case series and cohort studies, though several small, randomized trials also exist.
One of the primary deterrents in enrolling patients undergoing pulmonary resection for malignancy into a
standardized rehabilitation program has been of concern regarding a delay to definitive surgery in the
setting of malignancy. Benzo et al.10 from the Mayo Clinic reported on two simultaneous randomized
trials with two different preoperative rehabilitation programs. The first trial involved a time-specific (4-
week) program based on the joint guidelines from the American Thoracic Society and European
Respiratory Society. Patients with decreased lung function (FEV1 < 60% without symptoms or FEV1 <
80% with significant dyspnea) scheduled to undergo anatomic resection for lung cancer were eligible.
Due primarily to concerns over the length of the program and delaying a cancer operation, recruitment
was poor, with only nine patients randomized over the 18-month recruitment period. This fear of delaying
surgery in the face of lung cancer has been seen in several studies and is one of the primary deterrents in
greater adoption of preoperative rehabilitation. A recent analysis of patients in the National Cancer
Database with clinical stage I non–small lung cancer demonstrated that having surgery more than 8 weeks
after diagnosis is an independent risk of poorer outcomes.11 These patients had a higher pathologic
upstaging, decreased 30-day survival, and worse overall median survival. This was true in both a
multivariate analysis and propensity matched comparison. While propensity matching cannot control for
all variables, this suggests that there is a real biologic difference in cancer-related outcomes in delaying
treatment. Whether a shorter delay of 2 or even 4 weeks would see similar results is unknown, but is
important to consider when enrolling patient in any preoperative rehabilitation program. The second study
reported utilized a shorter, ten-session protocol with a focus on upper and lower extremity endurance,
strength exercises, and inspiratory muscle training similar to the above mentioned trial of patients
undergoing CABG. The authors also provided psychological support and encouragement during these ten
sessions to help improve patient expectations in the postoperative setting. While the trial was small (ten
patients in the treatment arm, nine in the control arm), the authors demonstrated a significant improvement
in total length of chest tube days (9 vs. 4.7) and many fewer patients who required greater than 7 days of
chest tube drainage (63% vs. 11%).10 There was no significant difference in respiratory failure,
pneumonia, or the need for therapeutic bronchoscopy, however the number of events in both groups was
extremely small.
Some of the most significant improvements from pulmonary rehabilitation in patients undergoing
pulmonary resection were seen in a prospective cohort study that enrolled patients preoperatively into a
multidisciplinary program that involved physical muscle training along with an emphasis on nutritional
supplementation with branched chain amino acids, and a regular group review of each patient’s progress
by the surgeon, physical therapist, dietician, and nurses.12 The program length was variable to allow
flexibility in when the patients underwent resection, but ranged between 2 and 5 weeks. These patients
were compared to a historical cohort of patients who underwent only physical preoperative rehabilitation
and training. The sample sizes were small, 21 patients in the historical group and 29 in the intervention
group, but the results were striking. There was a 20% absolute risk reduction in the postoperative
complication rate, which increased to over 40% in higher risk patients (Charlson Comorbidity index ≥ 2)
for a number needed to treat of only 2.5. The degree of the absolute risk reduction is tempered by the high
complication rate in both groups (27% and 47%) relative to contemporary studies. Part of this may be due
to a more strict classification of complications, though it remains several fold higher than most reports in
the literature for patients undergoing anatomic resection less than pneumonectomy. Patients who
underwent multidisciplinary care also saw significant improvement in vital capacity and FEV1, while
patients who received conventional therapy did not. The nutritional aspect of preoperative pulmonary
preparation is a unique aspect of this study and builds on prior data demonstrating a deficiency in
branched chain amino acids in COPD patients, and the improvement in outcomes seen in patients with
heart failure, trauma patients, and diabetic patients who undergo nutritional supplementation. The authors
of this study posit that the nutritional component allows patients to derive greater benefit from the
physical training, though that remains speculative. Nonetheless, poor nutritional status, across a range of
disease processes and surgical interventions, is strongly correlated with worse outcomes, and may be an
important aspect of the preoperative preparation of patients undergoing a pulmonary resection, especially
those that are at high risk for malnourishment from chronic pulmonary disease.
The involvement of a multidisciplinary team targeting several areas of improvement was also studied
in a small randomized-trial that combined physical training, nutrition, smoking cessation, and patient
education. There was no set time period for intervention and surgery was not delayed in order to
participate in the program. The average number of sessions attended was four, and the authors
demonstrated a significant improvement in 6-minute walk test. There was a trend toward fewer
postoperative pulmonary complications as well as a shorter length of stay, but neither was statistically
significant. Still, these studies in total show that a comprehensive preoperative program focusing not only
on physical training but also on nutritional assessment and supplementation along with patient education
and multidisciplinary assessment can be implemented without the need to delay surgery, and can lead to
improved lung function along with a reduction in postoperative complications. Older patients (greater
than 70 years of age in the above studies), those with moderate to severe COPD (the definitions vary
among studies, but certainly all patients with an FEV1 < 60% of predicted, along with patients with an
FEV1 < 75% who either have dyspnea on exertion or who are on bronchodilators for COPD), and patients
with significant medical comorbidities (CHF, diabetes) benefit the most from preoperative pulmonary
rehabilitation. Enrolling these patients in a program prior to any pulmonary resection should be strongly
considered.
SMOKING CESSATION
As smoking remains the primary risk factor for pulmonary disease, it also remains one of the primary risk
factors for perioperative complications in patients undergoing thoracic surgery, especially those
undergoing pulmonary resection. Smoking’s impact on postoperative lung complications is multifactorial,
but it is related to decreased lung function with decreased FEV1 and DLCO, increased mucous
production, and other related comorbidities such as cardiovascular disease. The increased risk of
postoperative pulmonary complications in smokers has been seen in studies from as early as 1944. More
recent studies specific to pulmonary resection have demonstrated similar results. Barrera et al.13
prospectively looked at a study of 300 patients undergoing pulmonary resection for cancer and found
significantly worse outcomes in ever-smokers versus nonsmokers. Smokers had a higher overall
pulmonary complication rate (19% vs. 8%), a higher pneumonia rate (11% vs. 3%), and an increased
length of stay. Two large retrospective studies demonstrated similar results with ever-smokers having
prolonged length of stay, increased postoperative pulmonary complications, and increased perioperative
mortality.14,15 Beyond perioperative complications and mortality, smoking is an independent predictor of
decreased overall survival in patients with lung cancer. Smoking cessation, demonstrated across several
studies, has been shown to reduce the risk of death from lung cancer. As expected, the earlier in life a
smoker quits, the larger the benefit, but regardless, all smoking cessation was associated with a decreased
risk of death from lung cancer.16 Smoking cessation is also associated with improved overall survival in
patients already diagnosed with lung cancer. In a study of 1,155 patients with lung cancer, active smokers
had a hazard ratio of 1.37 for death compared to nonsmokers or former-smokers. Given that smoking is
associated with numerous comorbid conditions and that this may affect how these patients are treated, the
authors adjusted for 18 comorbid conditions and treatment types. After controlling these factors, they still
found a significant increased risk of death associated in smokers versus nonsmokers or former-smokers.17
FIGURE 25.1 Incidence of post-operative pulmonary complications (PPCs) in patients who underwent pulmonary surgery. The
percentage of patients with PPCs in the four groups is shown. *p < 0.05 in comparison with the never-smokers. (From
Nakagawa M, Tanaka H, Tsukuma H, et al. Relationship between the duration of the preoperative smoke-free period and the
incidence of postoperative pulmonary complications after pulmonary surgery. Chest 2001;120(3):705–710. Copyright © 2001 The
American College of Chest Physicians. With permission.)
Given these findings, there has long been interest in promoting preoperative smoking cessation in the
hopes of reducing the excess risk associated with smoking on outcomes in patients undergoing pulmonary
resection. While the cellular effects of smoking cessation occur almost immediately, improvement in lung
function, even at the small airway level, may take weeks to even months. And while nonsmokers clearly
have better outcomes than smokers, the data on former-smokers is less convincing, as is how long a
period of smoking cessation is required before an improvement in outcomes can be expected. A
retrospective analysis of nearly 8,000 pulmonary resections showed a significant decrease in mortality
and complication rate for former-smokers; however the improvement was gradual, and even those
smokers who quit more than 1 year prior to resection had an increased risk of both perioperative
mortality and major pulmonary complications compared with never-smokers.14 Similar results were seen
in the previously discussed prospective analysis of 300 patients from Memorial Sloan-Kettering, with a
marked difference between ever-smokers and nonsmokers, but no significant difference between smokers,
recent quitters, and former-smokers (active smoking, quit less than 2 months prior, and more than 2
months prior, respectively).13 In contrast to these studies, a retrospective analysis by Nakagawa et al.18 of
288 patients undergoing pulmonary resection showed that after 9 to 12 weeks of smoking cessation, rates
of postoperative pulmonary complications began to approach, but did not reach, the level of nonsmokers.
There is some concern that rather than providing a benefit, smoking cessation, if it occurs too close to
surgery, can actually increase the risk of pulmonary complications. In the short term, smoking cessation
can be associated with increased sputum production associated with improved ciliary movement and
macrophage activity. Studies of small airway function show most of the improvement by 6 to 12 months,
but generally some improvement as soon as 4 to 6 weeks after smoking cessation. Based on this, it has
been suggested that postoperative pulmonary complications may paradoxically increase in the first
several weeks after smoking cessation. Two retrospective studies of patients undergoing pulmonary
resection demonstrated, consistent with earlier studies, a significant increase in postoperative pulmonary
complications in current smokers compared with former-smokers. Importantly, “recent smokers” or those
who quit within 1 month of surgery had a higher complication rate than active smokers (Fig. 25.1).18,19
The optimum time period for smoking cessation was approximately 2 months, with those patients
demonstrating similar complication rates to never-smokers (Fig. 25.2).18 One of the largest studies to
suggest a paradoxical increase in risk was in patients undergoing coronary artery bypass grafting. In this
blinded prospective study, smoking cessation within the first 2 months before surgery was associated with
a four-fold increase in pulmonary complications compared with those patients who quit more than 2
months prior. After 6 months, the risk of pulmonary complications was the same as that for nonsmokers.20
It is based on these studies that many surgeons advise patients not to quit in the immediate preoperative
period. This has important clinical consequences, as this may discourage smoking cessation more broadly
since it is frequently difficult asking a patient, their family, and referring physicians to delay surgery,
especially for up to 2 months, as was discussed for preoperative pulmonary rehabilitation. More recent
studies, however, have called this paradoxical increase into question. Specifically, the large retrospective
study by Mason et al.14 and the prospective analysis by Barrera et al.13 both showed no significant
increase in postoperative pulmonary complications or mortality with recent smoking cessation. In these
studies all smoking cessation was beneficial, but as discussed above, the rate of complications improved
very slowly over time, and never approached that of nonsmokers. There was no single cut-off time after
which one could expect a major clinical improvement in postoperative complications.
FIGURE 25.2 Incidence of postoperative pulmonary complications over 4-week moving averages among current smokers,
recent smokers, and ex-smokers. W, week. (Adapted from Nakagawa M, Tanaka H, Tsukuma H, et al. Relationship between
the duration of the preoperative smoke-free period and the incidence of postoperative pulmonary complications after pulmonary
surgery. Chest 2001;120(3):705–710. Copyright © 2001 The American College of Chest Physicians. With permission.)
With respect to the best current clinical guidelines, the preponderance of the available literature
suggests that we should be actively encouraging patients with lung cancer to quit smoking. The concern
for paradoxical risk comes from older retrospective studies and from a single prospective study in
patients undergoing CABG. More recent studies do not demonstrate increased risk.13,14 Just as
importantly, the newer studies also show there is no magic bullet on when to quit, and delaying surgery
for some predetermined time is unlikely to improve outcomes. The primary benefit of smoking cessation
is with respect to the patient’s long-term survival, which is undoubtedly improved with smoking
cessation, and should be encouraged throughout one’s care of the thoracic surgical patient.
TOOLS FOR SMOKING CESSATION

The available means to facilitate smoking cessation are varied, but broadly include psychosocial
counseling, nicotine replacement, and medications. Most formal smoking cessation programs combine
some form of counseling and nicotine replacement. A recent Cochrane review found that for successful
smoking cessation at the time of surgery, both brief intervention programs and more intensive programs
were successful in achieving smoking cessation. With respect to long-term cessation (i.e., cessation at 1
year), only the more intensive programs, which involved face to face weekly counseling over a 4- to 8-
week period, along with nicotine replacement therapy, led to sustained smoking cessation. The brief
interventions, which typically included a single counseling session, along with nicotine replacement,
were not as successful.
The primary medications available are bupropion (Wellbutrin) and varenicline (Chantix). Bupropion
is a nicotine receptor antagonist, while varenicline is a weak agonist. Both are superior to placebo. In
direct comparison in an industry-sponsored randomized controlled trial (RCT) the 1 year cessation rates
were 23% for varenicline, 14.6% for bupropion, and 10.3% for placebo.21 In this study, participants in
all three arms underwent weekly smoking cessation counseling. A meta-analysis of three RCTs comparing
pharmacologic smoking cessation found a similar benefit for varenicline compared with bupropion and
nicotine replacement therapy.22
ESOPHAGECTOMY
Nutrition
Esophagectomy, whether it is trans-hiatal, Ivor Lewis, 3-Hole (McKeown), or minimally invasive,
remains one of the highest morbidity operations across surgical disciplines, with most reported series
having a major morbidity rate of over 30%.23 These patients are often malnourished secondary to both
cancer cachexia and from dysphagia in patients with locally advanced disease. Patients are increasingly
obese, and in the majority of cases will require neoadjuvant chemotherapy and radiation prior to any
surgical intervention. While this may improve their dysphagia rates, it is somewhat taxing on the patient
and may decrease the performance status of an already weak patient, further increasing the operative
morbidity. Optimal preparation of these patients is essential to improving surgical outcomes.
Malnutrition is undoubtedly associated with worse outcomes after most major surgery and
esophagectomy patients in particular.24–26 For patients undergoing esophagectomy for cancer, the
malnutrition and immunologic effects of the cancer compound this risk. Poor nutritional status has been
associated with increased rates of sepsis, anastomotic leak, pulmonary complications, mechanical
ventilation, impaired wound healing, and death.25,26 Cancer patients, especially those with advanced
cancer, frequently show significant weight loss and cachexia. This fat loss and muscle wasting is
explained by a combination of inadequate dietary intake along with increased metabolic expenditure.
Several studies have shown that cancer patients have increased energy expenditure, an increased
inflammatory state with rising C-reactive protein, erythrocyte sedimentation rate, and either an unchanged
or reduced caloric intake.26,27 This is especially true in patients with esophageal cancer with concomitant
dysphagia.
Tools for measuring nutritional status vary across studies and include basic laboratory work such as
serum albumin and prealbumin levels, the amount of preoperative weight loss, or multifactorial models
such as the nutritional risk index, geriatric nutritional risk index, and mini nutritional assessment. The
geriatric nutritional risk index, initially developed to quantify the malnutrition common in elderly patients,
has also been shown to predict poor outcomes in patients undergoing esophagectomy.25 The index, based
on albumin and body weight, was associated with increased pulmonary compilations in 122 patients
undergoing esophagectomy. As discussed, patients often have significant weight loss as part of their
clinical presentation and a preoperative weight loss of greater than 10% is associated with increased
perioperative mortality.
The challenge in optimizing nutritional status preoperatively involves deciding which assessment tool
is most effective, which interventions to undertake, and how to measure meaningful improvement. Options
for patients undergoing esophagectomy depend on the degree of preoperative weight loss, dysphagia, and
motivation of the patient. For a patient with greater than 10% weight loss with complete dysphagia and a
performance status too poor for neoadjuvant therapy, enteral feeding access either with a percutaneous
gastrostomy tube or feeding jejunostomy is the ideal therapy. There is some controversy as to whether a
PEG or jejunostomy tube is superior. The advantages of the PEG include avoidance of a laparotomy or
laparoscopy, the ability of the patient to receive bolus feeds, and the general ease of placement. There is
often a discussed concern that a gastrostomy tube may compromise the gastric conduit. However in the
authors’ experience these tubes are almost never on the greater curvature and are not difficult to deal with
at the time of esophagectomy. The primary advantage of a jejunostomy tube is that it makes a subsequent
esophagectomy more efficient as the feeding access is already in place. On the other end of the spectrum,
a patient without significant weight loss, or one who has some dysphagia to solids only and is otherwise
fit for neoadjuvant chemoradiation, no specific intervention is necessary. Most patients see a significant
improvement with their swallowing after the initiation of induction therapy and therefore can be given
nutritional supplementation without the need for a feeding tube or stent. Nutritional guidelines specific for
esophageal cancer patients are limited; however, patients should be getting at least 25 kcal/kg/day and 1 g
protein/kg/day. Consultation with a registered dietician, especially one who works with cancer patients,
should be a part of any perioperative nutritional plan. An alternative in these patients, especially those
with more significant dysphagia, is placement of an esophageal stent. Stents have been shown to decrease
dysphagia and improve PO intake. The downsides of stents are pain, especially in patients with bulky
tumors as they apply radial force to the tumor, migration and displacement, and even potential erosion if
they are kept in for long periods of time. It is generally our practice to encourage supplementation with
liquid nutritional supplements in patients who do not have dysphagia to liquids and who are otherwise fit
enough for induction therapy. For patients with more profound dysphagia, esophagoscopy with dilation
with either Savory or Maloney dilators generally can provide most patients with enough improvement
with their swallowing to be maintained on a high calorie liquid diet. Patients with more significant weight
loss and decreased performance status are considered for enteral access. The authors do not frequently
use stents in the preoperative setting.
Functional Outcomes
The physical and psychological effects of esophagectomy, both in the short term and long term are not
insignificant and preparation of the patient for these changes, especially with respect to swallowing
function, is an important part of preparing these patients preoperatively. Nearly 50% of esophagectomy
patients report some difficulty with swallowing in the postoperative period and another 50% require
dilation. Over 50% deal with some degree of dumping and reflux.28 These symptoms can be mitigated by
dietary modifications and patients should be counseled preoperatively and prior to hospital discharge to
eat more frequent, smaller, high protein, low carbohydrate meals. It is also important to counsel patients
that swallowing function is not the sole determinant of quality of life after esophagectomy. Several studies
have looked at quality of life after esophagectomy and have found that issues related to the creation of the
gastric conduit, that is, dysphagia, dumping, and reflux, are not the primary drivers of decreased quality of
life.28–30 In the short term, the primary drivers are perioperative complications and physical weakness. In
the long term, emotional factors, such as patient’s perceptions of poor health due to persistent cancer at
the time of resection, drove most quality of life issues.31 Most of the detriment in quality of life is in the
perioperative period and quality of life frequently returns to preoperative levels within 6 to 9 months
(Fig. 25.3).29,31,32 Resources available to patients include esophagectomy support groups and forums,
providing patients with a list of prior esophagectomy patients who are willing to act as peer counselors,
publications on esophagectomy from the patient’s perspective (Table 25.1),33 and preoperative counseling
from nutritionists on the postoperative dietary modifications. Helping patients prepare prior to undergoing
surgery may help improve their long-term well-being.
MEDIASTINUM
Thymectomy
Preparation for resection of mediastinal masses refers primarily to patients undergoing thymectomy for
myasthenia gravis. As discussed in greater detail elsewhere, the primary indications for thymectomy in
patients with myasthenia gravis are patients with a thymoma or in those patients without thymoma who
have at least moderate generalized disease. Myasthenic crisis refers to patients requiring mechanical
ventilation due to an exacerbation of their disease. This is most frequently a result of infection, but can be
precipitated by surgery as well. Not infrequently, a patient in myasthenic crisis is intubated in an ICU
under the care of neurologists when the thoracic surgeon is consulted for thymectomy. The thoracic
surgeon must resist the temptation to operate on these patients in an urgent fashion since, as the benefits of
thymectomy for MG accrue over years. Remission rates even at 5 years for patients without thymoma who
undergo thymectomy range from 20% to 50% while reaching 67% at 15 years.34,35 Surgery is not an
effective treatment for myasthenic crisis and improvement should not be expected to occur immediately.
Patients undergoing thymectomy for MG should be neurologically optimized prior to any surgical
intervention. This includes titration of cholinesterase inhibitors, corticosteroids, plasmapheresis, and
IVIG. Plasmapheresis for myasthenia was first introduced in 1977.36 The efficacy of preoperative
plasmapheresis was demonstrated as early as 1985, with a significant reduction in postoperative
mechanical ventilation and ICU days in patients with respiratory weakness who underwent
plasmapheresis prior to thymectomy.37 This led some to suggest that all patients undergoing thymectomy
for myasthenia gravis should receive preoperative plasmapheresis. The risks of plasmapheresis include
bleeding, as plasmapheresis requires full anticoagulation, cardiac arrhythmias, line complications
including infection, and hypotension related to the extracorporeal plasma exchange.38 This has led to
interest in employing a more selective use of preoperative plasmapheresis. In a retrospective review of
164 patients, one group (74 patients) received routine pheresis while in the other group (90 patients) only
patients predicted to be at increased risk for prolonged mechanical ventilation received pheresis. The
complication rate was reduced from 26% to 9% in the routine versus selective group, without any change
in mechanical ventilation, ICU length of stay, or overall hospital length of stay.
FIGURE 25.3 Median dysphagia scores stratified by patients surviving more than 2 years, patients surviving less than 2 years,
and patients who received only palliative treatment. A high score is equivalent to more symptoms. (Adapted from Blazeby JM,
Farndon JR, Donovan J, et al. A prospective longitudinal study examining the quality of life of patients with esophageal
carcinoma. Cancer 2000;88(8):1781–1787. Copyright © 1988 by John Wiley Sons, Inc. Reprinted by permission of John Wiley &
Sons, Inc.)
TABLE 25.1 Patients’ Perspective on Quality of Life After Esophagectomy

To be able to adequately eat and enjoy it
To be able to drink as desired, with moderate alcohol consumption
To be able to do both of the above socially
To have weight stability
To be able to sleep comfortably in a normal position
To be free of pain
To be able to earn one’s living
To be able to participate in sports or hobbies
To have unimpaired libido
From Kirby JD. Quality of life after oesophagectomy: The patients’ perspective. Dis Esophagus 1999;12(3):168–171. Copyright © 1999
International Life Sciences Institute. With permission.
Patients should have their disease medically optimized and be maintained on their anticholinesterase
inhibitors and corticosteroids if indicated. If deemed at increased risk for postoperative respiratory
complications, the patients should receive preoperative plasmapheresis with a goal of reducing
circulating antibody levels. A thoracic epidural should be placed preoperatively and any neuromuscular
blockade should be avoided. With proper preoperative assessment and preparation, in coordination with
the patient’s neurologist and anesthesiologist, thymectomy for myasthenia gravis should be able to be
performed with minimal risk for postoperative mechanical ventilation and myasthenic crisis.
SUMMARY
Outcomes after thoracic surgical procedures continue to improve with enhanced surgical technique,
anesthesia, and postoperative care. Optimizing the patient prior to an operation is too often marginalized
or ignored due to concerns that it may delay an operation, is too difficult to coordinate, or does not
improve outcomes. This is no longer true. The data shows that preoperative preparation can often be done
without delaying surgery, without excessive burden on patients and providers, and that doing so can
improve perioperative outcomes. Adequate pulmonary rehabilitation, counseling on smoking cessation,
and nutritional assessment play a role in all patients undergoing a thoracic surgical procedure. They
should be considered an integral part in the care of the patient and are an effective strategy to improve
outcomes in thoracic surgery.
REFERENCES
1. Licker MJ, Widikker I, Robert J, et al. Operative mortality and respiratory complications after lung resection for cancer: impact of
chronic obstructive pulmonary disease and time trends. Ann Thorac Surg 2006;81:1830–1837.
2. van der Schaaf MK, Tilanus HW, van Lanschot JJ, et al. The influence of preoperative weight loss on the postoperative course after
esophageal cancer resection. J Thorac Cardiovasc Surg 2014;147:490–495.
3. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts
and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013;188:e13–e64.
4. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for
severe emphysema. N Engl J Med 2003;348:2059–2073.
5. Ries AL, Make BJ, Lee SM, et al. The effects of pulmonary rehabilitation in the national emphysema treatment trial. Chest
2005;128:3799–3809.
6. California Pulmonary Rehabilitation Collaborative Group. Effects of pulmonary rehabilitation on dyspnea, quality of life, and healthcare
costs in California. J Cardiopulm Rehabil 2004;24:52–62.
7. Cambach W, Wagenaar RC, Koelman TW, et al. The long-term effects of pulmonary rehabilitation in patients with asthma and chronic
obstructive pulmonary disease: A research synthesis. Arch Phys Med Rehabil 1999;80:103–111.
8. Lacasse Y, Wong E, Guyatt GH, et al. Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. Lancet
1996;348:1115–1119.
9. Hulzebos EH, Helders PJ, Favié NJ, et al. Preoperative intensive inspiratory muscle training to prevent postoperative pulmonary
complications in high-risk patients undergoing CABG surgery: A randomized clinical trial. JAMA 2006;296:1851–1857.
10. Benzo R, Wigle D, Novotny P, et al. Preoperative pulmonary rehabilitation before lung cancer resection: Results from two randomized
studies. Lung Cancer 2011;74:441–445.
11. Samson P, Patel A, Garrett T, et al. Effects of delayed surgical resection on short-term and long-term outcomes in clinical stage I non-
small cell lung cancer. Ann Thorac Surg 2015;99:1906–1913.
12. Harada H, Yamashita Y, Misumi K, et al. Multidisciplinary team-based approach for comprehensive preoperative pulmonary
rehabilitation including intensive nutritional support for lung cancer patients. PLoS ONE 2013;8:e59566.
13. Barrera R, Shi W, Amar D, et al. Smoking and timing of cessation: Impact on pulmonary complications after thoracotomy. Chest
2005;127:1977–1983.
14. Mason DP, Subramanian S, Nowicki ER, et al. Impact of smoking cessation before resection of lung cancer: A Society of Thoracic
Surgeons General Thoracic Surgery Database study. Ann Thorac Surg 2009;88:362–370; discussion 370–371.
15. Wright CD, Gaissert HA, Grab JD, et al. Predictors of prolonged length of stay after lobectomy for lung cancer: A Society of Thoracic
Surgeons General Thoracic Surgery Database risk-adjustment model. Ann Thorac Surg 2008;85:1857–1865; discussion 1865.
16. Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst
1993;85:457–464.
17. Tammemagi CM, Neslund-Dudas C, Simoff M, et al. Smoking and lung cancer survival: The role of comorbidity and treatment. Chest
2004;125:27–37.
18. Nakagawa M, Tanaka H, Tsukuma H, et al. Relationship between the duration of the preoperative smoke-free period and the incidence
of postoperative pulmonary complications after pulmonary surgery. Chest 2001;120:705–710.
19. Bluman LG, Mosca L, Newman N, et al. Preoperative smoking habits and postoperative pulmonary complications. Chest 1998;113:883–
889.
20. Warner MA, Offord KP, Warner ME, et al. Role of preoperative cessation of smoking and other factors in postoperative pulmonary
complications: A blinded prospective study of coronary artery bypass patients. Mayo Clin Proc 1989;64:609–616.
21. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs.
placebo or sustained-release bupropion for smoking cessation: A randomized controlled trial. JAMA 2006;296:56–63.
22. Mills EJ, Wu P, Spurden D, et al. Efficacy of pharmacotherapies for short-term smoking abstinance: A systematic review and meta-
analysis. Harm Reduct J 2009;6:25.
23. Fernando HC, Murthy SC, Hofstetter W, et al. The Society of Thoracic Surgeons practice guideline series: Guidelines for the
management of Barrett’s esophagus with high-grade dysplasia. Ann Thorac Surg 2009;87:1993–2002.
24. Kuzu MA, Terzioğlu H, Genç V, et al. Preoperative nutritional risk assessment in predicting postoperative outcome in patients
undergoing major surgery. World J Surg 2006;30:378–390.
25. Yamana I, Takeno S, Shibata R, et al. Is the geriatric nutritional risk index a significant predictor of postoperative complications in
patients with esophageal cancer undergoing esophagectomy? Eur Surg Res 2015;55:35–42.
26. Nozoe T, Kimura Y, Ishida M, et al. Correlation of pre-operative nutritional condition with post-operative complications in surgical
treatment for oesophageal carcinoma. Eur J Surg Oncol 2002;28:396–400.
27. Bosaeus I, Daneryd P, Svanberg E, et al. Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer
patients. Int J Cancer 2001;93:380–383.
28. McLarty AJ, Deschamps C, Trastek VF, et al. Esophageal resection for cancer of the esophagus: Long-term function and quality of life.
Ann Thorac Surg 1997;63:1568–1572.
29. Blazeby JM, Farndon JR, Donovan J, et al. A prospective longitudinal study examining the quality of life of patients with esophageal
carcinoma. Cancer 2000;88:1781–1787.
30. Headrick JR, Nichols FC 3rd, Miller DL, et al. High-grade esophageal dysplasia: long-term survival and quality of life after
esophagectomy. Ann Thorac Surg 2002;73:1697–1702; discussion 1702–1703.
31. Fernandez FG, Meyers BF. Quality of life after esophagectomy. Semin Thorac Cardiovasc Surg 2004;16:152–159.
32. Zieren HU, Jacobi CA, Zieren J, et al. Quality of life following resection of oesophageal carcinoma. Br J Surg 1996;83:1772–1775.
33. Kirby JD. Quality of life after oesophagectomy: The patients’ perspective. Dis Esophagus 1999;12:168–171.
34. Zielinski M, Hauer L, Hauer J, et al. Comparison of complete remission rates after 5 year follow-up of three different techniques of
thymectomy for myasthenia gravis. Eur J Cardiothorac Surg 2010;37:1137–1143.
35. Masaoka A, Yamakawa Y, Niwa H, et al. Extended thymectomy for myasthenia gravis patients: A 20-year review. Ann Thorac Surg
1996;62:853–859.
36. Pinching AJ, Peters DK, Davis JN. Plasma exchange in myasthenia gravis. Lancet 1977;1:428–429.
37. d’Empaire G, Hoaglin DC, Perlo VP, et al. Effect of prethymectomy plasma exchange on postoperative respiratory function in
myasthenia gravis. J Thorac Cardiovasc Surg 1985;89:592–596.
38. El-Bawab H, et al. Plasmapheresis before thymectomy in myasthenia gravis: Routine versus selective protocols. Eur J Cardiothorac
Surg 2009;35:392–397.
26
Conduct of Anesthesia
Brian P. Barrick
Thoracic surgical patients often present with significant comorbidities in addition to compromised
pulmonary function. The anesthesiologist, aside from being able to manage such patients, must also
acquire a body of knowledge concerning physiology, techniques, and devices unique to the practice of
thoracic anesthesia.
Thoracic surgery encompasses a number of procedures involving the airway, bronchial tree, chest
wall, mediastinum, and lung parenchyma. This chapter focuses primarily on procedures requiring one-
lung ventilation (OLV), such as pulmonary resection. There is also a discussion of respiratory physiology,
and anesthetic considerations for some of the other procedures performed in thoracic surgery. Last, a
discussion of anesthetic management would not be complete without a word on postoperative analgesia.
CHARACTERISTICS OF THE IDEAL ANESTHETIC

The thoracic anesthesiologist must have an understanding of airway, thoracic and bronchial anatomy,
pulmonary physiology, gas exchange, airway and lung isolation devices, cardiac–pulmonary interaction,
and pain management to meet all of the objectives of providing an anesthetic to the thoracic surgical
patient. Some of the characteristics of the ideal anesthetic are explained in more detail later in the chapter.
• Hemodynamic (HD) stability during induction of the anesthetic

• Use of appropriate devices and techniques to both secure the airway and optimize surgical exposure
• Maintenance of oxygenation (minimization of shunt) and minute ventilation (elimination of carbon
dioxide)
• Utilization of ventilator parameters to minimize barotrauma and air trapping, as well as protective
ventilatory strategies to avoid acute lung injury (ALI)
• Titration of pharmacologic agents to maintain adequate anesthetic depth, maintain HD stability, and
optimize the effects of hypoxic pulmonary vasoconstriction (HPV)
• Fluid management that optimizes end-organ perfusion and also decreases the potential for ALI during
intrathoracic cases
• Application of appropriate agents and techniques to initiate pain control intraoperatively as well as to
maintain analgesia and optimum respiratory function postoperatively
RESPIRATORY PHYSIOLOGY
Some of the physiologic changes that take place with positioning, anesthetic induction, and paralysis are
discussed later in the chapter.
AWAKE PATIENT WITH SPONTANEOUS RESPIRATION

The distribution of ventilation changes with position in the chest. Pleural pressure can be considered
“less negative” (7.5 cm H2O less) as one progresses from the apex to the base of the lung, primarily
owing to the effects of gravity.1 This difference causes the apical alveoli to be relatively more distended
than the basal alveoli. The basal alveolar units are thus more compliant and distend more per change in
unit pressure. The result is distribution of the majority of ventilation to the basal regions.2
Distribution of perfusion to the normal lung is mostly gravity-dependent, decreasing as blood ascends
in the chest. West et al.3 divided the lungs into those based on the relationship between alveolar,
pulmonary artery, and pulmonary vein pressures. In zone 1 (apical), alveolar pressure exceeds pulmonary
vascular pressures and there is relative collapse of vessels. In zones 2 and 3, there is relatively more
perfusion as first pulmonary artery pressures (PAPs) and then pulmonary venous pressures exceed
alveolar pressures.
Blood flow increases more rapidly than does ventilation as one moves basally. Therefore apical
alveoli are relatively overventilated (ventilation/perfusion ratio, or V./Q., > 1) while basal alveoli are
overperfused (V./Q. < 1). Uneven V./Q. relationships in the lungs have a more profound effect on arterial
PO2 than PCO2. CO2 is more diffusible and can be eliminated by the overventilated alveoli. However,
these same alveoli cannot give up much more oxygen, since the oxyhemoglobin dissociation curve is
relatively flat in this region (PO2 >90).4
The vertical gradient of blood flow is the same when an awake patient assumes a lateral decubitus
position, resulting in more blood flow to the dependent (down) lung than to the nondependent (up) lung.
This effect is exaggerated when the right lung is down, but the average effect is for 60% of blood to go to
the down lung.5 Gravity has the same effect on pleural pressure and the distribution of ventilation.6 The
lower diaphragm is positioned higher in the chest, resulting in a sharper curve and more efficient
contraction than the upper diaphragm. Perfusion to the down lung increases more than ventilation (as
above), so V./Q. ratios are not greatly altered.4
LATERAL DECUBITUS, GENERAL ANESTHESIA

While the inhalational induction of general anesthesia does not cause significant changes in the
distribution of perfusion, it does cause changes in the distribution of ventilation.
The major change seen is a decrease in volume (and functional residual capacity [FRC]) in both lungs
secondary to loss of chest wall tone. The down lung moves down to a lower, flatter portion (less
favorable) of the pressure–volume curve and the up lung moves to a lower but steep portion (more
favorable).2 The net result is that the majority of ventilation is switched to the up lung.4
TABLE 26.1 Effects of Various Anesthetic and Vasoactive Agents on Hypoxic
Pulmonary Vasoconstriction
Volatile (inhalational) anesthetics Inhibit HPV in a dose-dependent manner, but not clinically significant at ≤1 MAC
IV induction agents (thiopental, propofol, No significant effect on HPV
ketamine)
Dexmedetomidine (alpha-2 agonist) Greater pulmonary vascular resistance as bolus
Does not adversely affect oxygenation when used as an infusion
Narcotics (fentanyl, morphine, and possibly No significant effect on HPV
remifentanil)
Vasoconstrictors (phenylephrine, epinephrine, Constrict pulmonary vasculature in normoxic areas, perhaps the same effect as
dopamine) inhibition of HPV
Most vasodilators (nitrates, calcium channel Very significant inhibitors of HPV
blockers, beta agonists)
Hydralazine Not shown to affect HPV
Thoracic epidural (local anesthetics) Not shown to affect pulmonary vascular tone in dogs, possibly diverting blood from
hypoxic areas (enhancing HPV)
Inhaled nitric oxide Dilates vessels in better-ventilated areas (same effect as enhancing HPV)
HPV, hypoxic pulmonary vasoconstriction; MAC, minimum inhibitory concentration.
Paralysis and controlled ventilation result in even greater maldistribution of ventilation and perfusion
for several reasons. With paralysis, the lower diaphragm no longer contributes to ventilation distribution.7
The mediastinum rests on the down lung, and the abdominal contents push the lower diaphragm cephalad.
Flexing the operating table puts more pressure on the dependent chest, decreasing the FRC of the down
lung even further.
Opening the nondependent chest eliminates the constrictive effect of the chest wall, allowing the up
lung to expand even further. The changes outlined above result in an up lung that is very well ventilated
but poorly perfused (dead space) and a down lung that is poorly ventilated but well perfused (shunt). This
could result in significant hypoxia. However, measures to assist oxygenation, ventilation, and surgical
exposure during open chest procedures are discussed below.
ONE-LUNG VENTILATION AND HYPOXIC PULMONARY

VASOCONSTRICTION
The surgical lung is often not ventilated during thoracic procedures so as to facilitate exposure. The result
is that all blood flowing to the up (nonventilated) lung is shunt flow. This is in addition to anatomic shunt
and flow in atelectatic areas of the down lung. Both clinical experience and studies show a lower arterial
PO2 and higher alveolar–arterial O2 gradient during OLV.4,8 Arterial CO2 is much less affected (as stated
above) as long as minute ventilation is maintained.
If there were no compensatory mechanisms to minimize shunt, roughly 40% of the right heart output
would go to the nonventilated lung. Fortunately, many such mechanisms exist. Gravity increases blood
flow to the down lung. Surgical compression of the pulmonary vasculature and ligation of branches of the
involved pulmonary artery further reduce shunt. A severely diseased surgical lung may already have
restriction of its blood flow, in which case initiation of OLV would not cause as dramatic a change in
arterial oxygenation as expected.4,9
By far the mechanism that has the most effect on the pulmonary vasculature is HPV. The normal
response of the pulmonary precapillary arterioles to atelectasis/hypoxia is vasoconstriction.2 The
mechanism behind HPV is not well understood. Though pulmonary artery smooth muscle has been shown
to display this response in vitro, pulmonary venules and capillaries seem to play a role as well.10
Mediators that have been studied include voltage-gated potassium channels,11 prostaglandins,12 calcium
channels,13 and nitric oxide.14 In the absence of agents that blunt this response, it is possible to reduce the
blood flow through the nonventilated lung by up to 50%, meaning that about 20% of right heart output will
go to that lung as opposed to 40% without HPV.8 The effects of anesthetic agents and vasoactive drugs on
HPV are not only summarized in Table 26.1, but are also discussed and referenced later in this chapter.
INDICATIONS FOR ONE-LUNG VENTILATION

In general, the indications for lung isolation can be divided into absolute and relative. Absolute
indications fall into three categories. The first involves prevention of a disease process whereby one lung
contaminates the contralateral lung. The second involves control of ventilation. The objective here is to
divert ventilation from diseased lungs in potentially life-threatening situations (listed in Table 26.2)
where a large air leak or a tension pneumothorax can occur with conventional two-lung ventilation. The
third is for unilateral bronchopulmonary lavage, which is used to treat primary alveolar proteinosis.
All surgical procedures fall under the heading of relative indications for OLV and can be further
divided into higher and lower priority. High-priority indications are technically challenging procedures
that benefit greatly from a wide exposure of the lung hilum or the length of the thoracic aorta. Another
indication is for video-assisted thoracoscopic procedures (VATS). Visualization of the surgical field is
nearly impossible if the surgical lung is ventilated. It should be noted, however, that if OLV proves
difficult or impossible (because of significant hypoxia or prohibitive airway pressures), consideration
should be given to converting to an open technique (where surgical traction can be placed on the lung for
exposure) or abandonment of the procedure. Lower-priority indications include surgical procedures that
are technically less demanding and more amenable to surgical traction or packing of the operative lung.15
Indications for OLV are summarized in Table 26.2.16
TABLE 26.2 Indications for Lung Isolation/One-Lung Ventilation

Absolute indications Isolation of healthy lung from disease process in contralateral lung (e.g., hemoptysis, purulence)
Diversion of ventilation from a diseased lung (e.g., bronchopleural fistula [BPF], large bullous disease,
tracheobronchial disruption)
Bronchoalveolar lavage (such as that used to treat primary alveolar proteinosis)
Relative indications: high Pneumonectomy
priority Upper lobectomy
Video-assisted thoracoscopic surgery (VATS)
Surgery on the thoracic aorta
Relative indications: low Middle and lower lobectomy
priority Exposure of the anterior thoracic spine
Esophageal resection
Data from Pedoto A, Heerdt PM, Yao FF. Bronchoscopy, mediastinoscopy, and thoracotomy. In: Yao FF, ed. Anesthesiology: Problem-
Oriented Patient Management. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:32–49.
DOUBLE-LUMEN ENDOTRACHEAL TUBES
In the early part of the twentieth century, thoracic surgery was performed on a spontaneously breathing
patient without an airway device. Surgeries were limited to quick procedures such as empyema drainage
and superficial resections because patients would quickly decompensate. Survival rates greatly increased
after endotracheal intubation and controlled positive-pressure ventilation became the standard of care.
For the intricate, sometimes time-consuming thoracic procedures we see today to become reality,
techniques had to evolve that allowed selective ventilation of the nonsurgical lung to maintain a static
surgical field, a hemodynamically stable patient, and a contralateral lung free of contaminants.
Bjork and Carlens17 introduced the first practical method to achieve lung separation, later modified by
Robertshaw18 and Carlens. Although several devices have since been introduced into practice, the
double-lumen endotracheal tube (ETT) can still be considered the mainstay of thoracic surgery. It allows
for rapid deflation of the operative lung, is relatively stable once in proper position, and allows
insufflation of oxygen or application of continuous positive airway pressure (CPAP) to the operative field
without much difficulty.
The basic left-sided double-lumen ETT (used for most procedures) consists of a bronchial lumen
meant to be placed down the left mainstem bronchus and a tracheal lumen that stops short of the carina
and can be used to selectively ventilate the right lung. Two cuffs, one in the trachea above the tracheal
lumen opening (transparent) and one above the bronchial opening (blue), make lung isolation possible.
Several manufacturers have sizes 35, 37, 39, and 41 Fr for adults. The Mallinckrodt Broncho-Cath (the
brand most familiar to the author) also comes in sizes 32 and 28 Fr for pediatric patients. Rusch
(Teleflex, Morrisville, NC) manufactures a 26-Fr ETT as well.
Selection of an appropriate-sized double-lumen ETT is important. The bronchial lumen should have a
leak around it with the cuff deflated and require no more than 3 mL of air to produce a seal. An
excessively large ETT can damage the tracheobronchial tree. It is now recognized that placement of a
double-lumen ETT that is too small can lead to problems as well. Small ETTs are more prone to
dislodgement when the patient’s position is changed (supine to lateral decubitus). They require more air
in the bronchial cuff to prevent leak, placing more pressure on the bronchial mucosa. There is also more
opportunity to advance a small ETT too far, so that a tidal volume meant for two lungs can be delivered to
one lung or even a single lobe, resulting in barotrauma.19
Although it is acknowledged that selection of a double-lumen ETT of proper size is important, there
are no uniform guidelines. Many practitioners have satisfactory results with a 37-Fr tube for adult females
and a 39-Fr tube for adult males. It is the author’s bias to reserve 35-Fr ETTs for patients <63 in tall and
41-Fr ETTs for those >72 in tall. Attempts to correlate left bronchial width (and hence appropriate ETT
size) with readily measured clinical parameters have met with little success. Hannallah and colleagues20
found a weak correlation of age and height with bronchial size in adult males but not in females. They
went on to measure left bronchial diameter from computed tomography (CT) scans and made
recommendations based on these. Brodsky and colleagues21 based recommendations of double-lumen
ETT size on measurements of tracheal diameter. Brodsky and Lemmens22 later noticed a correlation
between tracheal width and left bronchial width. Although not listed here, the recommendations of both
Brodsky and Hannallah suggest that a 39-Fr ETT is appropriate for many women and a 41-Fr ETT for
many men.
Many practitioners still take patient height into consideration in determining ETT size. In a recent
commentary, Slinger,23 while recognizing the lack of consensus among thoracic anesthesiologists, put forth
recommendations based on height and gender, suggesting that a 37-Fr ETT was best for most women and
a 41-Fr for most men. A properly sized left-sided ETT would have a bronchial lumen tip about 1 to 2 mm
less than the width of the left mainstem bronchus. This would have to be measured for each individual
tube, as this information is not part of the package insert and variations in the manufacturing process can
lead to small variations in size.24
PLACEMENT OF LEFT-SIDED DOUBLE-LUMEN ENDOTRACHEAL TUBES

The double-lumen ETT is initially placed by laryngoscopy. In contrast to a single-lumen ETT, a double-
lumen tube has a larger circumference and is more rigid. A thin stylet comes with the tube and is placed in
the bronchial lumen. By holding the tube so that the bronchial lumen faces anteriorly, the tip can then be
bent to resemble the curve of a single-lumen ETT. It is also suggested that a small amount of water-
soluble lubricant be placed on the bronchial cuff. The author also recommends warming the ETT by either
submersion in sterile saline or placement (in the package) next to a desflurane vaporizer to soften the tube
and minimize the risk of airway injury.
The author’s preferred method of placement has previously been described by Ovassapian.25 With the
larynx in view, the tube is placed carefully in the mouth to avoid tearing the tracheal cuff on the teeth. One
should be able to view the bronchial cuff as it passes through the vocal cords. Once this occurs, the stylet
is removed by an assistant. The tube is then turned 90 degrees counterclockwise and advanced until the
clear tracheal cuff passes through the vocal cords. The goal is for the bronchial lumen to be above the
carina. Placement of the ETT in the trachea is confirmed by condensation in the tube, chest rise (unilateral
or bilateral), and the detection of sustained end-tidal carbon dioxide. A bronchoscope is inserted down
the bronchial lumen. The carina should be clearly visualized. For orientation, the anterior and posterior
aspects of the trachea can be identified by the presence and absence of rings, respectively. If one suspects
that the ETT is left of right main-stemmed, the ETT can be retracted until the carina is clearly seen. The
left mainstem bronchus is then inspected. The scope remains in the left mainstem bronchus and acts as a
stylet over which the tube is advanced into position. The scope is withdrawn and then advanced into the
tracheal lumen (Fig. 26.1).
FIGURE 26.1 The author’s approach to flexible bronchoscopic placement and positioning of left-sided double-lumen tube. A:
The flexible bronchoscope (FB) is passed through the bronchial lumen into the left mainstem bronchus. The patency, length, and
anatomy of the left mainstem bronchus and the position of the orifice of the left-upper-lobe bronchus are evaluated. B: The FB is
withdrawn and its tip is positioned 10 mm above the origin of the left-upper-lobe bronchus. C: The tracheal cuff is deflated and
the tube is advanced over the FB into the left mainstem bronchus until it comes into view beyond the tip of the FB. D: The FB is
advanced beyond the bronchial lumen to visualize the left-upper-lobe bronchus. E: The FB is passed through the tracheal lumen
to check the position of the bronchial cuff and the opening of the right mainstem bronchus.
The bronchial lumen should be seen passing down the left mainstem bronchus. In using a Broncho-Cath
tube, a black radiopaque ring on the bronchial lumen (that reflects gray or white with the bronchoscope
light) should be seen just above the carina. The superior edge of the inflated bronchial cuff should be
barely visible. To confirm that the other bronchus is the right mainstem bronchus, the bifurcation of the
right-upper-lobe bronchus and the bronchus intermedius should be seen about 1.5 cm from the carina. A
look into the right-upper-lobe bronchus should reveal three segmental bronchi. Once proper placement is
confirmed, the bronchial cuff is inflated and OLV is instituted. Alternately, one may institute OLV after
lateral decubitus positioning so that gravity will redirect flow to the ventilated lung and minimize shunt.
Whichever method is chosen, placement must be reconfirmed once the patient is in the lateral position.
The bronchial lumen should be reinspected as well to check for misplacement and possible lobar
occlusion.
Another way to confirm proper placement is by auscultation of the chest. Initially the tracheal cuff is
inflated, the tube is attached to the breathing circuit by a special plastic adaptor, and tracheal placement is
confirmed as above. Once this is accomplished, the bronchial cuff is inflated with no more than 3 mL of
air. If the connection between the circuit and the bronchial lumen is clamped, one should hear clear breath
sounds on the right but not on the left. Asymmetric chest rise should also be seen on the right. Likewise,
when the connection to the tracheal lumen is clamped, breath sounds should be heard and chest rise seen
on the left.24 It should be noted that as our patient population has become more obese, auscultation and
observation of unilateral chest rise have become less reliable indicators of proper ETT placement.
RIGHT-SIDED DOUBLE-LUMEN ENDOTRACHEAL TUBES

Left-sided double-lumen ETTs are preferred over right-sided tubes for the vast majority of procedures
requiring lung isolation. The right mainstem bronchus is much shorter because the origin of the right-
upper-lobe bronchus is about 1.5 cm from the carina. By contrast, the left mainstem bronchus bifurcates 5
cm from the carina, providing a wider margin of safety26 in placing left-sided tubes. Right-sided tubes are
potentially more prone to malposition, leading to right-upper-lobe obstruction (and improper deflation
when the right side is the surgical side) and atelectasis (if right-sided ventilation is desired).
There are, however, times when it is difficult or impossible to use a left-sided tube. A classic example
is when there is an intraluminal tumor of the left mainstem bronchus. Other situations include an exophytic
tumor compressing the left mainstem bronchus or distorting left-sided anatomy, if a left bronchial stent is
already in place, or there is left-sided tracheobronchial disruption.27 Other possible indications include
unilateral left lung transplantation or left pneumonectomy. A left-sided tube, if used in these situations,
may need to be withdrawn to prevent interference with an anastomosis or bronchial stapling. Bear in mind
that this may result in loss of an adequate seal or obstruction of the carina if the bronchial cuff is
withdrawn too far.
All right-sided tubes have an additional slot near the distal end of the bronchial lumen to allow
ventilation and/or decompression of the right upper lobe. The Mallinckrodt Broncho-Cath tube, used at
the author’s institution, has a single angled, pear-shaped cuff that encompasses the proximal end of the
bronchial slot, allowing a single cuff to provide an adequate seal of both the right upper lobe and the
bronchus intermedius. Other manufacturers accomplish this by incorporating two cuffs into the bronchial
lumen, one proximal to the bronchial slot and one distal.24,28
Placement of the right-sided tube can be more difficult, and fiberoptic bronchoscopy should be used in
the process.29 After intentional shallow placement of the tube in the trachea, the scope is advanced down
the right mainstem bronchus. If the space between the carina and right-upper-lobe bronchus is at least 1.5
cm, one can place a right-sided tube.30 One can then either advance the tube over the scope while the
right-upper-lobe bronchus is in view or retract the scope until its tip is just distal to the most distal lumen
and advance them together into the right main stem. With either technique, one must then be able to view
the right upper lobe with its three segmental bronchi through the bronchial slot to ensure proper
placement. The scope can then be advanced down the tracheal lumen to inspect the left-sided anatomy and
check for bronchial cuff herniation. As always, tube position must be rechecked once the patient is placed
in the lateral decubitus position, and must often be rechecked during the procedure if conditions are not
ideal (Fig. 26.2).
OTHER LUNG ISOLATION DEVICES

Although double-lumen tubes offer a reliable way to provide absolute lung isolation, they are not ideal for
every situation. The most obvious is the patient for whom direct laryngoscopy is difficult or impossible
(difficult airway). Double-lumen ETTs are more rigid, have a larger outer circumference, and are longer
than their single-lumen counterparts. While there have been reports of successful placement of double-
lumen ETTs with awake fiberoptic intubation, this is an extremely difficult task even for the most skilled
anesthesiologist for the reasons mentioned above.31 There are a couple of alternatives. One is to initially
intubate with a single-lumen tube with a difficult airway device. The tube is then exchanged for a double-
lumen tube with an exchange device that is at least 14 Fr in circumference and 83 cm long.32 Another
option is to use one of the bronchial blocking devices discussed further on.
There are many instances when a patient will remain ventilated after the procedure. Leaving a double-
lumen tube in place for a prolonged period has several disadvantages. The large outer circumference and
long bronchial lumen increase the chance of airway damage. The small lumens (less than 5 mm for 39-Fr
tubes and smaller) mean that higher peak airway pressures will be needed for adequate ventilation and
pulmonary toilet will be difficult. Double-lumen tubes are most frequently changed out for single tubes
before transport to the intensive care unit. For critically ill patients who have single-lumen tubes already
in place and those for whom the planned procedure may require the administration of a large amount of
fluid and blood products (resulting in facial edema and making the airway more difficult to manage), a
bronchial blocker will eliminate the need for tube exchange.
FOGARTY EMBOLECTOMY CATHETER

The Fogarty embolectomy catheter was one of the first devices described for use as an endobronchial
blocker.33,34 The most common size used for adults is 8 Fr, with a 14-mL-capacity balloon at the end. The
catheter contains a wire stylet, which makes it relatively rigid. The wire does not extend to the distal end
of the balloon, so the tip is soft and unlikely to cause bronchial trauma.35 The catheter can be passed
through the ETT to the intended bronchus, or direct laryngoscopy can be used to place the catheter through
the vocal cords alongside the ETT, so the lumen is not compromised (a consideration for small ETTs). A
30-degree bend at the tip will facilitate placement.35 As with all bronchial blockers, fiberoptic
bronchoscopy is recommended to confirm placement into the desired bronchus. If the catheter is to be
used within the ETT, an adaptor with an adjustable diaphragm (such as the Arndt multiport adaptor)
should be used to allow passage of a fiberoptic scope as well as provide an airtight seal around the
catheter, allowing ventilation without significant leak.35
There are several disadvantages to using a Fogarty catheter for lung isolation. Unlike other bronchial
blockers, it does not have a hollow lumen that communicates with the lung, so deflation of the surgical
lung is strictly by absorption atelectasis and takes a long time. Selective application of CPAP to the
surgical lung is also not possible. The balloon is not designed for lung isolation. The spherical low-
volume, high-pressure balloon could potentially place a large amount of pressure against the bronchial
mucosa, but there are no case reports of such complications. Dislodgement of the catheter is common with
changing of patient position or surgical manipulation. As with any bronchial blocker, it is recommended
that position be confirmed with a fiberoptic scope after changes in patient position (e.g., from supine to
lateral) (Fig. 26.3).
FIGURE 26.2 Flexible bronchoscopic placement and positioning of right-sided double-lumen tube. A: The FB is passed through
the bronchial lumen into the right mainstem bronchus. The patency, length, and anatomy of the right bronchial tree are evaluated.
B: The FB is withdrawn inside the bronchial lumen. The tip of the FB is placed at the proximal end of the slit of the bronchial
cuff rotated 90 degrees to the right and the tip is angulated anteriorly toward the lateral wall of the trachea. C: The tube and FB
are then advanced together inside the right mainstem bronchus until the orifice of the right upper lobe comes into view through
the slit of the bronchial cuff. D: The FB is advanced 2 to 3 mm through the bronchial slit inside the right-upper-lobe bronchus to
visualize its three segments. E: The FB is passed through the tracheal lumen to check the position of the bronchial cuff and the
opening of the left mainstem bronchus.
UNIVENT TUBE
Introduced in 1982, the Univent is a tube with two lumens: a larger lumen designed for ventilation and a
smaller one that acts as a channel for an incorporated bronchial blocker (Fig. 26.4).36 Tube sizes are
based on the internal diameter (ID) of the ventilatory lumen, ranging from 6.0 to 9.0 mm ID. The
ventilatory lumen is larger than the blocker channel; it has an oval, almost “D” shape. Thus when we
discuss the ID of Univent tubes, this refers to the diameter in the larger dimension. The smaller channel
has an incorporated 2-mm movable blocker that can be advanced into the desired bronchus or retracted
when not in use. This channel increases the anteroposterior (AP) diameter, and it should be noted that
Univent tubes have a larger external diameter in general than their single-lumen counterparts. For
example, an 8.0 single-lumen ETT has an outer diameter (OD) of 10.8 mm. Contrast this to the 8.0
Univent, which has an OD of 13.5 mm AP and 11.7 mm left to right.25
It has been suggested that, because of its reduced bulk and anatomic angulation, there is less potential
for airway trauma with insertion of the Univent compared with a DL ETT.37 While the author was not able
to find studies to support this claim, these characteristics certainly may make this tube easier to insert in a
patient with a difficult laryngoscopy. However, if a fiberoptic intubation is anticipated or needed after
failed intubation attempts, the Univent may be too rigid and bulky to manipulate into the airway over a
scope. It would then be the author’s recommendation to intubate with a conventional single-lumen ETT
and use one of the independent bronchial blockers described below.
The blocker has a high-volume, low-pressure cuff that requires 4 to 8 mL of air to achieve occlusion of
the mainstem bronchus and about 2 mL for selective lobar occlusion.24 The blocker has a plastic grip at
its proximal end35 to facilitate guidance into the desired bronchus. Like other blockers, the device has a
hollow lumen that allows for lung deflation either passively or by suctioning. It also allows for CPAP if a
connector for a 3-mm-ID single-lumen ETT is placed first.38 The Univent is relatively versatile, with
reports of use in patients with tracheostomies39 and to facilitate jet ventilation during sleeve
pneumonectomy.40 The blocker is somewhat rigid and can be repositioned during a case. The main
proposed advantage of the Univent tube is that, at the end of the case, the bronchial blocker can be
retracted and the tube used for conventional ventilation in patients with postoperative ventilatory
dependence.
FIGURE 26.3 A: Proximal end of Fogarty embolectomy catheter demonstrating rigid, replaceable wire stylet. B: Distal end of
Fogarty catheter. The balloon is inflated with 3 mL of air. Notice the relatively spherical shape.
The Univent is placed by laryngoscopy. The bronchial channel facies forward so that the larger AP
diameter passes longitudinally through the vocal cords. Once through the cords, the channel is turned 90
degrees toward the bronchus to be isolated. A fiberoptic scope is advanced to the distal end of the
ventilatory lumen to visualize blocker placement. As with other bronchial blockers, if the right upper lobe
is to be included in the isolation, it may need to be deflated with suction through the scope. The ability to
torque the blocker with the plastic grip may help with placement. The blocker should be 3 to 5 mm down
the desired bronchus and inflated with enough air to prevent a noticeable leak.
In addition to those already mentioned, the Univent has other potential disadvantages. Recall that the
Univent has an oval lumen with a smaller cross-sectional area than that of a single-lumen ETT of the same
labeled ID. The ventilatory lumen is further compromised as tube diameter decreases. Indeed, Slinger and
Lesiuk41 showed disproportionately higher resistance to airflow in smaller (less than 7.5 mm ID) Univent
tubes. It must also be kept in mind that the bronchial blocker can migrate back into the trachea
postoperatively. Inadvertent inflation of the bronchial cuff can lead to difficulty with ventilation or
respiratory arrest.42 If the pilot balloon to the blocker is cut prior to transport to the ICU, this
complication can be avoided. Pneumothorax, as a complication, has been reported,43 but this was felt to
be due to insertion of the entire tube initially inserted into the left mainstem bronchus, resulting in
bronchial trauma. Other complications include detachment of the blocker balloon of a 3.5-mm Univent
tube and fracture of a sliver of plastic into a patient’s airway (which was recovered) from the proximal
end of the tube, possibly because the slip joint of the connector was a bit larger than the ventilatory
lumen.44,45
FIGURE 26.4 Univent tube. A: Retractable blocker extended somewhat beyond distal end of tube for display. The pilot balloon
for the blocker has a smaller syringe attached than the pilot for the cuff of the endotracheal tube. B: Closeup of the blocker
inflated with 3 mL of air. Notice that it has a somewhat more spherical shape than the Arndt cuff, potentially applying more
pressure to the isolated bronchus.
WIRE-GUIDED ENDOBRONCHIAL BLOCKERS

A wire-guided bronchial blocker is used much more commonly in modern anesthetic practice. Arndt et
al.46 developed the first such device in the late 1990s. It comes as a 7- or 9-Fr catheter with two lumens:
one small (0.4 mm) for inflation of the distal balloon and another larger for lung deflation or application
of CPAP. It comes in lengths of 65 cm (7 Fr) and 78 cm (9 Fr), with depth markings on the surface. There
is also a 5-Fr, 50-cm device meant for pediatric use. The original design incorporates an elliptical high-
volume, low-pressure balloon that has a greater contact surface area than the Fogarty catheter (Fig.
26.5).35 However, a more spherical design is now available. It has been recommended by Campos35 that
the spherical balloon be used in the bronchus intermedius in blocking the right side so as not to include
the right-upper-lobe bronchus and to use the elliptical design for occlusion of the left side. If the elliptical
balloon is used for right-sided occlusion, right-upper-lobe deflation will have to be achieved before
inflation of the balloon for lung isolation. This can be done by manual compression from the surgeon with
the balloon deflated once the chest is open or by applying suction to the right-upper-lobe bronchus through
the fiberoptic scope.
This device was meant to be placed within a conventional single-lumen ETT. It comes with a multiport
adaptor which has three ports: one with an adjustable diaphragm for passage of the blocker to allow an
airtight seal around the device, one for passage of the fiberoptic scope, and one that connects to the
breathing circuit. It is recommended that at least a 7.0-mm ID ETT be used with a 7-Fr catheter and an
8.0-mm ID tube be used with a 9-Fr catheter,35 keeping in mind that the tube will have to accommodate a
3- to 4-mm scope as well. There is a flexible nylon wire in the larger lumen, which terminates in a loop at
the distal end of the blocker. The loop is meant to accommodate the fiberoptic scope, coupling the scope
and blocker to be advanced simultaneously.
FIGURE 26.5 A: Cuff (distal end) of Arndt bronchial blocker inflated with 5 mL of air. Notice the elliptical shape and potentially
broad contact area with the isolated bronchus. B: Multiport adaptor with fiberoptic bronchoscope and Arndt blocker in place.
Notice the coupling of the blocker and scope provided by the distal wire loop of the blocker.
Before placement of the blocker, it is recommended that the blocker and fiberoptic scope be placed in
the multiport adaptor before the adaptor is attached to the breathing circuit. A small amount of water-
soluble lubricant may be placed on the blocker cuff. It is important to deflate the balloon fully and have
the blocker port of the adaptor fully open to avoid damage to the balloon. The scope should be passed
through the nylon loop before placement of the adaptor on the ETT. The author prefers to “snare” the
scope with the nylon loop by placing traction on it from the proximal end. In ventilating the patient during
blocker placement, it may be necessary to use high fresh gas flows to compensate for leaks around the
scope and blocker. As mentioned above, the scope and blocker are introduced into the desired bronchus
simultaneously. This is often a two-person task. The snare can then be loosened and the blocker advanced
a bit further. The wire loop and balloon will be seen past the distal end of the scope. The scope is then
retracted above the carina and 6 to 10 mL of air is used to inflate the cuff. The proximal edge of the
balloon should be at least 5 mm below the carina in the targeted bronchus. Blocker position is rechecked
after patient position is changed from supine to lateral. One study found the Arndt blocker to be more
prone to malposition than other devices (DL ETTs and Univent tubes), but this was not a statistically
significant difference—perhaps due to sample size.47 As anesthesiologists have gained more experience
with various blockers, this has become less of an issue.48
Once the tube is in position, the nylon wire is removed. The larger lumen can now be used to facilitate
deflation of the surgical lung, an advantage over the Fogarty catheter. The large lumen can also be used to
apply CPAP to the surgical lung if the patient experiences profound hypoxia. A connector for a small
single-lumen ETT (3.0 mm) can be used to attach it to a CPAP delivery device. If the blocker becomes
malpositioned after wire removal, the wire can easily be placed back into the large lumen and coupled
with a scope like before. A possible disastrous complication is extrusion of the inflated balloon above the
carina and occlusion of the entire airway. Although there are no case reports of this resulting in significant
morbidity, it should be suspected if airway pressures rise suddenly during a case and should be acted on
immediately.
The Arndt wire-guided bronchial blocker takes longer on average to properly position than other lung
isolation devices for both thoracic and nonthoracic anesthesiologists and, as mentioned above, may be
more prone to malpositioning than other lung isolation devices.47,49 However, bronchial blocking devices
designed for use with single-lumen ETTs provide surgical conditions comparable to other techniques
when used properly and have a clear place in the anesthesiologist’s armamentarium. For those patients
with difficult airways or anticipated postoperative ventilatory dependence, bronchial blockade offers a
safe and effective alternative.50
TIP-DEFLECTING ENDOBRONCHIAL BLOCKER

The Cohen Tip Deflecting Endobronchial Blocker by Cook Critical Care (Bloomington, IN) shares many
of the characteristics of the Arndt blocker. The 9-Fr, 65-cm catheter has a low-pressure, high-volume
balloon and a central 1.6-mm lumen for lung deflation and CPAP application. The kit comes with a
multiport adaptor for use with a fiberoptic scope. However, the device does not have a distal loop for
direct coupling with the scope. It has a soft nylon tip that is coupled with a plastic wheel at the proximal
end. The wheel can be turned to deflect the tip as much as 90 degrees, but only in one direction (indicated
by an arrow on the distal end of the blocker). In addition, there is a 2-cm external sleeve that can be used
to grip the blocker and torque it toward the desired bronchus. Although it is not coupled with a scope, the
device should still be placed under direct visualization with the scope placed above the carina. The distal
arrow can then be visualized and indicate the direction of deflection of the tip.51
FIGURE 26.6 A Cohen Flextip catheter placed through an Arndt-style multiport adaptor and a single-lumen endotracheal tube
(ETT). Notice the wheel assembly on the proximal end. The cuff of the blocker (most distal) has a more spherical shape than
that of the Arndt blocker.
This blocker shares many of the advantages of the Arndt blocker. The central lumen allows for lung
deflation and CPAP application. One additional advantage is relative ease of repositioning, so that it
could be used for sequential lung isolation if needed.52 As with the Arndt, it is recommended that an 8-
mm ID ETT be used with the blocker to allow for its manipulation, as well as a 4-mm fiberoptic scope.52
There is one report of the wheel assembly becoming separated from the blocker,53 suggesting that multiple
manipulations of the wheel may lead to device failure (Fig. 26.6).
NEWER ENDOBRONCHIAL-BLOCKING DEVICES

The quest continues to produce lung isolation devices that are less bulky (less potential for airway
trauma) than the double lumen ETT, provide adequate lung isolation, and can be more easily placed by
nonthoracic anesthesiologists. Two devices recently introduced into practice will be discussed below.
The EZ-Blocker (Teleflex) was introduced into practice in 2010 (Fig. 26.7).54 It is a bifurcated (Y-
shaped), 7-Fr device that is designed to “straddle” the carina.15 A spherical balloon is at the tip of each
limb, allowing the user to isolate either lung by inflation of the proper balloon. Like other blockers,
fiberoptic bronchoscopy should be used to initially place and reconfirm position with lateral patient
positioning. One recent small study showed that there was less incidence of malpositioning when
compared to tip-deflecting blockers.55 Two recently randomized trials demonstrated that the EZ-Blocker
provides comparable lung isolation to double lumen ETTs.56,57 The latter study went on to show that there
were fewer complaints of sore throat, and less postoperative bronchoscopic evidence of airway irritation
and/or bleeding.57 One recent case report detailing failure to isolate the right lung raised concern that this
device may not be optimal if the right upper lobe bronchus ostium is proximal and/or the bronchus
intermedius is short.58
FIGURE 26.7 The EZ-Blocker has two hollow lumens and two cuffs, allowing for isolation of either lung. The device was
meant to straddle the carina.
The Uniblocker (Teleflex) is an independent blocker that is more rigid and has a fixed “hockey-stick”
angulation at its distal end (Fig. 26.8).15 Unlike wire-guided or tip-deflecting blockers, it allows for
torque control for placement, does not have a wheel assembly at its proximal end, and does not need to be
directly coupled with a fiberoptic scope.32 A recent randomized trial of 104 patients found that various
types of blockers (including the Uniblocker) provided comparable lung isolation to left-sided double
lumen ETTs. The authors noted that the blockers needed to be repositioned more frequently, especially
wire-guided blockers.48
FIGURE 26.8 The Uniblocker has a fixed bend at its distal end, and was meant to be placed by torque control from the
proximal end.
MANAGEMENT OF ONE-LUNG VENTILATION

The institution of OLV carries the potential for hypoxia, hypoventilation, and HD instability for a variety
of reasons. In selecting ventilatory parameters, one must take into account the effects of HPV, absorption
atelectasis, diffusion capacity of both O2 and CO2, the risk of barotrauma to the lung tissue, and the effects
of lung volumes on venous return.
Even in the healthiest patients, OLV results in a significant shunt fraction. Oxygen toxicity, initially
seen in patients exposed to a high PaO2 for a prolonged period, has become a topic of discussion during
the intraoperative period as well.16,59 Elderly patients have less ability to clear oxygen-free radicals than
younger patients when exposed to even brief periods of hyperoxia.60,61 The use of hyperoxic fresh gas
during OLV should be considered on a case-by-case basis, balancing the risk of end-organ ischemia due
to hypoxia and the potential for oxygen toxicity. The author’s current practice is to use 100% oxygen only
during the initial portion of a thoracic case. In addition to preventing hypoxia during tube placement and
confirmation, denitrogenation of the surgical lung allows for more rapid deflation and improved surgical
exposure.62 Once the surgical lung is isolated, an oxygen/air mixture is titrated to keep the arterial
saturation 90% or greater. This should allow for adequate oxygen delivery in the setting of normal cardiac
output and hemoglobin. Should the situation change, increasing oxygen saturation may be necessary to
avoid end-organ damage.
Previous practice had been to achieve the same minute ventilation on OLV to eliminate an equivalent
amount of CO2 as with two-lung ventilation. This resulted in recommendations of tidal volumes of 8 to 12
mL/kg in patients with reasonable compliance. More recent literature has shown that not only is the
incidence of profound hypoxia far less than in the past, but also that the use of high tidal volumes has been
associated with postresection pulmonary edema.63,64 Higher tidal volumes also raise dependent lung
vascular resistance and decrease nondependent lung HPV, resulting in shunting of blood to the
nonventilated lung and potential worsening of oxygenation.10 More recent literature recommends tidal
volumes of 5 to 8 mL/kg (less in some circumstances), the addition of a modest amount of positive end-
expiratory pressure (PEEP), and regular recruitment breaths of 30 cm H2O to avoid the cyclic
overdistention and atelectasis seen with previous regimens (though to predispose to ALI).61
Normocapnia, which can be defined as a PaCO2 of 40 mm Hg, would result in an end-tidal CO2 of 30
to 35 mm Hg for most individuals. If tidal volumes are reduced from those seen in two-lung ventilation,
respiratory rate would have to be increased to maintain minute ventilation. However, an increase in
respiratory rate means a shorter exhalation time for each breath and may result in dynamic hyperinflation
in patients with increased airway resistance and impedance to exhalation. This phenomenon is also
known as “breath stacking” (or autoPEEP), and can result in barotrauma, decreased venous return
secondary to increased intrathoracic pressure, and HD instability. Methods to limit/manage this include
increasing the expiratory part of the respiratory cycle, temporarily disconnecting the patient from the
ventilator to allow a full exhalation, and intentionally decreasing the respiratory rate.
Permissive hypercapnia is frequently used in the ventilation of critically ill patients with lung
compliance issues, such as those with acute respiratory distress syndrome (ARDS).65 Hypercapnia has
become more acceptable in the setting of OLV as well. In fact, some degree of hypercapnia may actually
enhance tissue oxygenation by two mechanisms. Activating the sympathetic nervous system would
increase cardiac output, and a shift to the right in the oxyhemoglobin dissociation curve would encourage
the release of oxygen at the tissue level.66 The degree of hypercapnia permissible is debatable, but most
would agree that the pH should routinely be no less than 7.20 so as to limit pulmonary vasoconstriction,
indiscriminate cerebral vasodilation, and the arrhythmogenic effects of CO2. If the acidosis is purely
respiratory, this would correlate with a PaCO2 of 65 mm Hg.67
It is the author’s preference to use pressure-control ventilation (PCV) during OLV. The fact that the
tidal volume is pressure-limited reduces the risk of barotrauma. The peak pressure is adjusted to achieve
a tidal volume consistent with what was described above without excessive pressure. In addition, the
tidal volume is delivered with continuous flow during volume-control ventilation (VCV), with the peak
airway pressure achieved at end-inspiration. By contrast, the tidal volume is delivered with decelerating
flow during PCV. Peak pressure is sustained during the entire inspiratory period, with the potential to
recruit more alveolar units. However, a study from 2007 showed no appreciable difference in
oxygenation when PCV is compared with VCV during OLV.68 The same study showed that peak pressures
were lower with PCV when tidal volumes were maintained at 9 mL/kg. It should also be noted that PCV
requires more vigilance on the part of the anesthesiologist. Should conditions change during the case
(change in compliance, secretions, ETT positioning), the same peak pressure may result in a lower
delivered tidal volume. In this situation, though, there will be no alarm to alert the anesthetist, as opposed
to volume-limited settings, where increases in peak pressure due to changes in compliance will result in
an alarm sounding if the peak pressure is above a set limit (usually 40 mm Hg).
In general, higher peak airway pressure will be the result when OLV is instituted. But it should not
routinely be 50% above what was seen with two-lung ventilation.30 A good deal of this is the result of
delivering an adult-sized tidal volume through a small ETT lumen. Even in a 41-Fr DL ETT, the ID of
each lumen is only 5.4 mm.24 A better assessment of the pressure the alveoli are exposed to may be
plateau pressure. This is measured during a brief pause at end-inspiration, allowing pressures in the
entire airway–alveolar system to equilibrate. Plateau pressures of 30 to 35 cm H2O are accepted in
critically ill patients for whom the avoidance of ventilator-induced lung injury is desired.65 Most
anesthesia delivery systems, however, do not have this capacity. The author prefers to limit peak
pressures to 30 cm of H2O on OLV for most patients.
HYPOXIA DURING ONE-LUNG VENTILATION
When hypoxia (O2 saturation <90%) is encountered, the steps taken to address the situation depend on a
couple of things: (1) Was the drop in saturation sudden or did it occur more gradually? (2) Was the
desaturation accompanied by a change in peak airway pressures and/or HDs? If it occurred suddenly with
a change in other parameters, possible explanations include tube malpositioning, mucus plug or blood in
the airway, and contralateral tension pneumothorax. Increasing the FIO2 is 1.0 and that the ETT is
properly positioned are the initial steps in management. DL ETTs can migrate during the course of a case,
usually upward, with the bronchial cuff approaching the carina. ETT position should be verified with a
fiberoptic scope. Suctioning of the airway to remove debris is usually the next step. In an emphysematous
patient with known bullous disease, desaturation, increased airway pressures, and compromised HDs,
contralateral tension pneumothorax should be high on the differential. One should have a discussion with
the surgeon, however, before attempting needle decompression of the contralateral pleural cavity.
Assuming that the above problems are not at issue, the reasons for hypoxia and ways to manage it can
be grouped into two categories: V./Q. mismatch in the ventilated lung and shunt to the nonventilated lung.
In the author’s algorithm, V./Q. mismatch is usually tended to first unless profound hypoxia is encountered
(sustained O2 sat ≤85%). Interventions to the nonsurgical lung will allow a modest increase in
oxygenation without compromise of the surgical field. If possible, increasing tidal volumes to around 8 to
10 mL/kg will decrease areas of atelectasis. An increase in FRC, and thus V./Q. ratio, can be
accomplished with the addition of a small amount of PEEP. Too much PEEP, however, can increase
resistance to blood flow in the dependent lung. This will divert flow to the nondependent lung and
worsening oxygenation. There is general agreement that the ideal level of PEEP is probably between 5
and 8 cm H2O.16,69 Slinger and colleagues70 showed that PEEP improved oxygenation if the additional
pressure increased lung volume to the lower inflection point (beginning of the steep portion) of the lung
compliance curve, suggesting potential benefit only in selected patients. Another study showed that
patients with a low initial PaO2 on 0.5 FIO2, and thus judged to have a low FRC, had much more of an
increase in arterial oxygenation with the application PEEP than those with a high PaO2 initially.71 These
findings taken together suggest that patients with a normal or supranormal FRC (as seen in severe
obstructive disease) may not benefit much from added PEEP and may be more prone to deleterious
effects, including dynamic air trapping.
If increasing tidal volumes and the application of modest PEEP does not improve oxygenation, or if
profound hypoxia occurs, shunt to the surgical lung must be addressed. An effective way to do this is to
apply CPAP to the nonventilated lung. Even low levels of CPAP can significantly improve oxygenation
during OLV.72 CPAP expands alveoli in the nondependent lung and allows them to participate in
oxygenation. CPAP as high as 10 cm H2O (without concomitant dependent PEEP) does not have
hemodynamically significant effects.73 CPAP should be initiated during the exhalation phase of a large
tidal volume to achieve its greatest effect. Thus CPAP distends the surgical lung somewhat.16 It has been
written that in lungs with normal compliance, the application of 5 to 10 cm CPAP should not result in
enough distention to interfere with surgery.4,15 Nevertheless, cooperation of the surgical team is necessary.
Many devices have been described for this purpose.4,74 The author uses a Mapleson F circuit attached to
the nonventilated lung lumen of the DL ETT or bronchial blocker. It has an oxygen inflow close to the
patient, corrugated tubing leading to a breathing bag, and an adjustable pressure-limiting valve at the end
of the bag. Selective occlusion of the valve limits the egress of oxygen and delivers sustained positive
pressure. The bag also allows one to intermittently hand-ventilate the surgical lung if necessary (Fig.
26.9).
FIGURE 26.9 Mapleson F circuit for application of continuous positive airway pressure (CPAP) to the nonventilated lung during
thoracic surgery. The smaller clear plastic tubing is attached to an oxygen source and serves as the inspiratory limb. The larger
corrugated tubing serves as the expiratory limb (“pop-off”) with an adjustable outlet at its distal end for the desired level of
CPAP.
Should these measures fail, blood flow to the surgical lung can be interrupted with a ligature around a
branch of the pulmonary artery. Indeed, one often observes an increase in arterial oxygenation when a
pulmonary artery is ligated during a lobectomy or pneumonectomy. This will acutely decrease shunt
fraction but may place strain on the right heart, since pulmonary vascular resistance will be increased. It
may be necessary to ventilate the surgical lung intermittently in certain situations. This, of course, requires
cooperation from the surgical staff and may be more practical in procedures where OLV is of lower
priority.
CONDUCT OF ANESTHESIA
Anesthesia for thoracic surgery can use a number of anesthetic techniques. Sedation with surgeon-
administered local anesthesia, regional anesthesia, general anesthesia, and a combination of regional and
general anesthesia are all techniques described for thoracic surgery or related procedures.15,75–77 By far
the most often used technique is general anesthesia. This provides a comfortable environment for the
patient, allows for lung separation to improve surgical conditions, and has the flexibility to last as long as
required to accomplish the surgical task. The specific surgical requirements and the patient’s physical
status determine the exact agents, monitors, and airway management technique.
PREINDUCTION MEDICATIONS
Benzodiazepines are frequently used preoperatively in small doses for anxiolysis prior to anesthetic
induction. They also aid in reducing the incidence of intraoperative awareness.78 The major side effect of
benzodiazepines is respiratory depression, especially in patients taking narcotics perioperatively. The
risks versus benefits of administering benzodiazepines should be weighed carefully in the elderly,
critically ill, or patients with respiratory compromise.
Antisialagogues may be useful for bronchoscopy, esophagoscopy, or during awake fiberoptic
intubations in patients with known or suspected difficult airways. Glycopyrrolate is an anticholinergic
agent and an effective antisialagogue. Glycopyrrolate’s quaternary structure prevents it from crossing the
blood–brain barrier, reducing the potential for CNS side effects and sedation.79 Glycopyrrolate’s
muscarinic blocking effects (and the subsequent increase in heart rate) need to be balanced against the
risk of tachycardia, particularly in patients with risk factors for ischemic heart disease.
Prior to thoracotomies, an epidural catheter will often be placed and tested. It should be placed prior
to anesthetic induction to monitor the patient for paresthesias. Infusion of a local anesthetic through the
catheter intraoperatively will lessen the amount of anesthetic and opioid needed, but may be a source of
intraoperative hypotension (see “Regional Anesthesia and Pain Management,” below).
INDUCTION AGENTS FOR GENERAL ANESTHESIA

General anesthesia can be induced with either intravenous medications or inhalational agents. Inhalational
inductions are used when spontaneous ventilation may have a benefit, as in patients with mediastinal
masses or airway pathology that precludes positive-pressure mask ventilation. Currently, sevoflurane is
the most efficacious agent for mask induction. It is the least pungent of all agents now on the market and
has a rapid equilibration phase with the blood, owing to its low blood solubility.80
Intravenous induction for general anesthesia is the most common technique when airway compromise
is determined to be minimal with loss of spontaneous ventilation. Frequently, neuromuscular blocking
drugs (NMBDs) are used as part of an intravenous induction to produce muscle relaxation and facilitate
intubation. Use of an NMBD is not always necessary and can even be relatively contraindicated (e.g.,
myasthenia gravis).81,82,83
Common intravenous induction agents are propofol (1 to 2 mg/kg), etomidate (0.3 mg/kg), or ketamine
(1 to 2 mg/kg).84 Propofol is excellent for induction because of its rapid effect and clearance. Etomidate
is said to affect systemic vascular resistance (SVR) and myocardial contractility less than propofol, and
produce a lesser drop in blood pressure with induction. Ketamine can have psychotropic side effects,
which are usually diminished or eliminated with use of preoperative benzodiazepines. Ketamine has
sympathomimetic properties, can produce tachycardia, and may be relatively contraindicated in patients
with coronary artery disease. Nevertheless, it is effective at producing a dissociative state suitable for
intubation. Unlike other intravenous induction agents, ketamine has analgesic properties, is a potent
bronchodilator, and does not lead to respiratory depression.84,85 This may be advantageous in certain
patient populations.
Opioids are frequently administered at induction to blunt the sympathetic response to intubation and
provide an analgesic base for surgical incision. Fentanyl 2 to 5 μg/kg is used to blunt blood pressure
increase with intubation with a total fentanyl dose of 5 to 10 μg/kg for the total case for intraoperative and
immediate postoperative analgesia. Hydromorphone is less potent than fentanyl, but has a longer duration
of action and may be administered intravenously or epidurally. Morphine, a long-acting opioid, may
induce clinically important histamine release and vasodilatation.86 Opioids have not been shown to have
an appreciable effect on HPV in isolated animal lung tissue. Fentanyl has not been shown clinically to
have an effect on HPV with either intravenous or epidural administration.87
MAINTENANCE OF ANESTHESIA
General anesthesia is most often maintained with inhaled agents. After induction, any inhaled agent is
suitable for maintenance.77,88–90 Desflurane is very insoluble, achieves a rapid equilibrium between the
alveolar and blood phase, and is easily titrated. Isoflurane is an effective, cheap, and reliable agent. It has
less sympathetic stimulation than desflurane, and may be cardioprotective owing to its ischemic
preconditioning properties.91 Sevoflurane is an effective maintenance agent with a very similar profile to
isoflurane.88 All inhalational agents impair HPV in a dose-dependent manner and may have limited use in
patients with large shunt flow during OLV.90
Of particular interest is the effect of inhalational anesthetics on HPV. Isoflurane inhibits HPV in a
dose-dependent manner, so that impaired oxygenation during OLV is at least a theoretical concern.92
Benumof69 used the work of Domino and colleagues93 to show that one minimum alveolar concentration
(MAC) of isoflurane (or 1.15%) would inhibit HPV by 21% (or approximately one-fifth). The effect
would be to increase blood flow to the nonventilated lung from 20% of cardiac output to 24%. Assuming
an FIO2 of 1.0, this would reduce the arterial PO2 from 280 mm Hg to 205 mm Hg,4 but arterial saturation
would still be high (>97%) and the oxygen content of the blood would not be much less. In fact, clinical
studies from the 1980s showed that isoflurane and halothane made no significant difference even in
arterial PO2 when compared with intravenous agents (which are not believed to inhibit HPV).94,95
Sevoflurane and desflurane have also been shown not to have a clinically significant effect on
oxygenation.96–98 Desflurane has been shown to have the same dose-dependent effect on oxygenation as
isoflurane, but neither was significant. The author surmises that the decrease in cardiac output seen with
these agents, especially to the nonventilated lung, may offset inhibition of HPV.98
In situations with intermittent ventilation or a shared or open airway, inhaled agents may not be
appropriate, and total intravenous anesthesia (TIVA) is the method of choice.81–83 Although inhalational
agents generally do not contribute to decreased oxygenation (above), it is reasonable to use TIVA for
patients at risk for significant hypoxia. The goals of TIVA are exactly the same: proper level of sedation to
prevent awareness, appropriate analgesia, and optimal surgical conditions (a still patient). Propofol as a
continuous infusion is an excellent agent to accomplish TIVA. Depending on the patient’s age, physical
status, and the amount of other anesthesia already administered, infusions ranging from 50 to 150 μg/kg
per minute will achieve good conditions.82–84
Propofol has been shown not to have an inhibitory effect on HPV when used as an infusion
intraoperatively.97,99 Ketamine has also been used as a continuous infusion for OLV.100 Unlike propofol,
ketamine maintains cardiac output and systemic vascular tone, making it a good agent to use in patients
who are hemodynamically unstable. It also has not been shown to cause a significant decrease in arterial
oxygenation during OLV.
Another agent frequently used during TIVA is remifentanil, a very potent, rapidly metabolized synthetic
opioid. It is chemically related to fentanyl but has an ester linkage that can be hydrolyzed by nonspecific
tissue esterases. This gives the drug a half-life of minutes.86 Remifentanil has no amnestic properties,
which makes using it as the sole TIVA agent inappropriate. However, in combination with propofol it
produces excellent anesthetic conditions. Remifentanil produces excellent analgesia at doses of 0.1 to 0.3
μg/kg per minute following a loading dose of 1 μg/kg. Remifentanil provides little to no postoperative
analgesia, making it essential to load with a longer-acting opioid or to initiate an epidural infusion at the
conclusion of surgery.78,81–83 The effects of remifentanil on HPV have not been studied, but it has not
contributed to hypoxia on OLV in the author’s experience, and it is reasonable to assume that its effects
are similar to those of other opioids. Remifentanil’s extremely short half-life makes it ideal for other
applications as well. It can be used as a bolus with induction to blunt the HD response to laryngoscopy
and intubation. It can also be used as an infusion with inhaled anesthetics, decreasing the amount of
inhalational agent needed for anesthesia. This is also ideal if long-acting systemic opioid analgesia is not
desired for a particular patient, and especially if an epidural infusion will serve as the primary
postoperative analgesic.
TIVA is frequently achieved by using smaller doses of multiple, rapidly acting, and rapidly
metabolized agents. A combination of propofol, remifentanil, and a preoperative benzodiazepine
(midazolam) is a typical TIVA regimen. This allows the anesthesiologist to get the benefits of each drug
while minimizing side effects of large doses of single agents.
Dexmedetomidine is a newer intravenous anesthetic agent. This alpha-2 receptor blocker has sedative
and analgesic properties (an opioid-sparing effect). It is rapidly cleared (half-life of 2 hours) and
produces excellent sedation without significant respiratory depression. Thus it is useful for situations
where spontaneous ventilation is necessary or desired. The standard regimen is to give a loading dose of
1 μg/kg over 10 minutes, followed by a rate of 0.2 to 0.7 μg/kg per hour, depending on the desired depth
of sedation. Although rare, the primary side effects are decreases in blood pressure and, according to
case reports, occasional asystole in bradycardic patients.101,102 Animal studies show an increase in
pulmonary vascular resistance with bolus administration of the drug.103 However, a recent small study
showed that a dexmedetomidine infusion did not adversely affect oxygenation during OLV when used in
conjunction with inhaled desflurane.104
Vasoactive drugs may be used in certain patients to maintain myocardial contractility and/or vascular
tone. Vasoconstrictor drugs—such as phenylephrine, dopamine, and epinephrine—apparently constrict
vessels in normoxic areas of lung preferentially.105,106 While these agents may not directly inhibit HPV,107
the net effect is to divert blood flow to hypoxic regions, with a resultant reduction in oxygenation. Most
vasodilatory drugs either directly inhibit HPV or have a clinical effect consistent with inhibition of
HPV.10 These drugs include the nitric oxide donors nitroprusside and nitroglycerin,108,109 some calcium
channel blockers,13 and beta agonists such as dobutamine107 and isopreterenol.107,110 Inhaled nitric oxide,
however, may dilated vessels in better-ventilated areas of the lung, having the same effect as enhancing
HPV.10 Hydralazine has not been shown to inhibit HPV.111
FLUID MANAGEMENT
Fluid management during lung surgery is an evolving field. While newer, better-designed studies are
shedding important light on this issue, the underlying premise is that the specific therapy is dependent on
the specific surgery performed, the patient’s medical status, and the source and severity of surgical acute
volume change. It is impossible to list all of the variables that would lead to a specific fluid regimen.
This section will discuss generally accepted fluid management strategies for pulmonary resection.
Iso-osmotic crystalloids have an excellent safety record, no issues of transfusion or allergic reaction,
and are economical. Nevertheless, lung surgery poses unique problems in fluid management. The lungs
are uniquely susceptible to volume overload due to a variety of issues (cardiogenic, impaired lymphatic
drainage, inflammation, changes in pulmonary capillary permeability).64,112,113 Postresection pulmonary
edema is a dreaded complication of lung resection, with a high morbidity and mortality rate.64
Contributing factors include innate patient susceptibility, the extent of the resection (pneumonectomy >
lobectomy > wedge resection), length of surgery, and the amount of crystalloid administered in the first 24
hours of the perioperative period.15,114 One source calls for limiting crystalloid to less than 2 L
intraoperatively and less than 3 L in the first 24 hours.64
An emerging tenet in fluid management is to limit crystalloid administration throughout the
perioperative period when possible. Previous fluid regimens took into account maintenance fluid rates,
replacement of intravascular and extravascular (insensible) volume loss with mostly crystalloid, and
replacing volume lost to a theoretical “third space.” Recent literature has called the existence of a third
space into question.115 Furthermore, there is recognition that the endothelial glycocalyx layer (EGL),
which exists in the luminal side of capillaries, plays an important role in mediating the migration of fluid
into the extravascular space. Administration of crystalloid disrupts this layer, causing more extravasation
of fluid. Colloids do not seem to cause this problem.116 Even for gastrointestinal surgery, crystalloid-
restrictive regimens appear to reduce postoperative pulmonary complications.113,117,118 While the risk of
acute kidney injury exists, maintenance of adequate HD parameters and tissue oxygenation will minimize
this risk if restrictive crystalloid regimens are used.119,120 Maintenance of urine output of at least 0.5
mL/kg/hr seems less important.15
Current literature concerning pulmonary resection points to using crystalloid only to replace
extravascular fluid loss (maintenance) and/or as a carrier for necessary infusions. Intravascular volume
loss should be replaced 1:1 with colloid or appropriate blood product. Which colloid to use is a matter
of debate. The author’s institution uses 5% albumin, which is an excellent intravascular volume expander.
It should be noted that the potential for allergic reaction exists, and that chelation of calcium by albumin
may lead to hypocalcemia. Synthetic colloids, such as hydroxyethyl starch (HES) solutions, have been
shown to expand intravascular volume effectively.121 However, HES has been shown to produce platelet
dysfunction in large doses, possibly increasing blood loss postsurgically.122 HES has been implicated in
acute kidney injury in critically ill and postsurgical patients,123,124 but other sources have questioned
this.125
Blood transfusion in lung surgery is a topic that merits discussion. ABO incompatibility, allergic
reactions, and infectious disease transmission have greatly decreased over time, but other risks specific to
the thoracic surgery patient remain relevant. Transfusion-related acute lung injury (TRALI) is a severe
complication with acute onset. Immunologic factors (related to donor white blood cell antibodies in
plasma-containing products) and patient-specific factors (native vascular endothelial injury and adhesion
molecule formation due to surgery or critical illness) play a role. The end result is vascular leak and
acute-onset pulmonary edema that still carries a high morbidity and mortality rate. Research in blood
banking is developing strategies to limit the occurrence of TRALI (neutralization of HLA-reactive
antibodies, preference for male and nulliparous female plasma donors).126 While leukocyte-reduced
packed red cells are more commonly administered in developed countries, there is still a concern that
transfusion is associated with recurrence of resected cancer. A recent meta-analysis of over 6,400
patients demonstrated that allogeneic transfusion was associated with earlier recurrence and worse
survival in resected lung cancer patients, even when type of cancer and stage were taken into account.127
Taken together, recent findings suggest restrictive fluid and transfusion regimens in thoracic patients.
Nonetheless, risks and benefits of fluid and blood component therapy must be individualized to each
patient. For instance, elderly or anemic patients may need an intraoperative transfusion, while younger
patients with less comorbidity may tolerate a lower hematocrit better and not require transfusion for a
similar volume of blood loss. Strategies to treat preoperative anemia (erythropoietin, iron therapy, etc.)
limit blood loss (surgical technique, antifibrinolytic therapy), and blood retrieval in certain cases (cell-
saver use with appropriate filters for cancer cases) may help obviate the need for transfusion.128
INTRAOPERATIVE MONITORING
The American Society of Anesthesiologists (ASA) standard monitoring for all patients receiving care by
an anesthesiologist includes at least electrocardiography, pulse oximetry, temperature, blood pressure,
and ventilation/gas exchange. Under general anesthesia with an intubated patient, ventilation and
oxygenation are monitored with the addition of ventilation disconnect alarms, end-tidal CO2, and fraction
of inspired oxygen sensing.129 Monitoring beyond the ASA standard is dictated by the surgery’s
invasiveness, the patient’s physical status, risks of placing/using the monitor, and whether the data
gathered will be reliable in light of patient positioning or surgical intervention.
Cases involving OLV frequently use direct continuous arterial blood pressure measurement (arterial
line). This allows for early recognition of HD changes and easy arterial blood gas monitoring. An
evolving area of interest is the use of pulse pressure variation (PPV) and stroke volume variation (SVV)
calculations using the arterial line tracing. These are less-invasive tools than central venous pressure
(CVP) or pulmonary artery occlusion pressure (PAOP) to gauge fluid responsiveness intraoperatively and
in the intensive care unit. In the setting of positive-pressure ventilation, large (>10%) beat-to-beat
variations in pulse pressure and/or stroke volume indicate that the patient is intravascularly depleted and
may benefit from volume. This can be confirmed if a passive leg raise decreases PPV/SVV and/or
improves HDs. Initial research indicates greater sensitivity and specificity than CVP or PAOP.130 Despite
evidence and anecdote to the contrary, a couple of recent studies have suggested that SVV can be used
during OLV cases. However, tidal volumes were greater than 8 mL/kg, and the percent SVV used as a
threshold for fluid responsiveness was less than conventional values.131,132
Pulmonary artery catheters (PACs) may be useful for decision making in large pulmonary resections,
lung transplantation, or in severely compromised cardiac patients. For example, increases in PAP during
lung transplant may significantly guide therapy (e.g., suggesting conversion to cardiopulmonary bypass
[CPB] because of impending right ventricular failure [pretransplant] or signaling an occluded donor-to-
recipient pulmonary artery anastomosis [posttransplant]).133 A significant rise in PAP during a “test
clamp” of a pulmonary artery may signify impending right ventricular strain. PACs also generate a large
amount of other data. However, these can be difficult to interpret. Recently, transesophageal
echocardiography (TEE), either singly or in conjunction with a PAC, is being used to better interpret data
and guide intraoperative management.134–136
TEE provides a qualitative aspect in cardiac monitoring. In addition to ventricular volume and global
function, TEE is useful in monitoring for complications such as ischemia (ventricular wall motion
abnormalities), systemic air embolism, pulmonary vein tumor extension, right ventricular strain during a
“test clamp” of a pulmonary artery, and sequelae of pulmonary embolism.137–139 TEE can estimate PAP
and left ventricular end-diastolic pressure; it can also measure cardiac output, utilizing Doppler
technology.140 PACs may still be indicated when extensive cardiac monitoring is needed, but TEE is
medically (e.g., esophageal varices) or surgically contraindicated (e.g., in esophagectomy).
A WORD ON SEDATION
Sedation is defined by the ASA as care rendered to a patient in order to enable him or her to tolerate a
procedure with reduced anxiety and maximal comfort.141 Sedating medications (smaller doses of
midazolam, low-dose infusions of propofol or dexmedetomidine, etc.) are provided in an appropriately
monitored environment to produce a level of relaxation and even unconsciousness. However, the patient
should have the ability to maintain spontaneous ventilation, retain the airway reflexes, and be able to be
aroused with minimal stimulation. Sedation is an appropriate technique for minor procedures such as
superficial biopsies, flexible bronchoscopy, and chest tube insertion.15,76,89 Use of local anesthesia is
often necessary. For example, placement of a chest tube with sedation only will not address the need for
analgesia. With local anesthesia at the incision together with sedation, the patient can have the chest tube
placed with good pain control, reduced anxiety, and better cooperation with the surgeon.
A widespread misconception is that sedation is a milder and safer level of anesthesia and that surgeons
can execute major procedures on frail patients if only sedation rather than general anesthesia is used.
Related to this is the misconception that if a patient is uncomfortable during the procedure, the sedation
should simply be deepened. The more appropriate analysis is that sedation is a distinct type of anesthetic
care with a specific goal. If a patient does not tolerate a procedure under sedation, making the sedation
deeper converts it to general anesthesia, often with an uncontrolled airway, increased risk of aspiration or
insufficient ventilation, and HD compromise. The bottom line is that the limits of a technique must be
realistically assessed prior to surgery. If the invasiveness of the surgery or procedure is minimal and
local anesthesia is used properly, then sedation may be well tolerated. More invasive procedures,
regardless of patient frailty, probably require general anesthesia or a regional technique with appropriate
airway management and monitoring. This will place the frail patient at less risk for oversedation and
possible airway compromise.
ANESTHESIA FOR SPECIFIC PROCEDURES OTHER THAN

THORACOTOMY FOR PULMONARY RESECTION
BRONCHOSCOPY
Flexible diagnostic bronchoscopy is frequently accomplished with sedation and topical local anesthesia
to the airway. General anesthesia can also facilitate more involved bronchoscopy, especially if the
purpose is to obtain biopsies. Ventilation can be spontaneous or controlled, depending on the patient’s
disease. Airway management can be accomplished with either an ETT or a laryngeal mask airway
(LMA), usually depending on the location of the lesion. Subglottic intratracheal lesions in close
approximation to the vocal cords can be easily accessed via LMA airways; ETTs are appropriate for
more distal airway lesions. The emergence of the endobronchial ultrasound-guided biopsy (EBUS)
technique to sample mediastinal structures (e.g., lymph nodes) has increased anesthesiologists’
involvement with flexible bronchoscopy, and has reduced the need for mediastinoscopy (below).
TIVA, possibly with a short-acting NMBD, is the technique of choice for rigid bronchoscopy. Jet
ventilation is frequently used during these cases. The jet ventilator is not attached to a vaporizer,
eliminating the ability to administer inhaled agent. Furthermore, the lack of a gas analyser does not allow
for the detection of carbon dioxide with exhalation. Adequate ventilation is often assessed by visible
chest rise and maintenance of oxygen saturation.
MEDIASTINOSCOPY
When combined with bronchoscopy, general anesthesia with a large single-lumen ETT provides easy
access for the bronchoscope. A focus for patient monitoring has been to follow the right radial pulse to
detect compression of the brachiocephalic artery during mediastinoscopy. Often an arterial line is used
for this purpose. However, the author’s practice is to use pulse oximetry on the right hand in order to
monitor arterial compression, but to place an arterial catheter in the left radial artery for continuous
pressure monitoring. If the arterial line is placed on the right and the brachiocephalic artery is damaged,
the radial pulse waveform is lost, along with the capability for blood gas sampling and close HD
monitoring. Pulse oximetry has good sensitivity to detect arterial compression, and if the artery is injured
or compromised, it is far easier to establish a new site of oximetry than to place a second arterial line.
VIDEO-ASSISTED THORACOSCOPIC SURGERY

VATS is frequently accomplished with general anesthesia and a DLT. As in the case of thoracotomy,
arterial lines are often used to monitor both blood pressure and arterial blood gases throughout surgery.
VATS in sedated, spontaneously ventilating patients has been described, but is not part of the author’s
practice.75,76 VATS was originally used for less extensive procedures (wedge resection, pleurodesis,
empyema drainage, etc.). Recently, more intricate procedures (lobectomies, mediastinal mass resections)
are routinely performed using VATS. Here, good lung isolation is critical, and CPAP may distort the
surgical field. Reliable intravenous access is necessary in case there is acute blood loss necessitating the
need to convert to thoracotomy.
ANTERIOR MEDIASTINAL MASS

Anesthesia for mediastinal mass surgery depends on the goal of surgery. For diagnostic biopsy, sedation
with local anesthesia provides acceptable (and safe) conditions for both the patient and the surgeon.142
Tumor resection requires general anesthesia, an arterial line, and possible invasive monitors if symptoms
of cardiac compromise are present.
Subglottic airway collapse and the inability to ventilate are the major concerns in anesthetizing a
patient with an anterior mediastinal mass. Various approaches, ranging from inhalational induction to
preserve spontaneous ventilation to preinduction femoral cannulation to initiate CPB for extracorporeal
oxygenation and circulation have been described.143–145 The specific approach depends on the likelihood
of airway collapse.
Spirometry shows very low predictive value for airway collapse and intraoperative
complications.5,146 CT imaging showing 50% or greater airway compression has only slightly improved
predictive value, yet is a good predictor of potential postoperative respiratory complications.143 Severe
dyspnea, orthopnea, SVC compression, and radiologic evidence of tracheal displacement are predictors
of potential cardiac and respiratory complications.144,145 Transthoracic echocardiography (TTE) should
be performed preoperatively to accurately diagnose the severity of HD compromise by the mass.
The standard rescue measures for ventilatory or circulatory crisis are to (1) reposition the patient
lateral or prone, (2) use rigid bronchoscopy to open a compressed airway distal to the obstruction, (3)
use CPB, or (4) implement emergent sternotomy and direct elevation of the tumor. In the rare case of
severe symptoms, CT showing severe compression (>50%), and echocardiographic evidence of
cardiovascular compression, CPB via the femoral approach is a wise initial approach. CPB is not a good
rescue measure because it takes too long to obtain access. If CPB is thought potentially necessary,
cannulation should be established up front.144,145 Good communication between the surgeon and
anesthesiologist is vital for both the initial management and possible contingency plans. Necessary
equipment (rigid bronchoscope, CPB machine if deemed necessary) must be in the operating room, and
the attending surgeon should be present at induction.144,145
TRACHEAL AND CARINAL RECONSTRUCTION

Maintenance of anesthesia can be accomplished via inhalational or TIVA methods, depending on the site
of surgery. Upper tracheal procedures may require jet ventilation, which will make inhalational
maintenance impossible.103,147,148 Carinal reconstruction, where the surgeon can directly intubate the lung
sterilely on the surgical field, maintains the ability to use inhalational agents.149–151 Occasionally CPB is
indicated for oxygenation.147,149 TIVA is a reliable method for CPB cases, although modern CPB machines
have anesthetic vaporizers connected to their fresh gas flow. As above, there must be clear, thorough
planning and communication between the surgeon and anesthesiologist.
REGIONAL ANESTHESIA AND PAIN MANAGEMENT

The thoracotomy incision is believed to be among the most painful of all incisions. It is constantly
irritated by respiratory effort and virtually any movement of the upper body. The acute pulmonary insult,
on top of the often chronic lung disease found in these patients, makes pain management clinically
challenging. Together, the surgeon and anesthesiologist must strive to develop ways to treat these patients
less invasively and treat their pain more aggressively.
The most effective way to treat postthoracotomy pain is with nerve conduction blockade with local
anesthetics. The most effective way to deliver local anesthetic is extensively debated in the literature.
Multiple pathways have been explored for local anesthesia delivery: thoracic epidural catheters,
extrapleural catheters, subpleural catheters, intercostal nerve blocks (exterior and interior approach), and
intrapleural injection of local agents.152–155 Thoracic epidural anesthesia is extensively used at the
author’s institution. Used in combination with either sedation or general anesthesia, thoracic epidural
anesthesia produces a dense sensory block, reduces the sympathetic stress of surgery, and limits the need
for systemic opioids. Intraoperative analgesia and anesthesia can not only be attained in this way but, by
virtue of placing an epidural catheter, analgesia can also be maintained for an extended period into the
postoperative setting (see below). Patients with severe respiratory compromise who may not tolerate the
respiratory-depressant effects of opioids may benefit greatly.77,81,89 Epidural anesthesia, as mentioned
above, blocks sympathetic output to areas affected by the anesthetic. Ishibe and colleagues showed that
while thoracic epidural anesthesia in dogs decreased heart rate and cardiac output, pulmonary vascular
tone was not affected at baseline or during lobar hypoxia. Epidural anesthesia enhanced the diversion of
blood away from hypoxic areas, suggesting no ill effects and perhaps enhancement of HPV.156
Single-shot paravertebral or intercostal nerve blockade is another regional technique employed in
thoracic anesthesia. These blocks are only effective for the time that the local anesthetic remains at the
site of injection. This technique requires blockade of four to five vertebral levels to anesthetize the entire
surgical field, and may take several minutes to perform preoperatively. The theoretical benefit of
paravertebral blockade is that only half of the thorax is blocked, and may be indicated for patients with
exceedingly poor pulmonary function. Single-shot paravertebral blockade may be the technique of choice
for surgeries of lesser insult (limited chest wall resections, nonthoracic surgeries such as mastectomy,
etc.).152,157
Paravertebral catheters are used at many institutions. In addition to blocking only the involved half of
the thorax, there is less chance of a significant sympathectomy and resulting HD compromise. A catheter
placed at one level can provide analgesia for three to four levels, making it an attractive alternative to
multiple single-shot blocks. Placement of a catheter for continuous local anesthetic infusion while
avoiding the neuraxial space is a potential advantage over epidural analgesia. Some have called the
thoracic epidural status as the “gold standard” for postthoracotomy pain into question.158,159 However, the
choice of an epidural or paravertebral catheter must take into account provider expertise with the
technique, patient-specific conditions (e.g., coagulopathy as a contraindication to epidural), and patient
preference.
The most commonly used local anesthetics for neural blockade are lidocaine, bupivacaine, and
ropivacaine. Lidocaine is often used to initiate a block because of its rapid onset and dense sensorimotor
block. Bupivacaine takes longer to initiate a block but has a longer duration of action and produces less
motor blockade than lidocaine. Bupivacaine has a higher potential for cardiac toxicity than lidocaine due
to its higher lipid solubility and affinity for myocardial voltage-gated sodium channels. However, the
concentration of bupivacaine needed for postoperative epidural analgesia is well below the toxic dose of
the drug. Ropivacaine, a pure S-isomer, has a speed of onset and duration of action similar to
bupivacaine.160 In clinical studies, ropivacaine in equal milligram doses with bupivacaine showed less
potential for cardiac toxicity.161 Nevertheless, in doses that are currently used, both ropivacaine and
bupivacaine are excellent and safe agents for regional anesthesia.162 Patients receiving infusions of local
anesthetics via an epidural catheter are followed by an acute pain service to adjust the infusion
appropriately, change the type of infusion or add any adjuncts, or troubleshoot a poorly functioning
catheter.
Regardless of local anesthesia administration, other principles of pain management should be
considered, namely multimodal therapy and preemptive analgesia.163,164 This is especially true if the
patient has a contraindication to continuous catheter placement. Attempting to address the many ways that
pain is caused and transmitted will result in less pain and a reduced risk of developing chronic pain.
Preemptive analgesia can be as simple as performing external intercostal nerve blocks prior to chest
incision to reduce noxious input. Dosing a thoracic epidural prior to incision can also provide surgical
anesthesia and blunt the sympathetic response to incision. Anti-inflammatories like ketorolac or ibuprofen
can have significant opioid-sparing effects in postthoracotomy patients. Acetaminophen is a simple but
effective adjunct for postthoracotomy pain.165 Drugs like gabapentin and pregabalin have been shown to
decrease acute pain and have an opioid-sparing effect for a wide variety of surgeries.166 The bottom line
is that these patients require aggressive pain treatment and all possibilities should be considered.
Consultation with the anesthesiologist or pain service may greatly improve patient comfort, satisfaction,
and even outcome.
SUMMARY
Anesthesia can be provided with various techniques tailored to the patient’s medical status and the
surgeon’s requirements. Anesthesia for a specific surgery is a summation of many pieces of information.
Invasive and noninvasive monitoring may assist the anesthesiologist with fluid management and
vasoactive drug choices. Pain management continues to be a challenge to both surgeons and
anesthesiologists. It is clear that aggressive pain management has a dramatic impact on postoperative
patient comfort, safety, and satisfaction.
Anesthetic regimens that have proven efficacy and exhibit a good safety profile make sense to repeat.
The point of this chapter, though, is not to list recipes for anesthesia but to explain the rationale and
background anesthesiologists use to arrive at the prescribed anesthesia plan. A clear understanding of the
surgical requirements and the patient’s physical status allow the anesthesiologist to create very specific
anesthetic regimens. With good communication between the surgeon and anesthesiologist, the best
experience and outcome for our patients can be ensured.
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Section
VIII
PULMONARY RESECTIONS
27
Thoracic Incisions
Dominic Emerson ■ M. Blair Marshall
INTRODUCTION
Preoperative planning is essential to successful thoracic surgical procedures. Due to the complex three-
dimensional anatomy of the chest, limited working room, minute margin for error, and the consequences of
complications, this planning is perhaps more essential, and difficult, than in any other surgical
subspecialty. The choice of approach is an integral part of this planning, as an incorrectly placed port or
incision may mean the difference between a quick resection and a long struggle with potential
complications. As thoracic surgery has moved toward minimally invasive techniques,1 the options of
incision for a given operation have grown significantly, to the general advantage of the patient and
surgeon. In this chapter, we seek to detail many of the more contemporary minimally invasive approaches
to thoracic operations, as well as the traditional approaches.
PATIENT POSITIONING
Historically, positioning a patient for an open thoracic operation generally involved one of two positions:
supine or lateral decubitus. With the advent of minimally invasive techniques, the positioning of a patient
has become more complex. Correct patient positioning can help one avoid struggles throughout the case;
as such, it is our practice to insist that the attending surgeon or an experienced senior resident is present
and involved with this portion of the case. Choosing the optimal position for the patient involves
maximizing two things: adequate access to port sites externally so that instruments may be used by the
surgeon in as ergonomic a way as possible (including insuring an adequate working distance from port
site to port site and from port site to target area); triangulation of ports to limit interference and the use of
gravity, understanding that allowing adjacent structures to “fall away” from your dissection field with the
help of gravity is often helpful, and that operating in the most dependent area will often result in the need
for more frequent suctioning of blood. To better describe the position of the patient the authors use
degrees of rotation, with supine position being 0 degrees, lateral decubitus being 90 degrees, and prone
being 180 degrees, and will continue to use this descriptive technique here. It is important to note that
positioning is a spectrum, and more or less degrees of incline may be required for an individual
operation. To assist in positioning a bean bag positioner (Universal Medical, Norwood, MA) provides
excellent malleable support, especially in the more challenging positions, and routinely use it on all cases
other than supine.
SUPINE (0 DEGREES)
The supine position is typically used for mediastinoscopy, other transcervical approaches, transoral
procedures, and mediastinal approaches requiring sternotomy (Fig. 27.1). For mediastinoscopy and
transoral procedures, complete neck extension is essential for success (Fig. 27.2). For parenchymal
resections, it is most commonly used for a transverse thoracosternotomy (the so-called “hemi-clamshell”
approach) and clamshell incisions. In addition, anterior approaches to the thoracic outlet for the resection
of an anterior Pancoast tumor will make use of this position.
SEMISUPINE (30 TO 45 DEGREES)

This position to be of the most use in VATS approaches to the anterior mediastinum, including thymectomy
or excision of anterior mediastinal masses, where visualization is excellent. For parenchymal resections,
this position is less often used with the exception being a limited wedge for tissue diagnosis or an anterior
thoracotomy (Fig. 27.3).
FIGURE 27.1 Supine position showing location of mediastinoscopy (A) and median sternotomy (B).
LATERAL DECUBITUS (ANTERIOR 80 TO 90 DEGREES; POSTERIOR 90 TO

100 DEGREES)
It is important to understand that the lateral decubitus position may involve a more anterior or posterior
approach, depending on the need of a specific operation. Traditionally the posterior approach was used
for open posterolateral thoracotomies, and this remains the optimal approach for this incision. However,
a more anterior approach conveys several advantages in the minimally invasive setting: (1) The
intercostal space is wider in the anterior chest, and as such port placement may lessen trauma to the
intercostal nerve; (2) opening the ipsilateral axilla moves the latissimus dorsi more posteriorly, allowing
this muscle to be completely spared; (3) when creating a utility port, it is more cosmetically acceptable to
have this scar located in the axilla than the posterior chest. Because of these advantages, it is our practice
to use the anterior lateral decubitus position for the majority of minimally invasive thoracic resections. In
addition to being generally preferred in VATS approaches, the authors also prefer the anterior axillary
thoracotomy approach for open surgery, with the main advantages being muscle sparing and cosmesis.
FIGURE 27.2 Showing full neck extension.
FIGURE 27.3 Semisupine position for left approach.

A posterior position, 90 to 100 degrees, is still utilized in our practice, primarily for posterior
mediastinal pathology, including posterior mediastinal masses and esophageal pathology. However, for a
posterior approach to the superior sulcus, this position is useful exposing the posterior chest wall up to
the base of the neck.
FIGURE 27.4 Left lateral decubitus position for right chest approach. Green line represents path of ulnar nerve.
When positioning for both the anterior and posterior approaches, the arm is positioned with the
shoulder in approximately 100 degrees of flexion and the elbow at 90 degrees of flexion, to facilitate
moving the arm out of the working area and open the axilla (Fig. 27.4).
PROPHYLAXIS
Inadequate padding or inappropriate positioning may lead to significant injury and is a source of
litigation.2 Prior to draping it is essential that the safety of positioning be addressed, and it is our practice
to verbalize an agreement of adequate positioning with anesthesia prior to draping. Key areas to support
include the shoulder, where an axillary roll or the bean bag should be placed under the dependent axilla to
support the chest and avoid brachial plexus injury. All pressure points should be padded, paying
particular attention to the elbow and ulnar nerve (see Fig. 27.4). Additionally, a pillow between the knees
helps to avoid pressure here and relieves strain on the nondependent hip, and the head should be built up
with pillows to keep the neck midline (Fig. 27.5).
FIGURE 27.5 Neck support in lateral decubitus positioning.
In addition to positioning-related injury, patients should receive DVT prophylaxis, in the form of
sequential compression devices and routine use of perioperative heparin, especially in patients with
malignancy.3
CLASSIC THREE-PORT VATS PLACEMENT

When minimally invasive thoracic surgery was first developed, the vast majority of operations were
performed using one port placement scheme: two working ports and a camera port placed in a triangular
arrangement (Fig. 27.6). Through this configuration, the entire surface of the lung may be palpated and as
such, this configuration continues to be used for the majority of parenchymal resections today, with small
adjustments. One important consideration during placement is the size of the expected specimen. The
intercostal spaces are wider anteriorly and inferiorly and in order to minimize trauma to the intercostal
nerves, it is best to choose the most anterior, inferior port site possible as the extraction site. However, if
the initial biopsy is likely to lead to a lobectomy, this strategy will be altered placing the anterior superior
incision as a planned utility port. This will be the port that is enlarged for specimen extraction. Other
adjustments in port location should occur to help facilitate access to specific pathology, with ports being
placed in a configuration that centers the working area between the ports. During these procedures, the
patient is positioned in the anterior lateral decubitus position, as noted above. The authors currently use
metal trocars that have the collars shaved down so that they do not interfere with the angularity of the
trocar. For cases where insufflation is required (see later), disposable laparoscopic ports are used. Port
size has decreased with better instruments and cameras, and it is our current practice to use primarily 3-
and 5-mm ports, when possible. Most 5-mm instruments are also available in a 3-mm size, and with
current cameras, there is no advantage to the larger 10-mm camera size over the 5-mm one. In addition to
limiting incision size, and potentially pain, the smaller ports allow more freedom of movement within the
confines of the intercostal space. Obvious limitations include the use of a stapler, which cannot fit through
a 5-mm port site, and removal of a large specimen.
FIGURE 27.6 Classic three-port VATS/VATS wedge scheme.
VATS WEDGE RESECTION

The choice of port site placement may be the most important factor for successful minimally invasive
thoracic surgery. Traditional port placement for a VATS wedge included three ports, one at the 7th or 8th
intercostal space in the anterior axillary line (for the camera) and two working ports in approximately the
4th intercostal space at the anterior axillary line and posteriorly approximately 2 fingerbreadths away
from the scapula (Fig. 27.6). This configuration allowed all surfaces of the lung to be directly palpated to
identify underlying nodules. Today, we often use instruments for this purpose. Consequently, is modified
port placement to optimize the stapler trajectory from the anterior side, minimizing instrumentation
posteriorly to reduce trauma to the intercostal nerve; placement of these ports will vary slightly based on
the location of pathology. Placement must allow for adequate movement of the working hands and must
account for the challenging anatomy of the chest.
LOBECTOMY
For the majority of lobectomies, a three-port configuration is sufficient. Some institutions prefer more or
less port sites, and good results have been had with these alternate configurations. Typically, three ports
are used for an initial wedge biopsy (where indicated), and then the superior most port is extended into a
utility port. The anterior inferior port is placed in the 7th intercostal space in the anterior axillary line.
The posterior port is most often placed in line with the tip of the scapula, two intercostal spaces below it.
Center the utility port over the hilum, at the level of the superior pulmonary vein for an upper lobectomy
and just below the fissure for a lower lobectomy (Fig. 27.7). This location allows for easier access to the
vascular structures during dissection, including conversion to open thoracotomy, if required. The stapler
may be fired from the utility port or from the anterior inferior port, which provides the best angle in the
majority of cases. The majority of dissection is carried out with the camera in the anterior inferior port as
well, though it is moved to other ports as needed to provide the best visualization. In particular, the
camera is moved to the posterior port for subcarinal mediastinal lymph node dissection.
SPECIAL CONSIDERATIONS
Carbon Dioxide Insufflation
Once limited only to the abdomen, use of CO2 insufflation has increased in thoracic surgery. We have
found this technique useful in a variety of situations and advocate its use. In patients without lung
isolation, insufflation of the chest often is sufficient to allow a working space. This may be useful in
individuals who require simple pulmonary resections, but where single lung ventilation is not feasible.
Another advantage is to assist in smoke evacuation during thoracoscopic procedures. When employing
this technique it is important to keep insufflation pressures lower than those used in the abdomen, at no
higher than 10 mm Hg. Higher pressures in the chest will impede venous return and may cause
hemodynamic compromise.4
FIGURE 27.7 Standard VATS lobectomy scheme.
Single Incision Minimally Invasive Thoracic Surgery

A single port approach is a relatively recent development in minimally invasive thoracic surgery.5 This
approach requires instruments that articulate and is more challenging than traditional VATS approaches.
The operative approach is similar to that in traditional VATS surgery, with the patient placed in the lateral
decubitus position. A 2- to 3-cm incision is created over the desired rib space (typically the 5th), over the
anterior axillary line. After gaining access to the chest, the camera and articulating instruments are
inserted in this same space, typically with the camera sitting between the two instruments. While the
potential benefit of fewer incisions may include decreased pain and more rapid recovery, this has not yet
been well demonstrated and further study into the single port technique is ongoing.
FIGURE 27.8 A. Posterolateral thoracotomy. B. Posterolateral thoracotomy.
OPEN APPROACHES
Location of Specific Incisions
The details of specific incisions for individual operations will be covered in the corresponding chapters;
a general discussion of incisions commonly used is included here.
Posterolateral Thoracotomy
The posterolateral thoracotomy is perhaps the most widely utilized approach in thoracic surgery, though
this is evolving as VATS becomes the norm. The primary advantage to this approach is the extent of
visualization, but this comes at the cost of longer time spent gaining access and the amount of muscle
transected. For this approach, the patient is placed in the posterolateral position. The incision is centered
over the 4th to 6th interspace, depending on the location of pathology. Classically, the incision begins at
or just anterior to the anterior axillary line and follows the interspace in a curvilinear line below the tip
of the scapula and extending to midway between the vertebral column and the medial edge of the scapula
(Fig. 27.8A). Using the electrocautery, the latissimus dorsi is divided, and if required, the inferior portion
of the trapezius is also divided. Anteriorly, the posterior most fascial attachments to the serratus are
divided and the muscle is spared and retracted anteriorly.
Following identification of the desired interspace, the intercostal muscle is divided off the superior
aspect of the lower rib with the electrocautery until access to the chest cavity is gained. A finger is then
inserted into the chest to evaluate for the presence of adhesions along the planned rib space, and the
intercostal muscle is divided anteriorly and posteriorly for the length of the incision (Fig. 27.8B).
Following this, a rib spreader is placed, taking care not to open the rib spreader too quickly, as this may
result in fractures. The addition of a Balfour retractor placed perpendicularly to the incision aids in
retraction of muscle and soft tissue.
Following placement of a chest tube or tubes through separate incisions, the incision is closed in
layers. This begins with the reapproximation of the rib space using a heavy absorbable suture, such as a
no. 1 or no. 2 Vicryl, with the suture placed in a figure-of-eight fashion around the ribs bordering the
incision. Care must be taken to avoid the neurovascular bundle on the inferior border of the lower rib
(Fig. 27.9A). Following this, the two musculofascial layers are closed with running suture and the skin is
finally reapproximated (Fig. 27.9B).
FIGURE 27.9 A. Thoracotomy closure. B. Thoracotomy closure.
Axillary (Muscle-Sparing) Thoracotomy

The axillary or muscle-sparing thoracotomy is a fairly versatile approach to the majority of the chest that
can be utilized for the majority of open thoracic resections. For some, this incision is also the preferred
approach when converting a VATS procedure to an open one. The main advantage to this approach is the
muscle preservation that is allowed, which in turn reduces blood loss and operative time spent gaining
access. Because of this, the axillary thoracotomy is used increasingly where an open approach to the chest
is required.
FIGURE 27.10 A. Axillary (muscle-sparing) thoracotomy, both incision options. B. Axillary (muscle-sparing) thoracotomy.
Positioning for this incision should be in the anterior lateral decubitus position, as described above.
The incision is centered at the anterior axillary line, over the 4th or 5th interspace, depending on the
location of pathology (Fig. 27.10A). It is best to use an incision parallel to the anterior axillary line for
cosmetic reasons. The incision is carried down through the subcutaneous tissue to the underlying muscle.
Depending on the length of incision, a variable amount of latissimus must be elevated bluntly and
retracted; unlike the posterolateral thoracotomy, the muscle is spared. The serratus is also preserved by
splitting the muscle in the direction of its fibers and then bluntly elevating it to reveal the desired
interspace (Fig. 27.10B). The intercostal muscle is divided as in a posterolateral thoracotomy to gain
entry to the chest. Following this, retractors are placed as in the posterolateral approach; the use of a
Balfour for soft tissue and muscle retraction is essential as no muscle has been divided.
The incision is closed in a similar way as the posterolateral incision, using a heavy Vicryl around the
ribs and a running layered closure above this.
SUPERIOR SULCUS APPROACHES

Anterior Cervicothoracic and Hemi-Clamshell
Tumors of the superior sulcus present many unique challenges and require additional preoperative
planning for successful resection. Successful dissection that avoids injury to numerous adjacent structures
is best ensured by a careful meticulous approach with adequate exposure.
The anterior cervicothoracic approach begins with supine positioning, the patient’s head extended and
rotated away from the side of pathology, and often a roll or inflatable pillow underneath the patient’s
shoulders. The “L”-shaped incision extends from the upper third of the sternocleidomastoid to the angle of
the manubrium and then curves laterally to follow approximately 4 cm inferior to the border of the
clavicle, terminating at the deltapectoral groove (Fig. 27.11). A subplatysmal flap is raised at this point to
expose the supraclavicular fat pad and assess for N3 disease. The anterior border of the SCM is then
dissected free, exposing the internal jugular vein. The first rib space is dissected, and the internal
mammary artery is identified and ligated. Following this, the manubrium is split in the midline and
perpendicularly at approximately the mid-body, forming an “L,” and preserving the sternoclavicular joint.
To facilitate retraction and exposure, the first costal cartilage is then divided. Careful slow retraction of
the osteomuscular flap is facilitated by dissecting the posterior surface of the clavicle and leaving
subclavian muscle attached to subclavian vessels. The pectoralis is split in line with its fibers, as needed.
FIGURE 27.11 Location of anterior superior sulcus incisions.

FIGURE 27.12 Posterior approach to superior sulcus tumors.
The location of the inferior border of the incision may be moved caudally to facilitate greater exposure
or chest wall resection, as needed, typically referred to as the hemi-clamshell approach. Here the “L”-
shaped incision to the sternum is extended to the desired rib space (Fig. 27.11). As noted above, prior to
division of the sternum, the rib space should be dissected and the IMA ligated. Closure for both these
incisions includes sternal wiring, with closure of the thoracotomy incision as described above, followed
by layered skin closure.
POSTERIOR APPROACH
This approach is a continuation of the posterior aspect of a posterolateral thoracotomy extending the
incision between the angle of the scapula and middle of the spine (Fig. 27.12). The trapezius and
rhomboids are divided and the scapula lifted off the chest wall to allow for access to the first rib and
thoracic outlet (Fig. 27.13).
MEDIAN STERNOTOMY
The median sternotomy is the most common approach for cardiac procedures and is also utilized for many
anterior mediastinal masses as well. This approach has the distinct advantage of being a rapid way to
gain entry to the chest and is often less painful in recovery than other open approaches. For parenchymal
resections, this incision is limited in exposure to the posterior hilar structures, especially on the left.
However, today it may still be used for synchronous bilateral metastasectomy. The patient is positioned
supine, with both arms tucked and a shoulder roll to facilitate neck extension. A vertical incision is made
from the jugular notch to the tip of the xiphoid and carried down to the sternal periosteum with the
electrocautery and the periosteum is then scored in the midline. The interclavicular ligament is divided
and a combination of blunt and sharp dissection using the electrocautery is used to develop the
retrosternal space superiorly (Fig. 27.14). The xiphoid is dissected free and the retrosternal space here is
again developed bluntly. The sternum is then divided using a reciprocating saw. The edges of the sternum
are gently retracted and bone wax is utilized to control bleeding from the marrow. Periosteal bleeding is
controlled with electrocautery. When resecting bilateral metastases, a Rultract™ retractor may be used to
elevate the chest wall and improve exposure to the side of interest and then move it to the contralateral
side when working on that side. At the conclusion of the operation, bilateral chest tubes are placed via
separate incisions inferior to the lowest point of the sternal incision. Sternal wires are used to
reapproximate the sternum, typically with two placed in the manubrium and four around the sternal edges,
though this is at the discretion of the individual surgeon (Fig. 27.15A). Alternatively, sternal plates may
be used, though this significantly increases cost and time. The pectoralis fascia is then closed using a
running absorbable suture, and a running deep dermal layer follows this (Fig. 27.15B). The skin is then
reapproximated and dressings placed.
FIGURE 27.13 Posterior approach to superior sulcus tumors, showing elevation of scapula.
FIGURE 27.14 Division of interclavicular ligament.
FIGURE 27.15 A. Closure of sternotomy. B. Closure of sternotomy.
SUMMARY
The advent of minimally invasive thoracic surgery has altered the way we view standard entry into the
chest and has made optimal positioning and choice of incisions all the more essential due to the limited
working conditions. Though the variety of pathologies approached by minimally invasive techniques
continues to grow, familiarity with “traditional” open incisions remains an important part of the modern
thoracic surgeon’s armamentarium. As the field continues to evolve, novel approaches to approaching
pathology will continue to develop, but the fundamental techniques described above will continue to be at
the core of any planned procedure.
REFERENCES
1. Paul S, Altorki NK, Sheng S, et al. Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-
matched analysis from the STS Database. J Thorac Cardiovasc Surg 2010;139:366–378.
2. Cheney FW, Domino KB, Caplan RA, et al. Posner nerve injury associated with anesthesia: a closed claims analysis. Anesthesiology
1999;90:1062–1069.
3. Guyatt GH, Akl EA, Crowther M, et al.; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis
Panel. Antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest 2012;141(2 Suppl):7S–47S.
4. Wolfer RS, Krasna MJ, Hasnain JU, et al. Hemodynamic effects of carbon dioxide insufflation during thoracoscopy. Ann Thorac Surg
1994;58:404–407.
5. Rocco G, Martin-Ucar A, Passera E. Uniportal VATS wedge pulmonary resections. Ann Thorac Surg 2004;77:726–728.
28
Technical Aspects of Lobectomy
Stanley C. Fell ■ Malcolm M. DeCamp ■ Richard H. Feins
Lobectomy by hilar dissection, first reported by Blades and Kent1 in 1940 for the surgical treatment of
bronchiectasis, is now performed most commonly for the definitive treatment of lung cancer. In recent
years, video-assisted thoracoscopic (VATS) lobectomy and robotic lobectomy have become a routine
procedure in many institutions, especially for early-stage non–small-cell lung cancer (NSCLC) (Chapter
32).2–4 Oncologic outcomes are similar to those seen after open lobectomy. However, competence in how
to perform open lobectomy via thoracotomy is essential for every surgeon doing thoracic surgery since
patients may well have postinfectious, postradiation, posttraumatic, and anatomic variations that preclude
a minimally invasive approach. This chapter will cover the key points in the performance of open
thoracotomy lobectomy, those being mobilization of the lobe, fissure dissection, and dissection and
management of the vessels and bronchus.
The incision for lobectomy is usually a posterolateral thoracotomy because it allows greater exposure
and maneuverability for the surgeon. Anterolateral thoracotomy, median sternotomy except for the left
lower lobe, and muscle-sparing lateral or axillary thoracotomy are also used. Posterior thoracotomy,
developed during the era of surgery for pulmonary tuberculosis and bronchiectasis—as described by
Overholt and Langer,5 and generally performed on a special operating table with the patient prone—is
now of historical interest.
MOBILIZATION OF THE LOBE

The pleural cavity is entered through the fifth intercostal space for upper lobectomy or any central lesion.
Entry through the sixth space is acceptable for peripheral lower lobe tumors. If adhesive pleuritis is
anticipated, entrance through the bed of the resected fifth rib allows for more expeditious mobilization of
the lung, either in the intrapleural or extrapleural plane. Web-like avascular adhesions are managed by
finger dissection and a sponge stick; cautery is applied for vascular adhesions. Inflammatory and cavitary
lesions adherent to the parietal pleura are mobilized in the extrapleural plane. Care must be taken to avoid
injury to the extraparietal pleural structures, most notably the azygous vein and branches on the right and
the posterior aortic intercostal branches on the left in addition to the apical structures bilaterally.
The need for chest wall resection for tumors adherent to the parietal pleura is controversial. Trastek
and colleagues6 advocate en bloc resection of lung and chest wall in this situation. Particularly in the
absence of chest wall pain, McCaughan and colleagues7 recommend attempting extrapleural dissection if
extrapleural extension is not documented preoperatively. If an extrapleural plane is readily achieved,
chest wall resection is not performed, because these tumors often involve only visceral pleura. If the
tumor is determined to be fixed to the chest wall during this dissection, the extrapleural approach is
abandoned and en bloc resection is performed. This approach does not adversely influence the survival
rate.
After mobilization of the lung, the mediastinal pleura is incised around the hilum, the pathology is
evaluated, and node sampling is performed as indicated.
FISSURE DISSECTION
Incomplete fissures result from congenital fusion of lung substance, inflammation, or extension of the
pathologic process to the adjacent lobe. Localized combined sharp and blunt dissection along the
interlobar plane is generally sufficient to identify the intralobar pulmonary artery. Once the pulmonary
artery branches have been identified, the fissure(s) can be completed with a linear stapler. The interlobar
arterial branches must be visualized prior to stapling to ensure that branches to the remaining lobe(s) are
not inadvertently divided. Fused lobes also may be separated by retrograde dissection and traction on the
divided bronchus using the intersegmental vein as a guide but this tends to divide small blood vessels and
creates air leaks which may require suturing. Diminution of lung volume and distortion of the remaining
lobes should be kept to a minimum when staplers are used.
Single-lung anesthesia and stapling devices have facilitated lobectomy, especially when using a VATS
technique, but total reliance on these methods is to be decried. The double-lumen endotracheal tube may
be unavailable, impossible to place properly, or may become displaced. In these circumstances, the
surgeon must be able to dissect the lobar hilum and the fissures of a partially inflated lung. Manual
ventilation by anesthesia can limit the expansion of the lung and the timing of inflation to provide the best
exposure.
MANAGEMENT OF LOBAR VESSELS

The key to an orderly lobectomy is thorough knowledge of the anatomy of the pulmonary artery, variations
in its branching, and its proper dissection (see Chapter 8). In contrast to the fragile pulmonary segmental
arteries, located deep within the fissures and intimately related to the segmental bronchi, the pulmonary
veins and their tributary trunks have relatively strong walls and are easily accessible at the anterosuperior
and posteroinferior aspects of the hilum. Occasionally, a common extrapericardial pulmonary vein is
encountered.
Safe dissection of the pulmonary artery and its branches requires identification of the subadventitial
plane and dissection in this plane. This dissection is best accomplished using scissors in the long axis of
the vessel. Once a sufficient length of the vessel has been exposed, the sheath is grasped on either side
and the artery is then rolled out of its sheath, allowing the passage of a right-angle or Semb clamp to
encircle the vessel and draw a ligature beneath it. Dissection of the artery with a clamp without prior
sharp dissection invites hemorrhage. A common error is the failure to dissect out an adequate length of
vessel since the vessel shortens when tied leaving inadequate length for safe division. If segmental
branches are short, additional length may be obtained by dissecting into lung parenchyma and dividing the
lung substance with cautery.
Bronchial closure is generally performed with a 3.5- or 4.8-mm stapling device, depending on the
compliance of the bronchus. Manual sewing of the bronchus may be indicated in some circumstances, an
example being to ensure that the bronchial resection is proximal to an endobronchial tumor. Suture
materials currently used include silk, polyglactin, and polypropylene. Manual closure proceeds as
follows: a suitably sized toothed bronchus clamp is applied to the specimen side of the bronchus and stay
sutures are inserted in the upper and lower borders of the bronchus. With the underlying vascular
structures protected by a Semb clamp, the bronchus is transected. Bronchial sutures are placed about 3
mm apart and 3 mm from the cut edge. Horizontal mattress sutures proximal to this line is used by some
surgeons. In the absence of single-lung ventilation, placing the first suture at the midpoint of the bronchus
reduces air leak. Surgeons’ knots reduce tension on the cartilage, the knots being placed over the suture
hole in the membranous portion to seal possible air leak from this area. The traction sutures may be tied
in place over the cut end. Coverage of the bronchial stump is of value after any lobectomy performed in
the face of active infection or previous radiation. Some surgeons prefer to cover lower lobe and
bilobectomy stumps routinely with parietal pleura or pericardial thymic fat although others do not find
this necessary. Upper lobe stumps are covered selectively in situations of purulence, immune suppression,
or when pre- and/or postoperative radiotherapy will be used. After middle lobectomy, flap coverage is
unnecessary, as the bronchial stump is readily covered by the remaining parenchymal tissue of the upper
and lower lobes within the hemithorax.
After removal of the specimen, the integrity of the bronchial closure is tested by the application of
positive pressure to the endotracheal tube with a saline-filled hemithorax. Parenchymal air leaks also are
localized and repaired. For most procedures, a single thoracostomy tube extending to the apex and with
additional holes made proximally is sufficient.8 In cases of poor lung re-expansion, extrapleural
dissection, excessive bleeding, and intrathoracic infection two thoracostomy tubes are placed through stab
wounds in the anterior axillary line. The lower tube extends posteriorly on the diaphragm, and the upper
tube lies anteriorly to reach the apex of the pleura. After closure of the chest, negative suction from 10 to
20 cm H2O may be applied to the drainage systems, although some surgeons advocate early if not
immediate use of waterseal drainage alone. The tubes are removed serially once drainage is less than 250
mL in 24 hours and the air leak has ceased.
RIGHT UPPER LOBECTOMY

The anatomy of the hilar structures of the right upper lobe is more complex than that of any other lobe, and
arterial anomalies are more common. In about 80% of individuals, the anterior segment of the right upper
lobe is partially or completely fused to the middle lobe, producing an incomplete minor or horizontal
fissure. This mandates a segmental dissection of this area to complete the lobectomy.
The mediastinal pleura is incised around the hilum of the right lung, lateral to the superior vena cava,
inferior to the azygos vein, continuing posteriorly over the bronchus, anterior to the vagus nerve (which is
visible subpleurally), to the level of the bronchus intermedius. Anteriorly, the incision is carried to the
level of the superior pulmonary vein, posterior to the phrenic nerve (Fig. 28.1A). A pledget dissector is
used to push the azygos vein superiorly, demonstrating the upper border of the right main bronchus and the
upper lobe bronchus originating from it. Inferior to the azygocaval junction, a lymph node is found. Just
below this lymph node is the upper border of the pulmonary artery. The areolar tissue overlying the
pulmonary artery is dissected, and the superior arterial trunk is visualized. This artery and its apical and
anterior segmental branches are dissected. The apical segmental vein crosses the anterior segmental
artery; it is often convenient to ligate and divide this vein before dealing with the artery (Fig. 28.1B). The
superior arterial trunk is doubly tied proximally with 0-0 silk. The specimen side can be tied or clipped.
The vessels are then divided leaving 3 to 4 mm on the proximal side and 1 to 2 mm on the specimen side.
Failure to leave adequate vessel beyond the ties risks the ties springing off during the subsequent
dissection or even postoperatively. If the segmental arteries are short, additional length may be obtained
by dissecting with a right-angle clamp into the pulmonary parenchyma overlying the branches, dividing
the parenchyma with cautery. Alternatively, a vascular linear stapler (2.0 mm staple height), which
simultaneously ligates and divides the vessels, may be used.
After division of the superior trunk of the pulmonary artery, the common stem of the apical and anterior
segmental veins is dissected and divided. The interlobar trunk of the pulmonary artery lies directly
beneath the upper and middle stems of the superior pulmonary vein, and this dissection must be performed
cautiously.
The remaining arterial supply to the right upper lobe is the posterior ascending artery, present in 90%
of patients. Dissection of this artery can be the most formidable task in the procedure. Three approaches
have been described: an anterior approach, an approach through the oblique fissure, and a retrograde
approach.
The anterior approach requires prior division of the posterior and inferior venous tributaries of the
middle stem of the superior vein, which is closely applied to the anterior surface of the inferior trunk of
the pulmonary artery. Further dissection of the interlobar artery is required because the posterior
segmental artery arises from the anterior aspect of the interlobar artery just above the superior segmental
artery to the lower lobe. Proximal control of the right pulmonary artery may be required because
laceration of the posterior ascending artery or the interlobar artery from which it arises may occur during
this dissection.
An approach to the posterior segmental artery through the oblique fissure is acceptable provided that
the oblique fissure is virtually complete. Otherwise, the artery is again at risk for injury. The retrograde
method for completion of the dissection is both safe and expeditious.
Retrograde exposure of the posterior ascending artery proceeds as follows: attention is directed to the
posterior aspect of the hilum. The vagus nerve is grasped with an Allis clamp and retracted, thus
demonstrating its branches to the right upper lobe. The branches are divided (Fig. 28.2A). Deep to the
vagal branches, the bronchial artery may be observed; it is clipped and divided. The lower border of the
upper lobe bronchus is dissected. In the crotch between the upper lobe bronchus and the intermediate
bronchus is a constant lymph node. This node is dissected toward the specimen, clearing the inferior
border of the right–upper-lobe bronchus. It is not advisable to pass a clamp from the lower border of the
right–upper-lobe bronchus medially to encircle the bronchus because the posterior ascending artery may
be lacerated. Rather, scissor dissection of the medial surface of the bronchus is performed, sweeping
areolar tissue and nodes toward the specimen (Fig. 28.2B). The bronchus is not denuded of its fascia,
which supplies the vascularity required for healing. An index finger can then be inserted along the
anterior aspect of the bronchus to reach its lower border (Fig. 28.2C). A right-angle clamp may then be
passed safely around the right–upper-lobe bronchus. A Semb clamp is used to widen the peribronchial
space, allowing for the passage of a 4.8-mm stapling device. The bronchus is either stapled and divided
or manually sutured. If stapled, the staple line generally includes the bronchial artery to the right upper
lobe. The cut edge of the specimen side of the bronchus is grasped with an Allis clamp. Traction is placed
on the Allis clamp, a toothed bronchus clamp is applied, and the Allis clamp is removed. By turning the
handle of the bronchus clamp medially, thus elevating the cut bronchus, the fissure dissection is
facilitated. With gentle medial traction on the bronchus clamp, the areolar tissue and nodes are readily
dissected off the interlobar pulmonary artery, and the posterior ascending artery is identified, ligated, and
divided (Fig. 28.3). Occasionally, an additional arterial branch to the anterior segment originates from the
interlobar artery. Rarely, the posterior segmental artery originates from the superior segmental artery.
FIGURE 28.1 A: Anterior aspect of the right hilum. Division of the apical segmental vein facilitates dissection of the superior
trunk of the pulmonary artery. B: The superior arterial trunk before ligation. The anterior as well as the apical segmental vein has
been divided to demonstrate the interlobar trunk of the pulmonary artery.

FIGURE 28.2 A: Posterior aspect of the right-upper-lobe hilum after division of the mediastinal pleura. Vagal branches
posterior to the bronchus are not yet divided. B: The right–upper-lobe bronchus is dissected. C: Finger dissection separates the
bronchus from the interlobar pulmonary artery.
Attention is next directed to the fissures, which may be managed by sharp dissection along the
intersegmental vein using partial inflation of the middle and lower lobes against the now airless upper
lobe, by stapled division, or by a combination of both methods (Fig. 28.4). With the bronchus divided and
the posterior segmental artery transected, it is safe to pass a stapling device to divide the posterior aspect
of the oblique fissure. The minor fissure is similarly completed. We emphasize that attempts to divide
fissures without prior identification of the segmental arteries may lead to hemorrhage. Medial traction of
the bronchus clamp and further dissection with the interlobar artery under direct vision lead immediately
to the middle trunk of the superior pulmonary vein and its posterior and inferior tributaries. At this point,
the operator can appreciate the intimate relationship of these branches to the inferior trunk of the
pulmonary artery (Fig. 28.5A). The common stem of the posterior and inferior veins is identified, and the
site of insertion of the middle lobe vein into the superior pulmonary vein is identified and preserved. The
venous stem is doubly ligated, as are the posterior and inferior veins, which are then divided;
alternatively a vascular stapler can be used if there is sufficient length of vein to pass the device. The
importance of minimizing air leak from the middle lobe cannot be overemphasized. The intersegmental
vein defines the proper plane of dissection.
After the specimen is removed, the pleural cavity is irrigated and the bronchial closure tested. The
inferior pulmonary ligament is divided, allowing rotation of the lower lobe to facilitate complete filling
of the pleural space. Because the fissure between the middle and lower lobes is generally complete,
torsion of the middle lobe is possible. To prevent such torsion, the edges of the partially expanded middle
and lower lobes are grasped with an Allis clamp, and a silk tie or 3-0 figure-of-eight suture(s) is used to
approximate these edges along the course of the fissure (Fig. 28.5B). A single application of a TA-30
stapling device accomplishes the same results, though at much greater cost.
MIDDLE LOBECTOMY
Middle lobectomy is not commonly performed as an isolated procedure except for small cancers in the
periphery of the lobe. In years past, it was performed for middle lobe syndrome. Incomplete fissure and
hyperplastic or calcified lymph nodes, adherent to segmental arteries and the middle lobe bronchus, made
it a formidable procedure, generally requiring proximal control of the right pulmonary artery.
FIGURE 28.3 The bronchus has been stapled and divided. Medial traction on the specimen facilitates dissection of the posterior
ascending artery.
FIGURE 28.4 The oblique fissure is completed by a sharp and blunt dissection and stapled where required.
FIGURE 28.5 A: Retracting the lobe medially and stapling the minor fissure exposes the middle trunk of the superior pulmonary
vein. Note the relationship of this trunk to the underlying interlobar pulmonary artery. The middle lobe vein has been identified
and preserved. B: Edges of the middle and lower lobes are approximated with silk ties to prevent middle lobe torsion.
FIGURE 28.6 A: Dissection of the oblique fissure at its junction with the horizontal fissure demonstrates the interlobar
pulmonary artery and its branches. B: Dissection of the oblique fissure at its junction with the horizontal fissure demonstrates the
interlobar pulmonary artery and its branches. One middle lobe artery is divided.
Most often, middle lobectomy is performed in association with either upper or lower lobectomy for
tumors that cross fissures (bilobectomy). Combined middle and lower lobectomy was often required for
the treatment of bronchiectasis.
If upper and middle lobes are resected, the bronchi are closed separately; for middle and lower
lobectomy, the bronchus intermedius is divided just distal to the right upper lobe bronchus. The major
fissure is opened, and the lower lobe is retracted posteriorly (Fig. 28.6A). By following the posterior
edge of the middle lobe as it joins the major fissure and dissecting deep within the fissure, lymph nodes
are noted, indicating the site of the interlobar pulmonary artery. The artery is dissected proximally in the
subadventitial plane, and the middle lobe artery is identified (Fig. 28.6B). Generally, two middle lobe
arteries exist; the first one identified arises from the interlobar artery anteriorly, more or less opposite to
the superior segmental artery arising posteriorly. Further proximal dissection of the interlobar artery
demonstrates a second and rarely a third artery to the middle lobe. Occasionally, an anomalous branch of
the middle artery to the upper lobe is identified. After ligation and division of the middle lobe arteries,
the table is rotated posteriorly and the anterior aspect of the hilum is dissected, isolating and ligating the
middle lobe vein, which enters the lower portion of the superior pulmonary vein (Fig. 28.7). After
division of the middle lobe vein, the bronchus is readily accessible (Fig. 28.8A). In difficult dissections,
it may be more expeditious to initiate a middle lobectomy in the anterior hilum. The readily visible
middle lobe vein is isolated and divided, exposing the middle lobe bronchus, which is controlled via
proximal stapling or sharply divided and closed with interrupted suture. Cephalad retraction of the
specimen side of the divided bronchus exposes the middle lobe arterial branches which are ligated and
divided in a retrograde fashion. Manual suturing may be easier than inserting a stapling device during
middle lobectomy.
FIGURE 28.7 The anterior mediastinal pleura is incised. The middle lobe vein is isolated and divided.

FIGURE 28.8 A: The middle lobe bronchus is identified. The line of bronchial transection is illustrated. B: Traction on the
specimen bronchus and differential inflation facilitate completion of the horizontal fissure. C: Hilum after middle lobectomy.
The closed middle lobe bronchus is deep within the parenchyma, and disruption of this bronchial
closure is virtually unknown. The distal portion of the transected middle lobe bronchus is grasped with a
bronchus clamp. Using differential inflation and traction on the bronchus clamp, the fissure may then be
completed along the lines of the intersegmental veins by a combination of sharp and blunt dissection and
stapling (Fig. 28.8B). After completion of the fissure and removal of the specimen, the raw surfaces of the
upper lobe may be approximated to the lower lobe by several ties or sutures to help seal air leak.
RIGHT LOWER LOBECTOMY

The oblique fissure is opened while retracting the right upper and middle lobes anteriorly and the lower
lobe posteriorly. The interlobar pulmonary artery is deeply situated in the region where the oblique and
horizontal fissures meet (Fig. 28.6B). The temptation to staple and divide areas of fusion between the
posterior segment of the right upper lobe and the superior segment of the lower lobe before demonstrating
the interlobar pulmonary artery and its branches must be avoided. The visceral pleura overlying the
interlobar artery is opened, and the pulmonary artery is dissected. The middle lobe artery, originating
from the anteromedial surface of the interlobar artery, must be demonstrated. Directly opposite and
posterolaterally lies the superior segmental artery. Rarely, the posterior ascending artery to the upper lobe
originates from the superior segmental artery. Occasionally, the superior segment of the right lower lobe
has two branches. Often it is best to isolate and divide the basal arteries first, distal to the middle lobe
and superior segmental arteries (Fig. 28.9). The basal arteries may have a short common trunk from which
two branches originate: one supplying the anterior and medial segments and the other supplying the
posterior and lateral segments. Occasionally, the four basal segmental arteries originate separately distal
to the middle lobe artery, and dissection into the lung parenchyma is required to obtain adequate length for
ligation and division. Attention is then directed to securing the superior segmental artery, taking care to
preserve the posterior segmental artery to the right upper lobe.
The lobe is retracted anteriorly and superiorly. The inferior pulmonary ligament is divided up to the
lymph node at the lower border of the inferior pulmonary vein (Fig. 28.10A). The posterior mediastinal
pleura is incised over the posterior surface of the inferior pulmonary vein, which is cleared of areolar
tissue, and the pleural incision is carried superiorly above the level of the bronchus intermedius. The
interval between the lower border of the bronchus and the superior pulmonary vein is dissected. The
anterior surface of the inferior pulmonary vein is then cleared. With an index finger serving as a guide, the
inferior pulmonary vein is then isolated, using a Semb clamp (Fig. 28.10B). The interval between the
lower lobe bronchus and the inferior vein is widened so that a vascular stapler may be inserted to
occlude the cardiac end of the vein. The extrapericardial portion of the right inferior pulmonary vein is
short. It is not advisable to ligate the vein because the tie may spring off the fibrous pericardium. Rather
than sacrifice length, application of a Sarot clamp to the specimen side of the vein and cutting on the
clamp ensures sufficient length of the vein to be clamped and closed by a vascular suture or divided after
the application of a vascular stapler (Fig. 28.10C). Alternatively, the superior and basilar segmental veins
are ligated individually. The lower lobe bronchus is then dissected. Because the middle lobe bronchus
and the superior segmental bronchus originate from the intermediate bronchus at almost the same level, it
may be necessary to close the basal segmental bronchus and the superior segmental bronchus separately to
avoid obstructing the middle lobe bronchus. A single oblique application of the 4.8-mm stapling device
that does not occlude the middle lobe bronchus is acceptable (Fig. 28.11A). It is advisable, though, to
apply the stapler, close it without firing, and then reaerate the right lung to ensure the patency of the
middle lobe bronchus. Intraoperative bronchoscopy using a small bronchoscope through the tracheal
lumen of the right-sided double-lumen endotracheal tube should be performed before the stapler is fired if
there is any doubt. Although a similar anatomic situation exists with regard to the left–lower-lobe
bronchus and the lingular bronchus, the risk of occluding the middle lobe bronchus is far greater than that
of occluding the lingular bronchus. Alternatively, the lower lobe bronchus may be sutured as previously
described.
FIGURE 28.9 Arterial supply of the right lower lobe. The origin of the middle lobe artery is visualized. Stapling the posterior
portion of the oblique fissure facilitates the dissection of the superior segmental artery.

FIGURE 28.10 A: The lung is retracted anteriorly. B: The inferior pulmonary ligament is divided. C: The inferior pulmonary
vein is then dissected, stapled, and divided.
LEFT UPPER LOBECTOMY

The most common anatomic variation encountered during left upper lobectomy is the number of segmental
arterial branches, which varies from three to eight.
For proximal control of the left main pulmonary artery, the left lung is retracted inferiorly and
posteriorly, and the mediastinal pleura overlying the pulmonary artery is incised (Fig. 28.12A). After the
course of the phrenic nerve is identified, the pleural incision is carried over the medial portion of the
superior pulmonary vein just lateral to the pericardium (Fig. 28.12B). Posteriorly, the incision is made to
a point below the level of the bronchus. The vagus nerve is visible subpleurally, marking the posterior
limit of the hilar dissection (Fig. 28.13). Areolar tissue overlying the convex surface of the pulmonary
artery is cleared. After division of vagal branches while protecting the left recurrent laryngeal nerve, the
upper border of the left main bronchus is defined. A pledget dissector is used to roll the pulmonary artery
away from the left main bronchus. Anteriorly, the space between the pulmonary artery and the superior
pulmonary vein is defined, and again the pulmonary artery is rolled out of its sheath, allowing an index
finger to encircle the artery (Fig. 28.14). Passing a clamp behind the left main pulmonary artery without
previously encircling it carefully with an index finger is fraught with danger. Once encircled, a Semb
clamp may then be used to draw a Silastic vessel loop or vascular tape around the artery. A Rumel
tourniquet, not cinched down over the vascular tape, should be left in place in case injury to the vessel
should occur.
The lung is retracted anteriorly, and the pulmonary artery is dissected in the oblique fissure (Fig.
28.15A). If necessary, the posterior part of the fissure is completed with a stapler once the pulmonary
artery branches are visualized. The pulmonary artery is dissected over the middle point of its presenting
surface as it curves around the left upper lobe bronchus. As the fissure dissection proceeds, the posterior
segmental arteries are noted opposite the superior segmental artery (Fig. 28.15B). Further distal
dissection demonstrates one or two lingular arteries; the arterial dissection is complete when the basilar
segmental branches are identified. With the lower lobe retracted inferiorly and the upper lobe retracted
superiorly, the lingular branches are isolated and divided. The upper lobe is then rotated clockwise and
the posterior segmental branches are ligated and divided. Proceeding in this fashion, from the lingular
arteries proximally and rotating the lobe, subsequent arterial isolation becomes easier until the apical
anterior trunk is addressed. Division of the apical anterior trunk represents one of the most challenging
parts of the left upper lobectomy. It is the first branch that comes off of the left pulmonary artery, is usually
quite short before dividing into apical and anterior branches and quite fragile. Especially in the face of
large bulky tumors, great care must be taken to not exert any excessive traction on this vessel as this could
result in avulsion or subadventitial dissection resulting in massive hemorrhage. If there is any doubt as to
the safety of exposing and dividing the apical anterior trunk, proximal control of the left pulmonary artery
is recommended, again, especially when approaching bulky or centrally located tumors. These branches
are the last to be divided (Fig. 28.16) and should be dealt with after the left upper lobe bronchus and left
superior pulmonary vein are divided, if the tumor is close to their origin on the pulmonary artery. This
allows for the specimen to be readily removed and out of the field should an arterial injury occur. If injury
should occur the bleeding can be controlled by tightening the previously placed tourniquet until a cross
clamp is placed proximally across the left main pulmonary artery. Use of a partial occluding clamp is
discouraged as it tends to slip and give inadequate exposure for repair.
FIGURE 28.11 A: Oblique transection of the right–lower-lobe bronchus preserves patency of the middle-lobe bronchus. B:
Oblique transection of the right–lower-lobe bronchus preserves patency of the middle-lobe bronchus.
Under normal circumstances, ligation and division of the apical segmental vein may enhance the
visualization of the apical and anterior segmental arteries. Once completely mobilized, the pulmonary
artery is rolled away from the upper lobe bronchus and is inspected for anomalous branches originating
from its medial surface. This maneuver facilitates the later transection of the bronchus.
FIGURE 28.12 A,B: The mediastinal pleura is incised and the pulmonary artery is dissected in the subadventitial plane. The
interval between the pulmonary artery and the superior pulmonary vein is defined.
The lobe is retracted posteriorly, and the anterior surface of the superior pulmonary vein is cleared of
areolar tissue. The posterior surface of the pulmonary vein is freed by carrying the dissection on the
anterior surface of the bronchus just external to the peribronchial connective tissue. Three or four
branches enter the superior pulmonary vein and are encircled with ligatures. The extrapericardial length
of pulmonary vein is often inadequate for safe ligation; therefore, it is an ideal place for the use of a
vascular stapler. In the absence of a stapling device, the branches are tied, a vascular clamp is applied
proximally, and the vein is divided and then closed with a vascular suture. It is often easier to divide the
bronchus first via a posterior approach. To divide the bronchus at the appropriate level, the interval
between the lingular bronchus and the lower lobe bronchus is defined by rolling the pulmonary artery
posteriorly, thus exposing the bifurcation of the left main bronchus (Fig. 28.17A). The upper lobe
bronchus is occluded with a stapling device. Differential inflation ensures that the lower lobe bronchus is
not compromised; the stapler is fired, and the bronchus is transected with a Semb clamp positioned
between the bronchus and the vein to protect the vein. After closure of the bronchus, the specimen end of
the bronchus is grasped with a bronchus clamp. Elevation of the clamp exposes the deep surface of the
superior pulmonary vein (Fig. 28.17B). The superior pulmonary vein is then managed as previously
described. The inferior pulmonary ligament is divided to allow the left lower lobe to advance upward to
better fill the thoracic cavity.
FIGURE 28.13 Dissection of the posterior aspect of the left–upper-lobe hilum medial to the vagus nerve.
LEFT LOWER LOBECTOMY

Provided that the oblique fissure is complete, left lower lobectomy is the simplest of all to perform;
vascular anomalies are not commonly noted. The lung is retracted anteriorly, and the posterior
mediastinal pleura is incised from the level of the bronchus to the inferior pulmonary ligament, which
should be divided at this time. The upper lobe is retracted anteriorly and superiorly, and the lower lobe is
moved posteriorly and inferiorly, exposing the pulmonary artery in the fissure (Fig. 28.18A). It is best to
commence dissection of the pulmonary artery from its sheath at the posterior aspect of the fissure. If the
fissure is obliterated by adhesions, dissection of the posterior segment of the upper lobe from the superior
segment of the lower lobe is accomplished by pledget dissection of the interlobar pulmonary artery from
the overlying parenchyma as well as by the creation of a tunnel so that a stapling device or clamps may be
inserted to complete enough of the fissure to allow further exposure of the interlobar artery. The
anteromedial portion of the fissure is easily completed after bronchial closure. The superior segmental
artery arises from the posterolateral surface of the interlobar pulmonary artery at a slightly lower level
than the posterior segmental artery to the left upper lobe. Dissection of the interlobar artery along its
midpoint is continued to delineate the origin of the lingular arteries, which must not be sacrificed. The
basal trunk is then dissected, exposing the basal segmental branches. Occasionally, it is possible to
double-ligate the basal trunk distal to the lingular arteries and have one distal tie, but usually the basal
branches must be ligated separately to ensure adequate length of the proximal stump (Fig. 28.18B).
The inferior pulmonary vein is then cleared of areolar tissue, demonstrating its superior segmental and
basal tributaries, and the interval between the bronchus and the vein is defined (Fig. 28.19A). The
extrapericardial portion of the left inferior pulmonary vein is longer than the right; double proximal
ligation is acceptable. The preferred management, however, is stapling the cardiac end of the vein with a
linear endostapler or a thoracic-abdominal (TA) stapler. When using the TA stapler, it is best to confirm
the proper firing of the staples prior to dividing the vessel by removing it and inspecting the staple line.
Application of a vascular clamp and suture can also be done. Additional length may be obtained by
occluding the specimen side with a Sarot or other nonslipping clamp (Fig. 28.19B).
The bronchus is cleared of areolar tissue, and the crotch below the upper lobe bronchus is dissected.
The stapling device is applied just distal to the upper lobe bronchus to avoid creating a cul de sac, or the
bronchus is closed manually as described previously (Fig. 28.20).
FIGURE 28.14 A,B: The left pulmonary artery is dissected from the left main bronchus and encircled with a Silastic loop.
FIGURE 28.15 A,B: The posterior portion of the fissure is completed by stapling, and the segmental arteries are demonstrated.
FIGURE 28.16 A,B: After division of the lingual and posterior segmental arteries, rotation of the lobe aids dissection of the
apical and anterior segmental arteries.

FIGURE 28.17 A: The pulmonary artery is rolled away from the left upper bronchus. The site of bronchial transection is
indicated. B: The left–upper-lobe bronchus is stapled and divided. The superior pulmonary vein is stapled and occluded distally
by a Sarot clamp. C: Left–upper-lobe hilum after lobectomy.

FIGURE 28.18 A: Oblique fissure is completed and pulmonary artery branches are demonstrated. B: The superior segmental
artery is ligated. Basal arteries are ligated and divided after the lingual arterial branches are demonstrated.

FIGURE 28.19 A: The interval between the pulmonary vein and the lower lobe bronchus is defined. B: The inferior pulmonary
vein has been stapled. A Sarot clamp is applied to the specimen side before transection.

FIGURE 28.20 A: Oblique transection of the bronchus prevents formation of a cul de sac. B: View of the hilum after left
lower lobectomy.
ACKNOWLEDGMENT
The authors gratefully acknowledge the support of the Feldesman Fund for Thoracic Surgery at
Montefiore Medical Center.
REFERENCES
1. Blades B, Kent EM. Individual ligation technique for lower lobectomy. J Thorac Surg 1940;10:84.
2. Daniels LJ, Balderson SS, Onaitis MW, et al. Thoracoscopic lobectomy: a safe and effective strategy for patients with stage I lung
cancer. Ann Thorac Surg 2002;74;860–864.
3. Rajaram R, Mohanty S, Bentrem DJ, et al. Nationwide assessment of robotic lobectomy for non-small cell lung cancer. Ann Thorac
Surg 2017;103(4):1092–1100. http://dx.org/10.1016/j.athoracsur.2016.09.108.
4. McKenna RJ Jr, Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: experience with 1100 cases. Ann Thorac Surg
2006;81:421–426.
5. Overholt RH, Langer L. The Technique of Pulmonary Resection. Springfield, IL: Charles C Thomas; 1951.
6. Trastek VF, Pairolero PC, Piehler JM, et al. En bloc (non–chest wall) resection for bronchogenic carcinoma with parietal fixation.
Factors affecting survival. J Thorac Cardiovasc Surg 1984;87:352.
7. McCaughan BC, Martini N, Bains MS, et al. Chest wall invasion in carcinoma of the lung. Therapeutic and prognostic implications. J
Thorac Cardiovasc Surg 1985;89:836.
8. Tanaka M, Sagawa M, Usuda K, et al. Postoperative drainage with one chest tube is appropriate for pulmonary resection: a randomized
trial. Tohoku J Exp Med 2014;232(1):55–61.
29
Pneumonectomy and Its Modifications
Stéphane Collaud ■ Philippe Dartevelle ■ Elie Fadel
INTRODUCTION
Pneumonectomy is an anatomic resection that consists in removal of the entire lung. Mortality after
pneumonectomy ranged between 0% and 26%, depending on patient selection, surgical expertise, and
perioperative management.1,2 Since pneumonectomy is the only lung resection leaving an empty pleural
space, perioperative management requires additional specific considerations compared to other standard
anatomic lung resections. Patient selection, surgical procedure, and postoperative management will be
reviewed here.
HISTORY
Evarts Graham performed the first successful one-stage left pneumonectomy in April 1933 on James
Gilmore, a 48-year-old physician with a biopsy-proven carcinoma of the left upper lobe.3,4 Graham had
planned a lobectomy, but the operative findings were that the carcinoma extended into the left lower lobe
bronchus. Graham decided that pneumonectomy was the only acceptable procedure. He initially occluded
the pulmonary hilum with a catheter to assess the effects of sudden obstruction of the pulmonary artery
(PA), fearing that the symptoms of pulmonary embolism might ensue. The patient remained stable,
however, and Graham proceeded with pneumonectomy by mass ligature of the hilum using chromic catgut.
Horrified by the size of the empty pleural space, he performed a seven-rib thoracoplasty and closed the
chest with catheter drainage. Gilmore’s pathology specimen was subsequently reviewed and noted to be
T2, N1, stage IIB. Gilmore actually resumed practice and lived for 30 more years, ultimately dying of
cardiac and renal disease. Ironically, he outlived Graham, who succumbed to widely metastatic lung
cancer in 1957.
INDICATIONS FOR PNEUMONECTOMY

Usually, pneumonectomy is performed for bulky and centrally located carcinoma of the lung. It is also
done in the presence of distinct synchronous carcinomas located on the ipsilateral lobes, when a lobar
carcinoma invades the fissure or in case of large hilar lymph nodes adhering to the bronchovascular
structures. Occasionally, pneumonectomy is indicated for benign disease such as a destroyed lung
secondary to chronic infections (tuberculosis, atypical mycobacterial infection, bronchiectasis, fungal
disease), primary lung sarcoma or for metastases from distant cancer (i.e., colon, sarcoma, urogenital).
Completion pneumonectomy (after ipsilateral previous anatomic resection) is mostly performed for an
ipsilateral second primary lung cancer or a local recurrence.5
PREOPERATIVE WORK-UP
Patient selection is of paramount importance. Therefore, all patients should undergo a careful evaluation
of both tumor stage and physiologic capacity to withstand the resection.
Mediastinal lymph nodes should be fully staged prior to pneumonectomy, including positron emission
tomography coupled to computed tomography (PET/CT), endoscopic bronchial/esophageal ultrasound-
guided fine needle aspiration (EBUS/EUS-FNA), mediastinoscopy, or intraoperative lymph node
sampling. Multistation N2-involvement is, in fact, a contraindication to pneumonectomy.
In addition to the standard physiologic work-up for other anatomic lung resection, work-up for
pneumonectomy should include perfusion scintigraphy to assess right/left lung perfusion ratio and in
selected patient, right heart catheter with unilateral PA occlusion.6 In the authors’ institution, candidates
for unilateral PA occlusion include patients with limited cardio-pulmonary function, suspected pulmonary
hypertension on preoperative transthoracic echocardiography, or persistence of a large perfusion in the
diseased lung on scintigraphy. Balloon occlusion (for 5 to 10 minutes) of the main PA is performed,
mimicking hemodynamics after pneumonectomy. Absolute contraindications to pneumonectomy were
defined as a 5 mm Hg increase in mean PA pressure or pulmonary arterial hypertension after PA
occlusion, where pulmonary arterial hypertension is defined as a mean PA pressure of 25 mm Hg or more
at rest. Careful patient selection including right heart catheter and unilateral PA balloon occlusion as part
of the preoperative work-up for pneumonectomy led to lower perioperative mortality for pneumonectomy
than for lobectomy in the authors’ institution (unpublished data).
In patients with bronchial obstruction and subsequent lung atelectasis, hypoxia is not a contraindication
to pneumonectomy. Indeed, a pulmonary shunt may result from this condition (lung perfused and not
ventilated) and PA clamping is sufficient to improve systemic blood oxygenation.
SURGICAL ANATOMY
After bifurcation at the tracheal carina, the right and left main bronchi enter the right and left pleural
spaces. The right and left main bronchi measure approximately 2 and 5 cm, respectively. This size
discrepancy explains why lung cancer invading the tracheal carina is more common on the right than on
the left. It also explains why a right carinal pneumonectomy is possible through a right thoracotomy, but a
left carinal pneumonectomy requires a median sternotomy. The right main bronchus is highly exposed in
the pleural space while, on the left, the main bronchus is naturally buttressed by neighboring mediastinal
structures. This difference accounts for the higher risk of broncho-pleural fistula after right
pneumonectomy compared to left-sided pneumonectomy.
The pulmonary trunk divides into the right and left main PA. The right main PA runs intrapericardially
under the aorta and behind the superior vena cava (SVC) before giving the first PA branch to the upper
lobe. The PA can be clamped on its long intrapericardial portion between the aorta and the SVC or
extrapericardially proximal to the first PA branch. On the left, the PA runs below the aortic arch before
entering the hilum, anterior to the main bronchus. The intrapericardial portion of the left PA is short and
intrapericardial PA resection is limited.
On each side, both pulmonary veins drain mostly as two distinct entities into the left atrium. Since
right-sided veins are shorter than on the left, left atrium tumor invasion is more common on the right. Left
atrium resection can be performed after opening the pericardium.
Phrenic nerves run cranio-caudally and anteriorly to the hilum. The phrenic nerve is closer to the hilum
on the right than on the left. Therefore the phrenic nerve is more prone to be invaded by right hilar tumors
than left ones.
Right and left recurrent laryngeal nerves loop below the right subclavian artery and the aortic arch,
respectively. The right recurrent laryngeal nerve is exceptionally invaded by an upper paratracheal node,
whereas, on the left, the infiltration from a node or tumor originating in the aorto-pulmonary window is
more common.
PNEUMONECTOMY
After induction of general anesthesia, single-lung ventilation with a double-lumen tube or a bronchial
blocker is instituted. In general, a left-sided double lumen tube is used and care must be taken to
withdraw the tube into the trachea before clamping/stapling the left main bronchus for a left
pneumonectomy. When a left pneumonectomy is planned, a right-sided double lumen tube could however
be preferred.
In most cases, the patient is placed in a lateral position for a fifth intercostal space posterolateral
thoracotomy. A median sternotomy is favored in case of proximal PA or left atrium invasion that may
require extracorporeal circulation or carinal invasion by a left lung cancer.
Upon entering the chest, tumor extension and resectability are first assessed. Pleural space is inspected
and biopsied if required, to rule out pleural carcinomatosis. Loco-regional tumor spread is assessed.
Invasion of the aorta, heart, SVC, esophagus, and trachea is evaluated. Major vascular or mediastinal
structures precluding complete en-bloc resection contraindicates pneumonectomy. Finally, the need for
pneumonectomy must be carefully evaluated. Occasionally, intraoperative findings allow lesser
resections to be performed—such as sleeve resection of the bronchus and/or PA—allowing for
conservative sparing of lung parenchyma.7,8 Sleeve resections should always be attempted and preferred
to pneumonectomy since they provide similar local tumor control with better early and long-term
outcomes.8
After the mediastinal pleura is incised circumferentially around the hilum, the dissection of the hilar
structures starts usually with the artery, followed by the veins and the bronchus. Indeed, having the artery
controlled decreases bleeding if distal vascular (arterial or venous) injury occurs. However, sequential
dissection mainly depends on intraoperative findings. As a golden rule, structures should be divided one
by one, leaving the lung pedicled on the invaded structure. For example, division of artery and bronchus
first, leaving the lung pedicled on the veins/left atrium will facilitate tumor resection invading the left
atrium.
The artery is now freed in the sub-adventitial plane. Finger dissection using the thumb and forefinger
or a dissector is used to encircle the artery. If preoperative occlusion of the PA was not performed, it must
be occluded to assess the patient’s hemodynamics. Instability would contraindicate pneumonectomy. If
additional PA length is required, further dissection is carried out. On the right, dissection and division of
the superior pulmonary vein is performed first, providing better exposure and access to the right main PA.
To achieve additional length or more proximal control, an intrapericardial dissection behind the SVC or
between the SVC and ascending aorta is performed. On the left the ligamentum arteriosum can be divided
taking care not to injure the recurrent laryngeal nerve. Further length is obtained by intrapericardial
dissection. The pericardium is opened posterior to the phrenic nerve and just superior to the entrance of
the superior pulmonary vein, extending superiorly to the inferoanterior edge of the PA. By sharp
dissection, the artery can be freed from its pericardial linings. If the artery is to be divided at its origin,
care should be taken not to compromise the lumen of the PA trunk, an event that would lead to obstruction
of the right ventricular outflow tract.9 The artery can now be safely divided, mainly with vascular stapler.
Alternatively, it can be divided between vascular clamps and the ends oversewn with a vascular suture
such as 5-0 polypropylene glycol.
The pulmonary ligament is divided up to the inferior border of the lower pulmonary vein. After a
suitable length is obtained, both veins are freed, and divided. The veins are transsected using the same
methods described for the PA. It can also be ligated proximally and distally with a 0-0 silk tie. In this
case, proximal tie must be reinforced with a suture ligature as the bulk of the vein makes this tie
vulnerable to slippage. In case of slippage of a proximal venous tie or stapler misfiring, Duval lung clamp
is used to blindly clamp the target vein or left atrium, before re-enforcing the vein stump.
Access to the bronchus is facilitated after division of vascular structures. The lung is now pedicled on
the bronchus. A gentle traction on the lung will facilitate dissection of the peribronchial tissue, where
peribronchial lymph nodes should be swept toward the lung and removed with the specimen. Dissection
along the bronchus should not extend proximally beyond its stapled or sutured line. Indeed, a denuded
bronchus is subject to impaired healing, with resultant bronchopleural fistula. Before dividing the
bronchus, the double-lumen tube or bronchial blocker should be withdrawn in the trachea. Most
commonly, the bronchus is divided with a scalpel and the lung is removed. For manual suturing, the
authors use a combination of the Sweet and Overholt techniques.10,11 The bronchus is closed by
approximating the membranous parts onto the cartilaginous part with interrupted 3-0 braided polyglactin
sutures (Fig. 29.1A). The sutures are tied. The stump is then longitudinally folded and sutured with
interrupted 2-0 braided polyglactin with both membranous parts facing each other (Fig. 29.1B). The goal
of this technique is to completely cover the bronchial membranous side, the main area of weakness for
bronchopleural fistulas. The sutures are tied (Fig. 29.1C). Although it is not the authors’ favored
technique, in case the tumor is far away from the carina, the bronchus may be mechanically sutured with a
bronchial stapler. Once the bronchial stump is tested under water and a leak is excluded, the stump is
buttressed with a local flap, since the absence of covering is a risk factor for perioperative morbidity.12
Options include parietal pleura, azygos vein (Fig. 29.2), pericardial fat pad, pericardium, and intercostal
muscle bundle. The procedure is completed with mediastinal lymph node dissections.
FIGURE 29.1 Closure of the bronchial stump by manual suture. A: The bronchus is first closed by approximating the
membranous part onto the cartilaginous part with interrupted 3-0 braided polyglactin sutures. B: The stump is folded
longitudinally and sutured with interrupted 2-0 braided polyglactin, invaginating the membranous parts. C: Final result after tying
the sutures.
Various drainage strategies are available after pneumonectomy but they all aim to balance the
mediastinum and avoid mediastinal shift. Indeed, mediastinal shift may cause dyspnea, arrhythmia,
cardiac herniation, or hypotension. Balancing the mediastinum can be accomplished through catheter-
aspiration, intermittent chest tube drainage, or the use of commercially available balanced drainage. In
case of catheter-aspiration, an intrapleural 8–12 Fr catheter capped with a three-way stopcock is left in
the empty pneumonectomy cavity. After the chest is closed and the patient is positioned supine, about 1 L
of air is removed with a syringe and the patient is extubated. Depending on the position of the
mediastinum on the postoperative chest x-ray, an additional volume of air is removed or added before
removing the catheter. In case of intermittent chest tube drainage (the authors’ favored approach to avoid
infection of the pneumonectomy cavity by iterative punction), a regular clamped 28–32 Fr chest tube is
left in the pneumonectomy cavity and connected to underwater-seal drainage without suction. The chest
tube is unclamped every 8 hours to check for bleeding. Commercially available balanced drainage unit is
composed of three chambers: a collection chamber and two underwater valves for controlling both
positive and negative pressures. Pressure in the pleural cavity is therefore maintained between +1 and –
13 cm H2O.
TECHNICAL MODIFICATIONS OF PNEUMONECTOMY

Based on preoperative imaging or intraoperative findings, pneumonectomy may be extended to
neighboring structures. Involved chest wall should be resected en bloc with the lung, achieving tumor-free
surgical margins (Fig. 29.3). Invasions of the pericardium, aorta, SVC, left atrium, carina, or superficial
muscle of the esophagus are not absolute contraindications to resection. If resection is deemed complete
and tumor-free margins can be accomplished, the procedure should be carried out.
Superior Vena Cava Resection

Most operable lung cancer invading the SVC requires pneumonectomy (Fig. 29.4).13 It is best performed
through a fifth intercostal space right postero-lateral thoracotomy. Once hilar structures are dissected and
resectability confirmed, SVC clamping is prepared. Heparin is administered at 50 IU/kg. Mean arterial
pressure of 90 mm Hg is targeted to maintain sufficient cerebral perfusion pressure. Azygos vein is
divided. SVC is then clamped proximally at the confluence of both brachiocephalic veins and distally at
the cavo-atrial junction. Proximal end-to-end veno-prosthetic anastomosis is performed first (5-0
polypropylene). The prosthesis is flushed and de-aired before suturing the distal prostheto-venous
anastomosis in an end-to-end fashion with 5-0 polypropylene. De-airing precedes removal of clamps.
SVC reconstruction must be carefully planned to diminish venous clamping time. The pneumonectomy
procedure can now be completed (Fig. 29.5). The vascular graft is covered with a pleural flap and
anchored with 3-0 braided polyglactin.
FIGURE 29.2 Construction of the azygos vein flap. A: The vein is ligated to keep a flap of suitable size. B: It is then divided at
the level of the SVC and a longitudinal incision is made to allow coverage of the bronchial stump. C: Final result after suturing
the venous flap on the stump.
Reconstruction of the SVC is performed with a polytetrafluoroethylene (PTFE) graft. An 18- or 20-mm
diameter large graft is used for SVC replacement. In case of right brachiocephalic vein invasion,
interposition of a 12- or 14-mm graft between the left brachiocephalic vein and the distal SVC/right
atrium is performed, leaving the stump of the right brachiocephalic vein free. Immediate postoperative
therapeutic life-long anticoagulation is advised to favor graft patency.
FIGURE 29.3 CT imaging showing lung cancer invasion of the chest wall, requiring right pneumonectomy extended to the chest
wall (4th rib).
Left Atrium Resection

Lung cancer may invade the left atrium through the pulmonary veins (Fig. 29.6). It is more common on the
right since pulmonary veins are shorter than on the left. After a postero-lateral thoracotomy in the fifth
intercostal space is performed, tumor resectability is assessed. The pericardium is opened and tumor
invasion along the pulmonary veins is assessed. If the tumor is deemed resectable, the PA is divided. A
vascular clamp is placed on the left atrium (Fig. 29.7). Hemodynamics is checked since reduction of left
atrium volume may cause hypotension. If clamping is well tolerated, left atrium is divided with a blade,
leaving the tumor on the specimen with free resection margin (Fig. 29.8). Before closing the atrium, two
corner stitches are placed in case the vascular clamp would slip. Primary atrial closure is done with a
running 4.0 polypropylene suture. Vascular clamp is removed (Fig. 29.9). Pneumonectomy is completed
with division of the bronchus (Fig. 29.10).
FIGURE 29.4 CT imaging showing lung cancer invasion of superior vena cava, requiring right pneumonectomy with superior
vena cava resection and reconstruction.
FIGURE 29.5 Intraoperative view after extended pneumonectomy including superior vena cava resection and reconstruction
using an 18-mm PTFE graft.
Most of left atrial resections can be performed off cardio-pulmonary bypass. However, when the risk
of tumor fragmentation and embolization into the systemic circulation is high such as when the tumor
extends far into the left atrial lumen, the authors prefer to institute cardio-pulmonary bypass through a
median sternotomy with the patient on the supine position. Bi-caval and aortic cannulation sites are used.
The aorta is clamped and cardioplegia is administered. After cardiac arrest, the left atrium is opened
away from the tumor. Atrial closure is done either primarily with a running 4.0 polypropylene suture or
with the use of a pericardial patch, when the left atrial volume is judged too small.
FIGURE 29.6 CT imaging showing lung cancer invasion into the left atrium, requiring right pneumonectomy with left atrium
resection.
FIGURE 29.7 Intraoperative picture showing the vascular clamp on the left atrium. Note that the lower pulmonary vein was
previously divided using a stapler.
FIGURE 29.8 Intraoperative picture showing the tumor protruding into the opened left atrium.
FIGURE 29.9 Intraoperative picture after closure of the left atrium with a direct 4.0 Prolene suture. Note the specimen is now
pedicled on the main bronchus.
FIGURE 29.10 Intraoperative picture after right pneumonectomy was completed. Note the bronchial stump, pulmonary artery
stump, left atrium stump, and inferior pulmonary vein stump.
Sleeve pneumonectomy is performed when the tracheal carina is involved. This procedure is
described elsewhere.
POSTOPERATIVE MANAGEMENT AND COMPLICATIONS

Depending on case series and the definition used, postoperative morbidity after pneumonectomy ranges
from 10% to 60%.2 Standard postoperative monitoring and management as for other anatomic lung
resection should be followed. However, some complications related to pneumonectomy are specific and
need to be timely recognized and treated. These complications are described below.
POSTPNEUMONECTOMY PULMONARY EDEMA

Postpneumonectomy pulmonary edema (PPO) is a diagnosis of exclusion; it is a noncardiogenic,
noninfectious pulmonary edema which in fact represents a form of adult respiratory distress syndrome
(ARDS) in the remaining lung.14 PPO occurs in 2% to 5% of patients after pneumonectomy.15 Despite
modern management, mortality of PPO remains extremely high.
Pathophysiology is poorly understood but evidence suggests that increased pulmonary perfusion flow
and the subsequent rise in net filtration pressure, a restricted capillary volume, endothelial damage,
amputation of the lymphatic system, and hyperinflation are the main causes.16 Prevention is key and should
aim at restricting fluid administration and limiting ventilation pressure during surgery. The use of
balanced drainage unit was also suggested to decrease postoperative lung hyperinflation.17
Treatment in the intensive care unit consists in judicious management of fluid volume and ventilatory
supportive care. Extracorporeal membrane oxygenation support may be required. The use of inhaled nitric
oxide is suggested by small studies.18 The use of corticosteroids is controversial. It is not recommended
due to the risk of impairment of bronchial stump healing.
POSTPNEUMONECTOMY EMPYEMA
Postpneumonectomy empyema (PPE) is divided into early and late PPEs, depending on whether the onset
of symptoms occurs earlier or later than 90 days after pneumonectomy. Symptoms of early PPE may
include malaise, chest pain, fever, dyspnea, and position-dependent cough. Symptoms for late PPE are
usually milder and may include fatigue or anorexia, mostly without fever. Flexible bronchoscopy should
be performed to assess whether a bronchopleural fistula is present or not. Imaging with chest x-ray and
computed tomography may show mediastinal shift to the healthy side, lowering of air-fluid level (in case
of bronchopleural fistula), as well as contrast-enhancement of the pleura. Diagnosis is confirmed with
diagnostic thoracocentesis or at surgery.
Multiple treatment options are available and depend on the type of PPE (early vs. late), patients’
general status, and center expertise. However, treatment strategy consists in nutritional support if
required, antibiotic therapy combined with surgical drainage, and debridement of the postpneumonectomy
space. Surgical drainage and debridement can be achieved with a single open drainage procedure such as
a Clagett window or with repeated debridement and curettage of the postpneumonectomy space in the
operating room, described as “accelerated treatment of PPE.”19,20 Treatment of the bronchopleural fistula
is adapted to the intraoperative appearance of the bronchial stump. If the bronchial stump is judged too
long, stump shortening with repeated suturing is advocated. If the stump is short, primary suture of the
stump defect followed by muscle or omental flap reinforcement is recommended. In case of large stump
defect, omental patching using the “parachute technique” allows closure of the defect. Overall, PPE is a
serious complication with mortality up to 50%.20,21
POSTPNEUMONECTOMY SYNDROME
It is classically described as a late complication after pneumonectomy (months to years) where increasing
dyspnea develops secondary to mediastinal shift.22 Extreme mediastinal shift and rotation toward the
pneumonectomy space results in central symptomatic compression of the airways (Fig. 29.11).23 It is more
common after right pneumonectomy.23 Optimal treatment consists in mediastinal repositioning through a
thoracotomy with insertion of saline-filled prostheses (Fig. 29.12).22,24
FIGURE 29.11 CT imaging showing extreme mediastinal shift and rotation two years after right pneumonectomy for lung
cancer. Note the left main bronchus compression on the aorta.
FIGURE 29.12 Follow-up CT imaging after mediastinal repositioning. Note the saline-filled prosthesis maintaining the
mediastinum in physiologic position.
REFERENCES
1. Gudbjartsson T, Gyllstedt E, Pikwer A, et al. Early surgical results after pneumonectomy for non-small cell lung cancer are not affected
by preoperative radiotherapy and chemotherapy. Ann Thorac Surg 2008;86:376–382.
2. Weder W, Collaud S, Eberhardt WE, et al. Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non-
small-cell lung cancer. J Thorac Cardiovasc Surg 2010;139:1424–1430.
3. Fell SC. Special article: a brief history of pneumonectomy. 1999. Chest Surg Clin N Am 2002;12:541–563.
4. Graham EA, Singer JJ. Landmark article Oct 28, 1933. Successful removal of an entire lung for carcinoma of the bronchus. By Evarts
A. Graham and J. J. Singer. JAMA 1984;251:257–260.
5. Chataigner O, Fadel E, Yildizeli B, et al. Factors affecting early and long-term outcomes after completion pneumonectomy. Eur J
6. Tanita T, Tomoyasu M, Nagumo T, et al. [Preoperative evaluation for lung resection using right ventricular hemodynamic functions by
unilateral pulmonary arterial occlusion test]. Kyobu Geka 2004;57:913–918; discussion 8–20.
7. Yildizeli B, Fadel E, Mussot S, et al. Morbidity, mortality, and long-term survival after sleeve lobectomy for non-small cell lung cancer.
8. Fadel E, Yildizeli B, Chapelier AR, et al. Sleeve lobectomy for bronchogenic cancers: factors affecting survival. Ann Thorac Surg
2002;74:851–858; discussion 858–859.
9. Flores RM, Murthy S, DeCamp MM, Jr. Contralateral pulmonary artery stenosis after left pneumonectomy. Ann Thorac Surg
2001;72:274–276.
10. Sweet RH. Closure of the bronchial stump following lobectomy or pneumonectomy. Surgery 1945;18:82–84.
11. Overholt RJ. General considerations pertaining to all resections. In: Overholt RJ, ed. The Technique of Pulmonary Resection.
Springfield, IL: Charles C. Thomas; 1949:24–68.
12. Stamatis G, Djuric D, Eberhardt W, et al. Postoperative morbidity and mortality after induction chemoradiotherapy for locally advanced
lung cancer: an analysis of 350 operated patients. Eur J Cardiothorac Surg 2002;22:292–297.
13. Dartevelle P, Macchiarini P, Chapelier A. Technique of superior vena cava resection and reconstruction. Chest Surg Clin N Am
1995;5:345–358.
14. Van Schil PE, Hendriks JM, Lauwers P. Focus on treatment complications and optimal management surgery. Transl Lung Cancer Res
2014;3:181–186.
15. Slinger PD. Perioperative fluid management for thoracic surgery: the puzzle of postpneumonectomy pulmonary edema. J Cardiothorac
Vasc Anesth 1995;9:442–451.
16. Bauer P. Postpneumonectomy pulmonary oedema revisited. Eur Respir J 2000;15:629–630.
17. Alvarez JM, Tan J, Kejriwal N, et al. Idiopathic postpneumonectomy pulmonary edema: hyperinflation of the remaining lung is a
potential etiologic factor, but the condition can be averted by balanced pleural drainage. J Thorac Cardiovasc Surg 2007;133:1439–
1447.
18. Mathisen DJ, Kuo EY, Hahn C, et al. Inhaled nitric oxide for adult respiratory distress syndrome after pulmonary resection. Ann
Thorac Surg 1998;66:1894–1902.
19. Schneiter D, Cassina P, Korom S, et al. Accelerated treatment for early and late postpneumonectomy empyema. Ann Thorac Surg
2001;72:1668–1672.
20. Schneiter D, Grodzki T, Lardinois D, et al. Accelerated treatment of postpneumonectomy empyema: a binational long-term study. J
21. Wain JC. Management of late postpneumonectomy empyema and bronchopleural fistula. Chest Surg Clin N Am 1996;6:529–541.
22. Bedard EL, Uy K, Keshavjee S. Postpneumonectomy syndrome: a spectrum of clinical presentations. Ann Thorac Surg 2007;83:1185–
1188.
23. Shen KR, Wain JC, Wright CD, et al. Postpneumonectomy syndrome: surgical management and long-term results. J Thorac
Cardiovasc Surg 2008;135:1210–1216; discussion 1216–1219.
24. Grillo HC, Shepard JA, Mathisen DJ, et al. Postpneumonectomy syndrome: diagnosis, management, and results. Ann Thorac Surg
1992;54:638–650; discussion 650–651.
30
Sleeve Lobectomy
Paul De Leyn ■ Herbert Decaluwé
A sleeve lobectomy is the removal of a portion of main bronchus in conjunction with the involved lobar
bronchus and associated lung tissue. The most easy and commonly performed sleeve resection is the
sleeve right upper lobectomy (Fig. 30.1). Figure 30.2 shows the different types of sleeve lobar resections.
A sleeve lobectomy is an alternative to a pneumonectomy for lung cancer; when compared with
pneumonectomy, it is achieved with less morbidity and mortality and similar long-term results.
In 1947, Price-Thomas1 carried out the first sleeve lobectomy for a bronchial adenoma. Allison2
reported in 1959 the first successful sleeve lobectomy for carcinoma and was the first to report resection
and reconstruction of a portion of the adjacent pulmonary artery infiltrated by tumor in the patient
undergoing sleeve lobectomy for carcinoma. Price-Thomas3 summarized the role of sleeve resection in
selected patients with lung cancer in 1960. Paulson and Shaw4 stressed the importance of preserving
functional lung tissue in 18 sleeve resections for benign and malignant lung tumors.
INDICATIONS
Sleeve resections are applicable in patients with lung cancer, bronchial carcinoids, other bronchial
tumors, benign bronchial strictures related to trauma or inflammatory disease, airway problems after lung
transplantation, acute traumatic disruption of the airway and metastatic malignancies with lobar extension
to the main bronchus. Approximately 6% to 8% of resections for primary lung cancer are sleeve
resections.
Tumor in a lobar orifice or a lobar tumor invading the main bronchus precludes a standard lobectomy,
and sleeve lobectomy becomes the procedure of choice (Fig. 30.1). Preoperative bronchoscopy can
identify the need for a sleeve lobectomy by the visualization of tumor in the lobar orifice. If cancer is
found at the lobar resection margin on frozen section analysis or there is extraluminal extension of the
tumor to the mainstem bronchus, a more extensive resection than standard lobectomy is required. Lymph
nodes involved by cancer can invade the bronchial wall (in case of extracapsular disease) at the lobar
bronchial margin, and resection of a portion of the main bronchus is required. In these cases,
bronchoscopy may be normal. Nodal involvement may be expected from preoperative imaging but
malignancy has to be proven by frozen section. Resections for second primary lung cancers require
conservation of lung tissue, and a sleeve lobectomy can avoid pneumonectomy.
Typical carcinoid tumors are ideally suited for sleeve resections. They frequently have a limited base
of invasion into the bronchus, and margins of resections can be relatively close. Long-term results are
excellent. Patients with mucoepidermoid and adenoid cystic carcinomas are also candidates for sleeve
resections; a complete resection with accompanying lymph nodes must always be achieved for these
lesions.
Kato and colleagues5 reported on various types of sleeve resection for tuberculous bronchial stenosis.
Blunt chest trauma can cause bronchial disruption; if it is not diagnosed acutely, the patient can present
months or years later with a benign stricture. Such strictures are located adjacent to a lobar bronchus or in
a mainstem bronchus and are ideal for sleeve resection. Major bronchial disruption as a result of
penetrating or blunt chest trauma requires debridement of the torn bronchus and reapproximation of viable
tissue. Sleeve lobectomy may be required to reconstruct the airway in association with traumatized lung
parenchyma. Another indication is stenosis or dehiscence after lung transplantation. On the left side, the
anastomosis can be reperformed by sleeve resection of the left main bronchus without parenchymal
resection. On the right side, often a sleeve upper lobectomy may be required.
Benign tumors that require conservation of lung tissue include hamartomas, large lipomas,
schwannomas, and granular cell myoblastomas. Metastatic carcinomas can extend to a mainstem
bronchus, and sleeve lobectomy is then indicated.
SURGICAL TECHNIQUE OF BRONCHIAL SLEEVE RESECTION

The standard double-lumen tube is the endotracheal tube of choice for the required one-lung anesthesia.
Endobronchial balloon blockers can be used for one-lung anesthesia, but bronchoscopy is required for
proper positioning and the balloon blockers are more difficult to maneuver pre- and intraoperatively.
Accurate positioning and the tendency to migrate present intraoperative problems. Hypoxia can occur
because of the shunting of unoxygenated blood through the nonventilated lung. The use of increased FiO2
and increased minute ventilation minimizes hypoxia. Occlusion of the main pulmonary artery on the
operated side to minimize the shunt is rarely indicated. Ancillary techniques to improve arterial
oxygenation include jet ventilation or continuous positive airway pressure (CPAP) of the operated lung
combined with intermittent positive-pressure ventilation of the dependent lung. The anesthesiologist must
be familiar with all of these techniques.
The posterolateral thoracotomy is the most commonly used incision and gives excellent exposure for
sleeve lobectomy. However, an anterior thoracotomy is also feasible and preferred by some surgeons due
to lower postoperative pain. Entrance into the chest through the fifth intercostal space is satisfactory for
bronchial sleeve procedures. A pedicled intercostal muscle flap can be mobilized as the chest is opened
and is preserved for later bronchial coverage. This muscle flap should be taken before the ribs are
distracted to avoid crushing of the intercostal vascular bundle (Figs. 30.3 and 30.4). Sleeve lobectomy
can be accomplished by video-assisted thoracic surgery (VATS), but this should be reserved for patients
with minimal tumor burden for ease of dissection. This technique should be utilized only by experienced
VATS surgeon.
FIGURE 30.1 Illustration of sleeve right upper lobectomy which is the most commonly performed bronchial sleeve resection. A:
The right main bronchus is taped. The venous and arterial branch for the right upper lobe are ligated. B: The lobe with a
circumferential part of its origin and right main bronchus are removed. C: The bronchus intermedius is reimplanted at the right
main bronchus.
The initial dissection deals with the lobar branches of the pulmonary artery to ensure that the resection
can be accomplished. If the tumor is in close proximity to lobar branches, proximal control of the main
pulmonary artery is recommended. Neoadjuvant therapy can create significant fibrosis with obliteration
of the normal tissue planes of dissection. The tumor may invade the wall of the pulmonary artery or
involve the origin of a large lobar branch (Fig. 30.5). In this situation, it may be necessary to carry out a
concomitant sleeve resection or patch angioplasty of the pulmonary artery, as described by Vogt-Moykopf
and colleagues.6 Major extension of tumor across the fissure will contraindicate bronchoplasty and if the
patient has a good pulmonary function, pneumonectomy will be required in these lesions.
FIGURE 30.2 Location of tumor for which a standard sleeve lobectomy can be performed. A: Sleeve right upper lobectomy.
B: Sleeve right lower bilobectomy. C: Sleeve left upper lobectomy. D: Sleeve left lower lobectomy.
In case of malignancy, systematic nodal dissection should always be performed.7 It is preferable to

accomplish the lymph node dissection prior to the bronchial sleeve procedure to avoid traction on or
manipulation of the anastomosis. After it has been determined that a complete resection can be
accomplished by sleeve lobectomy, the vascular structures of the lobe are transected in standard fashion
and attention is then directed toward the bronchus.
In the following, the lobar dissection is illustrated in a case of sleeve right upper lobectomy performed
through posterolateral thoracotomy. The proximal and distal areas of the main bronchi are
circumferentially dissected free of adjacent tissue and taped (Fig. 30.6). The right main bronchus and
bronchus intermedius are taped. The right upper lobe bronchus is transected (Fig. 30.7). In this case it
was already macroscopically clear that the margin was positive for tumor (Fig. 30.8). No attempt is made
to cut in any specific area of the membrane or cartilage ring. A straight transection of the main bronchus
and associated distal bronchus provides the best opportunity for a complication-free anastomosis. The
bronchus intermedius (Fig. 30.9) and the main bronchus (Fig. 30.10) are transected. Figure 30.11 shows
the discrepancy in size of the main bronchus and the bronchus intermedius. Frozen section analysis of both
the proximal and distal ends of the bronchus is done to determine the adequacy of cancer resection. A
margin positive for microscopic cancer indicates that more bronchus must be resected. It is essential that
the suture line is tension free. This can be obtained by dividing the pulmonary ligament and by incising the
pericardium around the inferior pulmonary vein as described by Vogt-Moykopf and colleagues.6
FIGURE 30.3 The intercostal muscle is harvested before the ribs are distracted. The muscle is divided anteriorly and gently
removed from the ribs.
FIGURE 30.4 The intercostal muscle is harvested before the ribs are distracted. The muscle is divided anteriorly and gently
removed from the ribs.
FIGURE 30.5 When the tumor invades both a lobar branch at its origin and the pulmonary artery at the origin of the first
branch, a combined sleeve resection of bronchus and pulmonary artery may be required.
FIGURE 30.6 Illustration of sleeve right upper lobectomy. The operation is performed through posterolateral thoracotomy (fifth
intercostal space). The main bronchus and bronchus intermedius are dissected and taped.
FIGURE 30.7 The right upper lobe is transected with a knife.

FIGURE 30.8 In this case, it was already macroscopically clear that the margin was positive.
FIGURE 30.9 The bronchus intermedius is transected.
The technique for the bronchial end-to-end anastomosis is illustrated with the following figures. The
case is that of a sleeve right upper lobectomy. The authors prefer to complete an end-to-end anastomosis
with interrupted monofilament absorbable 3-0 polydioxanone suture material (PDS, Ethicon company) for
the cartilaginous part and 4/0 for the membranous part. The anastomosis is begun by placing two sutures
at the deepest junction of the membranous-cartilaginous part (Fig. 30.12). These two sutures are tied (Fig.
30.13) and continued by separate sutures on the cartilaginous part and finish with the membranous part.
Sutures are placed at the cartilaginous part and then place sutures on the membranous part. All these
sutures are placed before they are being tied. They are tied with the knots outside to alleviate tension and
provide accurate placement of the remaining sutures (Figs. 30.14 to 30.16). Polyglactin is the preferred
suture of other surgeons.
FIGURE 30.10 The right main bronchus is transected.
FIGURE 30.11 The right main bronchus and bronchus intermedius have been transected. This figure illustrates the discrepancy
in lumen of these two bronchi.
In every patient, there is a discrepancy between the size of the main bronchus and the bronchus
intermedius. Separate stitches help to clear this discrepancy. To compensate for the difference in caliber
between the largest central bronchus and the smaller peripheral bronchus, the interval between sutures of
the central bronchus is made slightly larger than that of the peripheral bronchus. Lumen disparity is further
corrected by stretching the membrane of the smaller bronchus and crimping the membrane of the larger
bronchus. The authors prefer not to resolve lumen disparity by resecting a small wedge of the
cartilaginous part of the proximal bronchus to reduce its diameter as this technique creates more
opportunity for bronchial dehiscence and necrosis. The authors always wrap the anastomosis with an
intercostal muscle flap or a pericardial fat flap. Since there have been reports of stenosis (requiring
completion pneumonectomy) due to circumferential muscle wrapping with subsequent ossification of the
intercostal muscle flap,8 only apply the intercostal muscle flap for about 240 degrees of the anastomosis.
This tissue separates the pulmonary artery from the bronchial anastomosis and minimizes the complication
of a bronchial arterial fistula. Tissue coverage can also minimize the complication of a small bronchial
disruption. The protection of the bronchial anastomosis is a subject of controversy as will be discussed
later. Following the completion of the anastomosis, the lung is inflated and the saline covered bronchus is
observed for any evidence of air leak at 20 to 30 cm of airway pressure. Small needle-hole air leaks are
of no concern, but an air leak between the edges of the bronchi may require an additional suture of 5-0
polyglycolic suture. The lung should inflate and deflate readily, indicating a widely patent anastomosis.
Failure of the lung to deflate can indicate anastomotic distortion or narrowing.
FIGURE 30.12 This figure illustrates the authors’ technique of bronchial anastomosis after sleeve lobectomy (illustrated case:
sleeve right upper lobectomy). Two sutures are placed at the deepest part (at the membranous-cartilaginous part).
FIGURE 30.13 These sutures are tied.
FIGURE 30.14 The anastomosis is performed with interrupted absorbable monofilament sutures. The sutures used are 3.0 for
the cartilaginous part, 4.0 for the membranous part.
FIGURE 30.15 The anastomosis is performed with interrupted absorbable monofilament sutures. The sutures used are 3.0 for
the cartilaginous part, 4.0 for the membranous part.
When the suture is performed without technical problems, we do not perform intraoperatively a
bronchoscopy. Bronchoscopy is performed in the postoperative period whenever necessary (atelectasis,
new major air leak) and always before the patient is discharged.
FIGURE 30.16 The sutures are tied and cut.

SLEEVE LOBECTOMY BY VATS
SURGICAL TECHNIQUE OF PULMONARY ARTERY SLEEVE RESECTION

Angioplasty is readily accomplished in conjunction with sleeve lobectomy. This intervention is most
commonly performed on the left side because of the anatomical close relationship of the left upper lobe
with the first branches of the left pulmonary artery.
After complete hilar and mediastinal dissection, the extent of the tumor and the feasibility of the
procedure should be assessed. The intervention starts by gaining central vascular control with taping of
the main pulmonary artery, the superior, and the inferior vein.
Linear resection and closure of the main artery can be done, but the surgeon must be certain that the
arterial lumen is not significantly narrowed. It is usually more appropriate to carry out a patch angioplasty
with a piece of pericardium or bovine pericardium to ensure lumen patency. Tangential resections are
usually not included in the domain of vascular reconstructions, although they are sometimes included in
the series reported in the literature.
Partial resection and patch reconstruction of the pulmonary artery can be performed in case the
opposite wall of the vessel is tumor-free (Figs. 30.17 and 30.18). The first choice for reconstruction is
autologous pericardium. The pericardium is harvested anteriorly to the phrenic nerve. This allows to
prepare large patches (Figs. 30.19 and 30.20). The defect in the pericardium usually does not require
closure. The resected stump of the pulmonary vein can also be used to produce a patch. In that case, the
patch is quite small. The autologous pericardium tends to shrink and curl during suturing. Fixing the
autologous pericardium in a solution with two drops of 20% glutaraldehyde in 50 mL saline for a few
seconds improves stiffening and facilitates manipulation during suturing.
FIGURE 30.17 Partial resection and patch reconstruction of the pulmonary artery can be performed in case the opposite wall
of the vessel is tumor-free.
FIGURE 30.18 In the case of left upper lobectomy, the superior vein is divided first. The main pulmonary artery and the inferior
pulmonary vein are clamped. Avoid to put a clamp distally on the pulmonary artery.
Minor bleeding from the suture line usually stops after a short period. Delicate compression with a
gauze may be useful.
If a larger, full circumferential portion of the artery has to be resected, an end-to-end anastomosis can
be performed (Figs. 30.21 to 30.23). Very rarely, conduit reconstruction of the resected segment of the PA
may be needed.
The intervention (which is in 80% of cases left upper lobectomy + sleeve of the pulmonary artery)
starts with division of the left superior pulmonary vein. A sleeve resection of the pulmonary artery can be
done in conjunction with or without a sleeve lobar resection, and the arterial anastomosis is
accomplished with fine monofilament nonresorbable suture (Prolene 5/0 or 6/0) in a continuous fashion
(Fig. 30.10). The arterial anastomosis is done after the bronchial anastomosis has been completed to
minimize retraction and handling of the vascular anastomosis, and the transected artery permits excellent
exposure for the bronchial anastomosis. Before clamping of the PA, 5000 units of heparin sodium are
injected intravenously to prevent clotting. The main PA is occluded by placing a Satinsky clamp. It is
essential not to clamp the PA in the fissure but to clamp the vein of the residual lobe (Fig. 30.18). After
transection of the PA, backflow is allowed and bleeding will stop since the pulmonary artery and the
inferior vein are clamped. In this way, there are no vascular clamps in the surgeon’s view and there is
minimal traction on the pulmonary artery. The lower lobe is mobilized by incising the inferior pulmonary
ligament and the pericardium around the inferior pulmonary vein. The suture of the PA is difficult since
the tissue is fragile. Mainly the posterior side is deep and quite difficult. The anastomosis is performed by
running 5/0 or 6/0 monofilament nonabsorbable material. The lung and the anastomosis is de-aired by
opening the clamp on the pulmonary vein (backflow). Heparin is not reversed by Protamine. The authors
routinely interpose the intercostal muscle flap between the artery and the bronchus.
FIGURE 30.19 The first choice for patch reconstruction of the pulmonary artery is autologous pericardium. The anastomosis is
performed with 5.0 or 6.0 Prolene.
FIGURE 30.20 The patch reconstruction is completed.
FIGURE 30.21 In case a circumferential part of the pulmonary artery needs to be transected, everything is prepared for
primary anastomosis.
FIGURE 30.22 The end-to-end anastomosis of the pulmonary artery is performed with 5.0 or 6.0 nonresorbable monofilament
suture.
FIGURE 30.23 The anastomosis is completed.
After the operation, anti-thrombotic treatment with low–molecular-weight heparins is initiated.
POSTOPERATIVE MANAGEMENT AND COMPLICATIONS

After sleeve lobectomy, the most severe postoperative complications are related to atelectasis,
pneumonia, and bronchial dehiscences. In a survey of 1,125 sleeve lobectomies performed in various
centers, Tedder and colleagues9 noted that pneumonia and atelectasis occurred in approximately 6.7% and
5.4% of patients, respectively. This relates to an accumulation of secretions and blood at the anastomosis
due to mucosal damage and loss of ciliary function. Early mobilization and physiotherapy can minimize
this problem. Excessive secretions or recurrent atelectasis can be managed by bronchoscopy, if necessary
daily.
Risk factors that can have a significant effect on the development of postoperative complications
include an FEV1 under 40%, increased pulmonary artery pressure, coronary artery disease, current
smoking, right-sided resections, and bilobectomy. Age, gender, induction therapy, vascular sleeve
resection, and a positive bronchial microscopic margin appear to have no significant effect on the risk of
postoperative complications.10
The overall results after sleeve lobectomy in terms of morbidity and mortality depend mostly on the
anastomotic healing. The clinical indication for postoperative bronchoscopy includes a persistent coarse
wheeze at the anastomosis, continuing loss of volume noted on the chest radiograph, lobar consolidation,
or a persistent air leak at 7 days postoperatively. The authors always perform bronchoscopy before
discharge. A persistent air leak at 7 to 10 days postoperatively may indicate partial anastomotic
dehiscence, and the anastomosis should be inspected with the flexible bronchoscope. Bronchial necrosis
is indicated by a gray–white discoloration of the mucosa; a to-and-fro motion of secretions through a
partial dehiscence can also be identified. A dehiscence of 4 to 5 mm can be observed and treated
conservatively with prolonged chest tube drainage. This is particularly true if tissue has been placed over
the bronchial anastomosis. The development of an airspace and increasing volume of air leak indicate
further dehiscence requiring reintervention. An anastomotic dehiscence greater than 10 mm also requires
consideration of reintervention. During reintervention, the surgeon can try to perform suture anastomotic
reapproximation with fresh tissue coverage with a muscle flap but in many cases completion
pneumonectomy may be required. Careful judgment is required because the patient must be able to
tolerate the pneumonectomy procedure. Completion pneumonectomy carries a mortality rate of 15% to
20%, as reported by Kawahara11 and Van Schil, and colleagues.12 In a review of 1,125 patients who
underwent sleeve lobectomy, Tedder and colleagues9 reported an incidence of bronchial complications of
4.8% for stenosis, 3% for dehiscence, and 2.5% for fistula. In recent series, neoadjuvant therapy was not
associated with increased rates of bronchial anastomotic complications. Bronchial anastomotic
complications are seen in recent series in 6.4% of patients.10
The protection of the bronchial anastomosis is a subject of controversy. Kutlu and Goldstraw13
avoided the wrapping of the bronchial anastomosis and concluded that the careful handling of the airway,
with the preservation of as much peribronchial tissue as possible can avoid the need of any tissue flap on
the bronchial anastomosis. Rea and colleagues14 did not find any significant difference in 30-day
mortality between patients with or without pedicle flaps. Storelli and colleagues15 reported on 103
patients who underwent bronchial sleeve resection without covering of the anastomosis with a tissue flap.
They found no anastomotic dehiscences. They registered 1% narrowing of the intermediate bronchus that
did not need any surgical treatment.
Improved surgical technique has also minimized late complications such as bronchial stenosis or
bronchial kinking. The development of bronchial stenosis is successfully managed by bronchial dilation
and stenting techniques, as described by Kutlu and Goldstraw.13 In a recent publication from Marseille,
108 patients who underwent sleeve resection were followed.16 In this centre, the anastomosis was
routinely covered with an intercostal muscle flap and they performed systematic endoscopic follow-up.
The first bronchoscopy was performed within the first week after surgery, then at 30 and 60 days and
whenever a patient presented with a clinical or radiologic abnormality. Anastomotic stenosis was the
most common complication, arising in nine patients, including seven patients with fibrotic stenosis and
two with malacid stenosis. Anastomotic dehiscence occurred in seven patients and obstructive
granulomatous tissue in four patients. In total, 23 patients underwent therapeutic bronchoscopy. Only one
patient in which there was a stent placement failure required pneumonectomy as a result of anastomotic
complications. In this study, the anastomotic complication rate was 21.3%, only 13% required endoscopic
management. This high rate of anastomotic complication may be explained by the systematic endoscopic
follow-up performed in that center.
Hemoptysis in the postoperative period is of significant concern and can herald the development of an
impending bronchial arterial fistula. Immediate bronchoscopy is required to assess the anastomosis and
attempt to define the area of bleeding. Completion pneumonectomy is usually required to avoid this fatal
complication.
Function of the reimplanted lung is decreased in the early postoperative period and relates to
decreased bronchial arterial flow, damaged lymphatics, and transected parasympathetic nerves.
Decreased perfusion may last for 2 to 3 weeks. Khargi and colleagues17 evaluated the preoperative and
postoperative pulmonary function of 109 sleeve lobectomy patients and demonstrated that there was
complete recovery of function of the reimplanted lobe at 4 months. Deslauriers and colleagues18 studied
the functional results of sleeve lobectomy and determined that the reimplanted lung contributes
significantly to pulmonary function with minimal change in ventilation or perfusion. Preoperative and
postoperative lung function assessment was carried out by Gaissert and colleagues19 and their findings
clearly demonstrated that the operated lung carried out expected proportional function.
POSTOPERATIVE MORTALITY AFTER SLEEVE RESECTION FOR LUNG
CANCER
Tedder and colleagues9 reported in their review of 1,125 patients who underwent sleeve lobectomy a
mortality rate of 5.5%. It is evident that with increasing experience mortality can be reduced. Terzi and
colleagues20 noted an overall mortality of 11.2% (18 of 160 patients) in sleeve lobectomy for lung cancer.
Mortality in their early experience (1965 to 1993) was 14.6% and mortality in later period (1994 to
1999) decreased to 6%. Mortality in recent individual series (Table 30.1) varies from 1% to 12%. In a
recent meta-analysis,21 mortality after sleeve resection (n = 876) was 3.5%. From recent literature, we
can conclude that a sleeve lobectomy for lung cancer should be accomplished with a mortality rate under
5%.
TABLE 30.1 Postoperative Mortality, Morbidity, and Long-Term Survival After Sleeve Resection (Literature Data
Since 2000)
Study Year No. of Postoperative Early 5-Year Locoregional

Patients Mortality (%) Anastomotic Survival Recurrence
Complications Rate (%)
(%) (%)
Tronc and 2000 184 1.6 1 52 22
colleagues22
Rendina and 2000 145 1.4 1.4 37.9 NR
colleagues23
Terzi and 2002 160 11.2 7.5 NR NR
colleagues20
De Leyn and 2003 77 3.9 2.6 45.6 16.8
colleagues24
Ludwig and 2005 116 4.3 6.9 39 NR
colleagues25
Kim and 2005 49 6.1 2 53.7 32.6
colleagues26
Yildizeli and 2007 218 4.1 6.4 53 14.4
colleagues10
Rea and 2008 199 4.5 5.3 39.7 11.6
colleagues27
Deslauriers 2004 184 1.3 1.6 58 22
and
colleagues18
Yamamoto and 2008 201 1.4 3.3 57.8 12.9
colleagues28
Merritt and 2009 196 2 2 44 17.9
colleagues29
Konstantinou 2009 45 2 0 57 (4-y) NR
and
colleagues30
Storelli and 2012 103 2.9 1 63 7.8
colleagues15
NR, not reported.
LONG-TERM SURVIVAL AND LOCOREGIONAL RECURRENCE AFTER
SLEEVE LOBECTOMY FOR LUNG CANCER
The reporting of long-term results following sleeve lobectomy is variable because some series include
patients with carcinoid tumors which are known to have a much better prognosis than lung cancer.
Moreover, the methods of clinical staging may or may not include mediastinoscopy, neoadjuvant therapy,
and postoperative adjuvant therapy.
The 5-year survival rate and locoregional recurrence rate reported in recent literature (published since
2000) are reported in Table 30.1. The 5-year survival varies between 39.7%27 and 57.8%.28 It is evident
that survival depends on pathological staging and mainly of the involvement of hilar and mediastinal
lymph nodes. Tronc and colleagues22 reported complete follow-up in 184 patients who underwent sleeve
resection for lung cancer. At 5 and 10 years, the actuarial survival rate was 52% and 33%, respectively.
The 5-year survival for patients with N0 disease was 63%; for patients with N1 disease it was 48% and
for patients with N2 disease it was 8%. No patients with N2 disease survived 10 years, and these survival
differences were statistically significant. This is a large series of clinically well-staged patients and
indicates the results that can be achieved with careful patient selection. Locoregional recurrences after
sleeve lobectomy vary between 7.8%15 and 32.6%.26
Some surgeons believe that pneumonectomy is a more complete resection especially for patients with
N1 and N2 disease and state that sleeve lobectomy should be reserved for N0 and physiologically
compromised patients. Ferguson and Lehman31 performed a meta-analysis of 860 sleeve lobectomy
patients and 746 pneumonectomy patients. Despite a locoregional recurrence rate of 20% for the sleeve
lobectomy patients (vs. 10% in pneumonectomy group), 5-year survival was slightly better compared to
pneumonectomy (51.4% for sleeve lobectomy vs. 49.01% for pneumonectomy, p = 0.6). Utilizing quality-
adjusted life years (QALYs), sleeve lobectomy was strongly favored and was more cost-effective than
pneumonectomy.
In the last published meta-analysis,21 12 studies, including 3 matched studies and 1 prospective study,
were suitable for meta-analysis. Eight hundred and seventy-six patients underwent sleeve lobectomy and
2,108 underwent pneumonectomy. The postoperative mortality in the sleeve lobectomy was 3.5% which
was comparable with 5.7% in the pneumonectomy group. However, in studies with more than 50 patients
in each group, postoperative mortality was 3.0% in sleeve lobectomy compared with 5.7% in
pneumonectomy, suggesting that this is statistically significant (OR: 0.55). The pooled locoregional
recurrence in sleeve lobectomy was 16.1% as compared with 27.8% in the pneumonectomy group, this
did not reach statistical significance (OR: 0.91). The estimated combined hazard ratio (HR) for overall
survival in the 10 studies who reported survival was 0.7 in favor of sleeve lobectomy group which was
statistically significant. The overall 5-year survival was 50.3% for the sleeve lobectomy group, 30.6%
for the pneumonectomy group, and 38.7% for the pulmonary artery resection group. Survival difference in
patients with pN0 or pN1 at 5 years demonstrated a pooled risk difference (SL vs. PN) of 0.21 (95%
CI:0.07 to 0.36) and 0.06 (95% CI: 0.10 to 0.21) in patients with pN2 at 5 years. These results suggest
that sleeve lobectomy with or without pulmonary artery reconstruction can be accomplished safely in
selected patients without increasing the morbidity and mortality as compared to pneumonectomy, that
sleeve lobectomy even with pulmonary artery reconstruction offers better long-term survival than does
pneumonectomy, and that a more radical operation such as pneumonectomy is not a more appropriate
procedure, even in higher stage tumors.
RESULTS OF COMBINED SLEEVE RESECTION AND ARTERIAL
RECONSTRUCTION
In 1952, the first tangential resection with direct suture of the pulmonary artery was performed by
Allison,2 who also performed the first arterial sleeve resection in 1959. Throughout the 1970s and 1980s,
only a few groups gathered useful experience. One of the most significant studies was a publication by
Vogt-Moykopf in 1986 with a series of 37 arterial sleeve resections. They reported acceptable long-term
results but also an operative mortality up to 14%.32
TABLE 30.2 Results of Studies Reporting PA Reconstruction

Author (y) Patients Morbidity (%) Mortality (%) 5-Year Survival (%)
Rendina and colleagues33 52 13.4 0 38.3
Shrager and colleagues34 33a 45 0 46.7
Lausberg and colleagues35 67 NA 1.5 42.9b
Nagayasu and colleagues36 29 27.6 17.2 24.2b
Cerfolio and Bryant37 42 26 2.3 60
Alifano and colleagues38 93c 29 5.4 39.4
Venuta and colleagues39 105 28.5 0.95 44
Mean 60.14 28.25 3.91 42.21

a Only tangential resections.
b Overall survival for combined bronchovascular reconstruction.
cTangential resections (n = 88).
Reprinted from Ibrahim M, Maurizi G, Venuta F, et al. Reconstruction of the bronchus and pulmonary artery. Thorac Surg Clin 2013;23:337–
347. Copyright © 2013 Elsevier. With permission.
NA, not available.
Sleeve lobectomy in conjunction with pulmonary artery reconstruction is nowadays a viable procedure
for NSCLC. Rendina and colleagues23,33 reported several specific intraoperative techniques during sleeve
resection of the pulmonary artery. They published a study with 145 patients, of which there were 56
arterial reconstructions. Two postoperative deaths and a morbidity rate of 12.8% were reported. The
overall 5-year survival was 38.6% for combined arterial and bronchial reconstructions, and 36.4% for
patients with only an arterial reconstruction. They stated that bronchovascular reconstructions are equal to
standard lobectomy in terms of pulmonary function and that the long-term survival is comparable with the
one reported for standard resection. The preserved lung lobe contributes remarkably to the pulmonary
function and quality of life in contrary to pneumonectomy. Cardiological follow-up also confirms the
advantages in terms of right heart function and morphology due to the preservation of a normally perfused
lobe.
Since the evidence of the advantages of these technically demanding procedures has been provided,
several other recent publications followed. Table 30.2 shows an overview of the early and late results of
the recent literature.
SLEEVE RESECTION FOR OTHER TUMOURS
Bronchial carcinoids are rare neuroendocrine tumors. Mainly the typical carcinoids are found in fit and
young patients. Carcinoids arising within the bronchus with or without extension through the bronchial
wall are clearly suitable for bronchial sleeve resection (with or without parenchymal resection). Margins
can be in close proximity to the tumor, and long-term results are very good. In many series, results are
reported for both NSCLC and carcinoid tumors. Lowe and Sabiston40 reported results of bronchoplastic
procedures for carcinoid tumors in 112 patients; 100 patients (96%) survived 5 years. Fadel and
colleagues41 reported 100% 5-year survival for sleeve resection of carcinoid tumors. There were 25
typical carcinoids and 5 atypical carcinoid tumors in this group, which comprised 22 patients with stage I
disease and 8 with stage II disease. One patient died of myocardial infarction at 78 months, and the other
29 patients were free of disease at 10 years. The atypical carcinoid lesion is a more aggressive tumor,
and complete lymphadenectomy is always accomplished in association with the sleeve procedure. Sleeve
resections are also indicated for mucoepidermoid and adenoid cystic carcinomas of the bronchus. Nowak
and colleagues42 reported their results on 13 patients with pure bronchoplastic resection for
endobronchial carcinoid tumor without the resection of lung parenchyma. There was no significant
operative morbidity or mortality. After median follow-up of 6.3 years, there was no locoregional
recurrence.
BENIGN LESIONS
Sleeve resections are important in resecting benign lesions of the tracheobronchial tree because they
afford the opportunity to conserve lung tissue. Motor vehicle accidents are associated with traumatic
disruption of the mainstem bronchus at the origin of the lobar bronchus, and sleeve resection can be
indicated. Bronchial edges are transected to provide viable tissue for anastomosis, and it is important to
achieve a tension-free anastomosis. Late bronchial stenosis may occur in a distal mainstem bronchus or
compromise a lobar bronchus. In this instance, sleeve lobectomy will preserve the distal lung tissue; if
infection free, it will function normally in the postoperative period. Tuberculosis is rare, but an
occasional patient may develop a stricture related to this inflammatory process. Antituberculosis therapy
preoperatively is mandatory, and inflammation at the site of the stricture must be minimized. Patients with
Wegener granulomatosis and sarcoidosis can also present with lobar or bronchial compromise and can be
candidates for sleeve resection. Techniques for benign lesions are similar to those described for
neoplasms, and results are most satisfactory.
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3. Price-Thomas C. Lobectomy with sleeve resection. Thorax 1960;15:9–11.
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Thorac Surg 1994;57:1529–1533.
12. Van Schil PE, de la Rivière AB, Knaepen PJ, et al. Long-term survival after bronchial sleeve resection: univariate and multivariate
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13. Kutlu CA, Goldstraw P. Tracheobronchial sleeve resection with the use of a continuous anastomosis: results of one hundred consecutive
cases. J Thorac Cardiovasc Surg 1999;117:1112–1117.
14. Rea F, Loy M, Bortolotti L, et al. Morbidity, mortality and survival after bronchoplastic procedures for lung cancer. Eur J Cardiothorac
Surg 1997;11(2):201–205.
15. Storelli E, Tutic M, Kestenholz P, et al. Sleeve resections with unprotected bronchial anastomoses are safe even after neoadjuvant
therapy. Eur J Cardiovasc Surg 2012;42:77–81.
16. Bylicki O, Vandemoortele T, Orsini B, et al. Incidence and management of anastomotic complications after bronchial resection: a
retrospective study. Ann Thor Surg 2014;98:1961–1967.
17. Khargi K, Duurkens VA, Verzijlbergen FF, et al. Pulmonary function after sleeve lobectomy. Ann Thorac Surg 1994;57:1302–1304.
18. Deslauriers J, Gregoire J, Jacques LF, et al. Sleeve lobectomy versus pneumonectomy for lung cancer: a comparative analysis of
survival and sites of recurrences. Ann Thorac Surg 2004;77:1152–1156.
19. Gaissert HA, Mathisen DJ, Moncure AC, et al. Survival and function after sleeve lobectomy for lung cancer. J Thorac Cardiovasc
Surg 1996;222:948–953.
20. Terzi A, Lonardoni A, Falezza G, et al. Sleeve lobectomy for non-small-cell lung cancer and carcinoids: results in 160 cases. World J
21. Ma Z, Dong A, Fan J, et al. Does sleeve lobectomy concomitant with or without pulmonary artery reconstruction (double sleeve) have
favourable results for non-small cell lung cancer compared with pneumonectomy? a meta-analysis. Eur J Cardiovasc Surg
2007;32:20–28.
22. Tronc F, Grégoire J, Rouleau J, et al. Long-term results of sleeve lobectomy for lung cancer. Eur J Cardiothorac Surg 2000;17:550–
556.
23. Rendina EA, De Giacomo T, Venuta F, et al. Lung conservation techniques: bronchial sleeve resection and reconstruction of the
pulmonary artery. Semin Surg Oncol 2000;18:165–172.
24. De Leyn P, Rots W, Deneffe G, et al. Sleeve lobectomy for non-small cell lung cancer. Acta Chir Belg 2003;103:570–576.
25. Ludwig C, Stoelben E, Olschewski M, et al. Comparison of morbidity, 30-day mortality, and long-term survival after pneumonectomy
and sleeve lobectomy for non-small-cell lung carcinoma. Ann Thorac Surg 2005;79:968–975.
26. Kim Y, Kang C, Sung S, et al. Local control of disease related to lymph node involvement in non-small cell lung cancer after sleeve
lobectomy compared with pneumonectomy. Ann Thorac Surg 2005;79:1153–1161.
27. Rea F, Marulli G, Schiavon M, et al. A quarter of a century experience with sleeve lobectomy for non-small cell lung cancer. Eur J
28. Yamamoto K, Miyamoto Y, Ohsumi A, et al. Sleeve lung resection for lung cancer: analysis according to the type of procedure. J
29. Merritt R, Mathisen D, Wain J, et al. Long-term results of sleeve lobectomy in the management of non-small cell lung carcinoma and
low-grade neoplasms. Ann Thorac Surg 2009;88:1574–1582.
30. Konstantinou M, Potaris K, Sakellaridis T, et al. Sleeve lobectomy for patients with non-small cell lung cancer: a simplified approach.
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Ann Thorac Surg 2003;76:1782–1789.
32. Vogt-Moykopf I, Fritz T, Meyer G, et al. Bronchoplastic and angioplastic operations in bronchial carcinoma: long term results of a
retrospective analysis. Int Surg 1986;71:211–220.
33. Rendina EA, Venuta F, De Giacomo T, et al. Sleeve resection and prosthetic reconstruction of the pulmonary artery for lung cancer.
Ann Thorac Surg 1999;68:995–1002.
34. Shrager JB, Lambright ES, McGrath CM, et al. Lobectomy with tangential pulmonary artery resection without regard to pulmonary
function. Ann Thorac Surg 2000;70:234–239.
35. Lausberg HF, Graeter TP, Tscholl D, et al. Bronchovascular versus bronchial sleeve resection for central lung tumors. Ann Thorac
Surg 2005;79:1147–1152.
36. Nagayasu T, Matsumoto K, Tagawa T, et al. Factors affecting survival after bronchoplasty and bronchoangioplasty for lung cancer:
single institutional review of 147 patients. Eur J Cardiothorac Surg 2006;29:585–590.
37. Cerfolio RJ, Bryant AS. Surgical techniques and results for partial or circumferential resection of the pulmonary artery for patients with
non-small cell lung cancer. Ann Thorac Surg 2007;83:1971–1977.
38. Alifano M, Cusumano G, Strano S, et al. Lobectomy with pulmonary artery resection: morbidity, mortality, and long-term survival. J
39. Venuta F, Ciccone AM, Anile M, et al. Reconstruction of the pulmonary artery for lung cancer: long-term results. J Thorac Cardiovasc
Surg 2009;138(5):1185–1191.
40. Lowe JE, Sabiston DC Jr. Bronchoplastic techniques in the surgical management of benign and malignant pulmonary lesions. In:
Sabiston DC Jr, Spencer FC, eds. Surgery of the Chest. 6th ed. Vol. 1. Philadelphia, PA: Saunders; 1995:649–659.
41. Fadel E, Yildizeli B, Chapelier AR, et al. Sleeve lobectomy for bronchogenic carcinoma: factors affecting survival. Ann Thorac Surg
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42. Nowak K, Karenovics W, Nicholson A, et al. Pure bronchoplastic resections of the bronchus without pulmonary resection for
endobronchial carcinoid tumors. Interact Cardiovasc Thorac Surg 2013;17:291–295.
31
Tracheal Sleeve Pneumonectomy
Laura Donahoe ■ Marc de Perrot
INTRODUCTION
Tracheal sleeve pneumonectomy is an extended resection for tumors involving the tracheobronchial angle,
carina or lower trachea and lung. The most common indication is non–small-cell lung carcinoma, but
tracheal sleeve pneumonectomy can occasionally be required for other type of malignancies such as
carcinoid tumor or adenoid cystic carcinoma. Over the past two decades, refinement in techniques of
tracheal surgery and bronchial sleeve lobectomy has allowed tracheal sleeve pneumonectomy to become
a safe procedure in experienced centers. Careful patient selection and detailed evaluation is an important
component to good surgical results.
HISTORICAL NOTE
In 1946, Belsey described a successful case of lateral wedge resection of the distal trachea and carina
combined with the use of prosthetic material for reconstruction.1 In 1950, Abbott presented four patients
undergoing right pneumonectomy associated with lateral resection of the tracheal wall and transverse
closure above the right main bronchus.2 All four patients survived the operation but had problems with
kinking and obstruction of the trachea that were related to excessive mediastinal shift according to the
authors. Chamberlain et al.,3 Gibbon,4 and Hardin and Fitzpatrick5 described in 1959 successful resection
of primary bronchogenic carcinoma involving the carina, and Grillo et al. presented in 1963 the first
comprehensive approach to carinal resection and reconstruction.6 In 1966, Thompson et al.7 reported a
left carinal pneumonectomy with anastomosis between the right main bronchus and the distal trachea using
catgut sutures as well as a carinal resection after right pneumonectomy with anastomosis between the left
lung and trachea.8 Mathey et al.9 also presented in 1966 their experience on tracheal sleeve
pneumonectomy and suggested that circumferential carinal resection should be preferred to
noncircumferential excision. Other significant reports of tracheal sleeve pneumonectomy included those
from Eschapasse et al.,10 Perelman et al.,11 Jensik et al.,12 Deslauriers et al.,13 Dartevelle et al.,14,15 and
Tsuchiya et al.16 Although the operative mortality was about 30% in early series, Dartevelle et al.14 in
1988 and Mathisen and Grillo17 in 1991 were the first to demonstrate that tracheal sleeve pneumonectomy
could be performed with acceptable risk in large series of patients with bronchogenic carcinoma (Table
31.1).
TABLE 31.1 Results of Tracheal Sleeve Pneumonectomy in Large Selected Series
First Year of Period Number Operative 5-Year 5-Year 5-Year

Author Publication of of Mortality Survival Survival Survival
Study Patients Overall for N0 for N1
Disease Disease
Deslauriers13 1979 1969– 16 31% n.r. n.r. n.r.

1977
Jensik12 1982 1964– 30 29% 13% n.r. n.r.
1981
Dartevelle14 1988 1966– 55 11% 23% n.r. n.r.
1986
Mathisen17 1991 1973– 21 8% 19% n.r. n.r.
1991
Dartevelle15 1995 1981– 55 7% 40% n.r. n.r.
1995
Roviaro25 2001 1983– 59 8% 25% n.r. n.r.
1999
Mitchell19 2001 1973– 35 20%a 38% 51% 32%
1998
Porhanov36 2002 1979– 162 16% 25% 32% 32%
2001
Mezzetti35 2002 1979– 27 7% 20% 50% 12%
1999
Regnard37 2005 1983– 60 8% 26% 38% 38%
2002
de Perrot18 2006 1981– 100 8% 44% 50% 55%
2004
Eichhorn38 2013 2000– 64 3% 31% 70% 35%
2011
Shin39 2014 1996– 19 0% 66% 57% 50%
2011
aOperative mortality of 10% for last 10 years of their experience.
n.r., not reported.
FIGURE 31.1 A and B: CT showing a tumor of the right upper lobe extending to the carina.
PREOPERATIVE EVALUATION
Careful patient selection and detailed evaluation of the lesion is a key component to good surgical results
in tracheal sleeve pneumonectomy. All patients should be evaluated to ascertain that they can tolerate the
operation and withstand the necessary removal of pulmonary parenchyma. The preoperative workup
consists of chest radiography, chest computed tomography (CT) scan, pulmonary function tests, arterial
blood gas, ventilation/perfusion scan, electrocardiography, and echocardiography (Fig. 31.1A,B).
Positron emission tomography/CT (PET/CT) scans are also now used routinely in the investigation of
these patients (Fig. 31.2). Maximum oxygen uptake and exercise testing can be used in patients with
borderline lung function. The operation is an elective procedure and efforts should be made to prepare the
patients for surgery with chest physiotherapy, deep breathing, and cessation of smoking. Airway
obstruction, bronchospasm, and intercurrent pulmonary infection should be reversed. Steroids should be
discontinued before surgery.
FIGURE 31.2 PET/CT scan showing metabolic activity of right upper lobe tumor.
Flexible and/or rigid bronchoscopy is crucial to evaluate the overall length of the tumor, the adequacy
of the remaining airway, and the feasibility of a tension-free anastomosis (Fig. 31.3). Besides routine
investigation to rule out extrathoracic metastasis, endobronchial ultrasound and transbronchial needle
aspiration biopsy (EBUS-TBNA) of the mediastinal lymph nodes or mediastinoscopy should be
performed before or at the time of surgery in patients presenting with bronchogenic carcinoma to exclude
N2 or N3 disease.
Superior cavography and pulmonary angiography can be performed for carinal tumors arising from the
anterior segment of the right upper lobe, because invasion of right upper lobe (mediastinal) artery usually
indirectly reveals invasion of the posterior aspect of the superior vena cava (SVC). Transesophageal
echography is occasionally performed to evaluate tumor extension to the posterior mediastinum,
especially along the esophagus or the left atrium.
FIGURE 31.3 Bronchoscopy showing right mainstem bronchus tumor.

In patients with bronchogenic carcinoma, carinal resection should be considered for tumors invading the
first centimeter of the ipsilateral main bronchus, the lateral aspect of the lower trachea, the carina, or the
contralateral main bronchus. This applies usually for right-sided tumor, since left-sided tumor rarely
extend up to the carina without massively invading structures situated in the subaortic space. The safe
limit of resection between the lower trachea and the left main bronchus is usually considered to be 4 cm.
Upward mobilization of the left mainstem bronchus is limited because of the aortic arch and can result in
excessive anastomotic tension.
The long-term results of carinal resection for patients with bronchogenic carcinoma and N2 or N3
disease is poor, and therefore the findings of positive mediastinal nodes at the time of mediastinoscopy is
usually considered a contraindication to surgery.18,19 Induction therapy may be offered for these patients,
but this can increase the technical difficulty of the operation and be associated with greater operative
mortality and morbidity in patients undergoing tracheal sleeve pneumonectomy.
Invasion of the SVC is not necessarily a contraindication to surgery, particularly if a tangential
resection of the SVC can be performed. The series of tracheal sleeve pneumonectomy associated with
prosthetic graft replacement of the SVC, however, are limited to small numbers of patients and the long-
term benefit of patients undergoing tracheal sleeve pneumonectomy associated with prosthetic graft
replacement of the SVC is still to be determined, but appears to be associated with a 5-year survival
ranging between 10% and 20%.20,21
ANESTHESIA
Close cooperation between the anesthetist and the surgeon is important because of the need for adequate
surgical exposure and simultaneous control of the airway. Ventilation during carinal resection has always
been a major concern. Abbott2 recommended a long tube pushed through the divided end of the trachea
into the left main bronchus and Bjork et al.22 emphasized the role of the double lumen tube. However,
double lumen tubes are rigid and cumbersome, rendering their introduction distal to the carina difficult.
Grillo et al.6 suggested to ventilate the distal airway by a sterile tube passed by the anesthetist across the
operating field. El-Baz et al.23 advocated a high frequency jet ventilation, delivering a small tidal volume
at a rate of 100 to 150 respirations per minute. McClish et al.24 proposed continuous oxygen delivery
through a high-flow catheter, but this can lead to carbon dioxide retention. Roviaro et al.25 recently
described the use of a long thin endotracheal tube of 45 cm with a small self-inflating cuff that does not
leak if accidentally pierced.
Most authors currently use a technique similar to the one described by Grillo et al.6 The patient is
intubated with an extralong armored oral endotracheal tube that can be advanced into the opposite
bronchus if one-lung ventilation is desired. Once the carina has been resected, the opposite main bronchus
is intubated with a cross-field sterile endotracheal tube connected to a sterile tubing system (Fig. 31.4).
The tube can be safely removed intermittently to place the sutures precisely. Any blood spillage into the
contralateral lung should be carefully suctioned to preserve the lung. Reinflation of the ventilated lung
should be done gently to avoid overdistension and limit the risk of postoperative pulmonary edema. Once
the posterior part of the anastomosis is completed, the cross-field tube is withdrawn and ventilation
resumed with the original oral tube. Carinal resection should always be planned without cardiopulmonary
bypass. Cardiopulmonary bypass may be useful, however, if pulmonary edema of the contralateral lung
develops during surgery or if major bleeding is encountered.
FIGURE 31.4 The left lung is then intermittently ventilated through the surgical field with a sterile endotracheal tube connected
to a sterile tubing system. The tube can be safely removed intermittently to place the anastomotic sutures.
While the very vast majority of carinal resection can be done without extracorporeal support, on some
occasions extracorporeal membrane oxygenation (ECMO) can be an option that may be used to support
oxygenation during difficult cases of carinal pneumonectomy. Although traditionally used in the
management of severe acute respiratory failure in adults, ECMO is increasingly being applied in other
clinical situations in order to support patients, such as during rigid bronchoscopy for tracheal obstruction
or lung transplantation.26,27 Complication rates associated with ECMO use have decreased due to many
improvements in the oxygenators and ECMO circuits over the past decade. These include the introduction
of hollow-fiber polymethyl pentene (PMP) oxygenators, centrifugal pumps, tubing coated with a
biocompatible lining as well as the development of a dual lumen catheter (Avalon Elite, Avalon
Laboratories, Rancho Dominguez, CA) for veno-venous (VV) ECMO.28,29 In the case of carinal
pneumonectomy, ECMO provides the surgeon with sustained and reliable oxygenation without the need
for cross-table ventilation, thereby facilitating the ease with which the tracheobronchial anastomosis may
be performed. VV ECMO or VA ECMO with central or femoral cannulation can be used for oxygenation
support during the carinal pneumonectomy. One of the major advantages of ECMO over cardiopulmonary
bypass is the low amount of heparin required to run the circuit. ECMO requires a bolus of heparin of 50
U/kg with an ACT ranging between 180 and 200, while cardiopulmonary bypass requires 400 U/kg of
heparin and an ACT over 480.
There have been a few successful case reports of the use of ECMO for procedures involving carinal
resection. Veno-arterial ECMO has been used for both carinal pneumonectomy and carinal resection with
sleeve right upper lobectomy.30,31 The use of VV ECMO for support during carinal resection and
reconstruction has also been reported in three cases.32,33 Due to fact that patients proceeding to carinal
pneumonectomy should have preserved heart function, and the ease of cannulation using the single venous
cannula, VV ECMO may provide a safe adjunct for difficult carinal pneumonectomies in the future.
SURGICAL TECHNIQUE
Right Tracheal Sleeve Pneumonectomy
Right tracheal sleeve pneumonectomy is the most frequent type of carinal resection for bronchogenic
carcinoma. Right tracheal sleeve pneumonectomy is approached through a right posterolateral
thoracotomy in the fifth intercostals space. The posterior mediastinal pleura is incised longitudinally
along the trachea, the right main bronchus, and the esophagus. The hilum and esophagus are then dissected
and the esophagus is retracted posteriorly. The azygos vein is divided to mobilize the distal trachea.
Dissection should be limited to the anterior surface of the trachea to preserve the lateral blood supply as
much as possible. Umbilical tapes are passed around the distal trachea and left main bronchus at the level
of the anticipated resection. The fibrous fold of pericardium between the SVC and the pulmonary artery is
then opened if an extrapericardial pneumonectomy is required. No irrevocable step should be taken until
resection is certain. If there is no SVC involvement, the pulmonary artery and veins are stapled at their
extrapericardial origin in order to have the lung attached by the main bronchus only. Subsequently, the
cross-field intubation system is installed. The trachea and contralateral main bronchus are divided by
sharp, straight transection lines. It is important to perform a complete circumferential section of the
trachea and left main bronchus without leaving any rim of cartilage between the two structures (Fig. 31.5).
The trachea is often sectioned first to provide better exposure to section the left main bronchus. The left
main bronchus is then sectioned horizontally to prevent any tension on the right-sided part of the
anastomosis by the angle of the aorta (Fig. 31.6). The left lung is then intermittently ventilated through the
surgical field. In order to accomplish a tension-free anastomosis, it is crucial to limit the length of
resection between the distal trachea and left main bronchus to less than 4 cm. Frozen section are obtained
on the tracheal and bronchial margins. The decision to resect further trachea or bronchus or leave residual
tumor at the bronchial margin in case of positive margins is balanced by the necessity to perform a
tension-free anastomosis. Before starting the reconstruction procedure, the anterior part of the trachea and
left main stem bronchus are mobilized to lessen the tension at the anastomosis. The left main bronchus is
relatively fixed by the aortic arch, but gentle blunt dissection of the anterior part of the bronchus below
the aortic arch and surrounding tissue is done. The posterior portion of the bronchus is left intact. The last
1 to 2 cm of trachea and first 1 to 2 cm from the left main bronchus are freed circumferentially to perform
the anastomosis. Enlarged subcarinal nodes can be resected, but otherwise the soft tissue around the
carina should be preserved as much as possible to ensure adequate vascularization of the anastomosis and
good lymphatic drainage from the contralateral lung. After completing the anastomosis, the endotracheal
tube is pulled back a sufficient distance from the suture line to avoid any damage from the tip of the tube
and the anastomosis is checked for air-tightness. The anastomosis is then covered by the surrounding
tissue.
FIGURE 31.5 Intraoperative view showing complete circumferential section of the trachea (white arrow) and left main
bronchus (white arrow head). Note the pericardium was opened to facilitate exposure and section of the right pulmonary artery
in the interaorticocaval groove (black arrow head) and partial resection of the superior vena cava was performed (black
arrow).
FIGURE 31.6 This anterior view of a right tracheal sleeve pneumonectomy shows that the transection of the trachea and left
mainstem bronchus should be almost parallel in order to reduce tension on the right side of the anastomosis. The aorta overrides
the left mainstem bronchus and can increase tension on the anastomosis.
If resection of the SVC is planned, the vascular procedure is usually performed before division of the
airway. The SVC is clamped proximally at the confluence of the brachiocephalic veins and distally at the
cavoatrial junction, and divided on each side of the tumor. Section of the SVC facilitates exposure and
stapling of the right pulmonary artery in the interaortocaval groove. The SVC is reconstructed with a ring-
less straight 18- or 20-sized polytetrafluoroethylene (PTFE) graft. The PTFE graft is protected with gauze
soaked in betadine during reconstruction of the airway to prevent graft contamination.
LEFT TRACHEAL SLEEVE PNEUMONECTOMY

The aortic arch greatly hinders performance of the anastomosis in left tracheal sleeve pneumonectomy and
renders the procedure technically challenging. Several approaches have been suggested in order to
optimize the exposure. A one-step procedure with mobilization of the aortic arch is usually preferred over
a two-stage approach. The left lung and carina can be approached through a left posterolateral
thoracotomy, a sternotomy, or a clamshell incision. Each of these approaches has advantages and
drawbacks.
FIGURE 31.7 During left tracheal sleeve pneumonectomy, adequate exposure of the carina through a left thoracotomy can
require mobilization of the aortic arch anteriorly after sacrifice of the first few intercostal vessels.
The left posterolateral thoracotomy offers excellent exposure to the left pleural space and posterior
mediastinum. Exposure of the carina and distal trachea however is limited. The carina must be accessed
through the aortopulmonary window or by mobilizing the aortic arch anteriorly after sacrifice of the first
few intercostal vessels (Fig. 31.7). The clamshell incision provides an excellent exposure of both the
tracheobronchial tree and left chest, but this approach requires opening of the contralateral chest and
should be reserved for young and fit patients with excellent lung function.
The sternotomy offers several advantages. It provides superb exposure to the tracheobronchial
bifurcation, causes less incisional pain, and results in less ventilatory restriction than a thoracotomy. The
left lung can also be ventilated through the operating field while the carina is resected and reconstructed.
The main disadvantages of the transsternal approach are that freeing pleuroparietal adhesions can be
difficult and access to the posterior mediastinum is limited. Some authors have suggested combining a left
anterolateral thoracotomy to the sternotomy to improve visualization of the posterior mediastinum.34
The key to an adequate exposure through a median sternotomy is to perform a large circumferential
dissection of the ascending aorta up to the aortic arch and to section the truncus arteriosus to obtain
adequate mobilization of the aorta and left pulmonary artery to access the carina and left main bronchus
(Fig. 31.8). The anterior pericardium must be divided vertically down to the diaphragm. The innominate
vein and artery are exposed and the ascending aorta is mobilized up to the truncus arteriosus, which is
divided to allow optimal retraction of the ascending aorta to the patient’s left. A pledgetted instrument is
used to gently retract and protect the aorta (Fig. 31.9). Dissection of the right and left pulmonary artery
and division of the posterior pericardium then allow access to the tracheobronchial angle (Fig. 31.10).
The SVC must also be dissected off the pericardium, encircled and retracted laterally to the patient’s right
(Fig. 31.11). Care is taken not to damage the right phrenic nerve and right pulmonary artery since a left
pneumonectomy is anticipated. The left mediastinal pleura is opened anteriorly below the sternal edge to
access the left pleural space and perform the left pneumonectomy. The hilum is dissected to expose the
left pulmonary artery and both pulmonary veins. The pericardium can be opened anteriorly and
posteriorly around the hilum to improve exposure and facilitate stapling of both pulmonary veins and the
pulmonary artery if necessary. The pericardial opening should be limited around the hilum and closed at
the end of the procedure to avoid luxation of the heart into the left chest. The left lung can then be removed
after transecting the distal trachea and right main bronchus. An end-to-end anastomosis between the
trachea and right main bronchus is performed. This anastomosis can sometimes be performed before
removing the left lung in order to allow cross-field ventilation of the left lung while the anastomosis
between the right main bronchus and trachea is performed. The left pleura should be closed at the end of
the procedure in order to contain fluid accumulation into the pleural space. The anastomosis can be
covered with surrounding tissue and the anterior pericardium closed. The left pleural space and the
pericardium should be drained separately.
FIGURE 31.8 Exposure of the carina through a sternotomy requires large circumferential dissection of the ascending aorta up
to the aortic arch and section the truncus arteriosus to obtain adequate mobilization of the aorta and the pulmonary artery.
FIGURE 31.9 A pledgetted instrument is used to retract the aorta to the patient’s left so that the posterior pericardium overlying
the pulmonary artery can be divided. The plane between the aorta and right pulmonary artery can then be dissected.
FIGURE 31.10 The carina is fully dissected and both the right and left mainstem bronchi are encircled.
FIGURE 31.11 The superior vena cava is retracted to the patient’s left to provide access to the posterior pericardium, right
main bronchus, and right pulmonary artery.
ANASTOMOTIC TECHNIQUE
The tracheobronchial anastomosis is usually performed in an end-to-end fashion with interrupted
absorbable stitches. In order to avoid the difficult application of interrupted stitches on the deepest part of
the anastomosis, the posterior part of the anastomosis (with respect to the surgeon) can be performed with
a running 4/0 polydiaxone (PDS) suture. This represents the left aspect of the cartilage wall of the trachea
and left main bronchus in right tracheal sleeve pneumonectomy, and the membranous portion of the trachea
and right main bronchus in a transsternal approach for left tracheal sleeve pneumonectomy. The running
suture is then tied at each end with two independent PDS sutures whose knots are made outside the lumen.
Thereafter, several interrupted stitches of 4/0 PDS or 3/0 vicryl are placed in the remaining part of the
anastomosis (Fig. 31.12). They are tied after all of them have been placed to correct for size
discrepancies. In right tracheal sleeve pneumonectomy, the stitches applied on the membranous portion
are tied at the end to avoid any traction and potential tears.
The development of anastomotic complications is likely due to technical factors at the time of airway
resection and reconstruction. Careful dissection and precise placement of anastomotic sutures should limit
tissue trauma and avoid devascularization of the anastomotic site. In addition, airway resection should be
limited to a maximum of 4 cm at the carinal level if a right tracheal sleeve pneumonectomy is performed.
Upward mobilization of the left mainstem bronchus is limited because of the aortic arch and can result in
excessive anastomotic tension. Care should also be taken to preserve the left recurrent nerve.
FIGURE 31.12 The final anastomosis of the trachea and left mainstem bronchus is complete after right tracheal sleeve
pneumonectomy.
RELEASE MANEUVERS
Dissection of the pretracheal plane is always performed (usually at the time of the mediastinoscopy) to
reduce the tension at the anastomotic site. Before starting the reconstruction, mobilization of the anterior
wall of the right or left main stem bronchus is also performed to gain some length. Hilar release is not an
option for tracheal sleeve pneumonectomy, and laryngeal or supralaryngeal release does not provide any
anastomotic relaxation at the level of the carina. A chin stitch is usually not necessary in these patients.
POSTOPERATIVE CARE
The anastomosis is always controlled by bronchoscopy at the end of the procedure and secretions are
cleaned up from the airways. All patients are extubated in the operating room or shortly after arrival in
the recovery room. Pain relief is achieved with epidural analgesia or patient-controlled analgesia.
Adequate chest physiotherapy and occasionally repeated aspiration by flexible bronchoscopies is
required in the first few days postoperatively. A temporary tracheostomy can be performed to reduce the
physiological respiratory dead space and facilitate direct aspiration whenever the predicted residual
ventilatory functional reserve is borderline or the patient’s collaboration reduced. The tracheostomy
should be performed early in the postoperative period to prevent possible complications.
The most catastrophic complication is the development of noncardiogenic pulmonary edema. This
complication usually occurs within the first 72 hours after surgery. Its cause is unknown, but ventilator-
induced barotrauma and excessive fluid administration during the surgical procedure are probably the
main risk factors. Gentle reinflation of the left lung is therefore important during the intermittent
ventilation through the surgical field. Other risk factors for the development of postoperative pulmonary
edema may include preoperative alcohol abuse, silent postoperative aspiration, and/or interference with
lymphatic drainage. Once it develops, only few patients are able to recover. Fluid restriction, diuretics,
frequent bronchoscopy, and noninvasive ventilation are occasionally helpful to avoid reintubation and
overcome the problem.
The development of a bronchopleural fistula is another potentially fatal complication. Prevention
should include early and close bronchoscopic monitoring of any ischemia or necrosis of the
tracheobronchial anastomosis, and a tracheostomy should be performed if there is any evidence of
inadequate healing. If dehiscence occurs, the airway should be secured by placing a single lumen tube in
the main bronchus of the remaining lung beyond the anastomotic dehiscence to ventilate and protect the
lung from aspiration. The pneumonectomy space should be drained by a closed chest tube drainage and an
open thoracostomy should be performed to pack the contaminated pleural space.
RESULTS
The results of tracheal sleeve pneumonectomy for bronchogenic carcinoma have improved over time.
Recent series have shown that carinal resection is safe in experienced centers and can be associated with
good to excellent long-term survival. The operative mortality ranges between 7% and 10% in most recent
series and the 5-year survival can reach 53% at 5 years and 31% at 10 years if the mediastinal nodes are
negative (Table 31.1).18,19,35 Patients with bronchogenic carcinoma and positive mediastinal nodes, either
N2 or N3, have poor survival with a 5-year survival of 12% to 15% only (Fig. 31.13). Hence, the
presence of metastatic mediastinal nodes in patients requiring carinal resection should be considered a
potential contraindication. This finding underscores the importance of performing routine preoperative
invasive mediastinal staging in these patients. Mediastinal staging is currently done by EBUS at the time
of assessment of the endoluminal disease in our institution. However, if the method of invasive
mediastinal staging chosen is mediastinoscopy, it should be performed at the time of the planned carinal
resection in order to avoid the development of scar tissue along the trachea and to take advantage of the
tracheal mobilization to reduce tension at the anastomotic site. On the other hand, if the mediastinal nodes
are negative, surgery offers the best chance of cure for these patients and tracheal sleeve pneumonectomy
should be offered as the primary therapeutic option.
FIGURE 31.13 Actuarial survival of patients with bronchogenic carcinoma undergoing carinal resection. Survival was
significantly better in patients with pN0/N1 disease than in patients with pN2/N3 disease. The estimated 5-year survival was
53% in patients with pN0/N1 disease versus 15% in patients with pN2/N3 disease. P = 0.0009 by log-rank test. (Reprinted from
de Perrot M, Fadel E, Mercier O, et al. Long-term results after carinal resection for carcinoma: does the benefit warrant the
risk? J Thorac Cardiovasc Surg 2006;131:81–89. Copyright © 2006 The American Association for Thoracic Surgery. With
permission.)
Further studies should determine the role of induction therapy in patients presenting with bronchogenic
carcinoma and N2 disease. Induction therapy seems to improve survival if the mediastinal nodes can be
sterilized prior to the lung resection. Although traditionally the requirement for pneumonectomy has been
a contraindication to the use of multimodality therapy, improvements in both intraoperative and
postoperative care may allow these patients to proceed to surgery after induction therapy, recognizing that
there is an increased risk of complications.
CONCLUSIONS
In conclusion, tracheal sleeve pneumonectomy is a safe procedure in experienced centers and can be
associated with good to excellent long-term survival. Patients presenting with bronchogenic carcinoma
and negative mediastinal nodes should be considered for carinal resection without any induction therapy.
However, mediastinoscopy at the time of the planed surgery is important, since the presence of positive
N2 disease should be considered a potential contraindication to carinal resection because of the poor
long-term survival.
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18. de Perrot M, Fadel E, Mercier O, et al. Long-term results after carinal resection for carcinoma: does the benefit warrant the risk? J
19. Mitchell JD, Mathisen DJ, Wright CD, et al. Resection for bronchogenic carcinoma involving the carina: long-term results and effect of
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32
Segmentectomy and Lesser Pulmonary
Resections
Chi-Fu Jeffrey Yang ■ Thomas D’Amico
Although lobectomy is the standard operation for most patients with lung cancer, sublobar pulmonary
resections may offer similar benefits with lower risks for some patients with primary or secondary
pulmonary malignancy. The use of sublobar resections for patients with primary non-small–cell lung
cancer (NSCLC) may be particularly effective in patients with marginal cardiopulmonary function and
small peripheral tumors, especially ground glass opacities suggesting adenocarcinoma in situ or
minimally invasive adenocarcinoma. In cases where resection of pulmonary metastases may provide
prolonged survival, a lesser parenchymal resection can be considered.
SEGMENTECTOMY
The typical definition of a segmentectomy is anatomic resection of a single segment, although sometimes,
such as in the case of a lingulectomy, two adjacent segments are resected. The segmentectomy involves
individual ligation of the segmental artery, vein, and bronchus. Importantly, segmentectomy involves
dissecting the segmental bronchus back to its primary branch, along with all of the lung parenchyma and
lymph node groupings drained by the bronchus; this represents the oncologic advantage of segmentectomy
over nonanatomic wedge resection when employed for lung cancer. This technique was first used for the
treatment of pulmonary tuberculosis, bronchiectasis, and other suppurative pulmonary lesions. After
effective antituberculous chemotherapy and broad-spectrum antibiotics for suppurative diseases were
developed, the operation became less common in the United States. However, it remained a mainstay of
the surgeon’s armamentarium not only in other countries throughout parts of Europe and Asia but also in
countries as near as Mexico and South America.
Lobectomy became the standard for the resection of NSCLC, but the utility of segmentectomy was
demonstrated by Jensik and colleagues1 in 1973, by Shields and Higgins2 in 1974, and by other authors
since.3–6 However, there is only one randomized trial on this subject, which is from the Lung Cancer
Study Group (LCSG) and was reported in 1995 by Ginsberg and Rubenstein.7 This study analyzed the
outcomes of lobectomy compared to sublobar resection, and included either segmentectomy or wedge
resection in the sublobar group. Compared to lobectomy, sublobar resection was associated with a
threefold increase in the locoregional recurrence rate.
Of note, the LCSG study enrolled patients from 1982 to 1988, and since that trial, interest in
segmentectomy has been renewed due to the following developments.8 First, the identification of smaller
lung tumors (<2 cm) and less invasive forms of adenocarcinomas such as adenocarcinoma in situ
(previously termed “bronchoalveolar carcinoma”) and minimally invasive adenocarcinoma has increased
with high-resolution computed tomography (CT)9–11 and outcomes associated with resection of these
types of tumors were not assessed in the LCSG trial.7 Second, since 1995, newer staging modalities have
emerged which have improved patient selection for anatomic lung resection.7 Third, surgeons have
continued to advance video-assisted thoracoscopic surgery (VATS) and robotic surgery, and have had
increasing experience applying those approaches to segmentectomy. These new developments have led to
an increasing number of studies investigating the use of open, thoracoscopic, and robotic segmentectomy
for carefully selected patients with smaller tumors, especially in patients with marginal cardiopulmonary
function.8
Among the most significant of these studies are those performed by Okada and colleagues12 and
Landreneau and colleagues.13 Okada and colleagues performed a multi-institutional study in patients with
primary lung cancers less than 2 cm, comparing segmentectomy (n = 305) to lobectomy (n = 262).
Although patients had similar baseline characteristics between groups and all could tolerate lobectomy,
they were not randomized. The 5-year disease-free and overall survivals were not significantly different:
85.9% and 89.6% for the segmentectomy group and 83.4% and 89.1% for the lobectomy group,
respectively.
A retrospective propensity-score-matched analysis of patients who underwent segmentectomy and
lobectomy from a single institution for patients with stage I NSCLC and tumors less than 3 cm was
recently reported.4 There were 312 patients in each group. Segmentectomy did not have significantly
different locoregional, distant, and overall recurrence rates when compared to lobectomy. There were
also no significant differences in 5-year survival between the segmentectomy group (54%) versus the
lobectomy group (60%) (p = 0.26). Of note, in subgroup analyses, the authors found no significant
differences between groups with regard to time to recurrence when comparing patients with T1a (≤2 cm),
T1b (2 to 3 cm), or T2a tumors (3 to 5 cm).
Other studies have shown no differences in recurrence-free survival and overall survival between
open segmentectomy and open lobectomy,14,15 even in patients with greater comorbidities and worse
pulmonary function,16–18 in patients older than 75 years of age,19 and in patients with larger tumors
between 2 cm and 3 cm in size.16
However, not all recent studies suggest that lobectomy and segmentectomy have equivalent oncologic
outcomes. One study by Deng and colleagues20 was a retrospective propensity-score-matched analysis
that found no significant differences in survival for T1a lung cancers between the groups but did find that
lobectomy had a marginally significant better overall and disease-free survival than segmentectomy for
T1b tumors. However, the analysis of T1b tumors was limited by its small sample size in the
segmentectomy group (n = 31).
In addition, there have also been meta-analyses comparing lobectomy versus segmentectomy21,22 or
lobectomy versus sublobar resection23 for stage I NSCLC that have suggested that lobectomy confers a
significant survival advantage compared to segmentectomy for overall stage I NSCLC but that when
limited to stage IA disease, segmentectomy or wedge resection had similar survival to lobectomy, while
other studies have found that sublobar resection had worse survival compared to lobectomy even for
stage IA disease.24,25 A major limitation of these above-mentioned studies is that they are based on
retrospective data and often do not have information regarding comorbidities between the segmentectomy
and lobectomy groups. These studies frequently do not account for the selection bias that may occur when
surgeons select segmentectomies for patients with more comorbidities and reduced pulmonary function
and lobectomies for patients with better performance status; often patients may be selected for
segmentectomies because they are thought to be “ineligible” for a lobectomy.
To address some of these limitations, Cao and colleagues26 performed a meta-analysis that included 12
studies of patients who underwent sublobar resection for small, peripheral NSCLC after intentional
selection rather than ineligibility for greater resections. The authors found that patients who underwent
intentional sublobar resection had similar survival to patients who underwent lobectomies. In a meta-
analysis of lobectomy, segmentectomy, and wedge resection, Zhang and colleagues27 similarly found that
intentional sublobar resection had similar survival to lobectomy.
Based on all of these studies, it is reasonable to consider segmentectomy in patients with clinical stage
I NSCLC with tumors less than 2 cm in diameter who have either a predominantly ground glass nodule or
who are at higher risk for lobectomy (including patients with compromised pulmonary function, previous
resection(s), poor performance status, or other negative prognostic factors). It is also necessary for the
surgeon to ascertain an adequate margin of at least 2 cm and adequate hilar and mediastinal lymph node
assessment.28
THORACOSCOPIC (VATS) SEGMENTECTOMY

Several studies have shown that the thoracoscopic approach to segmentectomy for stage I NSCLC is
feasible and safe and associated with decreased perioperative mortality and equivalent or improved
overall survival when compared to the open approach.29–34 The thoracoscopic approach is also
associated with shorter length of stay, a trend in reduced costs, reduced rates of overall complications
including fewer cardiopulmonary complications and reduced length of chest tube duration.8
Studies have also demonstrated that although the thoracoscopic segmentectomy is a more complex
procedure than the thoracoscopic lobectomy, the two approaches have similar outcomes. Specifically,
there were no significant differences between the two approaches with regard to operative time,35–39
overall complication rates,35–41 local recurrence rates,35–38,40,41 5-year recurrence-free survival,35,36,41,42
and 5-year survival rates.35,36,41–43 In addition, the segmentectomy groups had similar35,36,38,40 or reduced
hospital length of stay37,39 when compared to the lobectomy groups.
There are limitations to the studies cited above. Some of these studies did not have tumor size
data.37,38,44 Others found that the lobectomy groups had significantly larger tumors than the segmentectomy
groups,35,40–43,45,46 which limits interpretation of results because tumor size is known to be a prognostic
factor of survival for NSCLC.36,47 However, one study by Zhong and colleagues36 of thoracoscopic
segmentectomy versus lobectomy did have both groups well-matched in tumor size, histology,
preoperative comorbidities, and pulmonary function. The authors found no differences between groups
regarding local recurrence rates, disease-free, and overall survival.
FEASIBILITY OF MEDIASTINAL LYMPH NODE DISSECTION

Mediastinal lymph node assessment is a critical component of segmentectomy for lung cancer. Mattioli
and colleagues48 found no differences in N1 and N2 lymph node harvesting between open segmentectomy
and lobectomy. When comparing the thoracoscopic segmentectomy to the thoracoscopic lobectomy, three
studies found no significant differences in lymph nodes harvested or nodal stations sampled36,39,40 while
one reported fewer lymph nodes harvested with segmentectomy.35 When comparing open versus
thoracoscopic segmentectomy, one study found no difference in lymph nodes harvested,29,39 while another
reported fewer lymph nodes harvested with the thoracoscopic approach.32
In addition, in a subset analysis of segmentectomies from a national study comparing the completeness
of lymph node evaluation during anatomic resection of primary lung cancer by open and VATS
approaches, the authors found that upstaging from cN0 to pN1 was seen in 4% among 170 VATS
segmentectomies compared with 5.3% among 280 open segmentectomies.49 The authors noted that the
differences in upstaging between VATS and open approaches may have been the result of selection bias
and that equivalent nodal staging may be possible with increasing experience with VATS. The authors
found no difference in mediastinal lymph node evaluation between VATS and open approaches, but had
included segmentectomies with lobectomies in the analysis thereby limiting the interpretation of results.49
Based on limited data described above, it appears that it is possible to achieve adequate lymph node
dissection with segmentectomy but that surgeon experience is important, in particular in the case of the
thoracoscopic segmentectomy. More detailed investigation on lymph node evaluation for segmentectomy
will be needed.
PREDICTORS FOR PROGNOSIS AND RECURRENCE

Koike and colleagues reported two studies on predictors of prognosis and recurrence for patients with
NSCLC who undergo sublobar resections. The first study examined outcomes of segmentectomies and
found age >70 years, gender (male), >75% consolidation/tumor ratio on high-resolution CT, and
lymphatic permeation to be independent poor prognostic factors.50 The second study evaluated patients
undergoing either segmentectomy or wedge resection and found four predictors of locoregional
recurrence: wedge resection, microscopic positive surgical margin, visceral pleural invasion, and
lymphatic permeation.51 Predictors of poor disease-specific survival were smoking status, wedge
resection, microscopic positive surgical margin, visceral pleural invasion, and lymphatic permeation.
In a multicenter analysis of CT and positron emission tomography (PET) of patients with T1 N0 M0
NSCLC reported by Okada and colleagues,52 the authors found that maxSUV is a significant preoperative
predictor of outcomes and noted that a tumor with maxSUV of 1.5 or less may be considered for sublobar
resection.
OTHER TYPES OF MINIMALLY INVASIVE SEGMENTECTOMY

Totally Thoracoscopic and Uniportal Segmentectomy
A few small case series have reported results on the “totally thoracoscopic” or “complete VATS”
technique for segmentectomy,53–60 which involves no access incision, retrieval of specimen through one
of the port sites that is enlarged at the end of the procedure, and use of only video-display and endoscopic
instruments.61 There have also been a few case series on the “uniportal” thoracoscopic segmentectomy
where the procedure is performed with one incision and through one port.62–65 Preliminarily, it appears
that single-incision segmentectomy is feasible and safe although further studies are needed, but no
advantages have been demonstrated compared to standard thoracoscopic approaches that also avoid
thoracotomy.
Robotic Segmentectomy
A review of a national database found that robotic pulmonary resections have increased from 0.2% in
2008 to 3.4% of cases in 2010.66 Most robotic procedures are lobectomies but there has been a small
increase in robotic segmentectomies performed as well. There are now a few studies reporting
reasonable short-term outcomes including a 0% perioperative mortality rate for robotic
segmentectomy.67–71 Preliminary data suggest that it is a safe and feasible operation although additional
studies reporting long-term outcomes and studies that compare the robotic segmentectomy to the VATS and
open segmentectomy will be needed.
Segmentectomy for Benign Disease

With the resurgence of Mycobacterium tuberculosis in urban areas and the development of drug-resistant
atypical strains, segmentectomy can treat suppurative disease while maximally preserving normal lung
function. Takeda and colleagues72 used segmentectomy alone or in combination for pulmonary
tuberculosis in 17% of cases, while Vashakidze and colleagues73 used segmentectomy in 35% of
multidrug-resistant or extensively drug-resistant tuberculosis. Agasthian74 and Ashour,75 and their
colleagues reported control of bronchiectasis by segmentectomy alone in 13% to 16% of patients.
Segmentectomy has been used in patients with severe Aspergillus and pulmonary mycotic infections.
Massard76 and Temeck,77 and their colleagues noted that segmentectomy has significant complications in
these patients but that these are not different from complications associated with other types of infections.
Even congenital lesions can be managed with segmental resections. Nuchtern and Harberg78 used
segmentectomy for intralobar lung cysts. Sapin and colleagues79 were able to use segmentectomy in one-
third of the patients they treated for congenital adenomatoid disease of the lung. The thoracoscopic
approach has also been shown to be safe and feasible for congenital lung lesions.80–82
PHYSIOLOGIC EFFECTS
Segmental resection is associated with greater preservation of pulmonary function45,83 and exercise
capacity45 compared to lobectomy, although the differences may dissipate over time. Preliminarily,
thoracoscopic segmentectomy was also shown to preserve greater lung function37,45 and exercise
capacity45 than the thoracoscopic lobectomy, although long-term follow-up data is needed.
PERIOPERATIVE OUTCOMES
The majority of studies have found no significant differences in morbidity and mortality between
segmentectomy and lobectomy. In studies comparing thoracoscopic segmentectomy to open
segmentectomy, there were no significant differences found in 30-day mortality, ranging from 0% to 7%
for the VATS group, compared to 1.7% to 7.7% for open group.29–32,34 In recent studies of segmentectomy
versus lobectomy, there were no significant differences found in perioperative morbidity and mortality
with 30-day mortality ranging from 0.0% to 1.2% in the segmentectomy group and 0.0% to 2.5% in the
lobectomy group.13,15,20,36
TECHNIQUE
The most popular approach at present is with thoracotomy, using general anesthesia with the ability to
provide single-lung ventilation. Initial steps in segmentectomy are the same as for any standard resection
of the lung. The surgeon must be familiar with the intraparenchymal anatomy of the bronchus and
pulmonary artery to accomplish a segmentectomy successfully (Fig. 32.1). The hilar structures are
identified and the major fissure is usually opened. On the right side of the chest, the bronchus is the most
posterior hilar structure. As one proceeds into the hilum, the upper lobe branches of the pulmonary artery
are the most superior hilar structures. In the major fissure, the pulmonary artery can be exposed,
demonstrating the continuation of the main pulmonary artery into the lower lobe. Anterior and posterior
branches originate opposite one another and go, respectively, to the middle lobe and the superior segment
of the lower lobe, forming a cross. Often, a posterior ascending branch arises from the posterior
segmental artery and supplies part of the posterior segment of the upper lobe.
On the left side of the chest, the pulmonary artery crosses superiorly above the left mainstem bronchus
to become the most posterior structure in the hilum. The apicoposterior and anterior and segmental
branches are located anteriorly and superiorly. A separate posterior segmental branch is often found
posteriorly on the main pulmonary artery, just at or above the major fissure. In the major fissure, the
lingular artery branches anteriorly and the superior segment branches posteriorly to form a cross on the
continuation of the pulmonary artery.
The artery and bronchus are ligated and divided. In performing a segmentectomy for suppurative lung
disease, it may be best to divide the bronchus first to prevent contamination of the normal lung.
Controversy about whether to divide the bronchus or artery first raged through the 1930s and 1940s and
has been carefully traced by Grismer and Read.84 However, in the United States today, the order of
division depends on the segment to be removed. For the apical and anterior segment of the upper lobe on
the right side, the artery is usually ligated first and elevated to locate the segmental bronchus. For the
posterior right upper lobe segment, it may be easier to divide the bronchus first and then the artery, which
may be deep in the parenchyma and not easily isolated anteriorly because of the other segmental branches.
On the left side, the arterial branches are more easily isolated first because the bronchus is the middle
structure on that side. Before dividing the bronchus, the segment to be removed should be differentially
deflated and inflated to help delineate the intersegmental planes, keeping in mind that filling of the
deflated segment may occur from adjacent segments by means of collateral ventilation. With the advent of
the double-lumen tube, it is often easier to inflate the entire lung, clamp the bronchus, and allow the rest of
the lung to deflate. The segment remains inflated for a longer period, even with some loss from collateral
ventilation. Once the appropriate segmental bronchus is identified, it is divided. The proximal stump may
be closed either with a mechanical stapler or with interrupted fine absorbable sutures. Additional
coverage of the stump is usually not necessary.
FIGURE 32.1 A: Segmental Anatomy of Right Lung. Right upper lobe. Apical segment (B1) Posterior segment (B2)
Anterior segment (B3) Right middle lobe lateral segment (B4) Medial segment (B5) Right lower lobe Superior segment (B6)
Medial segment (B7) Anterior segment (B8) Lateral segment (B9) Posterior segment (B10). B: Left upper lobe (superior
division) apicoposterior segment (B1,2) Anterior segment (B3) Superior lingular segment (B4) Inferior lingular segment (B5)
Left lower lobe Superior segment (B6) Anteromedial segment (B7 + B8) Lateral segment (B9) Posterior segment (B10).
(From http://www.cfmedicine.com/htmldocs/cftext/physiotherapy.htm#rlungs. Copyright © cysticfibrosismedicine.com. With
permission.)
After the bronchus and artery are ligated, traction is placed on the bronchus, and the segment is
removed in a retrograde manner. The plane may be developed using digital blunt dissection with division
of the pleura by scissors or cautery, or the intraparenchymal segmental fissure may be divided with a
linear stapling device. The pulmonary veins course through the intersegmental planes and provide an
excellent anatomic guide. Individual branches of the vein emanating from the segment into the fissure are
sequentially divided.
After removal of the specimen, the raw surfaces of the adjacent segments are inspected and any
significant bleeding is controlled. A sponge is applied to the expanded lung. After 5 to 10 minutes, the
sponge is removed and the lung surface is again inspected. If the dissection of the intersegmental plane
has been done carefully, only a few alveolar air leaks will be present. These tend to seal over promptly
with re-expansion of the lung during the postoperative period. Any leaking from small bronchi, however,
must be recognized and controlled; this type of leak may cause persistent problems and predispose to
postoperative space problems and infections. A variety of aerostatic agents are now available to deal
with air leaks. However, if the anatomic planes are respected and not violated, the leaks will be small.
Thoracoscopic Approach
The thoracoscopic approach may be used for any anatomic segmental resection, with the patient in the
lateral decubitus position (Fig. 32.2). However, the most commonly performed segmental resections are
lingula-sparing left upper lobectomy, lingulectomy, posterior segmentectomy of the right upper lobe,
superior segmentectomy, and basilar segmentectomy (single or multiple). The inability to achieve
complete resection thoracoscopically is the only absolute contraindication; the parenchymal margin
should be at least the diameter of the tumor in a cancer operation.85,86
Thoracoscopic segmentectomy is performed with division of segmental vessels and bronchi in a
manner similar to the open approach. Thoracoscopic segmentectomy starts with ligation of the segmental
pulmonary vein for most segments, followed by either the bronchus or artery, depending on the segment.
The parenchymal excision is accomplished by stapling in intersegmental fissures. When tumors are close
to intersegmental fissures, bi- or trisegmentectomy is performed. Specimens are removed in a protective
bag.
Technical Considerations
The most commonly performed single segmentectomy is the resection of the superior segment of the lower
lobe, illustrated in Figures 32.3 to 32.5. Dissection is begun by mobilizing the inferior pulmonary vein, to
identify and isolate the vein from the superior segment (Fig. 32.3). Division of the venous branch to the
superior segment, performed with the linear stapler, allows identification of the bronchial segment as
well as dissection and resection of lymph nodes at levels 12 and 13 (Fig. 32.4). The bronchial segment is
then divided. Hilar dissection is then completed by identifying and dividing the arterial segmental branch
(Fig. 32.5). The parenchymal division is then performed in the segmental fissure.
FIGURE 32.2 Positioning and port placement. Patient is placed in the lateral decubitus position. Our approach uses incisions
that are placed in (1) the 7th or 8th intercostal space along the posterior axillary line, (2) the 5th or 6th intercostal space
anteriorly. (Reprinted from Pham D, Balderson S, D’Amico TA. Technique of thoracoscopic segmentectomy. Oper Tech
Thorac Cardiovasc Surg 2008;13(3):188–203. Copyright © 2008 Elsevier. With permission.)
FIGURE 32.3 Posterior view of inferior pulmonary vein. In a superior segmentectomy, dissection is begun by mobilizing the
inferior pulmonary vein, to identify and isolate the vein from the superior segment. The superior segmental branch (under Scanlon
clamp) of the left inferior pulmonary vein (LIPV) is dissected and stapled. (Reprinted from Pham D, Balderson S, D’Amico TA.
Technique of thoracoscopic segmentectomy. Oper Tech Thorac Cardiovasc Surg 2008;13(3):188–203. Copyright © 2008
Elsevier. With permission.)
In the lower lobe, basilar segmentectomy may be performed, sparing the superior segment. Dissection
is again begun by mobilizing the inferior pulmonary vein, to identify and isolate the vein from the basilar
segment, and protecting the superior segment branch (Fig. 32.6). The arterial branches are then identified
by opening the major fissure (Fig. 32.7) followed by identification and ligation of the bronchus after
dissecting and resection of regional lymph nodes on the bronchus (Fig. 32.8).
In the upper lobe, multi-segment sub-lobar resections (lingulectomy, lingula-sparing lobectomy) are
also commonly performed. Lingulectomy is performed by first opening the major fissure, typically with an
energy device or stapler to decrease the risk of post-operative air leaks. The lingular vein is then
mobilized and ligated. Next, the lingular bronchus and one or more lingular arteries (in either order) are
ligated. The parenchymal division between the lingula and the remainder of the upper lobe is then
identified and stapled. Lingula-sparing (upper lobe tri-segmentectomy) is begun by dividing the posterior
pleura, allowing identification of the posterior segmental artery and facilitating anterior dissection to
follow. Subsequently, attention is turned anteriorly, to accomplish dissection and division of the venous
trunk, ascertaining that the lingular vein is preserved. The anterior apical trunk is then dissected and
divided; this is more easily performed if posterior dissection has previously been performed thoroughly.
Next, the tri-segmental bronchus is dissected, removing lymph nodes at levels 10, 11, and 12, followed by
division. The parenchymal division between the lingula and the remainder of the upper lobe is typically
easy to identify and staple.
The feasibility of thoracoscopic segmentectomy has been demonstrated,85,86 but there is still debate
regarding optimal segmentectomy techniques. In many cases, using the landmarks of the dissected hilar
anatomy can help with identification of segmental boundaries. However, certain techniques have been
developed to aid with identification. A commonly used technique involves temporary re-inflation of the
ipsilateral lung after bronchial ligation to demarcate the plane.85 An alternative approach, reported by
Okada and colleagues87 is to detect the intersegmental plane by partially inflating the segment of interest
using selective jet ventilation during bronchoscopy, after single lung ventilation has been achieved. After
demarcation of the segmental plane, completion of the parenchymal division may be completed in several
ways, using linear stapler energy devices85 or electrocautery.12
FIGURE 32.4 Posterior view of superior segment bronchus of left lower lobe. Division of the venous branch to the superior
segment, performed with the linear stapler, allows identification of the bronchial segment, which is then exposed and stapled,
sparing the basilar bronchi. (Reprinted from Pham D, Balderson S, D’Amico TA. Technique of thoracoscopic segmentectomy.
Oper Tech Thorac Cardiovasc Surg 2008;13(3):188–203. Copyright © 2008 Elsevier. With permission.)
FIGURE 32.5 Posterior view of superior segmental artery. Hilar dissection is then completed by identifying and dividing the
superior segmental branch of the pulmonary artery. LIPV, left inferior pulmonary vein; LLL, left lower lobe. (Reprinted from
Pham D, Balderson S, D’Amico TA. Technique of thoracoscopic segmentectomy. Oper Tech Thorac Cardiovasc Surg
2008;13(3):188–203. Copyright © 2008 Elsevier. With permission.)
FIGURE 32.6 Anterior view of basilar branch of right lower pulmonary vein. In a basilar segmentectomy, after mobilization and
division of the inferior pulmonary ligament, the basilar segmental branch of the inferior pulmonary vein is approached anteriorly,
stapled, and divided. RIPV, right inferior pulmonary vein; RPA, right pulmonary artery; RSPV, right superior pulmonary vein;
SVC, superior pulmonary vein. (Reprinted from Pham D, Balderson S, D’Amico TA. Technique of thoracoscopic
segmentectomy. Oper Tech Thorac Cardiovasc Surg 2008;13(3):188–203. Copyright © 2008 Elsevier. With permission.)
FIGURE 32.7 Right basilar arterial trunk. The basilar branch of the pulmonary artery is identified by opening the major fissure
and stapled. RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe. (Reprinted from Pham D, Balderson S,
D’Amico TA. Technique of thoracoscopic segmentectomy. Oper Tech Thorac Cardiovasc Surg 2008;13(3):188–203.
Copyright © 2008 Elsevier. With permission.)
FIGURE 32.8 Right basilar bronchus. The basilar segmental bronchus is dissected from an anterior approach and ligated.
(Reprinted from Pham D, Balderson S, D’Amico TA. Technique of thoracoscopic segmentectomy. Oper Tech Thorac
Cardiovasc Surg 2008;13(3):188–203. Copyright © 2008 Elsevier. With permission.)
Lung inflation techniques have limitations especially in cases of severe emphysema, where lungs can
be easily overinflated which can then limit surgical views.88 An alternative technique for visualization not
involving lung inflation is one that relies instead on infrared thoracoscopy with indocyanine green
injection to visualize adjacent lung segments.88–91 In addition, indocyanine green has been used to
facilitate intersegmental plane identification during robotic anatomic segmentectomy.92 Recently, a new
method using methylene blue injection into the bronchus of the target pulmonary segments has also been
described.93
To improve the technical completion of segmentectomy, some surgeons use multidetector row
computed tomographic (MDCT) angiography to assess the relationship of the pulmonary tree with the
tumor, to assist with isolation of the pulmonary vessels and to determine the resection line.58,94
Localization of small tumors in a specific segment may be challenging when the tumor is less than 1 cm
in diameter and not immediately subpleural. Techniques to localize small tumors include using local
injection of radiotracer,95 wire hook and coil markers,96,97 radiopaque markers using intraoperative
fluoroscopy,98,99 and navigational bronchoscopy with dye injection.100 Other surgeons have shown that
successful localization may be achieved in the majority of patients without these techniques.85
Use of brachytherapy has also been formally studied in the American College of Surgeons Oncology
Group (ACOSOG) Z4032 randomized controlled trial reported by Fernando and colleagues.101 In this
study, the authors compared sublobar resection plus adjuvant intraoperative brachytherapy with sublobar
resection alone, and found that brachytherapy did not reduce local recurrence rates. The authors note that
the benefit of brachytherapy may only provide an advantage in those patients with compromised margins.
The role of energy sources in vessel ligation has been studied in preclinical and clinical trials.102,103 A
technical challenge in thoracoscopic segmentectomy has been dissection of pulmonary arteries,
particularly the right upper lobe posterior ascending pulmonary artery—a task made more difficult with
current bulky stapling devices. Nicastri and colleagues,102 in a porcine model, demonstrated that a small
ultrasonic scalpel was successful in achieving vessel ligation in 76% of pulmonary arteries and 92% of
veins. There have also been preliminary reports demonstrating safety and effectiveness of the LigaSure
bipolar tissue fusion system for division of pulmonary arterial and venous branches during anatomic lung
resection.103–105 Further studies with long-term follow-up and larger sample sizes will be needed to more
definitively address applicability of the technology in the human pulmonary vasculature.
NONANATOMIC PARENCHYMA-SPARING RESECTIONS

Patients with secondary lung malignancy are ideal candidates for metastasectomy using nonanatomic
resections. These patients may have multiple lesions or may present with additional lesions on subsequent
occasions. Anatomic resections may remove a considerable amount of unaffected normally functioning
lung, which might render them oxygen or ventilator dependent and severely affect their quality of life.
Using the approach of metastasectomy has resulted in considerable survival based upon the primary
tumor type: up to 50% for osteosarcoma,106,107 up to 52% for soft tissue sarcoma,108,109 94% for
nonseminomatous germ cell tumors,110 45% for renal cell carcinoma,111 75% to 80% for breast
cancer,112,113 and greater than 20% and 50% for melanoma114 and colorectal cancers,115,116 respectively.
Of note, most of these studies on long-term survival after pulmonary metastasectomy included sublobar
and lobar resections, with the majority of procedures being wedge resections.
WEDGE RESECTION VERSUS ANATOMIC RESECTION FOR NSCLC
Multiple reports show decreased risk of recurrence and equivalent or improved survival for patients
undergoing segmentectomy compared to those undergoing wedge resections for stage I NSCLC.117 When
compared with wedge resection, segmentectomy has also been found to be associated with a larger
parenchymal margin,118,119 a higher yield of lymph nodes and rate of nodal upstaging,119 and reduced risk
of locoregional recurrence.51
With regard to the thoracoscopic approach for wedge resection, there have been two studies
comparing the outcomes of VATS wedge resection versus VATS segmentectomy and lobectomy. However,
the tumors were smaller41,46 or the patient population had greater comorbidities in the wedge resection
group, which limits interpretation of results.46 Further studies with groups that are better matched will be
needed prior to making any conclusions regarding the role of VATS wedge resection role in NSCLC.
Based on these above-mentioned studies, segmentectomy would be the preferred procedure for
patients who are considering sublobar resection for NSCLC. However, some surgeons have advocated a
limited wedge resection in the case of peripheral adenocarcinomas with bronchoalveolar features120 or
ground glass opacity-dominant clinical stage IA lung adenocarcinomas.121 In fact, there have been some
recent studies evaluating lobectomy versus sublobar resection that call to attention the need for greater
equipoise regarding wedge resection for clinical stage IA ≤2 cm.121–125 Tsutani and colleagues evaluated
610 clinical stage IA patients with >50% ground glass opacity-dominant tumors and found no significant
differences in 3-year recurrence-free survival between lobectomy (96.4%), segmentectomy (96.1%), and
wedge resection (98.7%) groups. Similarly, Schuchert and colleagues125 found that in patients with
tumors ≤1 cm treated by wedge resection, segmentectomy, or lobectomy, there were no differences in
disease recurrence and overall survival between the groups. Altorki and colleagues122 evaluated patients
from the International Early Lung Cancer Action Program (I-ELCAP) who underwent lobectomy versus
sublobar resection for stage IA NSCLC and found no significant differences in survival between the
groups. Of note, a significant majority of patients (37 of 53) underwent wedge resection in the sublobar
group. Of note, this was a well-designed study that had followed asymptomatic participants closely over
time in a protocolized screening program, had tightly controlled prospective collection of data (including
comorbidities, presence of emphysema, and coronary artery calcifications on the baseline CT scan), and
had used adjustment with propensity scores in their analysis.122 Two other recent population-based
analyses using the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER)
registry found no differences in survival between patients undergoing limited resection or lobectomy for
patients with tumors <1 cm124 or for patients >65 years of age with tumors ≤2 cm.123
PERIOPERATIVE OUTCOMES
The morbidity after a nonanatomic parenchyma-sparing resection is minimal. Complications, when
present, are most often due to either retained secretions or pleural problems. Persistent airspaces occur in
up to 10% of cases. Most of these spaces produce no symptoms and require no treatment. The mortality
rate after nonanatomic parenchyma-sparing resection is near zero in patients with benign inflammatory
disease. Reports by Saltman and LoCicero126 and Tovar and colleagues127 on VATS methods show that
such procedures can be performed even on an outpatient basis.
For lung cancer operations, there have been two national studies reporting perioperative mortality for
wedge resections. One study of the Society of Thoracic Surgeons database, reported by Linden and
colleagues128 compared the morbidity and mortality of wedge resections (n = 3,733) with that of anatomic
lung resections (lobectomy and segmentectomy) (n = 3,733) for stage I and stage II NSCLC using
propensity-score-matched analysis. The operative mortality rate was 1.2% for wedge resections versus
1.9% for anatomic resection (p = 0.01) while major morbidity occurred in 4.5% for wedge resections and
9.0% for anatomic resection (p <0.01). The authors noted the mortality benet was most apparent in
patients with FEV1 less than 80% predicted although the morbidity benefit was observed regardless of
age, lung function, or type of incision.129
A study of the National Cancer Data Base reported by Rosen and colleagues found a higher
perioperative mortality rate of 4.2% for wedge resections for NSCLC. In comparison, the segmentectomy
and lobectomy groups had a perioperative mortality rate of 3.6% and 2.6%, respectively. The difference
in perioperative rates may be explained by a difference in baseline comorbidities between the groups; the
wedge resection group was sicker than the other two groups.130 This study also included a significant
number of patients with stage III and stage IV disease.
TECHNIQUE
Several methods are available for performing nonanatomic resections of the lung, including open or
video-assisted stapling, electrocautery, and laser. The techniques for each of these are similar.
Patients undergoing limited lung resection using any one of the aforementioned methods may involve
any of a variety of incisions ranging from a standard posterolateral incision or sternotomy for bilateral
disease to those of minimally invasive video-assisted thoracic surgery (VATS). Most patients are placed
in the lateral thoracotomy position with double-lumen tube anesthesia. After entry into the chest, thorough
inspection is made to ensure that all areas of disease are identified. If the patient has multiple metastatic
lesions, each should be addressed separately.
Wedge resections are best performed by using a U-type rather than a V-type resection. This ensures an
adequate margin around the lesion. There is little advantage to using fewer staple loads, especially when
this may compromise the operation. Two methods can be used. Two parallel staple lines are placed into
the lungs several centimeters away from the lesion. Several open and endoscopic in-line stapling devices
made by a variety of companies are available to perform a nonanatomic wedge resection. The lesion is
then elevated, and one or two additional staple lines are placed at the proximal margin. Alternatively, the
staple line is begun near the lesion, the edge of the specimen to be removed is elevated, and additional
staple lines are fired until the lesion and the surrounding margin are resected. The last firing is usually
performed from a different angle. When done thoracoscopically, the latter technique is used. Such a
maneuver may require three to five staple applications, but it creates a contoured cut with an adequate
margin around the lesion. The use of a VATS resection has largely supplanted the subsequent techniques,
but they are nevertheless included for completeness.
Electrocautery may be used to remove a lesion. This device can cut and coagulate simultaneously. The
technique for its use was described by Urschel.131 A linear incision is made over the lesion in the
parenchyma, and the lesion is exposed. By using traction and countertraction and applying cautery just
beneath the lesion, it can be excised, leaving essentially all normal lung tissue. To accomplish this
excision, a setting of at least 70 W must be applied to coagulate the tissue. At this power, resection
proceeds with adequate coagulation of small and medium blood vessels. The major disadvantage is that
the hot cautery blade may stick to the parenchyma.
An alternative to this approach was presented by Cooper and colleagues,132 who described the use of
a bipolar cautery. When traction and countertraction are applied, small amounts of tissue are grabbed with
the bipolar forceps and coagulated. All larger vessels and bronchi are ligated individually. This technique
produces good results with minimal air leak or injury to the remaining parenchyma. It is laborious and
time-consuming, however, and any vessel >1 mm must be ligated individually.
Another tool for resection is the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, an excellent
cutting and coagulating tool for the surgeon. One major advantage of this laser is that it does not have to
touch the tissue and thus no sticking occurs. At a power setting of 40 W, it can coagulate vessels ≤2 mm in
diameter and seal air leaks from bronchi ≤1 mm in diameter. It produces a considerable smoke plume,
which must be evacuated through filtered suction. The technique for removing a lesion using this laser
was described previously.133 Traction and countertraction are applied, and the laser is used to excise the
entire lesion. Because the laser produces considerable shrinkage of tissue, one must aim about 1 to 2 cm
from the lesion. Larger blood vessels not coagulated by the laser should be individually ligated. One
theoretical advantage of the laser is that because of its depth of penetration, it may be destroying
additional small micrometastasis ≤4 mm away from the lesion. One disadvantage is that the desiccated
lung tissue at the resection margin produces a scar that is radiologically visible for many months. For that
reason, follow-up chest CT scans are necessary for an indefinite period of time to observe for recurrence.
PATIENT SELECTION FOR SUBLOBAR RESECTION

Based on the reviewed studies, segmentectomy is a reasonable option for patients with NSCLC who have
small, peripheral tumors that are less than 2 cm in diameter, when a segmental margin that is greater than
or equal to the tumor diameter is obtainable, particularly in patients with advanced age, poor performance
status, or poor cardiopulmonary reserve. Of note, with increased use of high-resolution CT, more patients
are identified with air-containing tumors with ground glass opacities suggesting bronchoalveolar
adenocarcinoma, adenocarcinoma in situ, or minimally invasive adenocarcinoma.11 Asamura and
colleagues11 found that noninvasive or minimally invasive adenocarcinomas can be selected on thin-
section CT using a radiologic criteria of a consolidation/tumor ratio of less than 0.50. For patients with
these types of tumors that are cT1a, sublobar resections including segmentectomy or wedge resections
with a wide margin may be appropriate; for cT1b tumors, the authors recommend segmentectomy.
LIMITATIONS
The majority of the studies reviewed above were retrospective in nature and subject to selection bias. In
addition, many of these studies compared groups that were not well matched in baseline preoperative
characteristics. Some studies also did not report the percentage of patients with bronchoalveolar
carcinoma, adenocarcinoma in-situ, and minimally invasive adenocarcinoma. It is important to account
for these histologic subtypes,8 as demonstrated by a study performed by Nakayama and colleagues134 that
examined the results of 63 patients with adenocarcinoma who underwent sublobar resection of clinical
stage IA NSCLC. Patients’ tumors were classified as either “air-containing type” (n = 46) or “solid-
density type” (n = 17) based on the tumor shadow disappearance rate on high-resolution CT. After
resection, 38 of the 46 air-containing tumors were identified as bronchoalveolar carcinomas whereas all
solid-density type tumors were nonbronchoalveolar carcinomas. Air-containing tumors were associated
with better overall 5-year survival than solid-density tumors (95% vs. 69%, p <0.0001).
To decrease the impact of treatment-selection bias and confounding, randomized controlled trials
should be performed (described below). In addition, future retrospective studies should also aim to match
variables that have confounding effects, use stratification or multivariable regression analysis where
appropriate, and use propensity score matching when possible.135,136
FUTURE RESEARCH
Because up to 11.5% of patients who undergo pulmonary resection for stage I NSCLC develop additional
primary lung cancers,40,137 it will be important for future research to focus on the tolerance of patients for
resection of secondary cancers following segmentectomy or lobectomy. By causing less trauma than open
segmentectomy, and preserving greater lung function than lobectomy, thoracoscopic segmentectomy
theoretically would offer patients higher tolerance of resection of secondary cancers when compared to
the open segmentectomy or lobectomy.8
Future studies also should aim to include data on the number and type of nodal stations sampled or
lymph nodes dissected. In addition, the effect of surgeon experience on outcomes in segmentectomy
deserves attention.
There are two ongoing large-scale randomized controlled trials that will improve our understanding of
the outcomes of limited resection for NSCLC: CALGB 140503 and JCOG0802/WJOG4607L.138,139
CALGB 140503, from the Alliance for Clinical Trials in Oncology, will evaluate the outcomes of patients
with peripheral tumors ≤2 cm who are randomly assigned to undergo limited resection (segmentectomy or
wedge resection) or lobectomy, with the VATS or thoracotomy approach determined by the surgeon.140
JCOG0802/WJOG4607L, from the Japan Clinical Oncology Group and the West Japan Oncology Group
will evaluate outcomes of patients with presumptive invasive adenocarcinomas (defined as a
consolidation/tumor ratio of 25% to 100% on CT) less than 2 cm who are randomly assigned to undergo
segmentectomy or lobectomy.138 There is also an ongoing phase II study (JCOG0804/WJOG4507L)
where patients with tumors of radiologic noninvasive adenocarcinomas and minimally invasive
adenocarcinomas with a tumor diameter of 2 cm or less are resected with a wide wedge resection or
segmentectomy.141 These studies will further elucidate the role of segmentectomy and wedge resection for
NSCLC.
ACKNOWLEDGMENTS
We would like to acknowledge Dr. Joseph LoCicero III’s work on the previous version of this book
chapter. Original language from the previous chapter, including sentences on the technique and benign
disease sections were kept in this version of the book chapter. We would also like to thank John Deng for
his assistance with preparing this chapter.
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33
Robotic-Assisted Surgery in Pulmonary
Diseases
Richard S. Lazzaro ■ Andrew Brownlee ■ Laurence N. Spier ■ Mark R. Dylewski
INTRODUCTION
Since the early 1980s, multiple permutations of the surgical robot have been developed in an attempt to
improve upon and address the limitations of minimally invasive surgery (MIS). Robotic surgery was first
widely employed in 1985 as the PUMA 560, which was used to orient a needle for brain biopsy. Shortly
following this, other platforms began to be used in other subspecialties (Probot, urology (1988);
Robodoc, orthopedics (1992); and Zeus, gynecology (1998)).1–3 In 1994, The Automated Endoscopic
System for Optimal Positioning (AESOP) was the first robotic device approved by the U.S. Food and
Drug Administration (FDA) for use in intra-abdominal surgery. In 2000, the da Vinci robotic system was
created. The system was developed by the Stanford Research Institute and NASA. The prototype was
originally designed for use by the military to provide immediate operative care on the battle field from a
remote surgical station.3
In 2001, the first series of robotic lobectomies was reported by Melfi et al. (n = 5).4 Subsequently,
Melfi et al. (2002) described a larger series of 24 lobectomies (11 left lower, 9 right lower, 3 middle,
and 1 right upper). The authors detailed the first description of the steps to a robotic lobectomy, which
were outlined including patient positioning, port placement, instrument use, and methods to avoid
collisions. Two of the 24 patients required conversion to a thoracotomy.5 In 2006, a retrospective case
series of 34 robotic lobectomies was published by Park et al. All types of lobectomies were represented.
All patients had an R0 resection with a median length of stay of 4.5 days.6
The robotic platform has evolved, and currently has the capacity for a connected second console,
which is used for proctoring and mentoring. The da Vinci system permits the exchange of one or more
instruments between consoles as well as the use of telestration to identify critical structures and
movements that can be used as an adjunct to proctoring and teaching.
The ability of a surgeon to control the robotic instrument at a remote site separate from the operating
room and patient is regarded as telepresence surgery. In a small series in Canada, a group of surgeons
performed robotic surgery with the console at a distance of 400 km from the operative site. Information
was transmitted using commercially available fiberoptic Internet lines, which have a latency of an
acceptable 135 to 140 milliseconds.7 Similarly, telemonitoring allows an experienced physician at a
remote site to mentor surgeons in real time. This has been implemented and shown to be a realistic
platform for future national and international mentorship programs.8 Finally, the integration of real-time
robotic surgery and preoperative imaging, using picture-in-picture and overlay techniques, such as fusion
imaging, holds great promise for increased ease and efficiency of identifying and delineating critical
structures and pathologies.
EVOLUTION OF PULMONARY LOBECTOMY

Lobectomy continues to be the standard surgical approach to the management of early-stage non–small-
cell lung carcinoma (NSCLC).9 Precise anatomic dissection at the hilum with individual ligation and
division of the hilar structures (bronchus, artery, and vein) with lymph node evaluation via sampling or
complete lymphadenectomy (preferred by the current authors) has traditionally been performed and
remains most commonly performed through posterolateral thoracotomy. In the early 1990s, with the
development of the charge coupled device (CCD) and the vision and persistence of Walker, Mack,
Landreneau, Lewis, and others, video-assisted thoracoscopic lung resection for the management of early-
stage NSCLC was proposed.10–12
CALGB 39802 established and standardized the technique of VATS lobectomy.13 Five principles were
established. The access or utility incision could be no longer than 8 cm without the spreading of the rib
cage. Anatomic hilar dissection with individual ligation of the vascular structures and the bronchus should
be performed combined to lymph node sampling or dissection. Finally, the lobectomy specimen must be
placed in an impermeable bag.13 Whitson et al.14 performed a systematic review of video-assisted
thoracoscopic surgery versus thoracotomy approaches to lobectomy and concluded that VATS lobectomy
yielded “lower morbidity and improved survival rates” when compared with thoracotomy for patients
with early-stage NSCLC.
Concerns regarding adoption rates and the oncologic adequacy of the VATS technique of lobectomy led
researchers to assess multiple databases to clarify potential issues. As an example, the extent and
adequacy of lymph node evaluation during the surgical management of NSCLC have been debated for
many years and controversies will probably continue for many more, but the truth is that extent of lymph
node evaluation and dissection lies more in the surgeon than the approach to the resection—open versus
VATS versus robotic. Finally, Gopaldas et al.15 observed an adoption rates of VATS lobectomy of 5.9%
within a Nationwide Inpatient Sample Database and 20% in the STS. In spite of the reported benefits and
improved outcomes associated with VATS lobectomy, and more than 2 decades since its inception, the
adoption rates of VATS techniques for early-stage NSCLC are effected by a selection bias toward smaller
tumors T1 versus T2, lower rates of nodal upstaging, and, adoption rates significantly less than 20% for
patients with early-stage NSCLC.
TABLE 33.1 Robotic Lobectomy Perioperative Outcomes

Study Patients (n) Conversion to Thoracotomy (%) Complication (%) Mortality (%) LOS (d)
Ninan and Dylewski21 74 2.6 12.2 0 3
Gharagozloo et al.22 100 1.0 21.0 3.0 4
Lazzaro et al.23 128 0.78 15.6 0 4.19
Cerfolio et al.24 119 11 27 0 2.0
Kent et al.19 403 43.4 0.2 5.9
Park et al.25 325 8 25.2 0.3 5

Dylewski and Lazzaro16 previously reported on the potential for the robotic VATS platform to
anatomic pulmonary resection to improve adoption of MIS as well as on the adequacy of the
lymphadenectomy. With experience, the increased cost associated with the robotic instrumentation,
compared to VATS lobectomy, can be minimized and overcome.16 Adams studied the impact of a
standardized robotic pulmonary lobectomy on safety and adoption rates of minimally invasive thoracic
pulmonary resection. He demonstrated robotic lobectomy outcomes equivalent to VATS lobectomy with
trends favoring robotics (LOS, chest tube duration, air leak). In addition, robotic lobectomy was
associated with reproducible minimally invasive lobectomy platform; was applicable to a broad
spectrum of patients; was able to be performed by surgeons of diverse background, technique, and
practice, irrespective of whether the surgeon had previous experience to a VATS approach.17 The learning
curve is often discussed but difficult to define. It is clear that consistent committed team approach is
essential to minimize the curve and maximize the benefits afforded by 3D visualization, bimanual
dissection, and enhanced degrees of freedom.
With regard to cost, robotic lobectomy has been shown to be associated with increased cost when
compared to VATS lobectomy, but offers a cost savings over thoracotomy. It should, therefore, be viewed
in context to the cost savings of a robotic approach when compared with thoracotomy.
PERIOPERATIVE ROBOTIC LOBECTOMY OUTCOMES

Takagi et al.18 concisely summarized the perioperative outcomes associated with robotic lobectomy.
Utilizing a Medline search through April 2011, the authors identified seven studies, which fulfilled their
inclusion criteria. In this paper, the mean operative time for robotic lobectomy was 215 minutes, and
favorably compared to a mean time of 222 minutes and 216 minutes for VATS lobectomy and open
lobectomy, respectively. In addition, conversion rate of robotic lobectomy to open thoracotomy was
9.4%, which compared favorably to VATS (8.1%).18
Kent and colleagues reviewed the State Inpatient Database (SID) from 2008 to 2010, and performed a
comparative analysis of open, VATS, and robotic lobectomy. A total of 33,095 patients from eight states
were identified. While 22,238 patients underwent open lobectomy, 12,427 patients underwent VATS
lobectomy, and 430 patients underwent robotic lobectomy. Since robotic lobectomy is an emerging
technology and early in its adoption compared to VATS lobectomy which has been well established for a
couple of decades, the majority of pulmonary resections were approached through open techniques.
Nevertheless, robotic lobectomy was associated with lower mortality (0.3% vs. 1.2% VATS 2.6% Open;
p = .003); shorter length of stay (6.0 d vs. 6.4 VATS 8.0 Open; p = .001); shorter prolonged LOS (4.6%
vs. 7.6% VATS 9.9% Open; p = .003); decreased complication rate (43.4% vs. 49.5% VATS 50.6%
Open; p = .036); and no difference in bleeding complication (Table 33.1).19
Paul and colleagues performed a comparative effectiveness study of robotic-assisted versus
thoracoscopic lobectomy, utilizing the Nationwide Inpatient Sample from 2008 to 2011. The authors
identified that robotic lobectomy was associated with higher complication rates (50.1% vs. 45.2%; p
<.05), iatrogenic bleeding (5.0% vs. 2.0%; p <.05), and cost (cost to charge ratio) associated with
robotic lobectomy over VATS ($22,582 vs. $17,874; p <.05). In spite of the increased complication rate
reported in this study, there was a trend toward improved mortality associated with robotic lobectomy
over VATS (0.7% vs. 1.3%; p = .15). Although the iatrogenic bleeding rate was higher with robotic
lobectomy in this study, the authors felt that with experience, “the rates of iatrogenic complications are
likely to decrease.”20 No data was reported regarding blood loss, transfusion rates, and conversion rates.
LYMPHADENECTOMY
Surgical resection remains paramount in the management of stage I–II NSCLC as well as a component of
multimodality therapy for patients with stage IIIA disease. The oncologic adequacy and/or equivalency of
the surgical approach (Open, VATS, robotic) to pulmonary lobectomy is validated by not only the ability
to attain an R0 resection, but the extent of the lymphadenectomy and consequent nodal upstaging, as well
as survival. “Complete mediastinal lymph node dissection is considered the standard of care for lung
cancer resection at most academic centers.”26 Wright et al.27 published the outcomes of a meta-analysis of
randomized controlled trials of surgery for NSCLC, which reported a significant reduction in death in the
patients who underwent surgery with complete mediastinal lymph node dissection versus those patients
who underwent resection with systematic sampling of the lymph nodes. Subsequent ACOSOG Z0030 was
a randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during
pulmonary resection for N0 or nonhilar N1, T1, or T2 NSCLC to determine the impact on survival.26 One
thousand twenty-three enrolled patients who underwent rigorous mediastinal and hilar nodal sampling and
found to be node negative on frozen section were then randomized to undergo no further lymph node
removal or complete mediastinal lymph node dissection. Although complete mediastinal lymph node
dissection conferred no difference in long-term survival for patients with N0 or nonhilar N1, T1, or T2
NSCLC following rigorous lymph node sampling, the authors still recommended that complete
mediastinal lymph node dissection be performed in all patients with resectable NSCLC. The rigorous
lymph node sampling in the Z0030 study is not generalizable to most patients undergoing lung resection
for NSCLC in the United States where it has been reported by Little and colleagues28 that 57.8% of
patients undergoing surgery as their initial treatment for lung cancer had any surgical mediastinal lymph
node evaluation.
The adequacy of lymph node dissection associated with VATS pulmonary resection has been
extensively evaluated by Boffa et al.29 in a review of the STS database, which demonstrated that VATS
lobectomy was associated with lower rates of N1 nodal upstaging than thoracotomy. Although Denlinger
et al.30 had demonstrated that fewer overall lymph nodes (7.4 vs. 8.9) were resected via a VATS approach
than an open thoracotomy approach and fewer N2 nodes (2.5 vs. 3.7) were harvested in the VATS group
when compared to thoracotomy, the authors were compelled to proceed with a more focused lymph node
evaluation when performing VATS lobectomy to mitigate this finding.
Wilson and colleagues31 performed a retrospective review of 302 patients undergoing robotic
lobectomy or segmentectomy at three centers; a 10.9% overall rate of pathologic nodal upstaging was
revealed, which was similar to VATS nodal upstaging and inferior to open thoracotomy. However, when
evaluating hilar nodal upstaging with clinical T stage, the authors noted that robotic resection was
superior to VATS and equivalent to thoracotomy. Lee and colleagues32 reported equivalent nodal
upstaging with VATS and robotic approaches (15.2% vs. 13.2%; p = 0.72), which was similar to 9.3%
N1 upstaging reported by Boffa et al.29 with open thoracotomy. Lee also noted that higher pathologic T
stage was a significant predictor of nodal upstaging (pT1a, 7%; pT1b, 13%; pT2, 31%; p <0.001). In
conclusion, higher T stage predicts higher incidence of nodal pathology and the extent and adequacy of
nodal assessment is more a function of the surgeon and can overcome the potential limitations of the
chosen surgical approach: open, VATS, or robotic.29,31,32
ONCOLOGIC OUTCOMES
Park et al. reviewed long-term oncologic outcomes of a robotic approach to pulmonary lobectomy in an
analysis of 325 patients over a 10-year period at three institutions. CALGB consensus technique was
followed. The robotic approach was associated with an 8.3% conversion rate and low morbidity with a
21.5% minor complication rate and overall complication rate of 25.2%. Overall 5-year survival rates
were reported as 91%, 88%, and 49% for stage IA, IB, and II patients, respectively. The authors
concluded that “stage-specific survival is acceptable and consistent with prior results for VATS and
thoracotomy.”25
COST
Increased cost is often cited as a reason not to perform robotic lobectomy. The capital cost of the robotic
instrument as well as the cost of the disposable instruments is often cited by VATS surgeons as a reason to
avoid robotics. Although VATS lobectomy is currently associated with a cost savings over thoracotomy,
early analysis of VATS lobectomy revealed that VATS lobectomy incurred $3,190 increased cost over
thoracotomy lobectomy. The increased cost of VATS lobectomy during the early experience with VATS
lobectomy had been viewed as a barrier to adoption, but was overcome.33
With experience, advancements in technology, manufacturing, and competition, the cost of VATS
lobectomy has decreased and is now often cited as a cost savings over thoracotomy. In 2010, Burfeind
and colleagues34 at Duke performed a cost minimization analysis of thoracoscopic analysis versus
posterolateral thoracotomy, where 113 patients were evaluated (37 underwent posterolateral thoracotomy
and 69 underwent thoracoscopic lobectomy). Thoracoscopic lobectomy was associated with a cost
savings of $2,035 over thoracotomy (p = .0012). The authors commented that applying VATS lobectomy
to newly diagnosed lung cancers amenable to resection in the United States (approximately 50,000)
“would yield a cost savings of approximately $100 million per year.”34
Park and Flores35 reviewed their institutional experience with thoracotomy lobectomy versus VATS-
only lobectomy versus robotic-assisted VATS lobectomy. Park noted that thoracotomy was associated
with a relatively increased cost of approximately $8,000 over VATS only; robotic lobectomy was
associated with $3,880 increased cost when compared with VATS only; but was associated with
approximately $3,988 savings when compared to thoracotomy.35 Further, more granular evaluation of the
costs of robotic lobectomy will further clarify the topic, but it is evident that VATS lobectomy is
associated with limited adoption and that safe adoption of robotic lobectomy will further enhance the
adoption of VATS lobectomy albeit with a robotic platform, and lead to overall healthcare cost savings if
associated with conversion from thoracotomy to a VATS platform. “If robotic technology can result in a
more widespread adoption of a minimally invasive approach in a safe and appropriate manner that has
not been achieved with VATS, the added cost may be justified by all the potential benefits over traditional
open surgery.”36
PULMONARY RESECTION
Dylewski in 2011 published his experience with 200 consecutive patients undergoing a complete port-
based robot-assisted approach to pulmonary resection. Of these, 154 patients underwent pulmonary
lobectomy. Complex minimally invasive resections were also performed including sublobar resection,
anatomic segmentectomy (n = 35), bilobectomy (n = 4), sleeve lobectomy (n = 3), lobectomy with en bloc
resections (n = 3), and pneumonectomy (n = 1). Overall 60-day mortality was 1.5% whereas the
complication rate was 26%.37 In addition, Lazzaro and Spier23 later presented their experience with 128
patients who underwent robotic pulmonary lobectomy. The feasibility and safety of standardization of a
robotically assisted VATS lobectomy across a single healthcare system was assessed in 128 consecutive
patients by multiple surgeons. There was no mortality and overall complication rate was below 15%.
Utilizing a mentorship model and focused assistance with a co-surgeon approach led to the successful
adoption of a robotic approach to pulmonary resection with no discernible differences in morbidity,
mortality, and lymph node assessment.
DISCUSSION
The management of locally advanced lung carcinoma has evolved from pneumonectomy to lobectomy and
subsequently from an open approach to a VATS approach. Standardization of the definition of what
constitutes a VATS lobectomy as per CALGB guidelines has clarified that the tenets of pulmonary
lobectomy are preserved through minimally invasive approaches: anatomic dissection, lymph node
assessment, and individual ligation of the anatomic structures. Lack of rib spreading and small utility
incision size are included as well. However, since the first VATS lobectomy was performed in 1991, and
noting the improved outcomes associated with VATS lobectomy compared with thoracotomy (better
tolerated by the elderly, less pain, quicker recovery, less inflammatory response, less complications,
improved mortality, tendency toward improved 5-year survival for stage I patients), the reality is that
VATS lobectomy adoption has been less than 30% in the STS database with a selection bias toward T1
tumors and understaging associated with decreased overall numbers and regions of harvested lymph
nodes.
The VATS platform to pulmonary resection, despite being introduced to clinical practice since 1991, is
widely considered safe, associated with improved outcomes (e.g., atrial fibrillation, atelectasis,
prolonged air leak, shorter LOS, less bleeding, and blood transfusion) over open lobectomy, and should
be considered the “gold standard”38 approach to pulmonary resection, but has not achieved adoption by
the majority of surgeons and currently remains limited to patients with early-stage lung carcinoma by a
limited number of surgeons. Barriers to adoption of a VATS lobectomy have been cited as ability to
manage operative bleeding minimally invasive as well as surgeon experience. Many surgeons learned the
VATS technique following residency training and current trainees (ABTS general thoracic focused)
require a minimum of 10 major VATS/robotic anatomic resections.39
Comparative analyses of the early experience of robotic lobectomy to the more maturely developed
VATS lobectomy have demonstrated that robotic lobectomy is overall safe, may be associated with
increased complications, costs more than VATS lobectomy utilizing a cost to charge ratio, but is
associated with decreased length of stay and mortality when compared to alternative approaches to
pulmonary resection.
Although there are centers which perform VATS lobectomy for more advanced tumors and complex
resections including reconstructions, the fact remains that the majority of surgically resected cases are
done with an open approach and that a robotic-assisted approach to pulmonary lobectomy is poised to
further enhance the adoption of VATS surgery to a greater number of patients, conditions, and surgeons.
The development of simulators, refinements in imaging, fusion of imaging into the video image which the
surgeon sees are opportunities to develop image-guided surgery and further enhance VATS adoption and
safety with or without robotic assistance.
OPERATIVE TECHNIQUE ROBOTIC LUNG RESECTION

A surgical timeout is performed confirming patient, procedure, imaging, indications, as well as the
preoperative evaluation and optimization of the patient. Intravenous antibiotics are utilized prior to
incision. DVT prophylaxis with compression boots is utilized. Following double lumen endotracheal
intubation, the patient is positioned into the left lateral decubitus position. An axillary roll is placed just
caudal to the axilla; an arm support is utilized for the right arm; and the patient’s position is secured with
rolls placed anterior and posterior to the patient.
The patient is prepped and draped, and a surgical timeout is performed confirming imaging as well as
laterality/positioning of the patient. Bronchoscopy is performed. Single lung ventilation is initiated, and
utilizing the rule of 10s40 for port placement, the chest is entered. At this point, CO2 is initiated to a
pressure of 8 mm Hg, communicating with the anesthesia team to prevent hypotension secondary to
decreased venous return, which can occasionally be seen. Four additional ports are placed under direct
vision as the robot is docked to the ports. The rule of 10s places the camera port and the main right and
left of arms of robot to be placed just caudal to the inferior pulmonary vein. This approach to port
placement allows for visualization and division of the inferior pulmonary ligament, and complete
visualization of the hilum and superior mediastinum. With a standardized docking strategy based on
internal anatomy, any resection can be accomplished robotically. The instruments are inserted under
visual guidance and the robotic resection commences with the surgeon sitting at the robot console.
Bedside assistance is provided with a “bedside surgeon.” The bedside surgeon needs to be trained and be
familiar with exchange of robotic instruments as well as endoscopic staplers. It is important for the
console or operating surgeon to be effectively communicating with the team (bedside surgeon, scrub
nurse, circulating nurse, and the anesthesiologist).
Radiographic staging of the mediastinum is routinely performed but should not supplant surgical
mediastinal lymph node evaluation either through EBUS, mediastinoscopy, or at the time of surgical
exploration.
The pulmonary artery is identified in the major fissure. The posterior fissure is completed from
anterior to posterior dissecting along the interlobar plane utilizing bipolar cautery as well as endoscopic
staplers. Identifying the space between the posterior ascending artery and the superior segmental artery is
essential to safe completion of the fissure. Passively retracting the lung anteriorly, with a sponge held by
the fourth robotic arm provides exposure of the mediastinal pleura, just posterior to the edge of the
parenchyma. Passive retraction prevents lung trauma by utilizing a sponge to mobilize the lung for
exposure without physically holding the lung. Dividing the mediastinal pleura and dissecting anterior to
the bronchus, and between the caudal aspect of the right upper lobe bronchus and the bronchus
intermedius facilitates completion of the fissure. Often hilar nodes are resected during this step, which
facilitates arterial dissection and isolation with endoscopic staplers as this provides a more skeletonized
arterial tributary. With nonrobotic VATS lobectomy, enough dissection is performed for the operating
surgeon to pass the stapler. With robotic VATS pulmonary resection, the hilar lymphadenectomy and
completion of the fissures mimics open surgical technique and may be responsible for the enhanced lymph
node dissection seen by some proponents of robotic pulmonary resection. Following this dissection, the
posterior fissure can be completed. Next, attention is focused on developing the space between the
confluence of upper and middle lobe veins into the superior pulmonary vein. This is best approached
anteriorly with bipolar dissection. Immediately, behind the vein lies the pulmonary artery, including the
right middle lobe tributary. Dissection of the upper lobe vein from the confluence toward the parenchyma
helps to develop the minor fissure and release the right middle lobe artery away from the parenchyma,
which will facilitate the division of the minor fissure with endoscopic staplers. Completion of fissures
enhances anatomical visualization and surgical dissection. Of note, nonrobotic VATS pulmonary resection
is often done through a fissureless technique, which avoids dissecting the pulmonary artery in the fissure,
and has been referenced as a technique to minimize bleeding during nonrobotic VATS lobectomy but also
may explain the diminished lymph node resection often seen in this technique.
Thorough hilar lymph node dissection provides a greater number of lymph nodes for pathologic
assessment as well as ensures excellent visualization to the robotic surgeon for the dissection of the
arterial structures. Hilar lymph nodes are sent for frozen section analysis. The posterior ascending artery
is dissected free and divided with an endovascular stapler. Next, the right upper lobe vein is dissected
and isolated with an endovascular stapler, taking care to preserve the right middle lobe vein. Division of
the right upper lobe vein enhances the dissection of the truncus branch of the pulmonary artery which is
divided as the last vascular structure.
The bronchus to the right upper lobe is clamped with an endoscopic stapler and ventilation is
confirmed to the right middle and lower lobes. Single lung ventilation is resumed and the bronchial
stapler is fired, transecting the upper lobe bronchus. The specimen is placed into a bag and retrieved via
the assistant port after enlargement of that incision. The specimen is sent for immediate assessment of the
pathologic margins as a systematic lymph dissection of the mediastinum is undertaken.
The robotic surgical approach to anatomic pulmonary resection allows the surgeon to replicate an
open surgical technique. Right middle lobectomy, right lower lobectomy, left upper lobectomy, and left
lower lobectomy proceed with similar setup. Left-sided procedures require the fourth arm of the robot to
be placed posterior to the patient, but port placement follows the rule of 10s. The robotic steps to these
procedures replicate the open surgical technique.
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37. Dylewski MR, Ohaeto AC, Pereira JF. Pulmonary resection using a total endoscopic robotic video-assisted approach. Semin Thorac
38. Hartwig MG, D’amico TA. Thoracoscopic lobectomy: the gold standard for early-stage lung cancer? Ann Thorac Surg
2010;89:S2098–S2101.
39. Case Requirements. American Board of Thoracic Surgery: www.abts.org
40. Lazzaro RS, Guerges M, Kadosh B, et al. Robotic harvest of intercostal muscle flap. J Thorac Cardiovasc Surg 2013;146:486–487.
34
Video-Assisted Thoracoscopic Surgery for
Wedge Resection, Lobectomy, and
Pneumonectomy
Miriam Huang ■ Mark W. Hennon ■ Todd L. Demmy
INTRODUCTION
Video-assisted thoracoscopic surgery (VATS) for formal lung resection is now well accepted, with
survival outcomes comparable to traditional muscle-splitting thoracotomy.1 Investigators have found
equivalent 3- and 5-year survival rates of VATS lobectomy for patients with clinical stage IA lung cancer
as compared to thoracotomy.2 There are advantages to VATS including improved pain control, shorter
chest tube duration, decreased hospital length of stay (faster recovery particularly with elderly patients),
diminished inflammatory response, and a better cosmetic result.3,4 VATS patients generally have less of a
systemic stress response and better preservation of cellular immune function than thoracotomy patients.5
Compared to open techniques, VATS lobectomy reduces the complications of atrial fibrillation,
atelectasis, prolonged air leak, pneumonia, and renal failure.6 Such advantages translate to resource
benefits, with not only lower hospital charges, but also less overall cost in direct comparison to open
lobectomy.7
Surgeons remain concerned regarding the optimal technique, difficult learning curve, and oncologic
effectiveness of VATS lobectomy particularly with lymph node assessment.8 This may be why, despite its
potential benefits and long time (over 20 years) since the first performance, its adoption is only about
50% in the United States based on the Society of Thoracic Surgeons Database.9
The indications and contraindications for VATS lobectomy have shifted over time in concert with
evolving techniques and instrumentation. Peripheral tumors less than 3 cm were the first target
indications.10 These have expanded to central locations and larger sizes with fewer absolute
contraindications than were proposed previously.11 However, particularly severe pleural fibrosis or
inability to selectively ventilate lungs may still prevent VATS lobectomy.
With continuing advances in technology over the last three decades, scenarios such as neoadjuvant
chemoradiation, chest wall invasion, and need for sleeve resection no longer preclude VATS resection for
experienced VATS surgeons.12 By allowing more patients to receive adjuvant chemotherapy compared to
patients who undergo thoracotomy, VATS could potentially improve survival of patients with advanced
non–small cell lung carcinoma (NSCLC) (Table 34.1).
TABLE 34.1 Results of Video-Assisted Thoracic Surgery (VATS) Anatomic Pulmonary
Resections
Reference No. of No. VATS Conversion Rate Mortality Morbidity Median LOS
Pts Lobectomiesa (%) (%) (%) (d)
Yim et al.77 216 189 0.9 0.5 21.9 6.8b
Walker78 178 159 11.2 1.8 NR 6
Iwasaki et al.79 140 100 NR 0 NR NR
Roviaro et al.80 344 253 23.1 1.03 7.7 NR
McKenna et 1,100 1,067 2.5 0.8 15.3 3

al.48
Onaitis et al.44 500 500 1.6 1.2 NR 3
Swanson et al.10 111 96 10.8 2.7 9.4 NR
Shaw et al.81 180 142 9.2 0.6 29.9 4
LOS, length of stay; NR, not reported.

a Other resections: segmentectomy or pneumonectomy.
b Mean.
DEFINITION
Although the definition for VATS lobectomy can vary widely, it is mainly derived from the consensus
definition in the CALGB 39802 feasibility trial and based on two-port incisions ( 1 cm), a utility incision
size of 4 to 8 cm, and the prohibition of rib spreading.10 Generally, an operation is considered a VATS
lobectomy if it has the following features: (1) visualization of intrathoracic structures using videoscopic
equipment; (2) no rib spreading; (3) individual dissection of the vein, arteries, and airway; (4) a utility
(access) incision less than 8 cm; and (5) standard node sampling or dissection.10 It is acceptable if the
surgeon prefers variations such as the number and size of port incisions, use of carbon dioxide
insufflation, type of thoracoscope, sequence of hilar structure division, and general instrumentation or
supplies (sutures, staplers, energy devices, etc.). Ultimately, a VATS lobectomy should achieve the same
safety and oncologic result of that performed through a thoracotomy. Conversion to open when performed
in an intentional, controlled manner should not be seen as a sign of failure.
The techniques for lung resection—wedge, lobectomy, and pneumonectomy—will be discussed in this
chapter, along with troubleshooting tips for each anatomic lobectomy.13 Guidance with regards to
instrumentation, retraction, and exposure are provided (Table 34.2). Synoptic videos will be provided but
the full versions can be viewed elsewhere online
(http://www.ctsnet.org/sections/videosection/videos/2013_video-atlas-thorascopic-lobectomy).14 As a
learning tool, difficulty encountered for any approach of minimally invasive lobectomy can be addressed
by following this mnemonic of “F’s” (Table 34.3).
VIDEO-ASSISTED THORACOSCOPIC WEDGE RESECTION

Performing VATS wedge (nonanatomic) resection for a solid pulmonary nodule or nonsolid lesion
(ground glass opacity [GGO]) is diagnostic and potentially curative. Morbidity and mortality for VATS
wedge resection is quite low in healthy patients; furthermore, this obviates image-guided percutaneous
biopsy for preoperative diagnosis. Frail patients with reduced functional status and pulmonary reserve
may be offered wedge resection as their best available therapeutic resection for primary NSCLC.
However, when wedge resection is performed with underlying parenchymal disease (especially
pulmonary fibrosis), postoperative morbidity and mortality can still be high.15,16
Surgeons correlate preoperative imaging (such as computerized tomographic) with the intraoperative
visualized lung anatomy to locate nodules. With improved high-definition video imaging technology, along
with low-profile instrumentation, finger palpation through a standard VATS access incision is often
successful (Video 34.1). In situations where identifying the nodule in question may be difficult (small
GGOs, nodules less than 5 mm in size, or distance greater than 2 cm below the pleural surface), various
options exist to assist with nodule localization.
Browser issues
Video 34.1 Thoracoscopic left upper lobe wedge resection.
LOCALIZING DIFFICULT TARGET LESIONS FOR WEDGE RESECTION

First reported by Mack et al.,17 preoperative placement of a CT-guided localization needle remains an
effective means for identifying potentially challenging lung nodules. This process often involves a
supportive interventional radiology department. Effective communications between radiology and the
surgeon in situations where multiple nodules exist are crucial. Potential drawbacks include needle
migration or dislodgement when isolating the operative lung. Also, patients may develop pneumothorax
with subsequent respiratory distress during transfer from the radiology suite to the operating room. For
institutions with intraoperative CT scanning capabilities, wire-guided localization and VATS resection
can be performed in one venue, thereby simplifying the overall process. Like Gill et al.,18 our institution
has switched to “T” fasteners rather than the Kopans hook wire for lung nodule localization because of
less frequent dislodgement.
A newer approach for localizing a potentially difficult lung nodule intraoperatively involves
navigational bronchoscopy.19 Specialized software creates a three-dimensional image model of a
patient’s airways so that a specialized bronchoscope can be driven out toward the nodule in question for
methylene blue injection or fiducial marker placement into the target lung parenchyma. Thereafter,
thoracoscopic viewing, intraoperative fluoroscopy, or ultrasonography can be used to plan resection.
Advantages of this approach are the decreased risk of pneumothorax, improved efficiency (localization
and VATS procedure are performed in same space), and greater practicality in cases of multiple
pulmonary nodules. Drawbacks include the potential for nonspecific ink staining in the targeted lung
region.
Several reports have described the usefulness of intraoperative ultrasound for nodule localization.20–22
This employs an articulating laparoscopic 10-mm ultrasound probe (B-K Medical, Herlev, Denmark)
with conductive gel applied topically to the lung surface. Once identified, the lesion can be removed with
standard wedge resection techniques. Potential drawbacks are the operator learning curve typical for
ultrasound interpretation; however, this comes with minimal risk to the patient. In a series of 54
consecutive patients who underwent transthoracic ultrasonography-assisted resection of 65 lung nodules,
intraoperative ultrasound was able to locate and identify 15/16 of nodules that were not identifiable by
VATS alone.22 Complementing any of the physical localization techniques noted above, a radiotracer can
also be used to allow probe guidance to find lesions.23,24
WHEN TO PROCEED WITH VATS SUBLOBAR RESECTION ALONE
Poor cardiopulmonary reserve is commonly a deciding factor in the decision to avoid lobectomy. A
national randomized trial evaluating the effectiveness for wedge resection for small peripheral tumors
less than 2 cm in size is currently underway (Cancer and Leukemia Group B [CALGB] 140503), and may
eventually provide an answer as to whether sublobar resection is adequate for small peripheral tumors in
all patients. In patients with multiple GGOs, a lung-sparing approach is preferred to enable multiple
future resections should they become necessary. Segmentectomy is preferred over nonanatomic wedge
resection for NSCLC and a margin of 15 mm of healthy tissue reduces local recurrence risk for tumors
smaller than 2 cm.25 Features that favor lobectomy over wedge resection include tumor size greater than 2
cm and high avidity on positron emission tomography. Lobectomy should also be considered for the
aggressive pathologic features of pleural invasion, micropapillary morphology, and angiolymphatic or air
space tumor spread.26–30
EVOLVING APPROACHES TO VATS WEDGE RESECTION

VATS wedge resection can be performed with a standard multiport approach, modified single incision
approach, or a complete single incision approach.31 Increasingly, single incision approaches are being
implemented in an attempt to reduce morbidity. To perform a single incision approach, low-profile (5
mm) surgical video cameras, low-profile graspers, and specimen extraction pouch with flexible rims
(Ponsky, US Endoscopy, Mentor, OH) are very helpful.
TABLE 34.2 Troubleshooting Video-Assisted Thoracoscopic Techniques

Problem Possible Solutions
Camera Use midaxillary 8th intercostal space
Anterior working Use camera port to guide placement, needle or digital testing.
Try 6th intercostal space. The more anterior and in line with major fissure the better. Keep the anterior incision as
anterior as possible to improve the angle of entry for the stapler.
Access incision Use 4–8 cm (typically 5 cm) incision, guided by camera, needle, or digital testing.
Upper lobe Try 4th intercostal space, anterior axillary line for exposure to dissect upper lobe venous and superior arterial branches.
Lower lobe Try 5–6th intercostal space, midaxillary line directly over pulmonary artery in fissure. Avoid injury to long thoracic
nerve if the wound is extended.
Camera Select another port site or access incision to place scope.
maneuvers Use 30-degree or flexible thoracoscope.
Train your scope holding assistant thoroughly before embarking on VATS lobectomy.
Use 5-mm scope so that can share port with other tools.
Patient position Try reverse Trendelenburg to lower diaphragm.
Tilt the table to move lung tissue off field.
Position the patient slightly posterior, or roll the table posteriorly to improve the anterior visualization.
Retraction Try internal retraction stitch on sturdy (tendon) portion of diaphragm to pull it out of way of the camera.
Use a 5-mm retractor through the working port alongside the dissection tool to push the diaphragm out of the way.
Alternatively, another 5-mm port site may be created.
Place sling around hilum and retract through access incision.
Use a 5-mm loop liver retractor through anterior working port and create loop around lung parenchyma; this is very
helpful in lifting the entire lung away from the rest of the hilar structures near the end of the case to be sure that
there are no more vascular connections.
Try angled instrument through access incision.
Try any fan-type retractor.
Lung maneuvers Collapse by mild airway suction or blunt compression.
Release adhesions limiting control of hilum.
Move hilum toward access incision to dissect.
Try partially dividing fissures.
Reduce the tidal volume so that the mediastinum drops, improving the effective working area.
Consider using pressure competent trocar ports and gentle carbon dioxide insufflation to assist in collapse of lung.
To prevent right middle lobe from flopping in the way, do not complete minor fissure prematurely during right upper lobe
resections.
Access incision Use pediatric retractor or Weitlaner to open wound soft tissue (no rib spreading).
Change table position to improve viewing angle.
Increase width of access incision (up to 8 cm considered minimally invasive).
Use wound protector or minimally invasive retractor (e.g., Heartport™ or Alexis™).
Trouble keeping Use different port.
lens clean Make sure vacuum not drawing fluid down onto scope.
Clean lens via access incision with squirt of saline.
Place corner of lap into trocar port site to act as a wick for oozing blood, then replace port.
Use angled scope.
Clean inside of port with cotton-tipped applicator.
General Dissect pleura from hilum as first step.
Start with veins, then arteries, then bronchus.
Use EndoKittner (peanut) retractor through access or other incision.
Tether peanut dissection sponge with suture to prevent loss.
Use different port exposure or retraction if tedious.
Try dividing part or all of the fissure.
Add another (perhaps more posterior) port. For example, this is useful for left level 7 lymph-node exposure.
Use as many curved instruments as possible.
Do all the posterior dissection first to obviate flipping the lung forward during the anterior dissection.
Use another low profile instrument (e.g., EndoKittner) alongside camera to aid dissection or exposure.
Inferior ligament Try 30-degree scope downward view.
Use cautery from medial port to start, then finish from access port.
Retract diaphragm from medial port.
Avoid cautery of pericardium or phrenic nerve.
Major fissure Dissect by direct view or scope through access incision if anatomy allows.
structures Move hilum under access incision by retractor from medial port.
Anterosuperior Try 30-degree scope or 0-degree scope from medial port.
hilum Place extra low-profile retractors to pull redundant lung tissue out of the way.
Divide upper vein to access pulmonary artery for upper lobectomies.
Spare vein branch to middle lobe for right upper lobectomy.
Posterior hilum Try 30-degree scope viewing medially.
Trouble Use peanut dissector to increase effective length of vessel.
encircling Use standard or large (e.g., Harrington–Mixter) right-angle clamps.
vessels Try passing right angle through anteromedial port.
Separate fissure to increase dissection room.
Use different port to view dissection.
General Use articulating stapler fully angled—rotate slightly once behind structure to facilitate passage.
Sling structure with silicone tape for gentle retraction and to open tunnel for passage.
Attach an 8F–14F red rubber catheter with excess flange trimmed to anvil; pass catheter first with large right-angle
clamp, then use catheter to guide anvil. Do not to pull catheter hard or out-of-line with the anvil. Pushing anvil will
self-guide it.
Dissect excess tissue away from structure.
Be sure additional unseen, undesired structures are not included.
Use appropriate cartridge size with desired tissue.
Superior vein Try passing stapler through camera port.
Inferior vein Try passing stapler through medial port.
Apical pulmonary Try passing stapler through medial port or camera port.
artery branches
Major fissure Try passing stapler through medial port.
pulmonary Take care not to accidentally divide superior segmental artery to lower lobe.
artery
Bronchus Be sure there are no missed PA branches.
Try passing stapler through medial port (lower) or camera port (upper).
Use red rubber catheter (or similar device like the Diamond-Flex) looped around distal bronchus and retracted through
access incision to expose proximal bronchus for division.
Try routine open bronchus stapler (standard or articulating, e.g., TA-30, 4.8 mm) directed through access incision. Cut
bronchus with no. 15 blade on long handle. Use camera to guide cutting. Can use red rubber catheter to pass this
type of stapler as well.
Partially inflate remaining lobe before firing stapler.
Trouble with Start with blunt dissection with blunt clamp through camera port to create “pocket.”
adhesions Once pocket is created, insert camera. Use camera to separate loose adhesions. Place port into “pocket” of free
pleural space.
Use ports to pass cautery and other dissection tools.
Use angled tools.
Connect two ports working from each port, then it becomes easier.
View inferiorly from superior port to separate lung from diaphragm.
Trouble with Place thrombostatic material, rotate tissue over it to compress, and dissect somewhere else for several minutes.
mild bleeding Try biologic sealant such as fibrin glue.
Try transcollation (e.g., Aquamantys™) technology™.
Try harmonic, bipolar, or other energy sealer on friable tissue.
If any question, enlarge access incision to obtain direct control.
Trouble with Reapply stapler as a clamp if occurs while removing stapler.
more serious Apply double looped tape (snare) around proximal main pulmonary artery when anticipating high risk for bleeding.
bleeding Apply peanut retractor to tamponade or kink bleeding source.
Apply ring forceps with sponge for massive bleeding while converting to open thoracotomy.
Replace sponge stick with native lung tissue (held by lung grasper) to tamponade bleeding so that out of way for
conversion.
Apply clip (standard or endoscopic) if appropriate.
Suture with 4-0 Prolene and use small clips to lock knot.
Avoid placing vascular clamps directly on the site of bleeding. Use advanced hemostatic sponge like TachoSil™ or
Evarrest™.
Trouble getting Triangulate opening with heavy sutures passed through bag then bring out through camera and medial or extra ports.
lobe into One corner of “triangle” can be grasped by instrument through access incision. Alternatively, a 5-mm triangular liver
extraction sac retractor can help hold open the bag.
Insert small end of specimen first, roll rest of specimen into sac with alternating instrument movements always
maintaining a grasp on the specimen.
Fill sac with saline to hold it open.
Make sure correct lobe is being inserted.
Suture sac edges to self-expanding loop of propriety extraction device.
Orient sac in direction so that other tissue does not impede progress.
Use large sacs (e.g., 8x10″) for big resections.
Trouble Aspirate fluid from sac first; make sure sac is open during extraction for air and fluid to egress.
extracting sac Remove any retractor from access incision.
through Orient sac with seams parallel to ribs.
wound Reorient specimen in sac so that thinner portion of lobe leads.
Pull alternately on one side of seam then the other (or in circular motion); may take several minutes for tissue to
extrude through.
Steady chest with counter traction.
Rarely, skin or intercostal incision will require expansion.
General Inflate residual lung under pool of water or saline.

Staple, suture, or apply lung sealant to sites of leak.
Inspect stump at 20 cm water sustained airway pressure.
Use stream of fluid to find air leaks.
Check water seal chamber for rate of leak while closing or ask anesthesiologist to estimate leak.
Use large enough chest tube to allow air to drain easily without too much suction.
Consider using medial port for second chest tube.
May need to create longer tunnel for chest tube path.
Find pulmonary artery in superficial location in major fissure or anterior hilum and use this as dissection plane beneath
parenchyma before division.
Use thick staple load for the bronchus and avoid double firings on bronchus by careful stapler application and use of a
60-mm length load.
Use digital chest tube system to track intermittent air leak and discern true air leaks from water seal bubbles from
residual spaces.
Large residual Divide inferior ligament.
spaces Consider apical tent.
Consider pneumoperitoneum if air leak large.
Subcutaneous Consider suturing local tissue or patch over access incision to reduce free movement of pleural air into tissues (since
emphysema intercostal space is not obliterated as after a standard thoracotomy).
Trouble with Do transpleural or posterior intercostal nerve block early in the case for its preemptive effect.
postoperative Use local anesthesia via chest tube.
pain Avoid rib spreading or over-torque of instruments in ports.
Use Toradol or other nonsteroidal analgesics rather than narcotics.
Adapted and updated from Demmy TL, James TA, Swanson SJ, et al. Troubleshooting video-assisted thoracic surgery lobectomy. Ann
Thorac Surg 2005;79(5):1744–1752; discussion 1753. Copyright © 2005 The Society of Thoracic Surgeons. With permission.
TABLE 34.3 The “F’s” for Approaching Minimally Invasive Lobectomy

Strategy Examples
Free all adhesions, all lobes Divide adhesions with energy to reduce oozing
Freeing diaphragm adhesions to chest wall on redo cases will increase working space
Find somewhere else to work View and dissect pleurae and lymphatic tissue
or view Divide more distally
Change camera vantage point (port)
Fissure division (opens Divide partially (outside in)

camera angles) Divide completely (blunt clamp or “tunnel technique”)
Flip order of anatomical Change to fissure-last technique

divisions
Fill the port/access incisions Provide traction—counter traction using additional tools (multiple-angled thoracoscopic graspers, vessel
loops) to help define anatomy
Fresh planes Open pericardium
Flatten the diaphragm Depress diaphragm with retractor to increase working space
Awake thoracoscopic surgery—which eliminates the need for general anesthesia, double lumen
intubation, and positive-pressure ventilation—has shown to be feasible and potentially beneficial in
select series.32,33 It may also be optimal for patients for which standard general anesthesia is dangerous or
impractical. This approach may reduce in-operating room time, and allows for faster postoperative
recovery. In a reported series of 60 patients randomized to two treatment arms, the 30 patients treated
with epidural anesthesia had a shorter hospital length of stay by 1 day, and reported higher anesthesia
satisfaction scores. There were no mortalities.32
MINIMIZING POSTOPERATIVE VATS WEDGE RESECTION MORBIDITY
Although VATS wedge resection generally has relatively low risk, patients with impaired lung function
and significant parenchymal disease may suffer prolonged air leak postoperatively. Application of
buttress layers to endoscopic linear cutting staplers may reduce air leaks as well as the application of
lung sealants.34 Creating an apical pleural tent or performing a pleurodesis may also reduce air leak
duration.35 Chest tube management can potentially be simplified by digital drainage devices capable of
accurately monitoring air leak flow.36 A digital drainage device (Thopaz, Medela, Inc., McHenry, IL) can
eliminate the subjectivity involved with assessing air leaks with conventional systems, by providing a
digital timeline flow recording (Fig. 34.1). It is hypothesized that by eliminating this subjectivity in air
leak assessment, chest tube duration and hospital length of stay can be reduced if this is the main issue
preventing discharge.
ANESTHETIC CONSIDERATION OF VATS

Using a double lumen endotracheal tube or bronchial blocker with single lung ventilation, the patient is
positioned in lateral decubitus position with an axillary roll approximately one hand’s breadth inferior to
the axilla and with the bed flexion point between the iliac crest to the xiphoid, to allow for opening of the
intercostal spaces. Padding of and avoidance of traction on major neural pathways reduces neurologic
injury. Teamwork with an anesthesiologist well-versed in thoracic anatomy is beneficial in efficient
positioning of the endotracheal tube to maintain adequate lung isolation. Initial bronchoscopy is
performed to evaluate for bronchoscopic lesions that may alter the surgical approach. Videobronchoscopy
(rather than a single-user viewing fiberoptic scope) encourages team interaction. A separate airway video
system also allows the anesthesiologist to display anatomy to the surgeon when applying staplers or
manipulating the airway thoracoscopically. If the lung remains inflated upon entering the chest cavity,
maneuvers such as ipsilateral bronchoscopic suctioning, CO2 insufflation, draining bullae planned for
resection, and topical lung compression using thoracoscopic instruments can be performed to encourage
atelectasis. Narrow intubating bronchoscopic equipment should be available at all times to reposition
dislodged endotracheal tubes and study airway alterations caused by the planned resection. Unlike
thoracotomy cases, epidural anesthesia is not required. Alternatively, an intraoperative intercostal nerve
block along multiple levels, as well as intrapleural instillation of 20 mL 0.5% ropivacaine every 6 hours
postoperatively by a chest tube side port reduces chest tube related pain.37
FIGURE 34.1 Digital, portable, chest tube drainage device (Thopaz, Medela, Inc., McHenry, IL) allows for early patient
mobilization and displays real-time and graphical flow tracking data to assist in chest tube management. (Image reproduced with
permission from Medela AG, Switzerland.)
APPROACH TO VATS LOBECTOMY

There are multiple approaches to performing VATS with port placement dependent on surgeon preference.
It is important to understand that each approach carries with it certain benefits and disadvantages related
to exposure and conformation with the operator’s open experience and mental construct of the anatomy. In
all cases, adjustments need to be made to account for certain exposure and instrument limitations inherent
with the chosen methodology. Otherwise, severe complications can result, generally as a result of
impaired exposure.38 As the surgeon matures, knowledge of more than one approach (just like in open
surgery) allows for faster, safer operations in cases when the patient’s anatomy or pathophysiology
impairs the preferred technique. An attempt to categorize these approaches is provided in Table 34.4.
The evolution of thoracoscopic surgery has progressed secondary to the advances of technology and
techniques. A comparison of various incision sets (Fig. 34.2) shows many similarities as well as
differences. Over time, changes involved alterations in the operative axis (used here to describe the
direction in which the hilar structures are divided) as well as step-wise reductions in size and number of
incisions.39,40 Before the introduction of articulating stapling instruments, the early three-port VATS
approach involved a posterior port just anterior to the tip of the scapula.41 The goal was to create a
triangulation of two 10-mm ports plus one 3- to 6-cm utility port, with the camera positioned in the 7th or
8th intercostal space in the midaxillary line and the utility port in the anterior axillary line (wider
intercostal space) of the 4th to 5th intercostal space. Advocates of the Edinburgh posterior viewing
approach tout the excellent view of the posterior hilum, thus facilitating dissection of the bronchi and
pulmonary artery branches.41
TABLE 34.4 Approaches to VATS Lobectomy

Technique Surgeon/Program General Recommended Comments
Approach Incision for Stapling
of Structures
Posterior Walker/Edinburgh Bronchus Posterior First report of VATS lobectomy
viewing 3–4 last Superior pulmonary Tools delivered anteriorly while viewing structures
incisions41,78 vein from posteriorly
Upper lobe arteries Emulates open techniques
Middle lobe artery Good view of posterior structures like left upper
and vein lobe segmental arteries
Upper lobe
bronchus
Utility
Anterior
Inferior pulmonary
vein
Lower lobe arteries
Lower lobe
bronchus
Posterior 3–4 McKenna/Cedars- Bronchus Posterior Open instruments used for most of operation
incisions Sinai last Superior pulmonary Viewing from inferior port
vein Port selection critical to proper alignment of non-
Upper lobe arteries articulated staplers
Middle lobe artery
and vein
Left upper lobe
bronchus
Utility
Right upper lobe
bronchus
Minor fissure
Anterior
(midclavicular)
Inferior pulmonary
vein
Lower lobe arteries
Additional left
upper arteries
Major fissure
Lower lobe
bronchus
Posterior 3- Swanson/Brigham Bronchus Posterior Viewing from inferior port while posterior port is
incision last Superior pulmonary used for retraction, dissection, and stapler
vein (nonarticulated) passage
Upper lobe arteries Emulates open techniques
Middle lobe artery
and vein
Upper lobe
bronchus
Utility
Anterior
Inferior pulmonary
vein
Lower lobe arteries
Lower lobe
bronchus
Anterior 3- Authors Bronchus Inferior Viewing from inferior port but also anterior port as
incision last Superior and necessary for anterior upper lobe structures
inferior pulmonary Articulated staplers used for most maneuvers
veins Emulates open (fissure division techniques)
Upper lobe arteries
Upper lobe
bronchus
Utility
Minor fissure
Anterior
Middle lobe artery
and vein
Lower lobe arteries
Lower lobe
bronchus
Major fissure
Posterior 3- Flores/Mt. Sinai Fissure last Posterior View from inferior port
incision82 Superior pulmonary Utility incision used for stapler passes, particularly
vein in fissure division
Upper lobe arteries
Upper lobe
bronchus
Fissure
Utility
Inferior pulmonary
vein
Middle lobe artery
and vein
Lower lobe arteries
Lower lobe
bronchus
Fissure
Anterior 2- D’Amico/Duke Fissure last Inferior View from inferior port but switched to utility
incision83 Superior pulmonary incision for anterosuperior structures
veins Anterior to posterior approach, to minimize back
Upper lobe arteries and forth retraction
Upper lobe Stapler passages from either incision depending on
bronchus the structure
Anterior (Utility)
Middle lobe artery
and vein
Inferior pulmonary
vein
Lower lobe arteries
Lower lobe
bronchus
Fissures
Modified Duke Fissure last Camera in satellite All viewing through the satellite incision
uniportal46 incision All dissection through the port
All other instruments Requires consideration of camera location relative
through single port to other instruments within the portal
incision
Uniportal40 Gonzalez- Fissure last All instruments All viewing and dissection through a single port
Rivas/Coruña, through single port Requires bimanual instrumentation and
Spain incision coordination with the assistant
Camera: posterior part of the incision
Instruments and staplers: anterior part of the
incision
FIGURE 34.2 Placement of incisions for video-assisted thoracoscopic multiport approach, with comparison of incision choices
described by several well-known VATS surgeons. Note that there is general similarity with a utility port near the anterosuperior
hilum to control emerging tubular structures, as well as the inferior ports, often in-line with the interlobar fissure to enable certain
advantages with viewing and division of structures. The roentgenogram indicates alternate options for the larger utility incision to
ease dissection over the major fissure for lower lobectomy or anterosuperior hilum for upper lobes. The two anterior, thin lines in
the Walker diagram represent the initial incision set but were consolidated into the single thicker line to yield a three port
approach.
This three-port approach was then modified to adjust for the change in axis of operation; rather than
from hip to head of the patient, the axis was directed from umbilicus toward the scapula. The camera port
was brought more anteriorly, and the posterior port was lowered to allow the stapler to approach hilar
vessels. In addition, the camera holder could then stand on the same side as the surgeon to allow for
improved coordination.42 Advocates of this approach find that this technique can be more easily adapted
by many surgeons, as it most emulates the open anterior approach, and is considered easier to teach as the
surgeon and the assistant stand on the same side. Advantages include: (1) having the access incision
directly over the hilum and major pulmonary vessels, (2) maintaining the surgeon’s position and place of
incision if conversion required, (3) allowing for same approach to all lobes, and (4) allowing lung tissue
retraction to be accomplished by gently pushing rather than grasping.43 In addition, moving VATS ports to
wider anterior intercostal spaces may reduce instrumental torqueing injuries to the ribs and thus reduce
pain. Note that by doing this, stapler articulation was required so as to be able to engage hilar structures
perpendicularly to allow its passage (Fig. 34.3).
With the movement toward a two-port VATS approach,44 with a 10-mm scope in the 7th or 8th
intercostal space along the midaxillary line and 4 to 5 cm anterior utility incision in the 5th intercostal
space, the biggest challenge was compensating for the lack of a posterior port. Thus, swapping ports for
lung retraction was critical in order to maneuver the correct angulation for application of the stapler. To
make this happen, the camera frequently moves to share the utility incision with other instruments to serve
as a better vantage point to enable retraction and dissection. Another innovation required by similar
approaches popularized by the Duke investigators, was the division of the fissure last after all the other
hilar structures.
Transition to the uniportal technique is seen as a natural progression of minimally invasive
thoracoscopic surgery. First described by Rocco and colleagues45 in 2004, a single 3- to 5-cm incision is
created in the anterior axillary line along the 5th intercostal space. Once all operators and assistants are
comfortable in sharing instruments in the same utility port, uniportal VATS teams transfer the thoracoscope
to the same port. Uniportal approaches have two main disadvantages: the camera competes for same
space with multiple operating instruments (requiring consideration where the camera resides in the
incision) and a single incision is closed around a chest tube. The modified uniportal VATS Duke approach
uses a 5-mm counterincision in the same interspace adjacent to operating incision. This allows the camera
to be separate from the operating instruments, as well as gives the chest tube its own incision.46
The authors perform a lobectomy with a standard anterior three-hole approach, using an initial 12-mm
posterolateral axillary incision along the 7th to 8th intercostal space to allow for introduction of the
thoracoscope. When the camera is first inserted, initial exploration of the chest cavity is performed to
evaluate for metastatic disease or any contraindication to VATS resection. This is followed by another 12-
mm incision as anterior as possible in the 6th intercostal space under thoracoscopic visualization. This
anterior working port is positioned in line with the oblique fissure, so that the stapler can be applied
easily to divide incomplete fissures and the adjacent hilar structures. This technique emulates the open
technique by enabling opening of the fissures and division of the bronchus last.
Most surgeons agree that placement of the incision midway within the intercostal space decreases the
incidence of torque and trauma to the neurovascular bundle, thus decreasing the incidence of
postoperative pain or neuralgia. Posterior incisions are generally avoided since the interspaces are tighter
and more likely to be subject to nerve injury. In addition, preemptive analgesia with intercostal nerve
blocks are performed prior to creating the access incision. Once the decision to perform lobectomy has
been made, the 4 cm access incision is then created in the midaxilla along the identified 4th intercostal
space usually overlying the superior pulmonary vein, depending on the planned lobar resection (Fig.
34.2). Our group employs a 4 cm access incision, using Weitlaner retraction or wound protector (Alexis,
Applied Medical, Rancho Santa Margarita, CA) for soft tissue retraction only, without any rib spreading.
The retraction provided by the small wound protector can occasionally be limiting for some
thoracoscopic instruments, depending on the extent of soft tissue (Fig. 34.4). The opening from the soft
tissue retraction of the chest wall is also necessary to prevent a vacuum created by suctioning, and thus
preventing the lung from expanding in the pleural space.
FIGURE 34.3 Articulation of the stapler in order to engage hilar structures perpendicularly and allow for its safe passage.
Coronal view of right chest during stapler division of upper lobe structures while viewing through the anterior port and
temporarily retracting through the access port. In order to make room for the stapler, the retractors have been swapped out of
the port that the stapler is using. Note that when the stapler enters the chest anterior to the midaxillary line, it requires articulation
to pass around structures emerging from the hilum. Before the introduction of articulation, the posterior port site (marked by X)
was necessary to achieve this angle.
FIGURE 34.4 Direct view into the thoracic cavity. The small-sized, self-retaining wound retractor provides circumferential,
atraumatic retraction for the access incision, but can occasionally be limiting for some thoracoscopic instruments depending on
the extent of soft tissue (Alexis, Applied Medical, Rancho Santa Margarita, CA). (Image reproduced with permission from
Applied Medical. © 2017 Applied Medical Resources. All rights reserved.)
The smaller incisions may provide more of a challenge to palpation of the lesion as compared to
thoracotomy; however, thoracoscopic tools and maneuvers such as retraction of the mobile lung toward
the incision can be used to more easily identify the pulmonary lesion. As mentioned previously, additional
useful adjuncts to localizing a nodule, such as intraoperative ultrasound, radiotracer with gamma probe,
navigational bronchoscopic placement of fiducial marker or dye injection, or CT-guided wire
localization, can also be used to assist in identification.
FIGURE 34.5 The flexible-tip thoracoscope allows for various viewing angles (Olympus, USA). (Image courtesy of Todd L.
Demmy, MD.)
VATS INSTRUMENTS
In the authors’ institution, we use either the 5-mm or 10-mm thoracoscope with a deflectable tip to allow
for various viewing angles (Fig. 34.5). Along with the high-definition video camera system, excellent
exposure can be obtained with simultaneous placement of multiple, angled, low-profile (5-mm)
thoracoscopic retraction instruments in a single port site (Fig. 34.6). The depicted flexible system also
has a 3D option which has been shown to reduce operative time and is now our preference for complex
cases. The surgeon is positioned anteriorly to the patient, and is able to begin dissection via the access
incision. The access incision facilitates instrument use on the most difficult anatomy, and provides access
for direct viewing as well as control of bleeding when necessary. Additional instruments used for blunt
dissection include the Rochester and Harken clamps, pediatric Yankauer suction tip, and EndoKittner
“peanut” dissector. These angled clamps are passed around structures to allow for subsequent stapling,
with adequate spreading of the clamp to allow passage of the stapler. Our choice of endoscopic stapling
device includes the articulating, straight, or curved tip, endoscopic linear cutting staplers such as the
Endo GIA™ (Covidien, Norwalk, CT), which afford improved maneuverability around sensitive vessels
(Fig. 34.7).47 One technique is to secure the cut end of a red Robinson catheter to the anvil of the stapler
to guide the stapler around structures, whether it be around the fissure, bronchus, or pulmonary vessels. A
nonlatex variety of red rubber catheter is stiffer and more likely to follow the intended path. Clip
application on delicate pulmonary artery branches is avoided as later tissue manipulation or accidental
stapler application over the clip can cause vessel avulsion.
FIGURE 34.6 Multiple-angled, low-profile (5-mm) thoracoscopic retraction instruments can be positioned in a single port site.
(Image reproduced with permission from DUFNER Instruments.)
TECHNIQUE COMPARISONS
An attempt to categorize and contrast the existing methodologies is presented in Table 34.4. In a large
sense, many of the techniques that have been developed can be sorted into fissure last techniques
(probably more common for VATS) and open-emulating bronchus last techniques. The description begins
with the fissure opening, bronchus last techniques and describe the fissure last as common technical
alternatives. Fissure last methods are popular because they are fast, possibly easier to learn, and
applicable for many cases. However, the authors have pursued fissure opening methods to expose
anatomy better for select cases and emulate open procedures. This has become easier with the
improvements in low-profile camera and grasper technology, but some VATS masters use open tools to
achieve these ends.48 By pursuing this strategy, the authors have advanced their technique to patients with
locally advanced cancers and achieve high reliability for our entire population.49–51 As was the case
before minimally invasive surgery, surgeons should be familiar with more than one approach in order to
adapt in the operation theater.
FIGURE 34.7 The curved tip stapler allows for improved maneuverability around vessels (Endo GIA™, Covidien, Norwalk,
CT). (Used with the permission of Medtronic. All rights reserved.)
VATS TECHNIQUES OF SPECIFIC LOBECTOMIES

The initial conduct of the operation is similar with regard to placement of the mid to posterior axillary
camera port, anterior working port, and access incision. After exploration of the chest cavity with
assessment for any metastatic disease, begin by dividing the inferior pulmonary ligament to the level of
the inferior pulmonary vein. Although there should be a plan for an approach to each specific lobe, the
surgeon must maintain flexibility and always be aware of anatomic variations. The general approach to
upper lobectomy is to perform hilar dissection, posterior pleural incision, and dissection to identify a
“landing zone,” and then proceeding with an anterior to posterior approach.

Although variable, one approach to the structures for a right upper lobectomy is to begin with dissection
and division of the upper lobe pulmonary vein, followed by truncus anterior, completion of the horizontal
and oblique fissures allowing unfettered access to the posterior ascending artery, and finally the upper
lobe bronchus. Prior to directing the camera to the hilum, the authors like to initially open the posterior
pleura over the inferior border of the right upper lobe bronchus and the pleura over the pulmonary artery
in the interlobar fissure. This allows dissection of the “landing zone,” facilitating completion of the
“tunnel” later. Then, with the camera directed toward the hilum, the pleura over the anterior hilum is
mobilized using blunt dissection, taking care to prevent injury to the phrenic nerve. Circumferential
dissection is then performed around the superior pulmonary vein, with identification and protection of the
middle lobe vein. A separate inferior pulmonary vein should be identified to prevent accidental division
of a common pulmonary venous drainage. A vessel loop is then used to encircle the superior pulmonary
vein, and space created to allow passage of the endovascular stapler from the most posteroinferior port.
Once the pulmonary vein is divided, the apical branches of the pulmonary artery are identified. The
truncus anterior is then similarly encircled and divided (Fig. 34.8). The pulmonary artery is then
identified in the fissure. The lung is then stretched to the chest wall, and partial completion of the minor
fissure is performed using the tissue load of the stapler lined up with the confluence of the veins. Using a
large, blunt, right-angled clamp, an avascular plane is developed along the superior edge of the
pulmonary artery from the anterior hilum and exiting in the major fissure in the region of previous
dissection over the pulmonary artery in midfissure. Using a red Robinson catheter as a leader, the minor
fissure can be completed by passing a stapler through this plane, thus exposing the full course of the
continuation pulmonary artery. The posterior ascending artery and any remaining recurrent branches can
be then visualized and divided, if convenient, or this step can wait until the rest of the fissure is divided.
The posterior fissure is then completed by starting in the midfissure and directing a blunt clamp safely
inferior to the posterior ascending and posterior to the ongoing artery toward the posterior pleural
opening made below the upper lobe bronchus origin created at the start of the case. The clamp can be
used to direct a leader to allow passage of the stapler anvil through the resultant tunnel. This is followed
by transection of the bronchus (the only remaining structure) using the thick tissue endostapler (Video
34.2). Pneumopexy is not routinely performed. However, if the middle lobe appears floppy and the major
fissure is complete, the middle lobe can be stapled to the lower lobe with a noncutting stapler to prevent
torsion.
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Video 34.2 Thoracoscopic right upper lobectomy.
FIGURE 34.8 Anterior camera view during right upper lobectomy, displaying the exposed continuation pulmonary artery. Once
the pulmonary vein is divided, the apical branches of the pulmonary artery can be visualized. Once the truncus anterior is
encircled and divided, the pulmonary artery can then be identified in the fissure.
COMMON TECHNICAL VARIATIONS FOR RIGHT UPPER LOBECTOMY

When using the above technique, an anterior vantage point is optimal for division of the vein, truncal
artery, and creation of the tunnel over the ongoing pulmonary artery. This is done by using the
posteroinferior typically “camera” port for retraction and stapler passage while viewing through the
anterior port. Similarly, the camera can share the utility incision for this anterior vantage point when using
the two-incision technique.
If a fissure last technique is preferred by the surgeon, the right upper lobe bronchus can be divided
before or after the vein by setting the camera with a posterior to anterior vantage point and dissecting with
a long vascular clamp. By doing this, the truncal artery is exposed and divided. Division of the posterior
ascending artery (sometimes more challenging with the fissure last technique) is next, followed by the
fissure last.
MIDDLE LOBECTOMY
Similar to a right upper lobectomy, the pleura along the anterior hilum is dissected to identify the superior
pulmonary vein. With the lung retracted posteriorly, the confluence of the middle lobe and upper lobe vein
is identified, and an angled clamp is used to mobilize the middle lobe vein. The vascular load of the
stapler is then passed through the posterior port to divide the middle lobe vein. This exposes the middle
lobe bronchus, so that it can also be mobilized through the access incision. Commonly there are large
lymph nodes surrounding the bronchus which if dissected and removed will facilitate division of the
bronchus and underlying pulmonary artery branch(es) to the middle lobe. Generally, it is easiest for a
middle lobectomy to use a fissure last technique after dividing the bronchus and artery (Video 34.3).
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Video 34.3 Thoracoscopic right middle lobectomy.
COMMON TECHNICAL VARIATIONS FOR RIGHT MIDDLE LOBECTOMY

For the above technique, much of the operation can be performed with an anterior to posterior viewing
vantage point such as that used for vein division in the upper lobectomy. Occasionally, it may be useful or
necessary (as in a bilobectomy) to divide the fissure before the bronchus. The middle lobe vein is divided
but the rest of the upper lobe vein is mobilized and retracted with a vascular sling to improve exposure to
the ongoing artery. Infrequently, the middle lobe arterial branches can be visualized, dissected, and
divided within the fissures, especially when they are nearly complete. To facilitate division of the middle
lobe artery by increasing exposure and mobility, the minor fissure is then partially completed (“outside-
in”) with a single firing of a 45-mm stapler. With the thoracoscope directed toward the hilum, the
continuation pulmonary artery can be identified and a large, blunt, right-angle clamp is then used to
develop the plane along the superior edge of the pulmonary artery from the anterior hilum to exit in the
major fissure near the pulmonary artery (similar to the upper lobe technique described above). Once the
minor fissure is completed, the pulmonary artery branch to the middle lobe can be visualized. After
dividing the middle lobe artery, the major fissure between the middle and lower lobe is completed,
leaving the bronchus well-exposed for its division.
RIGHT OR LEFT LOWER LOBECTOMY

After dividing the inferior pulmonary ligament and with the lung retracted superiorly, the pleura is
mobilized posteriorly and anteriorly (with the lung retracted the opposite direction for each) to allow for
mobilization of the inferior pulmonary vein. With upward (lateral) retraction of the lobe, the inferior
pulmonary vein is then circumferentially dissected and divided at this point if desired. If the fissure is
nearly complete and the ongoing pulmonary artery is prominent, it can be dissected and divided first. Care
should be taken to ensure that there is no variation in the arterial supply to the upper lobe such as an
ascending posterior or a lingular artery that arises more distally and could be divided inadvertently. To
dissect the artery hidden within an incomplete fissure, there are several approaches to open the
parenchyma. First, a “landing zone” is created opening the posterior pleura just inferior to the right upper
lobe bronchus just as described for the right upper lobe above (the posterior hilar termination of the
major fissure). On the left side, a similar dissection is created to expose the ongoing pulmonary artery in
the posterior hilum just above the superior segment artery. In both cases, a minimally curved blunt
vascular clamp directed through the utility incision can create a tunnel by gentle spreading, starting in the
interlobar fissure just posterior to the ongoing artery and exiting in the landing zone just previously
dissected. To do this well, two low-profile (5-mm) retractors placed posteriorly on the upper and lower
lobes on each side of the fissure create optimal traction and counter-traction forces. Once opened, this
will generally create sufficient exposure of the primary artery trunk to identify its anteromedial side and
enable its dissection with completion of the rest of the major fissure. The anterior fissure is opened by
starting with an “outside-in” firing between the middle and lower lobe (or lingula and lower lobe) if this
connection is long and incomplete. This is important because it greatly increases parenchymal mobility
and simplifies the fissure completion. Once done, a medial “landing zone” is created by opening the
pleura at the anterior hilar termination of the fissure and directing the same vascular clamp from the
avascular plane investing the pulmonary artery at its anteromedial border and exiting at the landing zone.
On the right side, care needs to be taken so that a distal origin of the middle lobe bronchus coursing back
up through the fissure is not inadvertently divided by this maneuver. Once the artery is exposed, it is
inspected for common variants that might require special care. Abnormal distal or shared arterial origins
on the right (ascending posterior or middle lobe) or left (lingula) may require individual ligation of the
basal and superior segmental branches. Once the artery and veins are divided, the bronchus is sectioned
with a surgical stapler for thick tissue (staple length of 4.0 mm or greater). Placing the bronchus on caudal
traction will allow application of the stapler, with care taken not to incorporate the upper or middle lobe
segmental bronchi (Video 34.4).
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Video 34.4 Thoracoscopic right lower lobectomy.
COMMON TECHNICAL VARIATIONS FOR LOWER LOBECTOMIES

The vantage point for a lower lobectomy can generally remain in the traditional posteroinferior VATS
port. If the lobe contains a large tumor that blocks the view of the artery or bronchus, the medial port can
be used for exposure. A popular approach for the lower lobe is a fissure last technique in which the vein
is taken as described above. Then the lung remains retracted superiorly to expose the airway beyond the
middle lobe or lingular bronchus. Dissection close to the airway will allow its division without injury to
the artery that lies cephalad as the next structure encountered. Upward retraction on the specimen side of
the divided bronchus improves exposure to the artery for its safe division. Until the surgeon becomes
familiar with viewing the artery from this approach, care is needed to avoid bleeding or occlusion of
branches destined for the upper lobes. Once divided, only the fissure remains, which is taken with
medium thickness (3.5-mm) stapler loads. Again, grasping the specimen side of the divided bronchus
helps guide the stapler into the correct path.
LEFT UPPER LOBECTOMY

Just as in open surgery, this resection can be the most challenging because of more variable arterial
branches and a shorter left main pulmonary artery anatomy (that can make it more difficult to control
vascular injuries). Similar to right upper lobectomy, the approach begins with mobilization of the pleura
along the anterior hilum with viewing from anteromedial port and retraction of the lobe from the
posteroinferior port. Dissection continues along the superior pulmonary vein and the anterior trunk of the
pulmonary artery. The superior pulmonary vein is mobilized and transected, with prior confirmation that
there is not a common trunk of the vein. Attention is then turned to dividing the apical pulmonary artery
branches seen entering the left upper lobe. Grasping the specimen side of the divided vein and retracting
it away from the mediastinum improves exposure of the artery branch when using an anterior vantage
point. Similarly, removal of lymphatic tissue or division of the bronchus (fissure last technique, below)
also helps in this regard. It is often easier to come back to this portion of the dissection later, once other
portions of the dissection are carried out yielding better arterial mobility. The next step is identification of
the pulmonary artery in the major fissure, with subsequent completion of the posterior and anterior
fissures as described in the lower lobectomy dissection above and the section below. With the pulmonary
artery exposed, the remaining branches to the left upper lobe including the lingular branch, posterior
segmental and apicoanterior branches (if not divided earlier) are thus divided. The left upper lobe
bronchus is thus exposed and can be subsequently divided with a thick stapler load (Video 34.5).
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Video 34.5 Thoracoscopic left upper lobectomy.
COMMON TECHNICAL VARIATIONS FOR LEFT UPPER LOBECTOMY
Because of numerous left upper lobe arterial branches and the natural obstruction to their exposure from
an anterior vantage point (because of the interceding bronchus), there have been two natural responses.
One is a posterior vantage point to improve visualization (ala Walker) because there is no intervening
structure. Instruments can still be passed from the wider, anterior interspaces to accomplish the resection.
Another popular method is a fissure last technique by which the intervening bronchus is divided with a
thick load stapler, and the distal end retracted away from the mediastinum after transection of the vein. If
choosing to take the bronchus prior to the pulmonary artery branches, care must be taken in passing a
clamp to mobilize the bronchus, as the artery is in the immediate vicinity. Thereafter, the apicoanterior,
posterior, and lingular arterial branches are divided, followed by completion of the fissure. Again, this
order may vary depending on the variability of exposed anatomy and placing a grasper on the cut
bronchus helps align the stapler for the final firings across the fissure. Until the surgeon is comfortable
with the anatomic structures viewed from a vantage point different from their open training, care is
needed to avoid dividing branches such as the superior segmental artery or narrowing or dividing major
airway structures.
APPROACH TO FISSURE DISSECTION

Some VATS surgeons expose the pulmonary artery by dissecting in the fissural parenchyma, with the
branches revealed as the fissures are divided. With this technique, report of air leaks can be moderate.
Others use the fissure last technique, after division of the bronchovascular structures, also allowing for
staplers to be used to divide the parenchyma. An alternate “fissureless” technique is to create a tunnel
(similar to that described in the prior lower lobectomy section) between the pulmonary artery and the lung
fissure, which is subsequently divided with staplers. This then allows for division of the subsequent
bronchovascular structures to complete the anatomical resection.52
If the pulmonary artery is not accessible within the fissure, optional strategies include: (1) reflecting
the lung anteriorly and dividing the pleural reflection on the posterior aspect of the hilum in order to
identify the pulmonary artery (left) or identify the take-off of the bronchus intermedius to allow for
creating a tunnel for division of the posterior aspect of the oblique fissure (right), or (2) employ the
fissure last technique. In this approach from the posterior pleural reflection, the artery, bronchus, and vein
are identified and serially divided first. This is rather straightforward for lower lobectomies, as these
structures are usually accessible after division of the pulmonary ligament.41 Although fissure last
technique may be one way to approach a lower lobectomy, this may cause some difficulty in defining the
complex anatomy associated with larger tumors.
SPECIMEN REMOVAL
Although rare, the risk of tumor seeding along a port site can occur (Fig. 34.9). Removal of the specimen
is performed using an endoscopic tissue retrieval system (Anchor Products Company, Addison, IL) to
prevent contamination from the tumor, with a narrow or more compressible portion of the lobe brought out
first to lead the remainder of the specimen. The remaining lung is then submerged and reinflated to assess
for air leak, both from the bronchial stump and parenchyma. With any parenchymal damage, some
surgeons choose to employ a pleural sealant such as Progel (Davol, Bard Inc., Warwick, RI) to temper a
potentially prolonged air leak. Otherwise a 2-0 chromic figure-of-eight suture may also provide both
hemo- and pneumostasis. A single 28F chest tube is left in the chest for postoperative drainage. Smaller
tubes (down to 18F) may be appropriate to reduce discomfort in patients with low risk of bleeding or air
leak.
FIGURE 34.9 A 67-year-old male who underwent thoracoscopic left upper lobectomy for sarcomatoid carcinoma, with
subsequent recurrence identified along previous port site on surveillance imaging 13 months later. A: Initial malignancy,
preresection. B: Port site recurrence. (Image courtesy of Elisabeth U. Dexter, MD.)
When encountered with challenges in specimen removal, the specimen can be oriented in the bag such
that the lung is streamlined and the tumor is dependent. The surgeon should apply gentle circular traction.
Adequate division of the intercostal muscle within the access incision should be verified, and if
necessary, the skin incision can be enlarged. As a last resort, consider dividing the rib anteriorly to
prevent fracture. For cases where rib fracture or division occurs, internal fixation of the rib may be
created with an absorbable plate (BioBridge, Acute Innovations, Hillsboro, OR). To avoid rib trauma,
some surgeons have used a separate extraction incision that is subxiphoid or subcostal.53,54
LYMPH NODE DISSECTION

Initial removal of lymph nodes prior to lung resection (level 10 on the right, or levels 5 and 6 on the left)
can facilitate safety of vessel mobilization. In cases where the potential for occult N2 metastases seems
likely and mediastinoscopy, EBUS, or other surgical staging method was not feasible or was performed
before induction therapy, nodal dissection before parenchymal resection gives the surgeon the option to
abort the planned lobectomy for neoadjuvant or definitive chemoradiotherapies. Once the lobe is
removed, a paratracheal and subcarinal lymph node dissection should be undertaken for upper
lobectomies, with additional level 7 and 9 lymph node dissection for lower lobectomies. To approach the
level 4 lymph nodes on the right, dissection begins with elevating and incising the pleura, superior to the
azygos vein. A ring forceps can be used to lift the pleura and the paratracheal nodes, with further
dissection performed along the superior vena cava and trachea. The subcarinal region is exposed by
retracting the lung anteriorly. The pleura is incised superiorly toward the bronchus intermedius, taking
care to prevent injury to the esophagus and vagus nerve. On the left, the pleura is opened along the
superior margin of the superior pulmonary vein with the nodes lifted to mobilize the tissue from the
pulmonary artery. Care is taken to protect the recurrent laryngeal nerve that may be visualized in the
aortopulmonary window. A complete review of the rationale and methodology for open and VATS lymph
node dissection is reviewed in Chapter 96.
Ongoing research continues with regard to the oncologic effectiveness of VATS lobectomy, particularly
in the adequate evaluation of mediastinal lymph nodes.55 In comparing whether VATS could achieve
equivalent lymph node evaluation to thoracotomy, a recent meta-analysis concluded that although the same
number of lymph node stations could be evaluated with both techniques, fewer total and mediastinal
lymph nodes were harvested by VATS.56 However, this did not translate into inferior survival outcomes
with VATS as compared with thoracotomy. This is consistent with the results of the investigation
performed by the American College of Surgeons Oncology Group (ACOSOG) Z0030 randomized clinical
trial from 1999 to 2004, comparing systematic mediastinal lymph node sampling versus mediastinal
lymph node dissection in N0–N1 NSCLC. The results showed no difference in overall survival, disease-
free survival, and recurrence ratio between the two groups. A subanalysis of this study showed no
statistical difference in the overall number of retrieved lymph nodes.57 Another explanation for the
differences in lymph node recovery between VATS and open operations in large databases may be
differences in case selection, difficult to quantify in such registries. This is because larger, central tumors
prone to more lymph node enlargement and regional dissection are less likely to have had VATS
approaches as per selection criteria listed at the beginning of this chapter.
INTRAOPERATIVE COMPLICATIONS
One known potential major complication during VATS is bleeding from a pulmonary vessel, as access for
control is limited. With anticipated difficult cases or those where the dissection by a large arterial branch
is tedious, it may be necessary to encircle the main pulmonary artery to achieve rapid proximal control. A
thick silicone vascular sling is preferred rather than the heavy silk introduced by Watanabe et al.58
Needless to say, a preoperative plan should be in place for conversion in any case. It is always prudent to
have a sponge stick available, and hemorrhage can be temporarily controlled with application of gentle
pressure through the access incision, to allow for decision whether thoracotomy is deemed necessary.
Most bleeding from minor vascular injuries will cease. Under adequate control, the situation can be
readily assessed, with a repair then performed thoracoscopically. Proximal control should be obtained,
and an attempt to clamp the pulmonary artery at the site of injury is not recommended as it may extend the
injury. Other options to gain access include approaching the pulmonary artery from a different angle,
whether from within the fissure or with opening of the pericardium. Another helpful trick is to exchange
the sponge stick with a low-profile retractor to allow holding lung parenchyma against the injury for
tamponade. This moves the compression to a different port site and frees the utility incision for
unencumbered extension to thoracotomy. Finally, there are several advanced hemostatic patches (e.g.,
Tachosil™ or Evarrest™) that are now available that can seal 5- to 6-mm artery injuries temporarily to
allow more time for planning definitive management.
Other complications include damage to adjacent lung tissue, subsequently requiring prolonged air leak
management. Keen intraoperative observation and care must be taken to prevent any damage to the
proximal airway, esophagus, and recurrent laryngeal nerve, given their attendant subsequent difficulties
for postoperative recovery.
ROUTINE POSTOPERATIVE CARE

The postoperative VATS patient typically does not need an intensive care unit. Our institution employs an
intermediate care unit, aligned with achieving consistent goals for the postoperative care of the thoracic
surgery patient.59 The literature varies with regard to management of the chest tube60; however, our group
chooses to initially place the 28F chest tube to −10 cm H2O suction. With no active air leak and
reasonable drainage (suggested as less than 400 mL over 24 hours), the chest tube is placed on water seal
and removed. So far, our experience with digital chest drain technology is favorable in that it provides
objective trending evidence that air leaks are not occurring during hours where staff are not at the bedside
monitoring the leak.36 Unless clinically indicated, chest x-ray after chest tube removal is avoided.61,62
Initial postoperative pain is controlled with patient-controlled analgesia of intravenous narcotic, as well
as intravenous acetaminophen and intrapleural ropivacaine as described previously. This is transitioned
to an oral pain medication regimen once the chest tube is removed, usually the following day.
With some exceptions, such as after a transcervical extended mediastinal lymphadenectomy (TEMLA),
advanced age (>75 years), previous history of head and neck surgery or radiation, or in patients noted
with hoarseness and suspected recurrent laryngeal nerve injury, patients are initiated on a clear liquid diet
and are advanced as tolerated. Routinely provide speech pathology swallowing consultation and
fiberoptic vocal cord screening for those high-risk factors just mentioned. Both ambulation and incentive
spirometer are aggressively encouraged immediately postoperatively. Routine laboratory blood work or
chest x-rays after postoperative day 1 are unnecessary, unless clinically indicated.
POSTOPERATIVE OUTCOMES
After a review of quality of life (QOL) measures following VATS lobectomy, our meta-analyses showed
that QOL is improved compared with open surgery as demonstrated by better scores on standardized QOL
instruments, improved physical activity after surgery, and an earlier return to work.63 In addition, frail
patients with poor baseline lung function and additional comorbidities can more likely tolerate VATS, thus
able to undergo curative pulmonary resection.64 One of the largest VATS series has reported morbidity
and mortality rates of 15% and 0.8%, respectively, with the most common complications to be atrial
fibrillation and prolonged air leak.48
VATS PNEUMONECTOMY
The incorporation of minimally invasive approaches for removal of the entire lung has been
understandably slower than that for lesser pulmonary resections. Unique challenges that have contributed
to a slower adoption of these techniques include the concern for loss of vascular control at the level of the
main pulmonary arteries, potential for difficult hilar dissection often associated with these tumors, and
difficulty with large specimen extraction through small VATS incisions.
FIGURE 34.10 A red rubber catheter is positioned in between two structures and used as a guide to safely bring a stapler
across the artery. In facilitating passage of the stapler, care must be taken after passage of the red rubber catheter to dissect off
any additional peribronchial or adventitial tissue that may limit stapler passage. (Image courtesy of Todd L. Demmy, MD.)
Despite these hurdles, reports from select centers have demonstrated both feasibility and safety for
VATS pneumonectomy.65–73 Due to a lack of large series, existing evidence may not clearly define
advantages for thoracoscopic pneumonectomy, but some advantages realized for VATS lobectomy would
be expected to translate to resections performed for more complex tumor pathology if open oncologic
principles are maintained.3,48,74,75 As surgeon experience, instrumentation, and video imaging technology
continue to evolve, previous exclusion criteria for a VATS approach to more complex resections are
being challenged, including that of whole lung removal.
PREOPERATIVE PREPARATION
Preoperative evaluation for thoracoscopic pneumonectomy is no different than that performed for open
pneumonectomy. Standard cardiopulmonary evaluation, including pulmonary function testing,
echocardiography, split lung perfusion testing, and when indicated, cardiopulmonary exercise testing, is
performed to ensure adequate cardiopulmonary reserve to tolerate pneumonectomy.
CONSIDERATIONS FOR VATS PNEUMONECTOMY

Surgical staging of the mediastinum is performed at the same operative setting as the planned lung
resection, and can be helpful in making the hilar dissection safer and easier. During video
mediastinoscopy or TEMLA, dissection can be carried onto the mainstem bronchus. This safely initiates
the separation of the pulmonary artery from the bronchus, and facilitates an easier and potentially safer
dissection of the main pulmonary artery from the bronchus within the chest. Dissection and isolation of
both pulmonary veins, before dividing either one of them, helps minimize the pulmonary congestion that
can occur as time is taken to isolate the pulmonary artery. Carrying out vein isolation within the
pericardial cavity is often necessary and helpful.
When dissecting the main pulmonary artery from the mainstem bronchus, care must be taken to dissect
toward the bronchus with blunt dissection. When this is achieved, a red rubber catheter can be placed in
between the two structures and used as a guide to safely bring a stapler across the artery (Fig. 34.10). In
facilitating passage of the stapler, care must be taken after passage of the red rubber catheter to dissect off
any additional peribronchial or adventitial tissue that may impede stapler passage. Prior to firing the
stapler, it is closed and the patient is monitored for any hemodynamic instability that may suggest
compromise of the main pulmonary artery.
Manipulating the specimen when dissecting the bronchus is aided with the use of a 5-mm laparoscopic
flexible liver retractor (Diamond-Flex, CareFusion, San Diego, CA). It allows for single, low-profile
instrument upward traction of the bulky parenchyma for safe and thorough dissection of the mainstem
bronchus, keeping the lung, and potentially large tumors out of the way (Fig. 34.11). Coverage for the
bronchial stump is routinely performed to minimize the dreaded complication of bronchopleural fistula.
This can be achieved by various methods, including a rotational pleural flap, thymic or pericardial fat
pads, intercostal muscle flaps, as well as the azygos vein on the right.
As with open right pneumonectomy, risk for postoperative respiratory failure is significant, but from a
purely technical standpoint resection can be less challenging due to easier exposure of the right main
pulmonary artery and proximal right mainstem bronchus. In contrast to right pneumonectomy, the risk for
postoperative respiratory failure with left pneumonectomy is less, though the technical demands for the
dissection can be more challenging. The shorter length of the left main pulmonary artery may require an
intrapericardial dissection to gain proximal control safely. The pulmonary veins are both isolated and
divided first, before attention is turned toward dissecting the left main pulmonary artery off the mainstem
bronchus (Video 34.6).
Browser issues
Video 34.6 Thoracoscopic left pneumonectomy.
FIGURE 34.11 Manipulating the specimen when dissecting the bronchus is aided with the use of a 5-mm laparoscopic flexible
liver retractor (Diamond-Flex, CareFusion, San Diego, CA). (Image courtesy of Todd L. Demmy, MD.)
RESULTS
Results from the authors single institution series have demonstrated that VATS pneumonectomy is both
safe and feasible when performed at experienced centers. Results from this series of 107
pneumonectomies, 67 of which were performed by VATS, showed that despite higher preoperative
comorbidities and similar pathologic staging, there was significant improvement in pain at 1 year for
patients undergoing VATS pneumonectomy as compared to those approached with thoracotomy. Improved
median survival was noted for patients with stage III–IV disease, warranting further study and/or
refinement to these approaches.49
SUMMARY
VATS pulmonary resection has developed into a safe and effective treatment for lung cancer. In patients
with early-stage lung cancer who can tolerate anatomic lung resection, lobectomy remains the standard of
care, as it is associated with lower rate of local recurrence and higher overall survival compared with
wedge resection. This premise may change over time, pending the results of the ongoing Alliance
(CALGB) 140503 randomized trial comparing lobar versus sublobar resection.76 With the increasing use
of CT scans for lung cancer screening in the high-risk population, the indication for both diagnostic and
therapeutic minimally invasive VATS will continue to be widespread. Surgical resection remains critical
in the cure of early-stage lung cancer. With VATS techniques, major pulmonary resections can be
performed with comparable long-term survival as thoracotomy, with improved morbidity and additional
benefit such as better pain control and subsequent recovery. As is expected with further advances in
technology, the debate now shifts from comparisons of VATS and open to VATS versus robotic-assisted
lobectomy, with similar considerations regarding safety, cost, and oncologic efficacy.
ACKNOWLEDGMENTS
Special acknowledgments to Thomas A. D’Amico, Raja M. Flores, Diego Gonzalez-Rivas, Robert J.
McKenna, Scott J. Swanson, and William S. Walker for their chapter contributions.
NOTE FROM THE AUTHOR

Additional full-length and high-definition videos for anatomic lung resection can be viewed at the Annals
of Cardiothoracic Surgery website, “Masters of Cardiothoracic Surgery: Video-atlas of thoracoscopic
formal lung resections emulating traditional open techniques,”
84
http://www.annalscts.com/article/view/483/579 or at The Cardiothoracic Surgery Network (CTSNet)
website, “Video Atlas of Thorascopic Lobectomy,”
http://www.ctsnet.org/sections/videosection/videos/2013_video-atlas-thorascopic-lobectomy.14
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35
Uniportal VATS Lobectomy
Diego Gonzalez-Rivas ■ Alan D. L. Sihoe
INTRODUCTION
If conventional video-assisted thoracic surgery (VATS) has advantages over open thoracotomy because it
reduces surgical access trauma,1,2 then by the same logic further advantages may be gained by further
reduction of such trauma. Uniportal VATS aims to achieve this by reducing the number of access incisions
needed in VATS and limiting any trauma to a single intercostal space.3,4
Whereas the uniportal VATS approach can readily be used for any thoracic procedure—ranging from
minor wedge resections to complex reconstructive surgery—its most common and proven usage is
currently for anatomical lobectomy.3,4 This chapter aims to describe the basic technique of uniportal
VATS lobectomy, summarize the current evidence for its use, and outline possible future directions for this
approach.
Please note that many authors also use the term “single port VATS.” The authors regard this as referring
to the same approach as uniportal VATS and use these terms interchangeably in this chapter.
THE BASIC TECHNIQUE OF UNIPORTAL VATS LOBECTOMY
PREPARATION
The criteria for selecting patients for uniportal VATS lobectomy are the same as those for conventional
multiportal VATS.1–3 Although the authors believe that there are no absolute patient-related
contraindications specific to uniportal VATS lobectomy, the individual surgeon must ultimately decide
whether he/she can safely and comfortably perform each operation. In general, the beginner may wish to
select “easier” operations during the early learning curve. These would include cases that feature smaller
tumors with no local invasion; evidence of complete fissures on CT scan; lack of fibrosis or calcified
lymph nodes on CT scan; patients with thinner chest walls and wider intercostal spaces; and no previous
ipsilateral thoracic disease or interventions.3,4
General anesthesia with one-lung ventilation is used. The use of preemptive regional blockade—such
as with paravertebral bolus injection of a long-acting local anesthetic—provides very effective
suppression of pain through the postoperative period and is recommended.5,6 In conjunction with the
uniportal approach, this allows most patients to experience virtual absence of significant pain after
surgery. More recently, the non-intubated technique for anesthesia has been described and can be used in
conjunction with uniportal VATS.7,8 Early experience suggests that this technique may promote faster
immediate postoperative recovery, although further evidence is required to better define its safety and
advantages outside of the few centers currently specializing in it.9
In the operating room, the patient is positioned identically as for conventional VATS (Fig. 35.1). A full
lateral position is used, with the operating table flexed to gently open the rib spaces on the operating side.
The issue of the patient’s hip possibly hindering camera movement does not exist in uniportal VATS.1–4
Because the single port is sited relatively anteriorly, it is more ergonomic for the surgeon to stand in
front of the laterally turned patient. The primary video monitor is placed opposite to the surgeon (i.e.,
behind the patient). The key is to ensure that the “axis” of the operation—from the video-camera, through
the wound, to the monitor—is kept in a straight line.3,4 When performing an upper lobectomy, the surgeon
typically works in a more cephalad-to-caudal direction, and the monitor is best placed more toward the
cephalad end of the patient. When performing a lower lobectomy, the surgeon works slightly more toward
the feet, and the monitor may be better placed slightly more toward the “feet” end. The camera-holding
assistant stands on the same side as the surgeon and needs to wield the video-camera along the axis. For
most lobectomies, the assistant stands toward the “feet” side and slightly behind the surgeon, but for a
lower lobectomy it may be more convenient for the assistant to stand toward the cephalad side. Some
surgeons may find it more comfortable for the assistant to stand on the opposite side of the operating table
and to have the monitor placed at the head of the table in the “anesthetist’s position.”10 This has the
advantage of minimizing “fighting” between the surgeon and the assistant. The disadvantage is that for
lower lobectomies, the surgeon may sometimes be still looking up toward the monitor at the cephalad end
but working toward the caudal end. Also, the control of the camera is less easy with occasional
paradoxical movement, so this positioning strategy may call for a slightly more experienced assistant.
In the early learning curve, all instruments that a surgeon previously used for lobectomy via
conventional VATS (or even open surgery) can still be used for uniportal VATS.3,4 Using familiar
instrument and techniques shortens the learning curve, reduces the intimidation posed by the new
technique, and allows the surgeon to fall back on tried-and-trusted methods of troubleshooting should
difficulties be encountered. Dedicated instruments for uniportal VATS allow the procedure to be done
more comfortably and easily. However, with the great variety of dedicated uniportal equipment currently
commercially available, surgeons should perhaps first try the approach using familiar instruments and
better understand their own preferences in uniportal surgery before buying those dedicated instruments
most appropriate for those preferences.
FIGURE 35.1 Positioning for uniportal VATS lobectomy. A: The patient is placed as for a conventional three-port VATS
procedure: full lateral position with the operating table flexed. The level of flexion should correspond to the site of the uniport to
allow maximum natural widening of the intercostal space at that point (blue lines). The flexion should be enough to allow the
shoulder and hip to fall on a horizontal line (red line). In females with wide hips, it is especially important to achieve this
horizontal line because otherwise the hip can interfere with camera and instrument movement. Notice that the upper arm is
positioned so that the elbow is more cephalad than the shoulder, so that it will not interfere with the surgeon’s movements. The
lower arm is flexed at the elbow and not left extended out beyond the edge of the operating table where it can interfere with the
surgeon and assistant’s positioning. B: The basic positioning of staff and monitors allows for a straight “axis” of surgery from the
camera (assistant), through the wound, to the primary video monitor. The surgeon works along this axis and his/her hands
approach the wound on either side of the axis. This ensures that the visual and motor axes for the surgeon are the same,
facilitating hand–eye coordination and reducing “fencing” between the camera and the instruments. When the surgeon and
assistant are all looking along the same axis, it is also less likely that the assistant cannot follow the operation or encounters
“mirroring” and other visual problems. (From Sihoe AD. Uniportal video-assisted thoracic (VATS) lobectomy. Ann
Cardiothorac Surg 2016;5(2):133–144. Copyright © Beth Croce. With permission.)
FIGURE 35.2 The importance of correctly siting the uniport.

Correct (left): The uniport in the fifth intercostal space allows approaching the hilar structures at a slight angle (red arrow),
facilitating passage of the stapler in a caudal to cephalad direction across the hilar vessels (see text). At the same time, the
left- and right-hand instruments can approach the hilum via the wound across a relatively wide, comfortable arc (purple
triangle).
Too high (middle): If the uniport is too high, the axis of operation is directly into the hilum (red arrow). Although dissecting is
not a problem, the lack of an angle means that the stapler cannot easily negotiate around the hilar vessels and instead impinges
directly onto the hilar structures behind.
Too low (right): If the uniport is too low, the axis provides a nice angle of approach for the stapler onto the hilar vessels.
However, the wound is far away from the hilum, and the arc through which instruments can be inserted via the uniport to
reach the hilum becomes greatly narrowed. Bimanual instrumentation to dissect the hilum becomes extremely tricky, and there
can be considerable “fencing” of instruments. (From Sihoe AD. Uniportal video-assisted thoracic (VATS) lobectomy. Ann
Cardiothorac Surg 2016;5(2):133–144. Copyright © Beth Croce. With permission.)
Before embarking on uniportal surgery, it is prudent to establish criteria for conversion. It is easy to
become so focused on the technique during a difficult case that one does not realize that more harm than
good is being done. The whole team should decide beforehand how much time should be spent on any part
of the operation (e.g., vein/artery dissection, adhesiolysis) or how much blood loss is allowed before
conversion is mandatory. When those limits are reached there should be no hesitation to convert.
BASIC PRINCIPLES
The rule of thumb is that for any lobectomy the uniport is best sited between the mid- and anterior axillary
lines in the fifth intercostal space (Fig. 35.2). This slightly anterior position takes advantage of the
naturally wider intercostal spaces at the front of the human body.3,4,11 If the wound is sited too high—in
the fourth space for an upper lobectomy—the dissection of the hilar vessels may be easier, but the
instruments enter directly toward the hilum so that there is a smaller angle for the stapler to pass without
impinging on the structures behind. If the wound is too low, there may be a good angle for the stapler to
pass, but the distance to the hilum becomes too great and the arc in which instruments can be placed
toward the hilum becomes too narrow—leading to more chance of “fencing” between the instruments and
camera.
It should be noted, though, that even amongst experienced practitioners of uniportal VATS lobectomy,
there can be slight variations in the siting of the uniport. Some would prefer a slightly more posterior
location near the mid-axillary line, allowing a posterior-to-anterior hilar dissection. With increasing
experience, the authors also occasionally tried a fourth space incision for upper lobes and a sixth space
incision for middle and lower lobes. Nevertheless, the above rule of thumb is generally preferable for the
majority of patients and is certainly the recommended option for beginners.
The incision itself is typically 3 to 4 cm long, although longer incisions can be used (e.g., for an
inexperienced surgeon, large tumor, thicker chest wall, etc.) without any obvious disadvantage to the
patient.3,11 For larger tumors, the limiting step preventing specimen retrieval is often the narrowness of the
intercostal space, not the length of the skin incision (which is slightly elastic). A simple technique of
cutting a rib anteriorly allows the intercostal space to open up without forceful rib spreading for large
specimen retrieval.12 The cut rib can be re-approximated using a simple figure-of-8 suture.
In handling the lung, ring forceps are used to grasp the lung, taking care not to use excessive force
which can tear the lung.3,11 The latter may lead to troublesome intraoperative oozing and postoperative air
leak. It is best to retract only on the lobe to be resected and not on the remaining lung. It is also possible
to use the sucker or a sponge stick to help retract the lung away: these are less traumatic but give less
directional control of the retraction.
When the surgeon stands in front of the patient, the single port appears as virtually a vertical keyhole
slit (Fig. 35.3A). A 3-cm incision typically allows the placement of the video-thoracoscope, an instrument
held by the surgeon’s right hand, and another held by his/her left hand: one above another in a “traffic
light” configuration.4 The video-thoracoscope is kept in the uppermost “red light” position, and the
surgeon’s left- and right-hand instruments are inserted underneath in the “yellow” and “green light”
positions. This is the ideal configuration because a human’s eyes are always above his/her hands. With
the scope in the “red light” position, the view on the monitor will show the left- and right-hand
instruments entering the field of view lower in the picture—giving a natural hand–eye coordination for the
surgeon. Also, keeping the video-thoracoscope pressed gently against the upper (posterior) end of the
wound in the “red light” position allows the assistant to rest it against a stable point, reducing
“wandering” of the camera all over the place and creating a chaotic view. This configuration works well
for the majority of the time during a typical lobectomy. With experience, the surgeon may request the
assistant verbally to place the video-thoracoscope in the “yellow” or “green light” positions in certain
situations. For example, if a view of the left upper lobe (LUL) bronchus is needed under the lung, a “green
light” position for the camera may sometimes be helpful.
FIGURE 35.3 Communicating with the assistant regarding controlling the video-thoracoscope. Standing in front of the patient,
the surgeon and assistant’s view of the uniport before them resembles a vertical slit with just enough room for the video-
thoracoscope and two instruments to be inserted, one above the other. In this “traffic light” configuration, the video-thoracoscope
should be kept at the top “red light” position, and the left- and right-hand instruments are inserted at the “yellow light” and “green
light” positions. This view keeps the visualization above the level of the instruments on the monitor, just like humans have eyes
above the level of the hands. Occasionally, the scope may be relocated to the “yellow” or “green light” positions for specific
views. Using this traffic light imagery, the surgeon can verbally communicate exactly where the assistant should be placing the
scope in the uniport. (From Sihoe AD. Uniportal video-assisted thoracic (VATS) lobectomy. Ann Cardiothorac Surg
2016;5(2):133–144. Copyright © Beth Croce. With permission.)
The assistant should always keep the view level, with the “buttons” on the camera head facing up
toward the ceiling (Fig. 35.3B). The surgeon can instruct the assistant to move the view in three ways.3,4
First, the scope can be moved “in” or “out” to achieve a closer or more panoramic view, respectively.
The assistant should physically move the scope in or out instead of relying on the “zoom” function on the
camera because adjusting the latter may affect the hand–eye coordination that the surgeon has become
accustomed to. Second, the camera can be moved to look “up,” “down,” “left,” or “right.” The assistant
should again be told that this means physically moving the camera instead of just rotating the 30-degree
lens because the latter may distort the visual perspective for the surgeon. Third, the assistant can be
instructed to manipulate the 30-degree lens as directed by the surgeon to look around structures. The
surgeon can direct the assistant using a clock face image for communication. When using a conventional
video-thoracoscope with a light cable attached to the scope from one side (Fig. 35.3B), a “12 o’clock”
view means to hold the light cable at the top side of the video-thoracoscope, so that the 30-degree view is
from the top looking downward. A “3 o’clock view” means to hold the light cable at the right side of the
video-thoracoscope, so that the 30-degree view is from the right looking leftward. In this way, the surgeon
can verbally guide the assistant to provide views all around a hilar structure.
OPERATIVE TECHNIQUE (RIGHT UPPER LOBECTOMY)

The following will describe step by step how a right upper lobe (RUL) anatomical resection can be
performed using a uniportal approach. This procedure is ideal to showcase the tips and tricks of doing a
uniportal lobectomy. Variations to perform resections of the other lobes are described separately below.
After preparing the patient as described above, the video-thoracoscope is first used to inspect the
thorax. Pleural adhesions are taken down. Contraindications to further surgery (e.g., unexpected
metastases) are excluded. If tissue diagnosis was not obtained prior to surgery, a biopsy of the primary
lesion may be taken if appropriate and sent for frozen section analysis.13
For upper lobes we have two options to start the dissection according to the distance located between
the RUL vein and truncus anterior. When the distance between both structures is longer enough, we can
follow option A: dissect and divide the vein first, and then the artery. However, when the distance is too
short, or the angle for stapler insertion is not optimal for the vein, the recommended strategy is option B:
dissect and divide the artery first and then the vein.
Option A: Divide Vein First, Then Artery
Pulmonary Vein
The lung is retracted laterally and posteriorly to expose the superior pulmonary vein (Fig. 35.4). The
mediastinal pleura over the vein is opened and the fascia over the vein is dissected to the subadventitial
layer using a combination of sharp and blunt instrumentation.3,4,11 Long Metzenbaum scissors for
spreading and a long curved sucker for blunt dissection may be used for this. It is essential at this stage to
identify and preserve the vein from the right middle lobe (RML) and only target the RUL vein.
The exposed pulmonary vein from the RUL is then looped by passing a curved forceps (such as a long
90-degree Rumel clamp) behind it. Repeatedly opening and closing the curved forceps gently behind the
vein helps to develop and open up that space for easy passage of the stapler. The curved forceps can be
used to bring a silk or elastic sling around the vein for gentle retraction.
A stapler with a roticulating head makes the stapling much easier. The thinner “anvil” jaw of the
stapler is inserted along the left (caudal side) of the RUL pulmonary vein. If the stapler is continued to be
inserted straight in, the anvil will impact on the structures behind (notably the pulmonary artery) and
stapling cannot be accomplished. Therefore, once the anvil is “engaged” at the left side of the vein, the
lung is retracted forward and in a cephalad direction. This movement opens up space behind the vein,
between it, and the artery behind it. At the same time, the stapler is also gently rotated clockwise so that
the reticulated head is not pointing straight into the hilum, but instead toward a more cephalad direction.
On the monitor, the head of the stapler is now seen to run almost horizontally parallel to the mediastinum
“floor,” and the stapler points from left to right across the screen (from caudal toward the cephalad). In
this direction, the stapler can be easily advanced left to right across the screen, with the anvil running
through the widened-up space behind the vein. When the tip of the stapler anvil emerges fully from behind
the vein, the stapler can be closed and fired.
In cases where the angle for stapler is not adequate for RUL vein, first divide the artery to facilitate the
rotation of the lobe and the insertion of the stapler for the vein.
Pulmonary Artery (Truncus)
With the original retraction of the RUL laterally and posteriorly, the pulmonary artery is seen running
almost horizontally across the monitor’s lower side from right to left behind where the vein once was
(Fig. 35.4). The RUL pulmonary artery truncus is seen running vertically (laterally) up from this to the
RUL.
The truncus is dissected using sharp and blunt dissection in the same manner as with the pulmonary
vein (Fig. 35.5). A curved forceps is again used to go around behind the artery truncus, and opening-and-
closing helps develop the space behind for passage of the stapler anvil.
A stapler with a roticulating head is opened inside the chest, and the thinner “anvil” jaw is inserted
along the left (“feet” side) of the RUL pulmonary artery truncus. Once the anvil is “engaged” at the left
side of the artery, the lung is retracted slightly forward and in a cephalad direction to open up space
behind the artery, between it, and the bronchus behind it. At the same time, the stapler is also gently
rotated slightly clockwise so that the reticulated head is not pointing straight into the hilum, but instead
toward a more cephalad direction to avoid impinging onto the bronchus behind. A relatively subtle
rotating action is usually sufficient for the anvil to avoid the bronchus behind and emerge. The stapler
should be fired steadily, avoiding rough, jerky movement which can tear or avulse the artery (which is
tightly gripped by the stapler during firing). Using a curved tip reload for the stapler again makes the
process easier, but may be more expensive.
Costs can be further cut by avoiding use of the stapler altogether.3,4,10 If the truncus is not too large, it
can be secured using polymer vascular ligating clips. The author prefers placing two clips proximally.
The distal end can be secured with another clip or simply sealed and divided using an energy device
(such as an ultrasonic dissection–division device). Another method would be to simply ligate the vessel
using ties (with knots secured digitally or with a knot pusher) and dividing the vessel between ligatures.
This is quite feasible with a uniportal approach.
Option B: Divide Artery First, Then the Vein

When the angle for the stapler to divide the RUL vein is difficult, the best strategy is to start dissecting
and dividing the truncus anterior first (the uniportal approach provides a direct view to dissect the artery)
(Fig. 35.6). Once the artery is divided, the soft tissue surrounding the interlobar artery should be removed
to facilitate the rotation of the lobe and the insertion of the stapler to transect the vein. It is always best to
insert the stapler with maximum angulation. In addition, the use of curved tip staplers is very helpful,
especially during the learning curve for upper lobe vein division.
Bronchus
Once the artery truncus is divided, the original retraction of the RUL laterally and posteriorly allows the
RUL bronchus to be seen clearly behind where the truncus once was (Fig. 35.5). With this retraction, the
RUL lobar bronchus rises vertically (laterally) up from the right main bronchus soon after it emerges from
under the azygous vein.
The landmark to look for is the black interlobar lymph node invariably found to the left (“feet” side)
border of the RUL bronchus, demarcating it from the bronchus intermedius (Fig. 35.5). This lymph node
can be grasped and removed (Fig. 35.7). This is occasionally a bit bloody as the node is prone to oozing,
but there should not be any major bleeding. Once the node is cleared, a curved forceps can be passed
along the left (“feet” side) border of the RUL bronchus, looping around behind it.
A stapler is inserted into the chest, and the thinner “anvil” jaw is inserted along the left (“feet” side) of
the RUL bronchus. Occasionally, emergence of the stapler anvil may be blocked by impingement against
the spine behind. If this occurs, the same trick of rotating both lungs forward and in a cephalad direction
is usually sufficient for the anvil to avoid the spine behind and emerge.3 The stapler should be fired only
after testing for inflation of the middle and lower lobes on closing the staple—even if it seems “obvious”
the correct RUL bronchus had been isolated—to avoid a potentially disastrous firing.
FIGURE 35.4 Dissection of the RUL pulmonary vein. A: The lung is retracted laterally, displaying the RUL pulmonary vein
running vertically down from the RUL on the monitor (with the mediastinum as the horizontal “floor”). Long Metzenbaum
scissors are used to open the pleura over the vein and dissect onto the subadventitial layer. The vein from the RML is clearly
seen on the left and is preserved. B: Blunt dissection using a long curved sucker or (in this case) a “peanut” pledget mounted on
a curved instrument allows gentle dissection around and behind the vein. C: A curved forceps is used to get around the back of
the vein. It is then used to open up the space behind by gentle opening and closing. It is finally used to grasp a silk thread to loop
around the vein, facilitating subsequent passage of the stapler. D: The stapler is inserted directly toward the vein, with the thinner
anvil engaging the left (feet) side of the vein. Notice that if the stapler were advanced further in this direction it would be forced
to stop as it impinges on all the hilar structures behind the vein. E: With the anvil engaged on the left of the vein, the lung is
retracted cephalad and forward. This widens up the space behind the vein. Simultaneously, the reticulated stapler is also rotated
clockwise. The head of the stapler is parallel to the horizontal “floor.” In this angulation, the anvil can be advanced in a left-to-
right (caudal to cephalad) direction, and it will emerge from behind the right side of the vein no longer impinging on anything. F:
After the vein is divided, using the original lateral retraction of the RUL, the pulmonary artery can now be seen clearly behind
where the vein once ran. (From Sihoe AD. Uniportal video-assisted thoracic (VATS) lobectomy. Ann Cardiothorac Surg
2016;5(2):133–144. Copyright © Beth Croce. With permission.)
FIGURE 35.5 Dissection of the RUL pulmonary artery truncus (Option A, after vein division). A: The lung is retracted laterally,
displaying the RUL pulmonary artery truncus running vertically up to the RUL on the monitor. Blunt dissection using a long
curved sucker allows further gentle dissection around and behind the artery. B: Energy devices can be used to dissect around the
truncus onto the subadventitial layer. C: curved thoracoscopic dissector is used to get around the back of the artery. It is then
used to open up the space behind by gentle opening and closing, facilitating subsequent passage of the stapler. D: The stapler is
inserted directly toward the artery, with the thinner anvil engaging the left (feet) side of the vessel. Notice that if the stapler were
advanced further in this direction it would be forced to stop as it impinges on the RUL bronchus behind the artery. E: With the
anvil engaged on the left of the artery, the lung is retracted slightly cephalad and forward. This widens up the space behind the
artery. Simultaneously, the reticulated stapler is also rotated clockwise very subtly. In this angulation, the anvil can be advanced in
an anterior-to-posterior and slight left-to-right (caudal to cephalad) direction, and it will emerge from behind the right side of the
artery no longer impinging on anything. F: After the artery is divided, using the original lateral retraction of the RUL, the RUL
bronchus can now be seen clearly behind where the artery once ran. Notice the black lymph node on the left (feet) side of the
RUL bronchus, which is a constant landmark indicating a safe point of entry for dissection of the bronchus. (From Sihoe AD.
Uniportal video-assisted thoracic (VATS) lobectomy. Ann Cardiothorac Surg 2016;5(2):133–144. Copyright © Beth Croce.
With permission.)
FIGURE 35.6 Dissection of pulmonary artery truncus (Option B, before vein division). A: The lung is retracted laterally,
displaying the RUL pulmonary artery truncus running vertically up to the RUL on the monitor. The direct view provides good
control to dissect the artery and then be divided by using an articulated stapler. B: Once the artery is transected, the insertion of
the stapler is facilitated to divide the RUL vein. The use of curved tip staplers improves this maneuver.
FIGURE 35.7 Dissection of the RUL bronchus. A: The lymph node on the left (feet) side of the RUL bronchus is dissected and
removed. B: Removal of that lymph node exposes the site where a dissector can be safely inserted to dissect around the RUL
bronchus in an anterior-to-posterior and slight left-to-right (caudal to cephalad) direction. C: The stapler is introduced in the same
anterior-to-posterior and slight left-to-right (caudal to cephalad) direction. At this point, this direction is virtually straight in from
the uniport, and roticulating staplers and curved tip reloads are usually unnecessary. Notice that the direction of introduction of
the stapler here is almost identical to that of the Roberts forceps in “B.” (From Sihoe AD. Uniportal video-assisted thoracic
(VATS) lobectomy. Ann Cardiothorac Surg 2016;5(2):133–144. Copyright © Beth Croce. With permission.)
FIGURE 35.8 Dissection of the RUL pulmonary artery ascending branch. A: After division of the RUL bronchus, further
“opening of the book” by continuing to retract the RUL laterally exposes the small RUL pulmonary artery ascending branch. This
is seen arising from the interlobar pulmonary artery up toward the RUL. Energy devices, dissector, or long Metzenbaum scissors
can be used to gently dissect around this vessel. B: Passage of a wide stapler across such a small vessel incurs a risk of avulsion
or tearing. Often using a polymer vascular ligating clip—with its finer introducer—may be more appropriate to secure the artery
branch. The use of a 45-degree thoracoscopic specific applier is helpful to place the clips. C: The ascending artery branch is
double-clipped proximally. It can then be divided distally using an energy device (in this case an ultrasonic dissector–divider) to
simultaneously seal and cut.
It is possible to avoid use of the stapler by cutting the bronchus and then suturing the proximal stump.
This is occasionally needed for lobectomies requiring bronchoplasty or sleeve resection.14–16
Pulmonary Artery (Posterior Ascending Branch)

Once the RUL bronchus is divided, the retraction of the RUL laterally and posteriorly often leads to better
exposure of any posterior ascending branch(es) of the pulmonary artery arising from the interlobar artery
and supplying the RUL (Fig. 35.8). With this retraction, the posterior ascending branch(es) appear as
suspended vertically up from the interlobar artery to enter the RUL.
The posterior ascending branch(es) are dissected in the same manner as with the pulmonary vein and
pulmonary artery truncus (Fig. 35.8). A curved forceps or right angle clamp is again used to go around
behind the branch(es), and opening-and-closing helps develop the space behind. It should be noted that
this dissection must be done gently. Without the support of the bronchus, excessive traction during
dissection can cause tearing and avulsion of these small branches yielding major bleeding.
The branch(es) can be divided with a stapler or between polymer vascular ligating clips.3,10 Besides a
cost-saving consideration, the use of these clips may be indicated since their applicators are often thinner
than a stapler, reducing the risk of vessels tearing/avulsion that rough passage of a standard stapler may
cause. The use of specific 45-degree thoracoscopic applier facilitates the insertion of the clips through
uniportal VATS (Fig. 35.8). Two clips are used proximally. The distal end can be secured with another
clip but it is better to simply seal and divide using an energy device to avoid interference with staplers
during fissureless procedures (such as an ultrasonic dissection–division device) (Fig. 35.8).
Fissure
The lobectomy is completed by now detaching the RUL from the right middle and/or lower lobes. Leaving
the fissure as the last item to be tackled during a lobectomy is known as the “fissureless” (or “fissure
last”) approach and has been reported to result in fewer air leak problems with conventional VATS.5,17,18
In some patients, the fissures between the lobes are nearly complete and can be simply developed
using an energy device (e.g., diathermy or an ultrasonic device). In others, the lobes may be fused by
incomplete or absent interlobar fissures or by dense post-inflammatory adhesions. In such cases, it is
preferable to staple-divide them (Fig. 35.9).3,17,18 The stapler is inserted via the uniport to engage the
fissure in an anterior-to-posterior direction. The lateral side of the stapler is checked to ensure it runs
along the fissure and does not stray excessively into one lobe or another. More importantly, the medial
side of the stapler must be checked to ensure that the stapling does not accidentally include major
structures (such as the middle lobe pulmonary vein or the interlobar pulmonary artery). If polymer
vascular clips had been used earlier in the operation, it is also necessary to ensure that none of these are
caught in the stapler jaws before firing, as they can totally disrupt or prevent the firing.
As a rule, the posterior ascending branch of the pulmonary artery to the RUL is very small and
individual ligation is recommended. However, in some cases, some surgeons choose not to separately
dissect and divide it. Instead, the posterior ascending branch is included in the staple line for the
completion of the fissure and stapled together with the fissure.3,4 If this is done, care should be taken after
firing to check whether there is any significant bleeding or oozing from the staple line.
Completion
The resected lobe should always be placed inside a specimen bag before being delivered out of the
uniport if malignancy has been confirmed or is suspected. If this is not done, there is the risk not only of
tumor seeding at the wound, but also of spillage of tumor content out into the whole pleural space as the
tumor is squeezed out of the small uniport. Dedicated specimen retrieval bags designed for use in
endoscopic surgery can be used, but are often expensive. Cheap, improvised alternatives include surgical
gloves, bags for intravenous fluids cut open on one side, or a sterilized plastic bag with a zip-lock
opening, used normally for sending samples to the labs.3–5,10 With the latter, the zip-lock ribbing actually
allows the mouth of the bag to open up spontaneously inside the chest (Fig. 35.10). A ring forceps is used
to hold one lip of the bag’s mouth, while another ring forceps grasps the resected lobe and feeds it into the
bag. The entire opening of the bag is then delivered out of the wound first, before the resected lobe is
pulled out of the incision as with conventional VATS—with the bottom of the bag still inside the chest to
catch any spillage.
As noted above, for large tumors, an anterior rib-cutting technique can be used to allow delivery of
even large specimens via a relatively small uniport.12
FIGURE 35.9 Completing the interlobar fissure using staple-division (in a “fissureless” strategy). A: The stapler is inserted from
the uniport to grasp along the fissure in an anterior-to-posterior direction. This view of the lateral side of the right lung shows the
stapler ideally sited right along the fissure between the RUL and RML without overtly veering into either lobe. B: It is important
to view the medial aspect of the staple line before firing. The lung is retracted toward the feet end and laterally. Here, it can be
seen that the stapler has not been placed across the important structures: the RML pulmonary vein and the interlobar pulmonary
artery. It is therefore safe to fire. C: After firing, the RUL and RML are separated and the staple lines on either side are intact.
The interlobar pulmonary artery is left fully intact, and the polymer vascular clips used on the posterior ascending artery branches
have been well avoided by the staple line. The remaining posterior fissure is similarly staple-divided to complete the lobectomy.
(From Sihoe AD. Uniportal video-assisted thoracic (VATS) lobectomy. Ann Cardiothorac Surg 2016;5(2):133–144. Copyright ©
Beth Croce. With permission.)
FIGURE 35.10 Delivery of the resected lobe. A: A simple surgical glove is inserted into the chest. A couple of ring forceps are
used to hold the mouth of the bag, while another is used to grasp the resected lobe and feed it into the bag. B: The mouth of the
bag is first delivered out of the wound. The resected lobe is then directly pulled out from within the bag. The intact base of the
bag prevents spillage of tumor contents into the pleural space as the lobe is squeezed through the small uniport.
FIGURE 35.11 Systematic lymph node dissection involving all ipsilateral mediastinal stations is routinely performed after
lobectomy for malignancy. The use of energy devices are especially helpful to maintain a clean operative field and remove the
package of lymph nodes en bloc. The curved long suction is inserted on the left hand and energy devices on the right hand in
order to accomplish a bimanual instrumentation and perform an advanced instrumentation (non-grasping technique). Gentle
grasping of the lymph nodes during the dissection will preserve the lymph node capsule intact for better pathologic analysis.
Dissection at two common stations are shown (A,B). The right paratracheal station (4R) is being dissected. The patient should
be placed in anti-Trendelenburg position to keep the lung away (no lung grasper is needed). The pleura below the azygous vein
must be opened and dissected, then remove the lymph nodes and fatty tissue in block by dissecting it away from the superior
vena cava, phrenic, and vagus nerve. The curve of the long sucker is used to retract the cava vein and expose the field (A). The
lower end of the lymph node “packet” had been partly dissected from a sub-azygous approach. The packet is now being pulled
up at the window above the azygous vein, and an energy device (in this case an ultrasonic dissector–divider) is used to dissect it
away from the mediastinum (B). The base of this dissection is the trachea, which can be seen. The lymph nodes then can be
finally exposed en bloc from remaining attachments by opening the pleura above and pulling them up (C,D). The subcarinal
station (7) is being dissected. Rotation of the operating table forward often is sufficient to expose this station. Placement of the
video-thoracoscope at the “red light” position and use of a 12 o’clock top-down viewing angle usually gives an excellent
visualization of the subcarinal station. The lymph node packet is grasped with one hand, and any energy device can be used to
dissect it and coagulate out of the subcarinal space. It is recommended to expose the left main bronchus (C). When dissecting
subcarinal station a sponge stick can be used by the assistant to retract the lung and improve exposure of station 7. This will
provide an excellent visualization and allow the surgeon to use both hands to remove the lymph nodes. Extra care must be taken
to retract away the esophagus and vagus nerve in order to avoid injury to it (D). For the aorto-pulmonary window and
prevascular space, exposure is also improved in anti-Trendelenburg position. Dissection should avoid injury to the recurrent
laryngeal nerve. The use of a long curved sucker very important in order to expose the deepest parts of lymph node stations
properly, specially important on levels 4L and 7L.
For all cases of malignancy, a systematic lymph node dissection is mandatory. On the right, stations
2R, 3a, 4R, 7, 8R, 9R, and 10R can be routinely dissected via the uniportal approach, and there is no
reason not to fully dissect stations 4R and 7 in almost all patients (Fig. 35.11).
The pleural space is then thoroughly lavaged with multiple instillations of warm, sterile water. Air
leak testing is conducted by reinflating the remaining right lung under water, and intraoperative
procedures to control detected leaks are used at the surgeon’s discretion. Spraying of aerosolized
flowable hemostats can be used liberally for parenchymal air leaks.3 The prolonged chest drainage
associated with air leaks may negate much of the faster recovery expected with the uniportal approach,5,6
making good aerostasis particularly important for uniportal surgeons.
A 20 to 24 Fr chest tube is inserted directly through the uniport and anchored (Fig. 35.12). It does not
matter whether the tube is placed at the anterior or posterior end of the uniport. The wound is then closed
in layers around the chest tube in the same manner as for the utility incision in conventional VATS.
Meticulous closure avoiding gaps between the layers is important to prevent subcutaneous emphysema,
which can develop as intrathoracic air sometimes escapes out along the chest tube tract.3,4 The outermost
skin layer must not be closed too tightly around the chest tube, as this may cause skin necrosis at the site
of the chest tube and result in a gaping or even infected wound after the chest tube is pulled out.
FIGURE 35.12 Chest drain placement and wound closure. A: A chest tube (in this case a cheap, home-made tube equivalent to
24 Fr in size) is placed at one end of the uniport and anchored with a silk suture. Notice that a long full-thickness silk suture (long
black thread) has been placed already across the position of the chest tube: this is used to close the wound at the time of chest
tube removal. The rest of the uniport wound is closed in layers. B: The cosmetic result at the end of the lobectomy is quite
satisfactory. The wound itself is in any case quite small. The deep layers of the wound should be meticulously and securely
sutured. However, the outermost skin closure should not be made too tight around the chest tube. This is to minimize the risk of
skin necrosis around the chest tube which can lead to further wound complications. (From Sihoe AD. Uniportal video-assisted
thoracic (VATS) lobectomy. Ann Cardiothorac Surg 2016;5(2):133–144. Copyright © Beth Croce. With permission.)
POSTOPERATIVE CARE
Uniportal VATS can only achieve its full potential in expediting patient recovery if it is complemented by
specifically designed postoperative clinical pathways.19 This should incorporate all aspects of
perioperative management, including chest drainage; analgesia; mobilization; physiotherapy;
investigations; communications with patient and family; and so on. Using such a pathway, lengths of stay
and complication rates amongst higher risk patients may be significantly reduced.19
If a pre-incisional paravertebral blockade with bupivacaine bolus injection was not given, intercostal
blockade with a local anesthetic may be given at the time of wound closure.3–5,19 Postoperatively, patients
receive regular oral analgesia—such as paracetamol (acetaminophen) 1 g 6 hourly, supplemented by oral
tramadol 50 mg 4 to 6 hourly only as required for breakthrough pain. The avoidance of parenteral opiates
is recommended. With uniportal VATS plus a regional block as above, parenteral opiates are almost
always unnecessary. Eschewing their use allows faster patient recovery to full diet and mobilization
within a few hours after surgery.6,19
The authors prefer to routinely connect the chest drain to a digital chest drainage system as this
complements the advantages potentially gained by the uniportal approach.20 A negative pressure of 15 cm
H2O is applied initially to allow full re-expansion of the lung. This full re-expansion ensures that there is
no problem of retained fluid collection inside the chest even with only one chest tube placed. The
negative pressure with digital system is then reduced to 8 cm H2O on the morning after surgery, which
approximates free drainage without suction on a conventional water seal drainage system. The authors
believe this may help to quickly cease any small air leak that may be present.19,20 The chest drain is
removed when the air flow measured on the digital system is less than 40 mL/min for 6 hours with no
“spikes” of air leak during that time. If a digital system is not available and a conventional water system
must be used, the same regimen of suction management as above may be applied but the drain is removed
when there has been no air leak detected for 24 hours. Drainage volume and color are no longer regarded
as major considerations when determining when to remove chest drains.
OTHER LOBES
Right Middle Lobe
The basic approach is similar to the RUL. The RML is retracted laterally and posteriorly for most of the
operation, allowing the hilar structures to be approached from anteriorly. Using an anterior-to-posterior
unidirectional approach, the sequence of dissection would typically be pulmonary vein, lobar bronchus,
pulmonary artery, fissure (oblique fissure often complete but horizontal fissure may require stapling).
The challenge with the RML is that its hilum is closest to the single port of all the lobes. In smaller
patients, it is sometimes slightly more difficult to insert the entire head of the stapler to the hilar structures
and to maneuver instruments inside. The key is sometimes to manipulate the lung with the left hand
holding the retractor, gently displacing it away from the single port to allow more room for insertion of
the stapler or dissecting instruments with the right or dominant hand.
Right Lower Lobe

The right lower lobe (RLL) is retracted in a cephalad and lateral direction to expose the pulmonary
ligament. Once this is divided, the inferior pulmonary vein is looped and divided. The stapler tip
sometimes impacts against the spine as it is inserted around the vein, preventing it from fully passing the
vein. Retraction of the lung forward and rotating the articulating stapler head clockwise (tip turned
toward the cephalad direction) allow the stapler to be passed more parallel to the spine from caudal to
cephalad and avoid impacting onto the spine.
After the vein is divided, the RLL is retracted slightly toward the feet, allowing the completion of the
oblique fissure between RLL and RML. This exposes the pulmonary artery in the fissure, which is
dissected with sharp and blunt dissection (as described for the RUL), looped, and staple-divided. The
interlobar (11R) lymph node at the top of the fissure is a useful landmark present in virtually all patients
and marks the bifurcation between RLL and RML pulmonary arteries.
Once the artery truncus is divided, retraction of the RLL laterally and posteriorly allows the RLL
bronchus to be seen rising vertically from the bronchus intermedius up to the RLL. This is dissected and
the stapler inserted from a right-to-left direction to divide it.
Left Upper Lobe

The same technique used with the RUL is applied to dissect and divide the pulmonary vein and then
artery. Using the rotation trick described above, there is usually no problem first transecting the vein using
an articulated stapler. Once the vein is divided, the apical and anterior pulmonary artery branches to the
LUL are seen behind. Retraction of the LUL laterally exposes these branches running vertically up to the
LUL. These can be dissected and stapled as described for the RUL. However, these artery branches are
often small and short, and use of polymer ligating vascular clips are often very useful to avoid forcible
insertion of a big stapler across them (which is when tearing and avulsion sometimes occur). An
alternative approach, should there be any difficulty dissecting the vein first, is to first divide the apical
and anterior artery branches. The plane between the upper vein and the artery is first dissected to better
expose these branches. Once they are divided, the tissue around the bronchus and the vein can be
dissected and removed, increasing the space behind the vein to facilitate transection with an articulated
endostapler.
The division of both the first and second branches of artery and upper vein allows for better lateral
retraction of the LUL laterally and hence better exposure of the LUL lobar bronchus. The bronchus is
dissected with extreme caution using a right-angled clamp which must be kept in contact with the back
wall of the bronchus at all times because deep straying of the dissection could damage the interlobar
pulmonary artery and its remaining branches to the LUL behind (lingula or posterior branch), resulting in
catastrophic bleeding. Partial dissection/division of the anterior part of the interlobar fissure may often
help further improve exposure to the lower border of the bronchus.
Once the bronchus is divided, lateral retraction of the LUL exposes the remaining pulmonary artery
branches to the LUL behind where the bronchus used to be. These are variable in number and are
dissected in the same manner as previously described. A curved forceps is again used to go around
behind the branch(es), and opening-and-closing helps develop the space behind. It should be emphasized
that this must be done very gently and extra care must be taken with the traction of the lobe at this moment.
Without the support of the bronchus, excessive force when dissecting these small branches can cause
tearing and avulsion with major bleeding. The branch(es) can be divided with a stapler or between
polymer vascular ligating clips. The use of polymer clips with a thoracoscopic 45-degree applicator is
advisable for small branches, reducing the risk of vessels tearing/avulsion that rough passage of a stapler
may cause.
Another interesting option for management of upper lobes in lungs with incomplete fissure is to open
the fissure as the first step, from a hilar view, and then create a tunnel between upper and lower vein with
identification of the bronchus and artery. The anvil of the stapler is placed over the artery, dividing the
anterior portion of the fissure and allowing for the mobilization of the lobe (to allow the stapling of the
vein from a different angle).
Left Lower Lobe

The above strategy as for the RLL is used to retract the left lower lobe (LLL) in a cephalad direction,
release the pulmonary ligament, and dissect and divide the pulmonary vein. The LLL is then retracted
toward the feet, and the pulmonary artery dissected from within the fissure. Branch(es) to the LUL lingula
are identified and preserved, and the terminal branches to the LLL and the LLL apical segment are
dissected and divided with stapler or polymer vascular ligating clips. Retraction of the LLL laterally and
posteriorly then allows the LLL bronchus to be seen rising vertically up to the LLL. This is dissected and
the stapler inserted from an anterior-to-posterior direction to divide it. As this is done, care must be taken
not to damage the interlobar pulmonary artery which runs behind and cephalad to the bronchus in this
position.
Often, the interlobar fissure may be too fused and thick to allow dissection of the pulmonary artery
from within the fissure. In this case, after division of the vein, the LLL is continued to be retracted in a
cephalad direction, exposing the LLL bronchus from a caudal to cephalad direction, and this is then
dissected and divided next. After division of the bronchus, with the LLL kept in this retraction, the
interlobar pulmonary artery is exposed from the same caudal to cephalad direction and its branches to the
LLL and its superior segment can be dissected and divided from this inferior approach. The lobectomy is
then completed by staple-division of the fissure.
THE EVIDENCE FOR UNIPORTAL VATS LOBECTOMY
SAFETY AND FEASIBILITY OF UNIPORTAL VATS

From February 2004 to October 2015, over 120 reports on uniportal VATS were published of which over
90% were case reports and simple, noncomparative case series.7,8,11,14–16,21–24 Although considered as
weak “evidence” scientifically, the considerable volume of these reports has served a useful purpose in
confirming the safety and feasibility of the uniportal approach for a large variety of thoracic operations.
Almost unanimously, these reports have concluded that uniportal VATS is safe and feasible with low
incidence of operative or perioperative complications.4,11,16,24 Furthermore, these have demonstrated that
the uniportal technique can be applied safely for an ever-increasing range of lung resection procedures—
ranging from segmentectomies to complex sleeve and double-sleeve resections.14–16,24 Over the same
period of time, there have been no notable reports that the uniportal approach for lobectomy has been
shown to be harmful to patients. This is further corroborated by the increasing use of uniportal VATS as
the preferred approach for lobectomy in centers around the world.3,4,21,25
Opponents of uniportal VATS often argue that with all instrumentation sharing the same access incision
alongside the video-thoracoscope, operative dexterity and in turn safety is compromised.21,26 However,
with the volume of clinical experience now reported, it is perhaps now reasonable to conclude that the
safety of using the uniportal VATS has been adequately demonstrated. The current volume of case reports
and case series on uniportal VATS approaches that on conventional multiportal VATS in the mid- to late-
1990s when the latter was becoming gradually accepted as an “alternative” to thoracotomy.1,5
COMPARISON OF UNIPORTAL VATS WITH CONVENTIONAL VATS

Controversy arises over claims regarding any supposed “advantage” of uniportal VATS over other
surgical approaches, particularly conventional multiportal VATS.21
TABLE 35.1 A Summary of the Studies Comparing Uniportal and Multiportal VATS Lobectomy
Study Uniportal Multiportal Study Operation Pain and Recovery
Patients Patients Design Morbidity
McElnay et 15 95 Retrospective — Pain score—ND Chest drain
al. Observational Analgesic use— duration—ND
(2015)32 ND Length of stay—
Complications— ND
ND
Chung et al. 90 60 Retrospective Operative time—ND Complications— Chest drain
(2015)33 Observational Nodes dissected— ND duration—ND
ND Length of stay—
ND
Liu et al. 46 46 Propensity Operative time— Complications— Length of stay—
(2015)34 matched uniportal faster ND ND
Blood loss—
uniportal less
Nodes dissected—
uniportal higher yield
Zhu et al. 33 49 Retrospective Operative time— Pain score— Chest drain
(2015)35 Observational multiportal portal uniportal lower duration—ND
faster Complications— Length of stay—
Blood loss—ND ND ND
Nodes dissected—
ND
Liu et al. 100 342 Retrospective Operative time— Complications— Length of stay—
(2105)36 Observational uniportal faster ND uniportal shorter
Blood loss—
uniportal less
Nodes dissected—
uniportal higher yield
Hirai et al. 60 20 Retrospective Operative time—ND Pain score— Chest drain
(2015)37 Observational Blood loss—ND uniportal lower duration—ND
Analgesic use— Length of stay—
uniportal less ND
Paresthesia— CPKmax—ND
uniportal less CRPmax—ND
frequent
Complications—
ND
Shen et al. 100 100 Propensity Operative time—ND Complications— Length of stay—
(2015)38 matched Blood loss—ND ND ND
Nodes dissected—
ND
Mu et al. 47 47 Propensity Operative time—ND Complications— Chest drain
(2015)39 matched Blood loss—ND ND duration—ND
Nodes dissected— Length of stay—
ND multiportal shorter
ND, no difference; CPKmax, maximum postop level of creatine phosphokinase; CRPmax, maximum postop level of C-reactive protein.
Reproduced with permission from Sihoe AD. Reasons not to perform uniportal VATS lobectomy. J Thorac Dis 2016;8(Suppl 3):S333–S343.
Proponents of uniportal VATS lobectomy have reasoned that if conventional multiportal VATS is
superior to open thoracotomy by virtue of minimizing surgical access trauma,4,11,25 then further reduction
in such access trauma should yield even greater benefits. Therefore, reducing the number of wounds from
three or four to just one should in theory lead to benefits in two key outcomes:
• Lower rates of morbidity (including pain, paresthesia)11,25,27–30;

• Faster postoperative recovery.11,25,27,28
It has been further argued that a third benefit is that the visualization geometrics afforded by uniportal
VATS allow a more ergonomic and natural hand–eye approach for the surgeon to operate with.31 This in
theory should allow improvement over conventional VATS in terms of intraoperative parameters.
The current literature can be analyzed to test these above-hypothesized areas where uniportal VATS
may be beneficial.
At the time of this writing, eight comparative studies have been published by seven groups comparing
uniportal VATS with conventional multiportal VATS for anatomical resection of lung cancer.32–39 These
are summarized in Table 35.1. All eight studies were retrospective, observational studies published in
2015, of which seven originated from Asia. Of the eight studies, three were case-matched studies, and the
rest were unmatched comparisons. All studies focused on simple postoperative clinical outcomes. None
of these studies had medium- or long-term follow-up and none looked at postoperative survival—whether
overall or cancer-related. No sample size estimation was conducted in any study,40 and this further adds
doubt regarding the clinical significance of the failure to find differences in many of the analyses.
1. Intraoperative parameters
Of the seven studies providing data in this area, two found that uniportal VATS gave shorter operation
times than conventional VATS (170 vs. 191 minutes and 3.0 vs. 3.5 hours, respectively), less blood loss
(53 vs. 95 mL and 56 vs. 78 mL, respectively), and higher yields from lymph node dissection (27 vs. 22
nodes and 28 vs. 25 nodes, respectively).34,36 However, both of these studies originated from the same
center. Another study actually showed that operation times were longer with uniportal VATS (180 vs.
151 minutes).35 The remaining four studies found no difference between the approaches in terms of
intraoperative parameters.
Thus, the current clinical data do not consistently show any advantage or disadvantage for uniportal
VATS in terms of intraoperative parameters.21 The theory of better visualization geometrics using the
uniportal approach remains at present unsubstantiated by measurable evidence. Further studies using
more detailed outcome measures to test this may be needed.
2. Pain and morbidity
Uniportal VATS was found to give lower postoperative pain scores in two studies (3.6 vs. 5.5 and 2.4
vs. 4.2, respectively), and one of these further noted quicker cessation of analgesic use and lower
frequency of paresthesia following uniportal VATS.35,37 However, in all of the remaining six studies,
uniportal VATS was not associated with any advantage in terms of postoperative morbidity. None of the
studies found that overall complication rates were lower amongst uniportal patients.
Hence, the evidence that uniportal VATS is superior to conventional multiportal VATS in terms of
postoperative pain is presently limited. Only two of the studies supported this notion,35,37 with the
remainder showing no difference. In both studies, the main assessment tool for pain was the simple
numeric scale, asking patients to subjective grade the pain with a score of 0 to 10. Although widely
used, this scale is inherently subjective to confounding variables—such as individual patient pain
thresholds and circumstances under which pain is scored (at rest, moving, etc.).5,21 This problem is
even greater amongst studies with small cohorts such as these. Moreover, in both the studies suggesting
an “advantage” for the uniportal approach, there is no evidence that intraoperative analgesia (e.g.,
regional blockade) or postoperative analgesia had been standardized amongst all patients.35,37 The
reliability of the conclusions is therefore subject to some doubt from such confounding variables.
Nevertheless, it should be noted that none of the studies have shown that uniportal VATS was inferior to
conventional VATS.
3. Recovery
Shorter postoperative length of stay was associated with uniportal VATS in one study (6.0 vs. 6.8 days),
but with conventional multiportal VATS in another (6.8 vs. 5.4 days).36,39 In all of the remaining six
studies, uniportal VATS was not associated with any advantage in terms of chest drain durations or
lengths of stay.
The authors of the study showing longer stays after uniportal lobectomy still argued in favor of this
approach and attempted to explain away the unfavorable finding by suggesting that lengths of stay were
prolonged in the uniportal group because of poorer wound healing at the chest drain site.39 Nonetheless,
they have not provided actual data to illustrate this latter point—and in any case, this would merely
point to another potential weakness of the uniportal approach that may nullify any supposed benefits in
terms of faster recovery. Ultimately, however, the issue of lengths of stay is a complex one that also
involves many confounding variables—including patient confidence, sociocultural influences on
readiness for early discharge and financial considerations against prolonged stay (or lack thereof).5,21,41
At this juncture, it seems reasonable to conclude that the purported advantages of uniportal VATS
have not been well supported by the (limited) available evidence in comparative studies.21 To be fair,
on balance these studies also show that the uniportal approach is not inferior to conventional VATS and
that there is a slight possible leaning in favor of uniportal VATS when it comes to immediate
postoperative pain specifically. The only definite conclusion to draw right now is that further studies
need to be conducted to answer the questions on the advantages of the uniportal approach.
UNRESOLVED ISSUES
Conventional multiportal VATS matured from a novel “alternative” to open thoracotomy in the early
1990s to become a well-established, mainstream—even preferred—approach for lung cancer
management it is today.1,5,42 In doing so, conventional VATS required a patient, systematic accumulation of
clinical evidence over many years to win over critics and establish its role in mainstream practice. This
accumulation took place over five phases:
i. Safety and Feasibility
In the early years of conventional VATS lobectomy in the 1990s, many case reports and then
increasingly larger case series gradually demonstrated that VATS lobectomy was feasible and could be
performed with reasonable safety.43–46 The emergence of similar case series from different centers
around the world emphasized that the technique itself was a sound, reproducible one.47–49
ii. Simple Benefit
Simple outcome measures of surgical access trauma (including reduction of pain, reducing crude
morbidity rates, and expediting recovery) were shown to be better with conventional VATS than with
open thoracotomy in the mid-1990s. The evidence came from comparisons between VATS cohorts with
historical thoracotomy cohorts,50 case-matched studies,51 and early attempts at randomized trials.52
ii. Objective, Quantifiable Benefit
More reliable outcome measurements (including validated quality-of-life questionnaires, patient
mobilization, shoulder function, inflammatory markers) were necessary to confirm irrefutably
conventional VATS causing less systemic and physiologic disruption than open surgery.53–58
v. Treatment Adequacy
The most important issue for conventional VATS was to demonstrate equivalent treatment outcomes as
open surgery (then the gold standard). In lung cancer surgery, this equivalent lymph node dissection was
used as a surrogate indicator of completeness of resection.59–61 Crucially, through the late 1990s and
early 2000s, multiple large clinical series were followed by a series of well-executed systematic
reviews and meta-analyses demonstrating that lung cancer survival after conventional VATS was not
only equivalent to open, but may even be marginally superior in terms of survival for early-stage lung
cancer.42,62–64
v. Sustainability
Besides safety, benefits, and efficacy, studies have continued to compare conventional multiportal VATS
to open thoracotomy in issues related to its sustainability in clinical practice, such as cost-effectiveness
and teaching of trainees.4,5,65,66
For uniportal VATS to gain similar recognition as conventional VATS for lobectomy, it is reasonable
that a similar process of evidence accumulation is required.
For uniportal VATS, the first two phases have already been addressed above. The volume of case
reports and case series on uniportal VATS being performed in many centers around the world and over
several years of experience has consistently demonstrated its safety and feasibility.4,8,10,11,14–16,23–25,30,67,68
On the other hand, the small volume of comparative studies has not delivered decisive conclusions about
the second phase of demonstrating simple benefits of uniportal VATS over conventional VATS—although
this may change with further studies published in coming years.21,32–39
Other than these two phases, there is a dearth of evidence currently regarding uniportal VATS
lobectomy in the other phases.
For the third phase, only one of the above studies looked at inflammatory markers.37 Maximum
postoperative levels of creatine phosphokinase and of C-reactive protein were measured, but no
difference was noted between patients receiving uniportal and multiportal VATS.
For the fourth (and arguably the most important) phase, it has been too soon from the advent of
uniportal VATS lobectomy for cancer survival data to emerge. The experience with conventional
multiportal VATS as discussed above has shown that good case series with sizeable patient cohorts only
emerge 5–10 years after the technique is introduced.5,21 In terms of adequacy of surgery of lung cancer, the
number of lymph nodes dissected can be looked at as a well-accepted surrogate measurement in the
meantime. This parameter was studied in six of the above comparative studies, and two of these (albeit
both by the same group of authors) found that nodal yields were actually higher in the uniportal group.34,36
Notably, none of the six studies showed that nodal yields were less in the uniportal group.
TIPS AND TRICKS
• Maintain ergonomic positions and a correct position of the screen, in order to avoid fatigue.
• Always keep the camera in the posterior part of the incision.
• The assistant must maintain the retraction of the lobe allowing the surgeon to perform bimanual
instrumentation.
• For a better exposure, the surgical table can be moved in some steps of the surgery, especially in
lymph node dissection.
• In upper lobectomies if the distance between artery and vein is longer enough, the vein can be divided
first. When the angle for the stapler to transect the vein is not good, dividing the anterior trunk first
helps to facilitate the division of the vein.
• Using a tie or the suction device to facilitate the passing of the stapler when dividing the vein are key
maneuvers to avoid injury to the artery in upper lobes.
• In incomplete fissures the artery can be exposed by dissecting upward from the hilum, first through the
space between upper and lower veins and then between upper and lower bronchus. The creation of a
safe plane in a tunnel view allows the anvil of the stapler to be placed over the artery, dividing the
anterior portion of the fissure.
RECENT ADVANCES IN UNIPORTAL VATS

The main advances of uniportal VATS during the last years are related to improvements in surgical
technique and implementation of new technology (better staplers and energy devices, 3D and ultra high-
definition view).69 The experience gained during the last years has allowed to modify the technique to
develop tricks to easily manage the upper lobe vein and bronchus (both being the most difficult structures
to divide), to use energy devices for hilar dissection, and to control most of the intraoperative
bleedings.70 The uniportal approach also facilitates the performance of radical lymphadenectomies by
using only long curved suction and energy devices (advanced VATS instrumentation) and reconstructive
complex tracheo-bronchial and vascular procedures. Furthermore, the use of a single incision can be
combined with non-intubated techniques as well employed for major pulmonary resections through a
subxiphoid or subcostal incision.
NON-INTUBATED MAJOR PULMONARY RESECTIONS: TUBELESS

PROCEDURES
The main advantage of non-intubated surgery is to avoid the perioperative morbidity derived from the
deleterious effect of general anesthesia and one-lung ventilation, in addition to the beneficial effects of
spontaneous ventilation in a non-intubated patient.71
Inclusion criteria for a non-intubated uniportal procedure include all selected patients for whom the
avoidance of morbidity of conventional thoracotomy and the risk of intubated general anesthesia could be
reduced.72
The choice of a single-incision technique in an awake or non-intubated patient could minimize even
more the invasiveness of the surgery and anesthesia.73 We call these uniportal procedures “tubeless
VATS”: single 3-cm incision, no endotracheal tube, no urinary catheter, no central vein, and no epidural.
We consider it very important in high-risk patients for general intubated anesthesia such as elderly
patients or those with poor pulmonary function.74,75 It is advisable to perform a careful selection of the
patients, especially during the learning curve. The contraindications for awake major resections are
patients with an expected difficult airway management, obesity (body mass index >30), dense and
extensive pleural adhesions, hemodynamically unstable patients, ASA >II, and big tumors (>6 cm).72
Thanks to the avoidance of intubation, mechanical ventilation, and muscle relaxants the anesthetic side
effects are minimal allowing most of the patients to be included in a fast protocol that avoids the stay in
an intensive care unit. Moreover, the perioperative surgical stress response could be attenuated in non-
intubated patients undergoing uniportal VATS as a result of the reduced postoperative stress hormones and
pro-inflammatory mediators related to mechanical ventilation. Oxygen (6 to 9 L/min) is supplied via nasal
cannulae or facial mask. The pharmacologic management is based on a target-controlled infusion of
remifentanyl and propofol, with a premedication of midazolam (0.15 to 0.25 mg/kg) and atropine (0.01
mg/kg) 15 minutes before anesthesia, adjusting real-time rate of infusion with the aggressiveness of each
period during the surgery. The use of an intraoperative vagus blockade is recommended to suppress
coughing that could be troublesome when performing lung traction and hilar manipulation during
dissection.
During a uniportal approach in a non-intubated patient it is recommended to perform a paravertebral
blockade or an intercostal infiltration under thoracoscopic view.72 The importance of avoiding epidural
thoracic blockade (avoiding opioids) will result in faster recovery and return to daily activities.
The non-intubated VATS major pulmonary resections must only be performed by experienced
anesthesiologists and uniportal thoracoscopic surgeons (preferably skilled and experienced with complex
or advanced cases as well as bleeding control through VATS). In some unpredictable difficult cases,
intraoperative conversion to general anesthesia is sometimes necessary. The anesthesiologist must be
skilled in bronchoscopic intubation, placing a double-lumen tube or an endobronchial blocker in a lateral
decubitus position.70–72
BLEEDING CONTROL
The learning curve of the uniportal VATS approach carries along an increase in the number of
intraoperative complications such as the intraoperative bleeding.76,77 This is inherent to the learning of
any new surgical approach and is the most frequent reason for an emergent conversion to a thoracotomy
during the learning curve.78
FIGURE 35.13 Drawing showing bleeding control. A: The first maneuver after a major bleeding is compression. A sponge stick
must be always ready. Once the bleeding site is compressed, the long curved suction must be used at the same time for removing
the blood. B: Bimanual instrumentation for suturing. The curved suction can be used to compress the bleeding site, same as a
finger function in open surgery, and allows to keep the bleeding point clear from blood.
During the last years, the experience gained through the uniportal VATS technique, development of
surgical instruments specifically designed for this approach, and the improvement of high-definition
cameras have contributed to improve outcomes and reduce the rate of conversion for intraoperative
bleeding. The minor bleeding normally does not cause too many problems and is easily controlled through
a single-incision approach by applying pressure and use of energy devices or sealants.79 However, a
minor bleeding can become a serious complication if inadequate steps are taken and therefore it must be
carefully managed.80
Direct compression must be the first measure to be taken when a major bleeding occurs. To this end it
is recommended to always have a sponge stick ready, if possible, mounted on a long thoracoscopic
forceps (Fig. 35.13). Sometimes, the use of the lung parenchyma as the first reaction to compress the
bleeding point is useful. At the same time it is important to suck up the blood around in order to have a
good view of the bleeding point as well as leaving a prepared field in case of the need for a later repair.
We always recommend an initial compression of 1 to 2 minutes and if the bleeding does not cease, a
second compression of 3 to 4 minutes.80
After the initial compression with a sponge stick, we consider very helpful the use of a preferably
curved suction device to compress the bleeding site. The suction can imitate the function of a finger
compressing to stop the bleeding and allows to keep the bleeding point clear from blood. This enables a
better assessment of the defect to be repaired. In addition, the curve of the suction does not interfere with
the suturing maneuver and the thoracoscopic view through a single-port.81
Bleeding that normally cannot be controlled with the previous measures must be repaired by means of
direct suture, use of sealants, or the use of vascular polymer clips, when indicated by the length of the
vascular stump. We do not recommend to apply a thoracoscopic clamp directly to the hole, because the
defect can be enlarged. If the bleeding does not stop after compression, it could be useful to use an
atraumatic instrument like a ring forceps to grab the artery and stop the bleeding as a first step to perform
a thoracoscopic suture.80
In order to repair the defect through a uniportal approach, bimanual instrumentation is crucial keeping
the camera at the posterior position and the instruments at the anterior. This way we have a very direct
vision and we can reproduce similar maneuvers as in open surgery. In the authors’ experience, the
uniportal technique facilitates the repair of bleedings due to the geometrical characteristics of the
technique as we work in a sagittal plane. The preferred method to suture the pulmonary artery is the
“suction-compressing angiorrhaphy technique” using the thoracoscopic long curved suction on the left
hand (compressing and maintaining clear the bleeding site) and the needle holder on the right hand81 (Fig.
35.13).
RECONSTRUCTIVE TECHNIQUES
One of the most recent advances in the uniportal VATS approach is the possibility to perform difficult
reconstructive broncho-vascular techniques. Thanks to the evolution and experience gained with the
uniportal VATS technique, the most complex resections including double sleeve, bronchial sparing lung
resections, and tracheal or carinal reconstructions can be performed when in expert hands.82–84
Performing the incision at the fourth or fifth ics, more anteriorly (anterior axillary line), facilitates the
positioning of the needle holder parallel to the hilum, making suturing similar to an open anterior
thoracotomy. When performing bronchial suturing using uniportal VATS, it is very important to maintain
the camera on the posterior part of the incision, operating with both hands below the camera (bimanual
instrumentation). Here we apply the same principle as when performing an anterior thoracotomy in open
surgery: direct view with the surgeon’s eyes above his/her hands. The geometrical explanation of the
approach is an important factor to facilitate the sleeve reconstructions through a uniportal approach.85 As
a result, in expert hands the anastomosis can be accomplished from a straight perspective. Using a wound
protector is helpful when dealing with obese patients because fatty tissue could interfere with the suture
threads. The positioning of the operating table helps to expose the lung and so easier to perform the
anastomosis (the 45-degree rotation of the table toward the surgeon positions the lung anteriorly and
makes the posterior bronchial suturing easier, especially the membranous portion).
FIGURE 35.14 Drawing showing left upper bronchial sleeve anastomosis using two threads. A: Completion of the posterior
wall anastomosis is done first by using a running suture in the membranous portion. B: Another running suture is started just
anteriorly from the previous one to complete the anterior half of the anastomosis. C: Both knots are tied at the front of the
bronchial circumference.
The sleeve anastomosis can be performed with interrupted or continuous suture. Placing interrupted
sutures by VATS can be more complex and time-consuming. The preferred method is to use a continuous
suture which makes the thread movement easier, as well as the tying. We have three options:
polydioxanone, PDS 3/0, where we need two threads and tying three times (Fig. 35.14), or a
monofilament prolene 3/0 with two needles, where we can do all the anastomosis with one thread, tying
only one time after completing the 365 degrees of the reconstruction (Fig. 35.15). The technique for
uniportal thoracoscopic suture is for the surgeon to tie the knot outside of the chest and then push it down
in the chest with a thoracoscopic knot pusher82 (Fig. 35.16). The anastomosis can also be performed by
using a novel absorbable barbed suture, the V-Loc™ wound closure device (Covidien-Medtronic,
Minneapolis, MN, USA), which avoids knot-tying while maintaining suture strength and security.85
For double-sleeve procedures, the use of a thoracoscopic clamp for the main PA and a bulldog clamp
for the distal end of the vessel is the most appropriate choice.86 The arterial clamp is placed in the
anterior portion of the incision and the camera always at the posterior portion. This makes the bronchial
and arterial anastomoses more comfortable.87,88
VATS lung sparing bronchial sleeve resection and reconstructions are technically more challenging
than a standard VATS sleeve lobectomy. The bronchial anastomosis after a VATS sleeve lobectomy is less
complex to perform because there is more space to expose the two bronchial ends for suturing once the
lobe has been removed.89,90
Tumors involving the trachea or carina require a total coordination with the anesthesiologist. To
perform this procedure through uniportal VATS there are three options in order to maintain lung
ventilation: the use of an intra-surgical field tracheal tube,82,91 through a high-frequency jet
ventilation,82,92 or even under spontaneous anesthesia in expert hands.93 The catheter for jet ventilation
can be introduced through the endotracheal tube and thanks to the small diameter of the catheter for
ventilation, it does not interfere with the anastomosis of the membranous portion (Fig. 35.16). This way
we do not need intra-field intubation. In the event of needing surgical field intubation, a sterile circuit is
passed onto the field and prepared to directly ventilate a single lung (through the same incision or adding
a second small port).
FIGURE 35.15 Running sleeve anastomosis. A: Drawing showing the first stitches during a right upper sleeve anastomosis by
using only a single thread with two needles. The running suture is started by one needle on the edge of the right main bronchus
and with the other needle on the bronchus intermedius. The medial part of bronchial wall is done first with the needle inside the
bronchus intermedius (running suture from back to front) and then the lateral wall of the anastomosis with the needle inside the
main bronchus. After completing the circumference of anastomosis, both threads are tied together. B: Surgical image showing
the surgical technique outside the chest holding the thread with left hand and using a thoracoscopic knot pusher with the right
hand.
FIGURE 35.16 Surgical image (A) and drawing (B) showing reconstruction after right upper lobectomy and carinal resection
(under high-frequency jet ventilation of the left lung). Lateral wall of the left main bronchus is anastomosed to the lateral wall of
trachea. A neocarina is then created with left main bronchus and bronchus intermedius. The anastomosis is completed by
anterior and posterior running sutures. LMB, left main bronchus; BI, bronchus intermedius. (Reprinted from Gonzalez-Rivas D,
Yang Y, Calvin NG. Advances in uniportal video-assisted thoracoscopic surgery: pushing the envelope. Thorac Surg Clin
2016;26(2):187–201. Copyright © 2016 Elsevier. With permission.)
SUBXIPHOID APPROACH
Recent innovations in single-incision approach include the use of subxiphoid or subcostal technique for
major resections (Fig. 35.17).94 Avoiding the incision through the intercostal space could be another
potential advantage to reduce postoperative pain but further studies will be required to demonstrate that
this approach is less painful.95 This approach has been used during the last years for different thoracic
procedures such as pericardial window, thymectomy, pulmonary metastasectomy, or bilateral wedge
resections.96,97 Liu reported in 2013 the first case of thoracoscopic lobectomy with mediastinal lymph
node sampling through a single subxiphoid incision for lung cancer patients.98 Recently, the Shanghai
Pulmonary Hospital team reported the largest experience with this technique showing excellent
postoperative outcomes.99
FIGURE 35.17 Subxiphoid uniportal lobectomy. A: The patient is placed in a semidecubitus position (45-degree angulation). The
surgeon stands in the front side of the patient and the assistant is located on the other side (back of the patient) to facilitate the
movements of the surgeon. B: Surgical image showing dissection of trisegmental bronchus during a subxiphoid lingular sparing
left upper lobectomy.
FIGURE 35.18 Uniportal VATS unisurgeon instrumentation. An articulated arm is holding the camera. The surgeon uses
bimanual instrumentation: with the left hand holds two instruments (lung grasper and long curved suction for exposure) and with
the right hand uses the energy device for dissection.
During the subxiphoid approach the xiphoid process and pericardial fatty tissue must be resected in
order to ensure a good exposure and diminish the interference with the instruments. A sternal retractor
could improve the access albeit in the authors’ experience it is not necessary. The subcostal approach
reduces the compression on the heart on the left side and avoids the resection of xiphoid process.
This approach has several limitations such as the handling of major bleeding, especially when happens
in the posterior part. When an emergent conversion to open surgery is necessary, an extension of the
subxiphoid incision is unlikely to be useful and an additional thoracotomy should be performed.98
Moreover, a complete lymphadenectomy is difficult to achieve via subxiphoid approach since it
provides limited access to the anatomy of the posterior mediastinum.100 From the subxiphoid to the hilum,
it is in an oblique and longer distance so the instrument fighting problem during uniportal surgery will be
more difficult than with transthoracic approach (Fig. 35.18). The instrumentation over the beating heart is
also a bother, especially during left-side procedures. However, thanks to the experience acquired during
the last years, this novel technique could be potential for widespread use by improving the instruments
and thoracoscopes, or with the possibility of including robotic technology through this approach. Further
studies are needed to document the applicability and compare clinical outcomes of the uniportal
subxiphoid versus the transthoracic approach, in order to show clear important benefits from this
technique.
FUTURE OF UNIPORTAL VATS

The uniportal technique has recently evolved to a concept that could be named “uniportal advanced
VATS.” This development could be described as a way of performing surgery with the least number of
devices possible, reducing this way a possible compression over the intercostal space when multiple
instruments are introduced through a single incision. The bimanual instrumentation is key as well as the
use of two specific instruments: a long curved stainless steel Dennis suction device on the left hand and
an energy device on the right hand. The coordination of both devices enables a fast and effective exposure
as well as dissection and coagulation (Fig. 35.11); in addition, the use of an external articulated camera
support allows for a firm and stable handling of the thoracoscope without the need for an assistant. In our
opinion, future technologic developments as well as the experience gained with the uniportal approach
will favor this type of surgery with a single surgeon, therefore enabling the optimization of hospital
resources (Fig. 35.18).
In conclusion, the uniportal approach has created new opportunities for collaboration with the industry
to develop new technology and to push the boundaries of the minimal thoracic invasive surgery. We
expect further development of improved technology like narrower staplers, sealing devices for all vessels
and fissure, refined thoracoscopic instruments, wireless cameras, and single-incision robotic platforms,
which will probably allow the uniportal approach to become the standard surgical procedure for major
pulmonary resections worldwide.
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36
Awake, Non-Intubated Transpleural
Surgery
Ze-Rui Zhao ■ Calvin S. H. Ng
INTRODUCTION
Non-intubated thoracic surgery (NITS) has been researched intensively in the past decade. Advocates of
this approach propose potential advantages over general anesthesia of avoiding endotracheal intubation,
mechanical ventilation, and general anesthetic drugs which are associated with certain complications and
side effects. Although the criteria for patient selection and the standard anesthetic care for NITS remain to
be elucidated, accumulating reports suggest that increasing number of thoracic centers are enthusiastic
about NITS and that it can be safely performed with very good outcomes.
PATHOPHYSIOLOGY OF NITS UNDER SPONTANEOUS VENTILATION

Iatrogenic pneumothorax leads to a drop in the lung volume in the operated hemithorax, guaranteeing
adequate space for surgical intervention. This leads to a series of physiological changes in lung
oxygenation and ventilation. The loss of negative pressure in the pleural cavity causes progressive
collapse of the operated lung and a mediastinal shift, decreasing the total lung volume. During this
process, the collapsed lung continues to be perfused, causing a right-to-left intrapulmonary shunt, which
increases the risk of hypoxemia. Constriction of the pulmonary arterioles at the hypoxic alveoli and
diversion of the blood flow to the dependent lung partially compensate for this undesirable effect,
improving oxygenation whenever the PaO2 falls below 70 mm Hg.1 In addition, gravity increases the
blood flow in the dependent lung, improving the ventilation–perfusion match. Moreover, the anesthetic
agents used for thoracic epidural anesthesia (TEA), such as propofol, have a lesser inhibitory effect on
the vasomotor response than do volatile anesthetics.
Compared with general anesthesia, NITS results in less interference with the functional residual
capacity of the dependent lung because diaphragm function is preserved (Video 36.1). In addition, the
spontaneously breathing lung exhales some of its air into the operated lung during the exhalation phase and
then rebreathes part of the air volume that just filled the nondependent lung; this is known as paradoxical
respiration (Fig. 36.1). Hypercapnia resulting from rebreathing carbon dioxide may induce a net increase
in cardiac output because of sympathoadrenal effects, and the hypercapnic acidosis increases cerebral
blood flow. Mild to moderate hypercapnia can also stimulate tachypnoea. Evidence has shown that a
degree of transient hypercapnia (<55 mm Hg) can be well tolerated.2
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Video 36.1 Non-intubated uniportal VATS right lower lobe wedge resection for colorectal metastasis.
Pompeo et al. investigated the spirometric changes induced by surgical pneumothorax in awake
patients in the lateral decubitus position and reported that the FEV1 declined by 52%, 49%, and 30% and
the FVC by 45%, 46%, and 34% in the relatively normal lung, lung with interstitial disease, and
emphysematous lung, respectively, noting a lower impairment of ventilation in the already diseased
malfunctioning lungs. Moreover, these patients may develop lesser degrees of hypoxemia during surgical
pneumothorax; the drop in PaO2 relative to the fraction of the inspired oxygen ratio was 91, 74, and 38
mm Hg in the relatively normal lung, lung with interstitial disease, and emphysematous lung, respectively.
Patients with existing ventilator obstruction and hyperinflation would have less ventilatory impairment,
which may be due to the lesser degree of lung collapse and prolonged exhalation time.3 These findings
also support the appealing idea of using NITS in patients with compromised lung function.
Video 36.1 Non-intubated uniportal VATS right lower lobe wedge resection for colorectal metastasis. Note that the patient is
spontaneous ventilating with associated diaphragmatic movement.
FIGURE 36.1 Ventilation (ovals) and perfusion (rectangles) changes in surgical pneumothorax in the decubitus position. Black
arrows show paradoxical respiration and the mediastinal shift. (Modified from David P, Pompeo E, Fabbi E, et al. Surgical
pneumothorax under spontaneous ventilation-effect on oxygenation and ventilation. Ann Transl Med 2015;3(8):106.)
ADVANTAGES OF NITS
A main advantage of NITS stems from avoiding perioperative complications associated with general
anesthesia and one-lung ventilation. Mechanical ventilation can result in barotrauma, volutrauma,
atelectrauma, and biotrauma caused by pro-inflammatory mediators.4–7 In addition, general anesthesia is
associated with higher risks of pneumonia, impaired cardiac function, and residual neuromuscular block
in patients with myasthenia gravis.8–10 Although there are numerous strategies described that can reduce
the risks associated with endotracheal intubation,11,12 nevertheless, awake anesthesia without
endotracheal intubation can avoid complications such as hypoxia due to displacement of the double-lumen
tube, hyperinflation of the dependent lung, re-expansion pulmonary edema, and ventilator-induced lung
injury (Fig. 36.2). In addition, endotracheal devices may cause local complications, of which
tracheobronchial rupture is the most troublesome and has mortality rates as high as 22%, although it is
rare (1/20,000).13 Atelectasis in the dependent lung is common during one-lung ventilation due to muscle
paralysis, while atelectasis in the contralateral lung may severely aggravate the intrapulmonary shunt and
increase the locoregional inflammatory response.14 In addition, regional anesthesia in NITS may attenuate
immunosuppression and neuroendocrine stress levels,15 indicating potential benefits compared with
general anesthesia.
FIGURE 36.2 Patient undergoing non-intubated VATS lung resection with airway protection by laryngeal mask.
CONTRAINDICATIONS OF NITS
Dr. Pompeo’s group, among the most enthusiastic pioneers of NITS, suggested that an American Society
of Anesthesiology score of >3, severe obesity, and an arterial CO2 tension of >55 mm Hg contraindicated
NITS.16 Gonzalez-Rivas et al.,15 and Mineo and Tacconi13 proposed more rigid exclusion criteria, which
can be classified into patient-, anesthesiologist-, and surgeon-related factors (Table 36.1). It should be
highlighted that these are expert opinions from experienced centers, and ultimately selection of patients
undergoing NITS need to be based on anesthesiologist and surgeon experience.
ANESTHESIA IN NITS
Minor thoracoscopic procedures can be performed using locoregional anesthesia, such as local wound
infiltration or selective intercostal nerve blockade. Major thoracic procedures usually need more
sophisticated anesthesia techniques. TEA blocking T2–T10 can have a durable effect on the chest wall
and pleural cavities bilaterally, making it useful for more extensive and longer operations, although the
bronchial wall smooth muscle tone and airway hyper-reactivity may increase.17 In addition, the epidural
catheter can be used for patient-controlled analgesia postoperatively. In comparison, a paravertebral
blockade that blocks the sympathetic system unilaterally can offer pain relief similar to TEA, but is
associated with fewer side effects.18 A catheter can also be inserted for local anesthesia at the T4–T5
level because there is no anatomical separation of the paravertebral spaces. Surgical manipulations
around the hilum during major lung resection under spontaneous breathing may provoke uncontrollable
coughing, which is a safety hazard particularly during delicate vascular dissection. Useful preventive
measures include the administration of lidocaine by either inhaling aerosols or spraying it on the pleural
surface, and intrathoracic stellate ganglion or vagus blockade, which can provide inhibition for around 3
hours or more.19 However, the need for these coughing preventive measures is not always necessary, often
depending on the patient and the type of and titration of anesthetic drugs by the anesthesiologist (Video
36.2). Furthermore, since it is argued that vagal blockade may inhibit cough reflex needed to expectorate
sputum in the early postoperative period, spraying of the pleural surface with local anesthetic may be a
more attractive option for some surgeons.
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Video 36.2 Manipulating and division of the left upper lobe bronchus during non-intubated uniportal
VATS left upper lobectomy for early stage non-small cell lung carcinoma.
TABLE 36.1 Contraindications to Non-Intubated Thoracic Surgery

Patient-Related Factors
Allergy to local anesthetic; coagulopathy (international normalized ratio >1.5 or current antiplatelet therapy); hemodynamically unstable;
elevated risk of regurgitation (<6 hours fasting); hypoxemia (PaO2 <60 mm Hg) or hypercapnia (PaCO2 >50 mm Hga ) preoperatively;
neurological disorders; obesity (body mass index >30b ); persistent cough or high airway secretion; spinal deformity or brain edema (if
thoracic epidural anesthesia to be used).
Anesthesiologist-Related Factors
Any contraindications for use of regional anesthesia technique specifically selected; difficult airway management.
Surgeon-Related Factors
Extensive pleural adhesions; inexperienced and poorly cooperative surgical team; previous ipsilateral thoracic surgery.
a >55 mm Hg in Pompeo’s criteria.16

b >35 in Mineo’s report.13
Video 36.2 Manipulating and division of the left upper lobe bronchus during non-intubated uniportal VATS left upper lobectomy
for early stage non-small cell lung carcinoma. The lung has good collapse, and even though no vagal blockade was used, hilar
manipulation did not cause any significant coughing.
Note that these techniques can be combined if the surgical team is experienced. For example,
Gonzalez-Rivas et al.15 presented an anesthetic protocol for totally awake major thoracic surgery using
TEA in combination with ultrasound-guided vagus and phrenic nerve blockade. The need for sedation
with uniportal video-assisted thoracic surgery (VATS) in the non-intubated patient remains unclear.15
However, sedation is often preferred for prolonged operations, with the use of short-acting agents like
remifentanil at below the hypnotic level being the first choice.20 One of the benefits of administering
sedation is that remifentanil may blunt the cough reflex during the anatomical dissection. However, such
agents can also be respiratory suppressants21 and accentuate hypercapnia, especially when treating
patients with severe chronic obstructive pulmonary disease. In such cases, monitored anesthesia care is
important during NITS and includes monitoring of the respiratory rate, exhaled partial pressure of CO2
(e.g., end-tidal capnography), and the bispectral index (Fig. 36.3).
INDICATIONS FOR AND SURGICAL RESULTS OF NITS
MINOR PROCEDURES
Increasing numbers of reports have demonstrated the feasibility of NITS for minor procedures such as talc
pleurodesis, mediastinal biopsies, and managing pericardial effusions.15 A small randomized trial
showed that awake VATS for bullectomy with pleural abrasion was associated with shorter hospital stays
and reduced procedure-related costs when treating patients with spontaneous pneumothorax compared
with general anaesthesia.22 Mineo and Pompeo’s group also introduced a novel awake nonresection lung
volume reduction technique involving fold plication of the most emphysematous lung regions in 2006 and
reported its feasibility in comparison with intubated surgery. While lung function 6 months
postoperatively and 36-month survival were comparable, the patients in the awake group had less
mortality (0.0% vs. 3.2%) and morbidity (22.0% vs. 52.0%) as well as shorter hospital stays.23 The
rationale for performing a non-intubated thymectomy in myasthenia gravis is to avoid muscle relaxants,
which would lower the risk of postoperative muscle weakness and respiratory insufficiency, hastening
patient recovery. Awake endoscopic thymectomy via an infrasternal approach has been reported and
allows the patient to eat, drink, and walk several hours postoperatively.24 With iatrogenic opening of the
pleurae, continuous suction through a nasogastric tube to the pleural hole would help to expand the lung
passively.
In 2004, Pompeo et al. reported randomizing 60 cases with solitary pulmonary nodules to general
anesthesia and awake VATS wedge resection groups. The conversion rates and technical feasibility were
comparable between the groups. Anesthetic satisfaction, the changes in arterial oxygenation, and the need
for nursing care were more favorable in the awake group. Importantly, the hospital stay was shorter in the
awake surgery patient group (47% vs. 17% of the patients were discharged within 2 days).25 The
application of NITS was then extended by Tsai and Chen26 to bilateral wedge resection of peripheral
nodules, avoiding sequential lung isolation which may reduce the risk of hemodynamic disturbance.
Further progress was made toward the goal of day surgery for management of pulmonary nodules by
Rocco et al.,27 as his group conducted the first awake uniportal VATS wedge resection by using the
Fogarty balloon under fiberoptic guidance to selectively occlude the target lung parenchyma, in this case
right middle lobe; the procedure was well tolerated, chest tube was removed on postoperative day one,
and the whole process was done in an ambulatory setting.
MAJOR PROCEDURES
Major lung resection in a non-intubated setting is more demanding technically because it is associated
with frequent hilar manipulation, a greater chance of bleeding, and longer operation durations. Major
thoracic procedures with TEA and stellate ganglion blockade were first described by Al-Abdullatief et
al.28 in 2007. They analyzed a cohort of 79 patients, including 11 anatomic lung resections, with an
overall conversion rate of 11%, and only five patients went to the intensive care unit postoperatively.
Consequently, several investigators have proposed using non-intubated techniques in VATS anatomic
pulmonary resection in the hope of improving postoperative experience, and reducing hospital stay and
complications when compared with general anesthesia (Table 36.2). While many studies favor TEA,
intrathoracic intercostal block can also provide satisfactory intra- and postoperative analgesic
outcomes.29
FIGURE 36.3 Monitored anesthesia care during VATS procedure using non-intubated spontaneous ventilation anesthesia.
TABLE 36.2 Non-Intubated Thoracoscopic Surgery for Anatomic Pulmonary Resections
Studies No. Surgery Anesthetic Sedation Oxygen Conversion HS Com

Methodology Supplement Rate Rate
Chen et 30 Lob TEA+ vagal Yes F 10% 5.9 10.0%

al.30 blockade
bComparable: anesthetic and surgical duration, blood loss, lymph node; Improvements: complication, fast
Wu et 36 Lob TEA+ vagal Yes F 2.8% 6.7 25%

al.31 blockade
bComparable: blood loss, complication, HS, lymph node, surgical duration. Improvements: anesthetic dur
Chen et 217 Lob (n = TEA or Yes F Lob: 5.8%; — —

al.29 189); intercostal Seg: 7.1%
Seg (n = block+
28) vagal
blockade
Guo et 15 Seg TEA+ vagal Yes F or L 0 5 13.4%
al.32 blockade
Hung et 21 Seg TEA+ vagal Yes F 4.8% 6 4.8%
al.33 blockade
Liu et 26 Lob TEA+ vagal Yes F or L 4%c 9.5 6.7%
al.34 blockade
bComparable: blood loss, chest-tube dwell time; Improvements: antibiotic duration, drainage, fasting, HS
complications
Liu et 136 Lob (n = TEA+ vagal Yes F or L 7.0% 7.4 8.6%
al.35 116); blockade 6.0 15%
Seg (n =
20)
bComparable: blood loss, chest-tube dwell time, complication, surgical duration, lymph node; Improveme
fasting, HS
aGeneral anesthesia as control group.
bOutcomes comparing to intubated general anesthesia.
cIncluding other minor procedures.
HS, mean hospital stays; Lob, lobectomy; TEA, thoracic epidural anesthesia; F, fascial mask; Seg, segmentectomy; L, laryngeal mask.
More recently, Gonzalez-Rivas et al.17 reported the first non-intubated uniportal VATS right middle
lobectomy. Local intercostal infiltration was used without vagal blockade, and the patient was discharged
36 hours postoperatively. The same group also subsequently reported their preliminary experience of
uniportal non-intubated major pulmonary resection with promising results. In their series, only 2 of the 30
patients (6.6%) required intubation (one due to bleeding and the other because of excessive diaphragm
movement); however, the operations could still be completed with uniportal VATS.15
CONVERSION
The overall conversion rate of NITS to general anesthesia ranged from <1% to 9% based on reports
involving more than 1,400 patients from 15 institutions.13 The compelling reasons for conversion included
surgery-related events such as excessive adhesions (0.69%) or bleeding (0.34%) and anesthetic problems
such as mediastinal movement (0.34%), hypoxemia (0.27%), intractable cough (<0.10%), or hypercapnia
(<0.10%), with major procedures at greater risk. The decision to convert should be made jointly by the
attending surgeon and anesthesiologist. Intubation of a patient in the lateral decubitus position under
fiberoptic bronchoscopic guidance is challenging, but is within the skill set of many experienced
anaesthesiologists.30 During conversion, an insertion of a chest drain through the surgical incision with
covering by transparent waterproof dressing would allow re-expansion of the operated lung for optimal
oxygenation and lessen the mediastinal shift.
CONCLUSION AND FUTURE PERSPECTIVE

NITS has been shown to be technically feasible for nearly all forms of thoracic procedures and appears to
result in fewer perioperative complications as well as expedite postoperative recovery. Determining the
patient population that can benefit the most from this approach and the long-term outcomes of NITS will
require large multicenter randomized trials.36 Furthermore, with the development of ultra-minimally
invasive VATS techniques in the future,37 it is logical and inevitable that NITS will be part of the journey
to provide the least traumatic approach for surgical patients.
REFERENCES
1. David P, Pompeo E, Fabbi E, et al. Surgical pneumothorax under spontaneous ventilation-effect on oxygenation and ventilation. Ann
Transl Med 2015;3(8):106.
2. Kregenow DA, Swenson ER. The lung and carbon dioxide: implications for permissive and therapeutic hypercapnia. Eur Respir J
2002;20:6–11.
3. Pompeo E. Pathophysiology of surgical pneumothorax in the awake patient. In: Pompeo E. ed. Awake Thoracic Surgery (Ebook).
Sharjah, UAE: Bentham Science Publishers; 2012:9–18.
4. Ng CS, Arifi AA, Wan S, et al. Ventilation during cardiopulmonary bypass: impact on cytokine response and cardiopulmonary function.
5. Ng CS, Wan S, Ho AM, et al. Gene expression changes with a “non-injurious” ventilation strategy. Crit Care 2009;13(2):403.
6. Ng CS, Wan S, Wan IY, et al. Ventilation during cardiopulmonary bypass: impact on neutrophil activation and pulmonary sequestration. J
Invest Surg 2009;22:333–339.
7. Ng CS, Hui CW, Wan S, et al. Lung ischaemia-reperfusion induced gene expression. Eur J Cardiothorac Surg 2010;37:1411–1420.
8. Gothard J. Lung injury after thoracic surgery and one-lung ventilation. Curr Opin Anaesthesiol 2006;19:5–10.
9. Ng CSH, Yim APC. Thoracoscopic thymectomy. In: Patterson A, Pearson G, Cooper J. eds. Thoracic & Esophageal Surgery 3rd ed.
Philadelphia, PA: Churchill Livingston; 2008:1705–1719.
10. Ng CS, Wan IY, Yim AP. Video-assisted thoracic surgery thymectomy: the better approach. Ann Thorac Surg 2010;89:S2135–S2141.
11. Ho AM, Ng SK, Tsang KH, et al. A technique that may improve the reliability of endobronchial blocker positioning during adult one-lung
anaesthesia. Anaesth Intensive Care 2009;37:1012–1016.
12. Ho AM, Wan IY, Wong RH, et al. Provision of stable lung isolation in an unstable patient: an endobronchial blocker through the Murphy
eye of the in situ endotracheal tube. J Anesth 2011;25:454–456.
13. Mineo TC, Tacconi F. From “awake” to “monitored anesthesia care” thoracic surgery: A 15 year evolution. Thorac Cancer 2014;5:1–
13.
14. Ng CS, Wan S, Yim AP, et al. Pulmonary dysfunction after cardiac surgery. Chest 2002;121:1269–1277.
15. Gonzalez-Rivas D, Bonome C, Fieira E, et al. Non-intubated video-assisted thoracoscopic lung resections: the future of thoracic
surgery? Eur J Cardiothorac Surg 2016;49:721–731.
16. Pompeo E. Nonintubated video-assisted thoracic surgery under epidural anesthesia-Encouraging early results encourage randomized
trials. Chin J Cancer Res 2014;26:364–367.
17. Gonzalez-Rivas D, Fernandez R, de la Torre M, et al. Single-port thoracoscopic lobectomy in a nonintubated patient: the least invasive
procedure for major lung resection? Interact Cardiovasc Thorac Surg 2014;19:552–555.
18. Davies RG, Myles PS, Graham JM. A comparison of the analgesic efficacy and side-effects of paravertebral vs epidural blockade for
thoracotomy—a systematic review and meta-analysis of randomized trials. Br J Anaesth 2006;96:418–426.
19. Kiss G, Castillo M. Nonintubated anesthesia in thoracic surgery: general issues. Ann Transl Med 2015;3(8):110.
20. Kiss G, Castillo M. Non-intubated anesthesia in thoracic surgery-technical issues. Ann Transl Med 2015;3(8):109.
21. Hedenstierna G, Edmark L. The effects of anesthesia and muscle paralysis on the respiratory system. Intensive Care Med
2005;31:1327–1335.
22. Pompeo E, Tacconi F, Mineo D, et al. The role of awake video-assisted thoracoscopic surgery in spontaneous pneumothorax. J Thorac
23. Pompeo E, Rogliani P, Tacconi F, et al. Randomized comparison of awake nonresectional versus nonawake resectional lung volume
reduction surgery. J Thorac Cardiovasc Surg 2012;143:47–54.
24. Matsumoto I, Oda M, Watanabe G. Awake endoscopic thymectomy via an infrasternal approach using sternal lifting. Thorac
Thorac Surg 2004;78:1761–1768.
26. Tsai TM, Chen JS. Nonintubated thoracoscopic surgery for pulmonary lesions in both lungs. J Thorac Cardiovasc Surg 2012;144:e95–
e97.
27. Rocco G, Romano V, Accardo R, et al. Awake single-access (uniportal) video-assisted thoracoscopic surgery for peripheral pulmonary
nodules in a complete ambulatory setting. Ann Thorac Surg 2010;89:1625–1627.
28. Al-Abdullatief M, Wahood A, Al-Shirawi N, et al. Awake anaesthesia for major thoracic surgical procedures: an observational study.
29. Chen KC, Cheng YJ, Hung MH, et al. Nonintubated thoracoscopic surgery using regional anesthesia and vagal block and targeted
sedation. J Thorac Dis 2014;6:31–36.
30. Chen JS, Cheng YJ, Hung MH, et al. Nonintubated thoracoscopic lobectomy for lung cancer. Ann Surg 2011;254:1038–1043.
31. Wu CY, Chen JS, Lin YS, et al. Feasibility and safety of nonintubated thoracoscopic lobectomy for geriatric lung cancer patients. Ann
Thorac Surg 2013;95:405–411.
32. Guo Z, Shao W, Yin W, et al. Analysis of feasibility and safety of complete video-assisted thoracoscopic resection of anatomic
pulmonary segments under non-intubated anesthesia. J Thorac Dis 2014;6:37–44.
33. Hung MH, Hsu HH, Chen KC, et al. Nonintubated thoracoscopic anatomical segmentectomy for lung tumors. Ann Thorac Surg
2013;96:1209–1215.
34. Liu J, Cui F, Li S, et al. Nonintubated video-assisted thoracoscopic surgery under epidural anesthesia compared with conventional
anesthetic option: a randomized control study. Surg In 2015;22:123–130.
35. Liu J CF, Pompeo E, Gonzalez-Rivas D, et al. The impact of non-intubated versus intubated anesthesia on early outcomes of video-
assisted thoracoscopic anatomical resection in non-small-cell-lung cancer: A propensity score matching analysis. Eur J Cardiothorac
Surg 2016;50(5):920–925.
36. Zhao ZR, Lau RWH, Ng CSH. Non-intubated video-assisted thoracic surgery: The final frontier? Eur J Cardiothorac Surg
2016;50(5):925–926.
37. Ng CS. Uniportal video assisted thoracic surgery—a look into the future. Eur J Cardiothorac Surg 2016;48(S1):i1–i2.
37
Extended Resection of Pulmonary
Carcinoma Including Chest Wall and
Mediastinum
Kelvin Lau
BACKGROUND OF EXTENDED RESECTION
HISTORY AND STAGING

Since Evarts Graham performed the first successful pneumonectomy for lung cancer in 1933, surgery
became a mainstay for treatment of localized lung cancer. However, tumors extending outside the lung,
including the bony thorax, were for a long time felt to be unresectable, until Coleman1 first reported five
cases of block excision of the chest wall with lung resection (including four pneumonectomy) and
regional lymph nodes in 1947.
Locally advanced lung cancer comprise of two distinct groups: those with direct contiguous invasion
of a neighboring organ, and those with noncontiguous spread, the most common being regional nodal
(lymphatogenous) spread. The former is managed by local treatment often with radical intent, while the
latter requires systemic therapy. This chapter concerns itself with the surgical management of locally
invasive cancer with direct invasion of neighboring structures of the lung.
Until recent times, doubt persisted as to the value of resection for locally invasive lung cancer. As
surgery progressed and became more common, and more prognostic data became available, its role
became clearer and this is reflected by changes in the staging systems. The early TNM systems developed
in the 60s and 70s by consensus grappled with meaningful definition of the descriptors, and tumors that
extended beyond a single lobe were grouped into one category (T3). In the fourth edition of the TNM
staging system, Cliff Mountain2 noted the observation by oncologists that subgroups of these patients did
better than those that were in general not operable, and so the T3 category was subdivided into T3—
representing those tumors that were candidates for resection (e.g., chest wall invasion), and T4
—“unresectable locally advanced NSCLC” (e.g., invasion of the heart), thus recognizing the association
between resectability and better prognosis.
As surgical, anesthetic, imaging, and critical care techniques improve, the outcomes of extended
resection improve as do the boundaries of what is considered resectable. Most neighboring structures of
the lung have at some point been resected and reconstructed. The subsequent revisions of the TNM staging
system noted better outcomes in some locally invasive tumors than expected for their stage grouping. This
led to a change of stage grouping of T3N0M0 tumors from stage IIIa to stage IIb in the 6th edition, and
T4N0–1M0 from stage IIIb to stage IIIa in the 7th edition. Similarly, in the latest staging database, tumors
within 2 cm of the carina that were previously classed as T3 were found to have no prognostic difference
compared to those >2 cm from the carina (T2), and so have been revised down to T2 in the current 8th
edition of the TNM. These changes in stage groupings in part not only reflect a better and more data
driven understanding of lung cancer biology, but they also reflect improvements in treatment outcomes for
these disease subgroups.
OUTCOMES
The incidence of resectable locally advanced tumors is low. In most registry studies, the incidence of
resected T3 or T4 disease in all lung cancer is only 4% to 10%3–5 and our understanding of outcomes is
mainly accrued from small, retrospective, descriptive studies.
The outcomes of T3 and T4 disease resection are good and often surpasses the outcome predicted by
disease stage. In general, surgery for T3 disease is safe with in-hospital mortality of 3%, and 5-year
survival rate of over 40%. The main predictors of outcomes are consistently nodal status and
completeness of resection.5,6 Of these, completeness of resection is a surgeon modifiable outcome and a
crucial determinant of long-term survival. In one series, the long-term survival of incomplete resection
approximates those who did not undergo resection.7 Resection of T4 disease is more challenging due to
involvement of vital organs, and the operative mortality is correspondingly higher at 4% to 9%.3,4,8 The 5-
year survival rate is generally 20% to 30%, but over time, the results have been improving and for many
T4 tumors the 5-year survival rates reach 40% to 50%.3
Nevertheless, T3 and T4 disease represent a very heterogeneous and nonoverlapping group of patients
with involvement of different anatomical structures and different operations, making meaningful
extrapolation to an individual patient’s case difficult. Furthermore, many papers report outcomes of
surgically treated stage III disease but including in their studies varying proportions of N2 and N3
disease. These aggregate outcomes are difficult to disentangle, and make comparisons and conclusions
about which treatment strategy is better, difficult.
ASSESSMENT
Resection of T3 and T4 tumors are very involved operations. They frequently require a pneumonectomy
and have higher mortality and morbidity than conventional lung resection. As would be expected from the
aggressive behavior of these tumors, they are also more prone to recurrence following surgery. Because
these are higher-risk operations that are less likely to effect a cure for patients, the careful selection of
patients and attention to detail in the perioperative care are paramount to ensure the potential benefits
outweigh the risks and the outcomes are good.
The accurate assessment of resectability is important to avoid understaging and consequent operating
on patients who are unresectable, and overstaging, where patients would be denied the opportunity for
curative treatment. Depending on the neighboring organ involved, different modalities are required for
accurate assessment of their involvement. Extent of T3 chest wall tumors is generally adequately assessed
by computed tomography and almost all are resectable. Superior sulcus tumors may additionally require
magnetic resonance imaging to assess involvement of the subclavian vessels and brachial plexus to
anticipate and plan resection and reconstruction. Cardiac involvement require cardiac magnetic resonance
to delineate the extent of myocardial involvement.
Of patients with clinical T4 disease, many have extensive and metastatic disease and less than 10%
undergo resection.4 For patients with borderline invasion, the ability to recognize true mediastinal
invasion by radiology is notoriously unreliable and clinical stages more commonly overstage rather than
understage the disease.9 In many instances, where there is juxtaposition between a tumor and an organ, it
is often not possible to distinguish noninvasion, inflammatory adhesions, superficial involvement of the
mediastinal pleura or pericardium, or underlying organ invasion. Even where there is intravascular
protrusion or extension of a tumor, the mural margins of the tumor can be difficult to appreciate on
imaging. New radiologic techniques are being developed to help improve the accuracy of T-stage
assessment.10 In the event of borderline disease suspicious of local advanced invasion, one should
consider giving the patient the benefit of the doubt and offer surgery; the alternative would be to deny
them the opportunity of complete resection and a chance of cure. At a population level, such a strategy is
accompanied by a modest rise in surgical risk but much greater improvement in population survival
outcomes.11
Nodal involvement and incomplete resection are the two poor prognostic factors consistently reported
for patients undergoing surgery. N2 disease is associated with a 1.5 to 2 fold increased risk of death
compared to N0/N1 disease.4,5 In the absence of randomized data comparing surgical and nonsurgical
treatment of T4N2 disease, there is considerable variation in the management of this group of patients,
ranging from up front surgery, induction therapy, and selection for patient with good response for surgery,
to definitive chemoradiation. Nevertheless, thorough mediastinal assessment is crucial to avoid offering
futile and morbid treatments. While a negative PET-CT is adequate mediastinal staging for many units for
early lung cancer, routine EBUS and mediastinoscopy are undertaken in many centers for pathologic
confirmation of the lack of nodal involvement in patients with T3 and T4 tumors, prior to embarking on
surgery. However, it is important to be aware of the possibility that central primary tumors can be
unsuspectingly biopsied instead of nodes, leading to a false-positive diagnosis of nodal involvement.12
CONTROVERSIES
Induction Treatment
Induction therapy has been used to increase the likelihood of complete resection and downstage nodal
disease prior to surgical resection, and in some case to render unresectable disease resectable. While
there are randomized studies examining the role of induction therapy in N2 disease, this is not the case for
locally invasive T3 and T4 disease. Nevertheless, the long-term outcome of T3 and T4 disease treated
with primary surgery is disappointing with 5-year survivals of 20% to 50%, and furthermore, a significant
number of patients with supposed node-negative T3/T4 disease were found to have pathologically
involved nodes at surgery,13 therefore many units offer induction treatment as part of multimodality
therapy for these patients in an attempt to improve outcome.
The regimen for induction therapy varies from unit to unit, and may involve chemotherapy or
chemoradiation. Even within these modalities, the chemotherapy regimen and the radiotherapy dose vary.
On the one hand, there is a dose–response relationship for radiotherapy,14 on the other, the operative risks
are higher following high-dose radiation, and hence initial radiotherapy regimens were limited to lower-
dose radiation of approximately 45 Gy. Subsequent studies showed surgery following high-dose
preoperative radiotherapy of 60 to 70 Gy can be carried out with acceptable surgical risk, even with
pneumonectomy, and achieves a higher pathologic complete response rate.15–17 Whether this translates to
improved long-term survival is less clear, with several recent meta-analyses reporting no long-term
survival benefit with the addition of radiation to the induction therapy regimen.18–21
Induction therapy and especially high-dose radiation causes tissue fibrosis and loss of tissue planes,
pneumonitis and poor tissue healing, and hence an increased risk of surgical complications including
difficult intraoperative dissection and bleeding, increased risk of bronchopleural fistula and respiratory
failure. Nevertheless, meticulous care to surgical techniques and perioperative care can help prevent
many of these complications. There are several principles in the surgical care of the patient who
underwent induction therapy.
Consideration should be made of harvesting an intercostal flap to reinforce the bronchial stump at the
time of thoracotomy. The flap should be taken with electrocautery at a low setting to avoid attendant
damage to the intercostal vessels. It is taken based on the posterior pedicle and should be taken as long as
possible anteriorly to avoid traction when attached to the bronchial stump. It should be kept moist in a wet
gauze during the operation to avoid it drying out.22
Dissection of the adherent pulmonary artery branches can be made safer by control of the main
pulmonary artery centrally. The bronchial dissection should be careful to assure a satisfactory margin
without excessive devascularization, and the stump should be buttressed with a viable flap as described
above. After testing the bronchus for air leak, the flap is parachuted down with the pleural aspect in
contact with the bronchus, and secured circumferentially to the soft tissue around the stump.
A lung protective regimen is necessary and begins with good analgesia, including in most cases a
thoracic epidural. Where possible a pneumonectomy is avoided using bronchoplastic and angioplasty
techniques. Furthermore, it can be difficult to differentiate at operation between tumor and scar tissue
without viable tumor. Where in doubt, the extent of resection should be assessed by frozen section, both to
assure a negative margin and to avoid overzealous resection in particular where a pneumonectomy can be
avoided. Postoperatively, care should be taken to avoid fluid overload especially since many T4
dissection calls for a pneumonectomy. Hypotension and oliguria resulting from the epidural should be
treated by titrating the infusion and use of vasopressors and only judicious use of filling.
The added benefit of induction therapy for node negative T3 and T4 disease has only been examined in
observational studies. Lococo et al. reported a retrospective series of 71 patients with T3–T4N0 non–
small-cell lung carcinoma, comparing patients who received induction chemoradiotherapy with those
treated with surgery first. Induction therapy was associated with 85% downstaging of the T-stage, but no
difference in 5-year survival. However, the authors noted that patients in the induction therapy group had
more advanced disease at presentation.13 Similarly, in a large series of 3,791 cT3N0M0 patients from the
National Cancer Database, Andersen et al.21 found that while induction treatment increases the complete
resection rate, it does not improve long-term survival.
Pneumonectomy
Of the lung resections, pneumonectomy is associated with the highest morbidity and mortality.23 Locally
advanced tumors involving the hilum and mediastinum frequently requires a pneumonectomy. At the same
time, systemic therapy has been shown to improve overall survival in some patients with locally
advanced disease. The addition of induction radiotherapy further increase the complete pathologic
response rate in a dose dependent manner and has been used to both improve the outcomes of resected
patients, and to ensure local treatment is not delayed for those who do not ultimately undergo resection.24
Induction therapy however, impacts on tissue healing and lung function, and could adversely affect the
outcomes of surgery, leading to reluctance for widespread adoption.
Early series of pneumonectomy following induction therapy reported high perioperative morbidity and
mortality. Fowler et al.25 reported 40 patients who underwent resection following concurrent
chemoradiotherapy with a dose of 60 Gy. Of the seven patients who underwent pneumonectomy, the
mortality rate was 43%. Many series subsequently substantiated the findings of high mortality and
morbidity, especially with right pneumonectomy.26–29 The risks also appear higher where higher dose of
radiotherapy was used. These findings were corroborated by multicenter, randomized trials. In the
EORTC 08941 study, patients with unresectable N2 disease were randomized following induction
chemotherapy to either surgery or radiotherapy. Patients who underwent pneumonectomy following
chemotherapy had a 7% mortality rate.30 This contrast with the INT0139 trial, where patients with N2
disease treated with concurrent chemotherapy and 45 Gy radiotherapy were randomized to surgery or
further radiotherapy, patients who underwent pneumonectomy following concurrent chemoradiotherapy
experienced a 26% mortality rate.31 These results have led some to conclude that pneumonectomy should
be avoided following induction chemoradiotherapy. Conversely, if pneumonectomy is anticipated,
preoperative radiation should be avoided.
The main causes of morbidity and mortality from pneumonectomy following induction
chemoradiotherapy are respiratory failure and bronchopleural fistula. Fowler’s initial series reported
among patients who underwent pneumonectomy following high-dose induction chemoradiotherapy to 60
Gy, 71% developed pulmonary infiltrates, and 26% developed a bronchopleural fistula. Several
strategies have since been adopted to mitigate these risks. In particular, careful patient selection, refined
radiotherapy techniques to reduce overall pulmonary toxicity, attention to perioperative care including
avoiding fluid overload by fluid restriction, diuresis and maintaining a negative fluid balance, and
meticulous buttressing of the bronchial stump with vital tissue.
Over the past few years, a number of groups have reported more favorable results of pneumonectomy
following induction chemoradiotherapy, showing this could be carried out safely. In a small series,
Sonnett and colleagues32 reported six pneumonectomies following high-dose radiotherapy (mean 61.8 Gy)
with no mortality and Steger and colleagues33 reported 78 pneumonectomies after sequential
chemoradiotherapy with 36 to 45 Gy with a 30-day mortality of 5.1% and 90-day mortality of 7.7%. In a
larger series and follow-up from their initial publication of high mortality from pneumonectomy of 11.3%
(23.9% for right pneumonectomy),26 Barnet et al.34 (2011) re-examined their contemporary outcomes 10
years on and showed that the mortality rate in their series of 70 pneumonectomy following induction
chemoradiotherapy with 50 Gy irradiation has dramatically improved to 4.3% (3.3% for right
pneumonectomy) over this period. In a similar vein, Weder35 (2010) reported a two-center study of 176
pneumonectomies (including 78% with extended resections) following induction therapy of which 80%
received induction chemoradiotherapy to 45 Gy. The 90-day mortality rate was 3%.
The long-term outcome following induction chemoradiotherapy and pneumonectomy remains guarded
with a 5-year survival of 20% to 40% despite frequent pathologic complete response and high complete
resection rates. Nevertheless, interpretation is fraught with difficulties due to heterogeneity between
series, in particular the variable contribution of patients with T3, T4, N2, and N3 disease and
combination thereof. Furthermore, there is significant variation in practice between different units,
countries and continents, this is due in part to inconsistent evidence for a correlation between the use of
high-dose radiotherapy, higher complete response and complete resection rates and its translation to
longer overall survival. It remains to be proven that while surgery can now be safely carried out
following high-dose radiotherapy, this strategy confers a survival benefit that justify the higher risk.24
Recent meta-analyses investigating the incremental survival benefit of radiotherapy over that of induction
chemotherapy alone have indeed questioned the added value of radiotherapy on long-term survival.18,20
CHEST WALL
In 1947, Frank Coleman described seven patients with lung cancer invading the chest wall, of which five
underwent chest wall resection with lung resection (four pneumonectomy and one “palliative lobectomy”)
and noted the poor outcomes of untreated patients. He concluded “successful treatment embraces block
resection of the chest wall leaving a margin of healthy tissue attached to the involved structures, total
pneumonectomy and resection of the regional lymph nodes”.1 Seventy years on, the same principles of
complete resection and accurate lymph node staging remains.
Lung cancer invading the chest wall is rare and occurs in 5% of lung cancers.36 No clinical factors can
reliably predict chest wall invasion. Severe pain is suggestive of chest wall involvement but does not
occur in all patients.37 Imaging is more sensitive when frank extension of tumor occurs into the intercostal
space or there is finding of bony destruction, but tumor in contact with the chest wall can represent
apposition without invasion, the presence of nonmalignant inflammatory adhesions, invasion of parietal
pleural or deep invasion into the musculoskeletal chest wall. Imaging modalities such as CT, MRI, and
PET-CT are useful for determining involvement of neighboring structures such as spine and diaphragm,
but are neither sensitive nor specific for evaluating the presence of invasion of tumors merely abutting the
chest wall.38 Given that the presence and exact depth of the chest wall invasion does not preclude surgery,
decision making concerns itself less with the decision to operate than the operative strategy itself.
Nodal disease is a very poor prognostic factor for tumors invading the chest wall. In the 8th edition of
the lung TNM staging system, T3N0 remains stage IIb disease whereas any nodal involvement upstages
the cancer to stage III disease with N1,2, and 3 involvement fitting the prognoses of stages IIIa, b, and c,
respectively. Patients with T3N0M0 undergoing complete resection have a 5-year survival of 40% to
50%, whereas patients with N2 involvement has a 5-year survival of 4.6% to 15%.7,39,40 Careful
assessment of the mediastinum with PET-CT and mediastinal sampling is therefore essential to identify
those with N2 and N3 disease for induction or definitive chemotherapy and radiotherapy.
Combined chest wall and lung resection is a more morbid operation than either chest wall resection or
lung resection alone, and is associated with an operative mortality of about 6%.36 The chest wall plays a
significant role in ventilation and therefore chest wall resection often compounds the respiratory
impairment following lung resection. Indeed chest wall resection causes a significant and long-lasting
restrictive defect.41 Respiratory complications develop in 11% to 25% of patients, of which over 40%
are grade 4 or 5, and are responsible for 70% of the mortality associated with this operation. These are
much more likely to occur in concomitant lung resection and chest wall resection,42–44 and the degree of
respiratory compromise is proportional to the extent of chest wall resection.44,45 Careful selection of
patients with adequate lung function and attention to preoperative optimization, pain control,
postoperative physiotherapy and bronchial toilet are essential to minimize this respiratory complications.
Despite complete resection for T3N0 tumors invading the chest wall, the 5-year survival for this group
remains 40% to 50%, and control of distant recurrence remains the holy grail for cure after complete
resection. With the encouraging results of induction chemoradiotherapy improving long-term outcomes for
superior sulcus tumors,46 the question of whether tumors invading the chest wall could also benefit from
induction therapy is naturally raised. The evidence for induction treatment for lung cancer invading the
chest wall but not involving the superior sulcus has so far been wanting, however a recent phase II trial
from Japan shed some encouraging light reporting an overall 5-year survival of 63% in T3N0/1 lung
cancer invading the chest wall following induction chemoradiation to 40 Gy.47
The role of adjuvant radiotherapy following complete resection is controversial. In the presence of
complete resection, some question whether local radiotherapy adds to disease control. After all, two-
thirds of recurrences are distant for which radiotherapy may not be effective at controlling. The reports in
the literature are conflicting with some series showing a benefit and others not.37,48–50 Furthermore, there
is an intrinsic bias in retrospective series where patients at higher risk of recurrence were more likely to
receive adjuvant radiotherapy.
PLAN
Prior to the operation, the plan for the approximate extent of resection and reconstruction should be clear,
and preparations made for the reconstruction prosthesis to be available. Where extensive soft tissue
coverage is required, early discussion with a plastic surgeon would be vital to coordinate the operative
steps and to protect potential flaps from damage during thoracotomy.
The anesthetic strategy is as for lung resection, with lung isolation with a double lumen tube or
bronchial blocker. Consideration should be given for regional blocks such as epidural catheter, especially
where the tumors lies very posteriorly precluding the placement of intercostal or paravertebral catheters.
Most lung cancer tumors invading the chest wall do so posteriorly and can be approached through a
posterolateral thoracotomy with the patient in the lateral decubitus position. In the less common scenario
of invasion of the anterolateral chest wall, the patient can be positioned tilted backward to enable better
access to the anterior chest wall.
TOOLS
Chest wall resection requires the exposure and division of ribs at a distance away from the tumor.
Periosteal elevator is used for subperiosteal dissection of the rib from the intercostal muscle, and
different angled rib cutters and ring costotomes can be used to divide the rib. The periosteal or Cobb
elevator can be used to disarticulate the head of the rib by levering off the vertebrae following sharp
division of the costotransverse ligament for tumors extending posteriorly.51
The first rib presents a unique problem of being thick, flat, and in close proximity to the subclavian
vessels. First rib shears or a Gigli saw passed using a right angle instrument can be used to divide this
rib.
Division of ribs in thoracoscopic chest wall resection can be carried out through open incisions and
use of open instruments through the incision, or can be carried out from within the chest with
thoracoscopic rib cutters. Thoracoscopic first rib cutters developed for thoracic outlet syndrome surgery
are also available.
Following resection, reconstruction of the chest wall defect depends on the size of the defect and the
material used. The options include simple mesh repair for small defects, rigid repair with polypropylene
mesh-methyl methacrylate composites, and hybrid repairs with artificial ribs. Newer materials include
biologic materials which have the theoretical advantage of being replaced by the body’s own tissue over
time and incorporated into the body, and thereby being more resistant to infection. Lung cancer invading
the chest wall rarely invades the soft tissue sufficiently to require extensive soft tissue resection.
However, in those rare circumstances soft tissue cover through pedicled and rarely free flaps may be
required and close collaboration with plastic surgeons may be required.
TACTICS
Most combined lung and chest wall resections can be approached through a posterolateral thoracotomy.
The incision is planned to allow access to the full extent of the resection. The pleural space is entered
away from the tumor so as not to disrupt the tumor and to enable en bloc resection. The tumor is then
palpated through the space and the chest wall resection carried out with a clear margin. While complete
resection is the most important prognostic factor for this operation, there is no consensus agreement for a
minimal margin necessary and different authors variably recommend from at least 1 cm to over 4
cm.37,52,53 In general, for lung cancer most authors advocate an uninvolved rib space above and below the
tumor, and at least 1 cm anterior and posterior to the macroscopic tumor margin in order to ensure a
microscopically clear margin.37,52 Thoracoscopy may be carried out prior to thoracotomy to assess
resectability. The better visualization also facilitates the selection of interspace for entry into the chest
and site of chest wall division under direct vision.
Following chest wall resection, the divided chest wall is dropped en bloc into the chest attached to the
tumor and lung. Lung resection is then carried out in a standard manner, facilitated by the opening created
by the chest wall defect.
After removing the specimen, consideration is given to reconstruction of the chest wall defect. In
general, defects smaller than 5cm or those protected by the scapula do not require reconstruction.
However, if the defect is in the vicinity of the tip of the scapula, reconstruction is required to prevent
impingement and entrapment of the scapula. Larger chest wall defects require reconstruction to prevent a
flail type respiratory defect and significant loss of volume.
Following reconstruction, adequate draining of the pleural space is required, especially because
subsequent insertion of chest drains through an area of reconstruction can be challenging. Seromas can
form in the wound; use of fenestrations in the reconstruction and suction drainage of the spaces can help to
reduce seroma formation.
TECHNIQUE
In some instances where the tumor invades only the parietal pleural, it is possible to resect the tumor with
extrapleural dissection if there is a clear extrapleural plane, without proceeding to full thickness chest
wall resection. This approach is controversial. While some authors report equivalent long-term results
for patients with extrapleural resection compared to full chest wall resection when there is only parietal
pleural invasion,7,40,54,55 others found inferior results with this technique.49 The importance of complete
resection in determining prognosis cannot be overstressed, and where there is any doubt about
completeness of resection, an en bloc full thickness chest wall resection should be considered.
As lung resections become more commonly carried out by thoracoscopy, so has chest wall resection.
This approach allows division of the ribs and retrieval of the specimen through the resected window
without scapular retraction or rib spreading of the rest of the chest wall, and therefore theoretically
reducing surgical trauma. This can be carried out in a hybrid fashion with a thoracoscopic lung resection
followed by chest wall resection through a counter incision over the lesion,56 or entirely
thoracoscopically with the specimen retrieved through the utility incision or through a subxiphoid
incision.57,58 The bony chest wall can be divided using conventional rib cutters or Gigli saw, or
alternatively, dedicated thoracoscopic rib cutters and shears as well as high speed drills have been used
to allow deployment through the utility incision.59,60 Energy devices are used to facilitate division of soft
tissue including intercostal muscles and development of the extrathoracic plane.57 Following resection,
chest wall reconstruction can then be carried out directly through the counter incision, through the utility
incision, or using a needle suture passer and stab incisions through the chest wall.57
Reports of thoracoscopic lung and chest wall resections remain sparse and studies are anecdotal or
small with no long-term outcomes. In one retrospective study on combined lung and chest wall resection,
17 patients who underwent VATS resection did not differ in overall morbidity or 90-day mortality rate
compared to 30 open resections, despite a shorter intensive care and in-hospital length of stay.61
Nevertheless the causes of deaths were different and those who underwent open resection were more
likely to succumb to respiratory complications.
Where the size of the chest wall defect is large or close to the scapular tip, the chest wall can be
reconstructed with a wide range of materials. There is no evidence based recommendation for a threshold
size of defect beyond which reconstruction is necessary. In fact, some authors do not routinely reconstruct
the chest wall37,62 but most authors recommend any defects over 5 cm, or over 10 cm in posterior chest
wall, or those involving four or more resected ribs should be reconstructed.42,63
The main objectives of the reconstruction are to preserve respiratory function by preventing
paradoxical movement, loss of volume of hemithorax and lung herniation, to protect the organs beneath,
and to prevent scapular entrapment. The ideal material was described as one which is both rigid and
malleable to prevent paradoxical movements while conforming to the shape of the chest, inert to allow
tissue ingrowth and prevent infection, and radiolucent to allow radiologic follow-up of the disease.64
This can be achieved by a rigid prosthesis, or nonrigid prosthesis pulled taut across the defect. Early
prosthesis were made from autologous tissue such as ribs, bone grafts and fascia but this requires
additional incisions and the associated morbidity of the donor site.65
Nonrigid reconstructions include muscle flaps and prostheses which include polypropylene and
polyglactin meshes and expanded polytetrafluoroethylene (ePTFE). Muscle flaps have the advantage of
being autologous and are resistant to infection and are suited to smaller defects where chest wall stability
is less of a problem.66 The meshes are porous and can reduce the formation of seromas and allow tissue
ingrowth, while ePTFE is a thicker material which allows for a more watertight seal, is more resistant to
adhesion formation but is resistant to tissue ingrowth.67
One of the most feared complication of chest wall repair is infection of the prosthesis which could
require explantation. This is more of a concern in ulcerated and infected chest wall tumors rather than in
lung cancer invading the chest wall where superficial erosion is rare. However, this concern has fueled
interest in the use of biologic prostheses in chest wall reconstruction. Absorbable meshes have been used
in infected fields because over time the mesh is reabsorbed and so does not require removal. Biologic
prostheses are decellularized animal or human tissue which retains the collagen matrix allowing tissue
and vascular ingrowth. Over time the prosthesis is incorporated into the body’s tissue with further laying
down of extracellular matrix, while the original matrix is resorbed, thus avoiding the problem of chronic
infection of a foreign body. Pre-modification of the material such as by crosslinking the collagen fibers
allows the duration of biopersistence to be varied. A large variety of prosthesis currently exists on the
market, they differ in their tissue and animal of origin, strength, and persistence in the body. Early results
indeed do suggest that biologic prostheses can be put in infected fields, and conversely infected biologic
prosthesis for chest wall reconstruction can be managed without explantation.68,69
Rigid reconstruction allows contouring of the prosthesis to the chest wall topology, better preserving
chest volume and shape, and so it is more often used following large resections where a taut non-rigid
prosthesis would “cut” into the chest cavity. It also provides protection of organs such as following
anterior chest wall resections, as well as improved cosmesis by avoiding the concavity defect arising
from a nonrigid anterior reconstruction. Again, there are no evidence based recommendations for what
size defects benefit more from repair with a rigid construct.70 Some authors recommend using rigid
constructs for posterior defects over 10 cm or anterior and lateral defects over 5 cm. The most commonly
used rigid prostheses consists of a layer of methyl methacrylate (MM) sandwiched between two layers of
polypropylene mesh which is prepared intraoperatively and moulded to the shape of the chest wall
defect.71 The methyl methacrylate construct is cut leaving a free margin of mesh to allow stitches to be
passed through. The disadvantages of rigid constructs include respiratory restriction, fatigue fractures
from repetitive respiratory movements, and migration of fragments of the hard material within the chest.
Variations of this mesh include the application of methacrylate in a cross-hatched fashion to allow better
fluid drainage and improved tissue ingrowth into the construct.43 This may also add a degree of flexibility
to the repair.
There is some evidence that rigid constructs may better preserve postoperative respiratory function
and reduce respiratory complications, however, in a large study of 262 patients who underwent chest wall
resection with or without reconstruction for a range of pathologies, there was no significant differences in
overall or pulmonary complication rates between rigid and nonrigid reconstructions, but wound
complications were significantly more common with rigid constructs. Nevertheless, they also included
one case where respiratory failure developed in a patient who received a nonrigid prosthesis, but who
made an uneventful recovery following replacement with a rigid prosthesis.43
The development of osteosynthesis systems for fixation of rib fractures also led to their use in chest
wall reconstruction, with the main difference being the use of the prosthetic metallic bars to bridge gaps.
Current systems include prefabricated bars that lock onto the rib stumps with a crimping tool (StraTos,
MedXpert, Germany) or with screws (DePuy Synthes, USA), and customizable 3D printed titanium
prostheses.72 The attraction of these systems is the better mimicry of ribs, theoretically allowing more
natural respiratory movements thus allowing better restoration of both anatomical and physiologic
function.73,74 While they allow contouring to the chest wall, they do not need to be placed at every single
rib level. Because of the spaces between the bars, it is usual to incorporate a mesh or soft tissue cover
which could be placed either inside or on both sides of the bars.53,75 Placement of cover over the bars
could prevent entrapment of the scapula on the bars especially where there is deficient soft tissue cover.
Early results suggest that osteosynthesis reconstruction with titanium plates is associated with low
perioperative mobility,53 however a follow-up of the largest series revealed a high rate of implant
fracture and displacement, requiring reoperation in 44% of patients. The median time to failure was 6.6
months.76 This reflects the orthopedic principle that in the absence of union even the strongest metal will
break eventually.77 Of note, only 7 of 24 patients with implant failure were symptomatic, and in 7 patients
the hardware failure could not be appreciated on the chest radiograph and was only seen on the computed
tomography scans. This highlights the importance of close CT follow-up, and the need for improvement in
both technique and technology to refine the quality and durability of this type of reconstruction.
TROUBLE SPOTS
It is essential to obtain a satisfactory margin to ensure complete resection. For tumors extending
posteriorly, it may be necessary to disarticulate the rib from its vertebral insertion with or without
resecting the transverse process.51 If the tumor invades the spine, a vertebral resection may be required.
The most common sequence of en bloc resection is chest wall followed by lung resection, however,
occasionally the location of the chest wall attachment may provide a convenient retraction of the lung. In
this situation the lung resection can be carried out first, especially when a thoracoscopic approach is
used.56 When adjacent structures such as spine or major vessels are involved, thorough planning and
coordination with other specialties such as spinal surgery to design a strategy suitable for a particular
case is required to allow ease of operation while ensuring accurate assessment of resectability prior to
committing irreversibly to a complex resection.
A particularly difficult area for reconstruction is the costal margin where failure is more common.78
Resection in this area may also involve the diaphragm and abdominal wall, reconstruction requires
creativity in planning the prosthesis and early involvement of plastic surgeons.79
For thoracoscopic chest wall and lung resection, it is essential to plan the utility incision away from
the tumor and to optimize the approach for both resections, and assessment from the other thoracoscopic
ports helps to identify the optimal position. Following resection, the reconstruction prosthesis can be
sutured in place either through the utility incision or through separate stab incisions.57
Another area of controversy is the combination of pneumonectomy and chest wall resection. Many
reports confirm the high risk associated with addition of chest wall resection to pneumonectomy with
mortality risks as high as 44%43 and some authors recommend avoiding this operation.40 Other centers
have reported good results with this operation. Cardillo and colleagues reported an overall mortality rate
of 2.9% for combined pneumonectomy and chest wall resection, with 7.1% mortality for right-sided
operations. They attribute their good results from careful selection of patients with near normal lung
function and institutional experience.80
SUPERIOR SULCUS
Tumors invading the thoracic inlet, variably called Pancoast tumor, superior sulcus tumors and thoracic
inlet tumors, were first recognized as a clinicoradiologic entity in 1924 by Henry Pancoast,81 who
correlated apical tumors with the clinical triad of shoulder pain radiating to the arm, Horner’s syndrome
and muscle wasting of the hand. Tobias,82 an Argentinian surgeon, subsequently recognized the nature of
the tumor as bronchogenic carcinoma. Subsequent to this, apical tumors of variable degrees of invasion
and extent have been called “Pancoast tumors.” To avoid confusion and allow meaningful comparison of
results, Detterbeck83 proposed a definition of Pancoast tumors to include only tumors that involve the
apical chest wall above the level of the first rib, with at least parietal pleural invasion, and regardless of
the presence of symptoms.
Advances in surgical approaches and techniques from various specialties such as instrumentation in
spinal surgery have allowed these tumors, which were previously considered unresectable, to be
radically treated. Outcomes with radiotherapy alone was dire84 but early studies of radiotherapy
combined surgery showed promising results with 5-year survival rates of 34% and 10-year survival rates
of 29%.85 The landmark Southwest Oncology Group Trial 9416 (Intergroup 0160) further showed the
value of multimodality therapy with induction chemoradiation to 45 Gy followed by resection achieved a
76% complete resection rate and overall 5-year survival of 44%, 54% for those with complete
resection.46,86 These outcomes were reproduced in other series87–89 and induction chemoradiotherapy
combined with surgery is now incorporated in many guidelines as the standard of care. Nevertheless, with
this treatment strategy, 80% of treatment failure were due to distant recurrence, and attempts were made to
improve systemic control with consolidation adjuvant chemotherapy. However, a phase II study of
induction chemoradiation and surgery followed by adjuvant docetaxel found only 45% patients were able
to complete the treatment course, while distant recurrences remained a problem.90
PLAN
Preoperative assessment includes accurate delineation of the tumor. CT is helpful to delineate
involvement of the bony structures including the chest wall and vertebrae, while MRI is more accurate for
the assessment of soft tissue structures including vessels and nerves.91 Involvement of T1 does not
preclude resection because of shared root contribution from the C8 root. In contrary, resection of both T1
and C8 roots would result in debilitating paralysis of the hand and claw deformity, and therefore
commonly contraindicates resection. Imaging to confirm an intact Circle of Willis is helpful where the
subclavian artery is proximally involved and the vertebral artery is anticipated to be sacrificed at
resection.
Tissue diagnosis is important as nonmalignant and in particular infectious causes of Pancoast tumors
have been described, and it is therefore important to establish a diagnosis is malignant prior to embarking
on multimodality therapy. Accurate staging is carried out as for lung cancers, but with the caveat that
supraclavicular node involvement may represent local contiguous spread and portend a better prognosis
in superior sulcus tumors than would be expected for N3 disease, and so should not necessarily
contraindicate radical intent treatment.83
The thoracic inlet may only be 5 cm in anteroposterior diameter, but it contains many important
structures closely related to each other and access to this area is limited. This is compounded by the
difficulty that division of some of the structures have long lasting sequelae. The space is often
conveniently subdivided into three compartments to guide surgical approach. The anterior compartment is
bound by the manubrium anteriorly and the anterior scalene muscle and contains the subclavian vein and
phrenic nerve. The middle compartment is bound by anterior scalene and middle scalene and contains the
subclavian artery and trunks of the brachial plexus. The posterior compartment extends from the spine to
the posterior scalene and contains the vertebrae, roots of the brachial plexus, the sympathetic chain and
stellate ganglion.92 Tumors in the posterior compartment may be better approached with a posterior
surgical approach, while tumors which mainly invade the vascular structures are better approached with
an anterior approach. For extensive tumors, a combined approach may be required, and for tumors
requiring vertebral resection, a staged procedure may be required with separate spinal and thoracic
approaches. Early engagement with a neurosurgeon or spinal surgeon will help ensure the best chance of
complete resection while minimizing complication rates.
The first surgical approach for thoracic inlet tumors was the posterior approach.93 Through a
parascapular extension of the posterolateral thoracotomy incision (the Shaw–Paulson incision) between
the spine and scapula up to the base of the neck, the chest can be accessed like a conventional
thoracotomy whilst affording excellent access to the posterior compartment with the scapula lifted off the
chest wall. The subclavian vessels can be accessed but exposure for control, resection and reconstruction
in this narrow space can be challenging and an anterior approach is much better suited to this. If spinal
resection and instrumentation is required, the parascapular incision could be made close to the midline to
incorporate access to the vertebral column.94 The patient is intubated for lung isolation and positioned in
the lateral decubitus position. If spinal instrumentation is required, the table may need to be kept flat with
the spine in correct alignment.
For access to the anterior and middle compartment, the anterior approach is favored, This approach
also gives excellent exposure to the anterior spine. Masaoka et al.95 first described an anterior approach
using the transsternal trap door incision but it was Dartevelle et al.96 who popularized the transclavicular
approach which entails resection of the medial half of the clavicle for an excellent, direct exposure of the
thoracic inlet. However, the clavicle cannot be reliably reconstructed or restored, and this incision is
associated with deformity and disability. Grunenwald and Spaggiari97 proposed the transmanubrial
approach where the thoracic inlet is accessed by elevating a osteomuscular flap comprising the clavicle,
manubrium and sternocleidomastoid off the thoracic inlet by dividing the first costochondral cartilage and
costoclavicular ligament, thereby laying open this otherwise very tight space.
For these anterior approaches, the patient is positioned supine with a roll behind the shoulder to
elevate the operative side, and with the head extended and turned away. If a separate incision is required
for access to the posterior spine or for a thoracotomy, the patient may be repositioned in the lateral
decubitus procedure after completing the thoracic inlet dissection.
TOOLS
With the posterior approach, rib cutters are required for chest wall resection. Resection of the first rib is
most safely carried out with a Gigli saw. The posterior end of the rib can be disarticulated with a
periosteal or Cobb elevator. For the anterior approach, a saw is required for manubriosternal or clavicle
division.
If resection of the subclavian vessels is required, the patient should be heparinized prior to clamping
the vessels. The vessel can often be anastomosed primarily, however if the gap is too large and the
anastomosis is under tension, an interposition graft such as a PTFE conduit can be used.
Chest wall reconstruction is usually not necessary unless the chest wall incision extends to below the
4th rib. In that case a patch repair would prevent scapular impingement or entrapment.
TACTICS
Depending on the location and the structures involved by the tumor, a decision on whether to use an
anterior, posterior or combined approach is made. If vertebral invasion is evident, discussion with a
spinal surgeon or neurosurgeon is essential to formulate a strategy including which approaches to use and
in which sequence. In general the tumor is freed en bloc from the apex and chest wall before carrying out
the lung resection. An anatomical resection is preferred over a wedge resection as it is associated with
better long-term outcome,98 but occasionally a wedge resection may be required first to facilitate tumor
extraction, followed by a completion lobectomy,99 or because the patient’s lung function dictate the need
for parenchyma-sparing resection.
TECHNIQUE
Posterior Approach
A limited posterolateral thoracotomy is carried out to allow assessment of resectability prior to extending
to a full Shaw–Paulson incision.99,100 The thoracotomy incision is extended posteriorly and superiorly
between the medial border of the scapula and the spinous processes to reach the base of the neck.
Latissimus dorsi and the inferior half of trapezius along with the muscular attachments of the scapula
including the rhomboids and serratus posterior muscles are divided. A rib spreader is placed with one
blade in the thoracotomy and the other blade under the scapula, and the scapula is elevated off the chest
wall, allowing exposure toward the apex (Fig. 37.1). The superior fibers of serratus anterior is divided
and the scaleni are then divided off the first and second ribs, thereby exposing the subclavian vessels and
brachial plexus (Fig. 37.2).
FIGURE 37.1 Posterior (Shaw–Paulson) approach to superior sulcus tumors. The thoracotomy incision is extended posteriorly
between the scapula and the spine up toward the base of the neck. The scapula is then elevated off the chest wall to allow
access to the apex. (From Nesbitt JC, Wind GG, Deslauriers J, et al. Thoracic Surgical Oncology: Exposures and
Techniques. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)
FIGURE 37.2 Posterior (Shaw–Paulson) approach to superior sulcus tumors. Following division of the insertion of serratus
anterior and anterior scalene muscles, the neurovascular bundle can be seen emerging above the 1st rib. (From Nesbitt JC, Wind
GG, Deslauriers J, et al. Thoracic Surgical Oncology: Exposures and Techniques. Philadelphia, PA: Lippincott Williams &
Wilkins; 2003.)
Attention is then directed to the chest wall resection. The thoracotomy is placed one rib space below
the tumor, the tumor is palpated through the thoracotomy to define the site of rib division at a distance
from the tumor. The anterior margin of the resection is first carried out with division of the ribs and
ligation of the intercostal muscles with their neurovascular bundle. At the first rib, the chest wall flap is
depressed to better expose the first rib, and under direct vision and protecting the subclavian vessels, a
right angled clamp is passed around the first rib. A Gigli saw is then passed to divide the first rib, or a
first rib cutter used.
Attention is then directed at the posterior chest wall. The paraspinous muscles are elevated off the
costovertebral gutter to reveal the transverse process. The ribs are disarticulated progressively starting
inferiorly. The costotransverse ligaments are sharply divided, the rib disarticulated from the
costotransverse and costovertebral joints with a periosteal or Cobb elevator and the radiate ligament at
the head of the rib divided. As the rib is disarticulated, the intercostal bundle is revealed and securely
ligated to prevent a CSF leak or pneumocephalus. This is repeated with each of the ribs. Care is taken
with the first rib as the T1 nerve root courses up the inner surface of the neck of the rib to join the C8
nerve root. Depending on whether it is involved, the T1 root may be preserved or sacrificed. If it is to be
divided, the proximal end at the neuroforamina must be securely ligated first to prevent a CSF leak or
pneumocephalus. If it is to be preserved, it may be easier to divide the first rib at the costotransverse joint
with an osteotome before coming back to resect the remaining head fragment of the rib when the T1 root
can be clearly seen.
With the chest wall resection complete, the dissection follows the extrapleural and prevertebral plane
medially onto the vertebrae where the stellate ganglion resides and this can be resected if involved. The
chest wall is then resected en bloc with the lung resection.
Anterior Approach
The Dartevelle transcervical approach96 is carried out with an L-shaped incision extending from the
anterior border of the sternocleidomastoid and curving back around the head of the clavicle to continue
below the clavicle (Fig. 37.3).97,99,101 This latter part of the incision can be placed variably at different
levels to facilitate later access to the hilum for lung resection. The sternocleidomastoid and pectoralis
muscles are divided off the manubrium and clavicle to fully expose the medial half of the clavicle. A
limited thoracotomy in the second intercostal space is carried out to allow inspection to ensure
resectability before dividing the clavicle. The subclavian vessels are protected from the posterior surface
of the clavicle to allow the clavicle to be safely divided with a saw. The clavicle fragment is then
disarticulated from the manubrium. This allows exposure of the first rib and subclavian vessels.
The Grunenwald transmanubrial approach97 is carried out with an L-shaped incision extending from
the anterior border of the sternocleidomastoid toward the manubrium and then turning laterally at the
superior border of the second rib toward the deltopectoral groove (Fig. 37.4). The sternocleidomastoid is
mobilized to reveal the internal jugular vein which is followed to its confluence with the subclavian vein.
The plane behind the manubrium is then developed at the sternal notch. The first intercostal space is then
opened and the internal mammary vessels ligated and divided. A finger can then be passed between the
sternal notch and the intercostal space, and the manubrium is divided with a saw preserving the
sternoclavicular joint (Fig. 37.5). A tape is passed around the manubrial stump and the osteomuscular flap
is retracted upward revealing the first costal cartilage on the underside. The costal cartilage is divided,
and the remaining costoclavicular ligament attaching the flap onto the first rib is divided, thus allowing
the flap to be easily elevated to reveal the 1st rib and subclavian vessels (Fig. 37.6).
FIGURE 37.3 Anterior (Dartevelle) approach. The medial clavicle is freed from its muscular insertions and resected to allow a
direct approach onto the anterior thoracic inlet with exposure of the subclavian vessels and brachial plexus. (From Nesbitt JC,
Wind GG, Deslauriers J, et al. Thoracic Surgical Oncology: Exposures and Techniques. Philadelphia, PA: Lippincott Williams
& Wilkins; 2003.)
FIGURE 37.4 Anterior (Grunenwald) approach. With the transmanubrial osteomuscular-sparing approach, an L-shaped incision
is carried along anterior to the sternocleidomastoid and turning laterally along the intercostal space, most commonly the first
intercostal space. (Reprinted from Grunenwald D, Spaggiari L. Transmanubrial osteomuscular sparing approach for apical chest
tumors. Ann Thorac Surg 1997;63(2):563–566. Copyright © 1997 The Society of Thoracic Surgeons. With permission.)
FIGURE 37.5 Anterior (Grunenwald) approach. The sternocleidomastoid is freed down to the sternal notch, and the intercostal
space is entered. An osteotomy of the upper lateral quadrant of the manubrium is carried out. (Reprinted from Grunenwald D,
Spaggiari L. Transmanubrial osteomuscular sparing approach for apical chest tumors. Ann Thorac Surg 1997;63(2):563–566.
Dissection of the thoracic inlet then proceeds from anterior toward the posterior compartment (Fig.
37.7). The subclavian vein is mobilized, the scalene, supraclavicular and anterior triangle fat pad and
lymph nodes are excised and sent to pathology. On the left the thoracic duct is identified and ligated. If the
subclavian vein is involved with tumor it can be ligated and divided without reconstruction, the venous
congestion that results is usually self-limiting. The phrenic nerve is identified on the anterior scalene and
protected with a loop, the anterior scalene is then divided off the first rib unless it is involved with tumor
when it is divided above the tumor. The subclavian artery is then exposed. If the artery is involved, it is
dissected and encircled on either side of the tumor. The patient is heparinized and the artery is clamped
and divided. The branches of the artery can be divided to help mobilize the subclavian artery.
The 1st rib is then divided anteriorly away from the tumor. This allows the tumor block to be retracted
downward to reveal the posterior 1st rib and brachial plexus behind. If the T1 nerve root is uninvolved,
the rib is divided beyond the subclavian artery to allow the tumor block to be freed before separately
excising the head of the first rib under direct vision. However, if the nerves are adherent to the tumor, they
will need to be dissected off the tumor. The involved T1 root is then ligated and divided away from the
tumor but before it joins the C8 nerve root. The dissection then continues on the prevertebral plane to the
stellate ganglion, which is divided if it is involved, and the costovertebral joint, which is disarticulated.
A separate posterior approach may be required to free the tumor en bloc if there is significant
involvement of the vertebrae.
FIGURE 37.6 Anterior (Grunenwald) approach. The costal cartilage of the 1st rib is then divided to allow the osteomuscular
flap to be elevated off the thoracic inlet. (Reprinted from Grunenwald D, Spaggiari L. Transmanubrial osteomuscular sparing
approach for apical chest tumors. Ann Thorac Surg 1997;63(2):563–566. Copyright © 1997 The Society of Thoracic Surgeons.
With permission.)
The artery is then reconstructed with a primary anastomosis or with an interposition graft if required.
The lung resection is then carried out. This may be possible through the existing incision or may require a
separate incision.
TROUBLE SPOTS
Care should be taken to protect the phrenic, vagus, and recurrent laryngeal nerves. The phrenic is
intimately related to the anterior scalene and should be carefully identified before dividing the scalene
muscle. The vagus descends within the carotid sheath medial to the internal jugular vein before crossing
anterior to the subclavian artery. On the right side, the recurrent laryngeal nerve arises here and loops
under the subclavian artery to ascend in the tracheoesophageal groove, while on the left it descends into
the thorax to loop under the ligamentum arteriosum. It is therefore at risk when dissecting the jugular vein,
when dissecting and dividing the right subclavian artery, and when retracting the tracheoesophageal block
when dissecting the prevertebral fascia.
Meticulous attention should be given to ligating and securing the nerve roots at the neuroforamina to
minimize the occurrence of CSF leak. In the context of a thoracic surgical patient, the treatment of this
complication involves prolonged lumbar drainage and bed rest and would compound the risk of
pneumonia and respiratory failure in these patients. Conversely, pneumocephalus can result from air
arising from an air leak entering the dural sac. This could be life threatening if it tensions, and difficult to
diagnose.
FIGURE 37.7 Anterior (Grunenwald) approach. The anterior and middle scalene muscles are divided to expose the subclavian
vessels and brachial plexus. (Reprinted from Grunenwald D, Spaggiari L. Transmanubrial osteomuscular sparing approach for
apical chest tumors. Ann Thorac Surg 1997;63(2):563–566. Copyright © 1997 The Society of Thoracic Surgeons. With
permission.)
The C8 and T1 nerve roots unite to form the C8–T1 trunk. The identity of the nerves can be confusing
when obscured by tumor, with the trunk appearing like the T1 nerve root. Both nerve roots and their trunk
should therefore be clearly exposed prior to dividing T1.99
On occasion the subclavian artery is involved proximally. In those situation it may be necessary to
resect the artery up to the aorta and place an interposition graft from the aorta to the subclavian artery.
Alternatively, a carotid–subclavian bypass could be used if a graft is not possible.102
VERTEBRAE
Lung tumors that invade the vertebrae are rare, and most of these do so as superior sulcus tumors. These
tumors were considered unresectable until recently and relied on advances in spinal instrumentation to
maintain spinal stability following resection. DeMeester et al.103 described the resection of transverse
process and tangential vertebrectomy without instrumentation through the Shaw–Paulson posterior
approach, however complete resection was not achieved in two patients with cortical bone involvement
and it was concluded this approach was not adequate for tumors invading the vertebral body. Grunenwald
subsequently described a three-incision approach starting with an anterior transcervical approach for the
thoracic inlet, followed by a posterolateral thoracotomy for a chest wall and wedge resection, and then
posterior approach for spinal stabilization and total vertebrectomy with en bloc removal of the tumor.
This was followed by anterior column reconstruction with bone graft taken from the clavicle. Pathology
confirmed complete resection.104 However, the patient needed to be kept in a corset for 6 months to allow
bone graft fusion to occur. This established the feasibility and principles of vertebral excision: that of en
bloc resection of the vertebrae with lung, and concurrent instrumentation for spinal stabilization.
Vertebral resection is an invasive operation and requires collaboration with a spinal or neurosurgeon.
There are two techniques used to resect tumours in the vertebra: en bloc resection and intralesional
resection. In the latter, the tumor is removed by drilling within the tumor, and concerns were raised that
this is against established oncologic principles of respecting tumor margins, and clearly it is difficult to
confirm a complete resection has been achieved using this technique. As with other lung cancers, the main
determinant of long-term outcome is complete resection, and not surprisingly results do suggest better
long-term outcome with en bloc rather than intralesional resection.105
The result of en bloc lung and vertebral resection is good. In a pooled analysis of 135 patients using
individual patient data from several centers, the overall 5 year survival rate for patients undergoing en
bloc resection was 43%, reaching 48% in those with complete resection.105
PLAN
Early engagement with a spinal or neurosurgeon is essential to plan the operative strategy for each
individual case, which is often carried out in two or three incisions in one procedure.
Spinal monitoring should be available for vertebral resections.
TOOLS
In addition to the usual lung resection instruments, spinal surgical instruments, drills, instrumentation and
image intensifier are required for vertebral resection.
TACTICS
In tumors that invade only the spine and posterior chest wall, a posterior approach may suffice. The
midline spinal incision could be separate from or incorporated into the posterolateral or Shaw–Paulson
thoracotomy incision depending on the spinal level involved.106,107 However, if the subclavian vessels
are involved, a separate anterior approach may be necessary. The anterior and posterior procedures can
be carried out in either sequence depending on each case and individual preferences.107–110 It is also
possible to execute the lung resection through the anterior incision, thus avoiding a separate posterolateral
thoracotomy.108
TECHNIQUE
Depending on the extent of invasion, a hemivertebrectomy or total vertebrectomy may be required. Due to
the diffuse nature of cancellous bone involvement, any sign of invasion of the vertebral body should be
treated with total vertebrectomy. Conversely, where only the costovertebral groove and neuroforamina
are involved, a partial or hemivertebrectomy may suffice (Fig. 37.8).108
A hemivertebrectomy is carried out with an ipsilateral laminectomy, followed by careful ligation of the
nerve roots and segmental vessels to avoid a CSF leak. The vertebral osteotomy is then commenced from
the spinal canal anteriorly toward the thorax. Posterior stabilization may be carried out with pedicle
screws and plates if required. Through the anterior incision, the vertebral body is freed from the midline
structures such as esophagus and aorta, and the osteotomy continued anteriorly under direct vision of the
spinal cord, tumor and intrathoracic organs to complete the hemivertebrectomy with the desired margin.
The anterior column is then stabilized with bone graft and ventral osteosynthesis.109
FIGURE 37.8 Vertebral resection. The extent of resection is dependent on the level of invasion. If the vertebral body is not
involved a hemivertebrectomy may suffice; however, if the vertebral body is involved, a total vertebrectomy may be required for
complete resection. (Modified from Oka S, Matsumiya H, Shinohara S, et al. Total or partial vertebrectomy for lung cancer
invading the spine. Ann Med Surg (Lond) 2016;12:1–4. Copyright © 2016 Elsevier. With permission.)
A total vertebrectomy is carried out first with bilateral pediculotomy and laminectomy. The segmental
nerves are carefully ligated. The intervertebral discs above and below the vertebrae to be resected are
excised. Posterior stabilization is put in place and the vertebral body is approached anteriorly where it is
freed from adjacent structures and removed en bloc with the lung tumor. Anterior stabilization with a cage
prosthesis and osteosynthesis is then carried out.109
An alternative approach is to carry out the anterior approach first with the lung and chest wall
resection, including dissection of the vertebral body from the mediastinal organs. This is followed by the
posterior approach. The paraspinal muscles are elevated off the costovertebral groove and wide bilateral
laminectomy is carried out at the level of resection as well as the levels above and below, and continued
on the unaffected side to include the pedicle, transverse process and a short segment of rib. This is
carried out to allow the unaffected side to rotate into the chest around the spinal cord to be removed later
in the operation. On the affected side, the pedicle and transverse process are preserved en bloc with the
tumor, and the rib dissected laterally to where it was divided. Posterior stabilization is then put in place
on the unaffected side. The segmental nerves are carefully ligated, and the vertebral block is released,
pushed forward and rotated toward to affected side and retrieved en bloc laterally through the posterior
incision (Fig. 37.9).108
TROUBLE SPOTS
Vertebral resections and stabilization are best carried out by spinal or neurosurgeons familiar with these
procedures to ensure optimal outcomes for the patient. Close liaison during the postoperative period
helps ensure that complications are recognized early and treated expediently.
FIGURE 37.9 Vertebral resection. Where the thoracic resection is carried out before the posterior spinal resection, the
specimen can be removed en bloc with a rotational movement around the spinal cord. (Reprinted from Gruenwald DH, Mazel C,
Girard P, et al. Radical en bloc resection for lung cancer invading the spine. J Thorac Cardiovasc Surg 2002;123(2):271–279.
Copyright © 2002 The American Association for Thoracic Surgery. With permission.)
DIAPHRAGM
Lung cancer invading the diaphragm is rare and constitutes <0.5% of all resected lung cancers.111–115
Resection is technically facile and operative mortality is low but unfortunately the long-term outcome of
patients, despite often complete resection, is poor. Five-year survival of completely resected tumors of
the diaphragm is about 20% and Inoue et al. first proposed in 1998 that diaphragm invasion should be
treated as T4 disease. The IASLC confirmed the very poor prognosis in their most recent database and
revised diaphragm invasion as T4 in the 8th edition revision.116
PLAN
Radiologic recognition of diaphragm invasion is not always easy, and only a fraction is identified
preoperatively.115 Where invasion is suspected, MRI could provide further information regarding
infiltration and transdiaphragmatic spread.
Anesthetic and operative set up are the same for standard lung resection. Preoperative insertion of
nasogastric tube for stomach decompression especially for left-sided operations can facilitate diaphragm
repair. Following surgery, a nasogastric tube on free drainage and nil by mouth on the operative day can
help minimize postoperative vomiting and stress on the diaphragm repair.
TOOLS
No special tools are required for diaphragm resection. The defect is most often repaired primarily with
interrupted heavy nonabsorbable sutures such as polypropylene. Stapler resection and closure of the
diaphragm has been described but there are reports of repair failure.117
In most series more than half of the closures are primary closures, while the remaining defects require
patch repair.113,114,118 A variety of patches has been used for reconstruction including pericardial, Vicryl
mesh, PTFE and biologic meshes.113,118,119 Despite their less common use, Rocco et al. found patch repair
being a significant prognostic factor for survival. They postulated that because of the extensive lymphatic
network in the diaphragm, the wider resection which necessitates a patch repair, more completely
extirpates these channels.
TACTICS
The hemithorax is examined at thoracoscopy or thoracotomy to assess for the presence of and extent of
diaphragm invasion. The diaphragm is resected with a margin from the tumor edge. In some units, the
margins are routinely sent for frozen section analysis. If the diaphragm margins could be approximated the
defect can be closed primarily with interrupted 0 or 1 nonabsorbable sutures. If the defect is large, a
patch repair can be carried out with interrupted or semicontinuous nonabsorbable sutures.
TECHNIQUE
Complete resection is a significant prognostic factor and many series report no long-term survivors in
patients with incomplete resection.114,115 Therefore diaphragm resection should be carried out with a
wide margin. Rocco et al.113 proposed a margin of up to 5 cm of uninvolved diaphragm and use of patch
repair.
TROUBLE SPOTS
Tumors that invade the diaphragm may also be close to or invade adjacent structures most commonly the
pericardium and chest wall; combined resection and reconstruction of other organs may be required.118
Often the diaphragm is continuous with the resected pericardial or chest wall defect and the same
diaphragmatic patch prosthesis can be extended to cover the other defects. When closing the pericardial
defect, the patch should not be too taut to prevent cardiac constriction or tamponade. The patch should
also be fenestrated and interrupted sutures used to allow free drainage of pericardial fluid while
preventing cardiac herniation.
Other structures to be aware of during diaphragm resection include the inferior vena cava on the left
and the esophagus on the right. Care should be taken not only when resecting close to these structures, but
also when reconstructing the diaphragm to avoid narrowing them.
PERICARDIUM
Invasion of the parietal pericardium may occur alone with tumor extending from across the visceral
pleura, or occur as part of more extensive mediastinal invasion in conjunction with invasion of other
structures such as SVC or atrium. When occurring alone it is classified as T3 in the 8th edition TNM
staging system.
PLAN
Lung cancer with pericardial invasion has a high likelihood of requiring a pneumonectomy. At the same
time, pericardial invasion is more often associated with nodal involvement and so meticulous care should
be taken with preoperative staging.120
Anesthetic requirements for resection are as for lung resection with lung isolation. Intraoperative
transesophageal echocardiogram is useful to assess for invasion of other cardiac structures. Cardiac
monitoring includes electrocardiogram, central venous pressure and arterial line are used.
Concurrent lung and pericardial resection is usually carried out thoracoscopically or through a
thoracotomy. For these, the patient is placed in the lateral decubitus position.
TOOLS
No special tools are required for pericardial resection. If pericardial patch closure is required, this may
be carried out with prosthetic porous meshes such as polyglactin or polypropylene meshes.
TACTIC
Pericardial invasion is difficult to diagnose with certainty preoperatively. After entering the chest, a
thorough assessment of resectability is carried out, especially for signs of pleural dissemination. An
attempt may be made to lift the tumor off the pericardium where it may be attached with only thin
adhesions, in which case these could be divided. If the pericardium is invaded, it is opened to assess
intrapericardial resectability before proceeding with lung resection.
TECHNIQUE
If pericardial invasion is suspected, the pericardium is opened away from the tumor, and the pericardial
space entered to check for epicardial invasion. In the absence of cardiac invasion, the pericardium is
divided at a margin away from the tumor. If the tumor invaded the phrenic nerve it may need to be
sacrificed. The lung tumor with the attached pericardial disc may then be resected en bloc. The
pericardial defect could then be closed.
TROUBLE SPOT
In the situation where the phrenic nerve is resected, concurrent and prophylactic plication of the
diaphragm should be considered which may help reduce postoperative pulmonary complications.121 Even
in patients who underwent pneumonectomy with a phrenicotomy, a concurrently plicated diaphragm may
help prevent paradoxical movement and the increase in work of breathing and respiratory failure which
may necessitate repeat surgery to plicate the diaphragm.122
The presence of a large pericardial defect especially in the presence of a pneumonectomy space, may
cause cardiac torsion or herniation. This life-threatening complication carries a 50% mortality rate.123 It
is more common on the right but can occur on the left with strangulation of the left ventricle. It may
present with arrhythmia, sudden cardiac failure or a patient in extremis, and requires immediate open
reduction of the herniation. Different ways of preventing herniation has been described including widely
opening the pericardium for left-sided operations, tacking the pericardial edge to the heart and patch
repair of the defect with parietal pleura, mesh prostheses such as polyglactin, polypropylene and PTFE
meshes and autologous flaps such as fascia lata and diaphragm.122,124 Prosthetic meshes have the benefit
of being simple and readily available, and are porous thus allowing drainage of pericardial fluid. The
pedicled diaphragm flap is based medially on the pericardiacophrenic or inferior phrenic arteries and can
be tailored to the size of the pericardial defect.125 The benefit of the diaphragm flap is that the same
procedure indirectly plicates the diaphragm with closure of the diaphragm defect and compensates for the
phrenic nerve resection. The size of any patch should comfortably allow the heart to beat and not be too
tight, to avoid cardiac constriction. The patch or flap should be sutured to the pericardial edge with
interrupted sutures to further allow drainage of pericardial collection to avoid tamponade. Care should be
taken to avoid suturing the patch on too tightly especially near the venae cava to avoid venae cava
constriction.
SUPERIOR VENA CAVA

With techniques of repairing and replacing the superior vena cava (SVC), lung cancer invading the SVC is
now considered resectable. Several series have shown perioperative mortality of 10% to 14%, and long-
term survival of 30% have been seen in those without nodal involvement.3,126,127
The SVC can be involved by direct tumor infiltration or from invasion by involved mediastinal nodes.
While some groups consider the latter group resectable,128 the outcomes for those with N2 disease are
dismal with 5-year survival as low as 6.6%.129 Induction treatment would be considered to downstage
nodal disease prior to resection.
The right phrenic nerve will almost certainly be sacrificed with SVC resection even though in many
cases it would already be nonfunctioning due to tumor invasion. Patients considered for surgery should
have sufficient lung function to tolerate a postoperative phrenic paresis, and intraoperative diaphragm
plication should be considered. Existing disease affecting the contralateral phrenic is a contraindication
to surgery.130
PLAN
An important consideration from the anesthetic point of view is ensuring uninterrupted head and neck
venous return and intravascular access. Early discussion with the anesthetic team to obtain venous access
in the lower half of the body is essential to ensure no loss of access for drugs and infusions once the SVC
is clamped.
Clamping of the SVC reduces venous return and causes systemic hypotension while increasing the
intracranial pressure from reduced cerebral venous drainage.131 Together they reduce cerebral perfusion
pressure. The systemic blood pressure and cerebral perfusion pressure need to be maintained with
vasoconstrictors and volume expanders.126,130 Preoperative use of angiotensin-converting enzyme
inhibitors is also associated with hemodynamic instability following clamping even where it has been
stopped for 24 hours, and consideration should be made to stop these drugs for a longer period prior to
surgery.132
SVC resection can be approached laterally through a thoracotomy or thoracoscopically, but an anterior
approach through a median sternotomy offers excellent exposure of the SVC and the innominate veins and
allows full control especially for complex reconstructions. Anterior approaches to pulmonary resection is
well described.133 A thoracotomy approach is useful where a concomitant bronchoplastic procedure is
required.
Depending on the particular extent of invasion and resectability of each of the structures, the SVC
could be resected or reconstructed before or after the lung resection. With a transsternal approach,
performing the SVC resection and reconstruction first may afford a better exposure of the pulmonary
hilum, whereas the SVC resection may be the last structure to be divided and reconstructed in a
thoracotomy approach.
TOOLS
A vascular set should be available with different sizes of side biting and straight clamps, as well as
snuggers to allow snaring of vessels.
A caval shunt can be used in particular where the SVC is clamped for a prolonged period and at a
level below the azygos vein, in order to reduce cerebral edema from obstruction to cerebral venous
drainage.134 Cardiopulmonary bypass (CPB) is generally not necessary.
The SVC defect would need to be patched if more than a sixth of its circumference is resected to
prevent narrowing and caval obstruction. Autologous or bovine pericardium or prosthetic patches can be
used. When the SVC has been resected circumferentially, an interposition graft needs to be placed.
Intraoperatively prepared saphenous or pericardial tubes have been used but ready-made prostheses are
now available off the shelf. A 20-mm diameter graft is generally used to avoid caval stenosis.135
TACTICS
The SVC resection and reconstruction can be carried out before or after the lung resection depending on
the individual situation and surgical approach. The extent of SVC involvement is assessed and the extent
of resection determined along with the need for patch reconstruction or interposition graft. Resection may
be carried out without occlusion using a side-biting clamp for tumors involving a small part of the
circumference, or with SVC occlusion for more extensive tumors. Small defects can be closed primarily
or reconstructed with a patch of pericardium if narrowing is expected, while circumferential resection
require reconstruction with interposition grafts.
TECHNIQUE
Upon entering the chest, the right pleural space is opened to look for contraindications to resection such
as pleural involvement. The lower part of the SVC is intrapericardial and so the pericardium is opened
between the ascending aorta and the SVC and continued superiorly to its reflection between the SVC and
aorta. Tapes are passed around the SVC and the aorta and they are retracted apart. In the space between
them lies the right pulmonary artery and the carina (Fig. 37.10).
The SVC is dissected superiorly to expose both innominate vessels as far as possible. Tapes are
passed above and below the area of invasion and the extent of tumor invasion can then be assessed to
determine the degree of resection required to ensure an adequate resection margin. The pulmonary artery,
veins, and bronchus are then encircled either intrapericardially or intrapleurally, and a determination of
resectability and level of resection is made.
Depending on the extent of involvement of the SVC both circumferentially and the longitudinal extent,
the SVC resection can be variably tackled.130 If there is involvement of a small area, a side-biting clamp
can be applied and the invaded area resected with a margin (Fig. 37.11). If the resected area involves less
than a sixth of the circumference then primary closure is possible whether by direct suture or with a
vascular stapler. Closing the defect transversely will also preserve the diameter of the vessel. However,
if a larger area is involved, primary closure may cause an unacceptable narrowing of the SVC and a patch
of vein or pericardium may be required (Fig. 37.12).
Where there is full circumferential involvement, the SVC is controlled above (which may be at the
innominate veins) and below the lesion prior to resection and reconstruction (Fig. 37.13). If possible, the
SVC should be occluded above the azygos vein to preserve some upper body drainage to the heart and
maintain hemodynamic stability.132 Patients with chronic SVC narrowing develop collateral drainage and
tolerate SVC occlusion well; however, patients with acute SVC obstruction who had not had time to
develop collateral flow do not tolerate SVC clamping. Patients where the SVC would be expected to be
occluded for a prolong period may require a caval shunt (Fig. 37.13) or placing an alternative conduit
prior to SVC resection.131,136 A conduit can be placed between the left innominate vein and the right
atrium before clamping to allow safe resection of the SVC (Fig. 37.14).
FIGURE 37.10 Approach to the intrapericardial SVC and the carina. (From Nesbitt JC, Wind GG, Deslauriers J, et al.
Thoracic Surgical Oncology: Exposures and Techniques. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)
FIGURE 37.11 SVC resection: Tumors involving a small area of the SVC can be resected by applying a side biting clamp.
(Reprinted from Garcia A, Flores RM. Surgical management of tumors invading the superior vena cava. Ann Thorac Surg
2008;85(6):2144–2146. Copyright © 2008 The Society of Thoracic Surgeons. With permission.)
FIGURE 37.12 SVC resection: Tumors involving more than a sixth of the circumference may require patch repair to prevent
stenosis. (Reprinted from Garcia A, Flores RM. Surgical management of tumors invading the superior vena cava. Ann Thorac
Surg 2008;85(6):2144–2146. Copyright © 2008 The Society of Thoracic Surgeons. With permission.)
FIGURE 37.13 SVC resection: Reconstruction with interposition graft following circumferential resection of the SVC. Drainage
of the head and neck can be maintained with the use of a shunt, which can be intra- or extraluminal. (Reprinted from Garcia A,
Flores RM. Surgical management of tumors invading the superior vena cava. Ann Thorac Surg 2008;85(6):2144–2146.
If the tumor involves both innominate veins, reconstruction can be made from one or both innominate
veins. When both veins are grafted, thrombosis of one of the limbs have been reported with no signs of
SVC obstruction.137,138 Usually one of the veins can be sacrificed and drainage from only one innominate
vein needs to be re-established. This appears to be well tolerated with only transient and self-limiting
unilateral arm swelling.139
A variety of interposition graft prostheses have been used for reconstruction of the SVC. The ideal
conduit has long-term patency with resistance to thrombosis and kinking, ease of handling, and its ready
availability. Autologous tissue such as the spiral saphenous vein graft and tubularised pericardium,
biologic tissue including bovine pericardium or jugular vein conduits and nonbiologic conduits such as
PTFE have been used.126,140–142
Graft patency has been variably reported between 0% and 86%,142,143 factors influencing patency
include multiple grafts or Y-grafts, and left innominate vein graft but there are no direct comparative
studies between prostheses.144
FIGURE 37.14 SVC resection: Construction of an interposition graft between the innominate vein and right atrium prior to SVC
resection allows uninterrupted venous drainage. (Reprinted from Garcia A, Flores RM. Surgical management of tumors invading
the superior vena cava. Ann Thorac Surg 2008;85(6):2144–2146. Copyright © 2008 The Society of Thoracic Surgeons. With
permission.)
TROUBLE SPOTS
Shunt placement during SVC occlusion is variably practiced. In primate studies SVC occlusion of 60
minutes without prior SVC obstruction to give time for collaterals to develop, led to very little evidence
of pathologic changes in the brain.131 Some surgeons advocate that short periods of occlusion, variably up
to 35 or 60 minutes, can be carried out without shunting as long as the systemic arterial pressure is
adequate to maintain cerebral perfusion.135,139 For longer periods of occlusion, however, shunts are
indicated.
Shunts used can be intraluminal or extraluminal.136,145 Intraluminal shunts can be difficult to place, to
operate around, and can thrombose.146 Extraluminal shunts can be placed either intraoperatively within
the chest, or preoperatively set up between the jugular and femoral veins.145
Interposition grafts should be placed with a degree of tension to avoid kinking. If anastomosis is
required to the right atrium, it is commonly carried out at the lateral wall of the right atrium to avoid the
sinoatrial node at the atriocaval junction.
Anticoagulation is usually required in the postoperative period, but intraoperative heparinization is
routinely used only by some authors.126,139 Long-term anticoagulation is recommended for interposition
grafts but is not required for primary closure or small patch repair.
LEFT ATRIUM
The left atrium can be invaded by lung cancer that extends along the pulmonary veins. True T4 tumors
invading the atrium invades not only the pulmonary vein but also the atrial muscle; however, occasionally
tumors invading down the pulmonary vein require resection of the atrial muscle to ensure an adequate
margin. The right pulmonary vein is shorter than the left, and so invasion is more common on the right.
The left pulmonary veins are also adjacent to other vital structures including the descending aorta and
esophagus and these structures are often involved, which renders left-sided tumors invading the atrium
less often resectable.
Left atrial resection remains a rare procedure with results reported in few retrospective series.
Nevertheless the published data are encouraging with operative mortality of 0% to 16% and 5-year
survival rates of 10% to 46%, despite the fact most patients reported require a pneumonectomy and have
lymph node involvement.147
PLAN
Patient selection is crucial to good outcomes for this extended resection of both the lung and the heart. The
ideal patient is young with few or no comorbidities, good lung function, and no cardiac history. Because
of the proximity of both the pulmonary veins, most tumors invading the atrium require a pneumonectomy
and adequate lung function is essential.
The extent of tumor invasion should be carefully studied. The extent of the atrial invasion is
investigated with cardiac magnetic resonance, with particular attention drawn to the interatrial septum,
right atrial wall, mitral valve, and distance from the contralateral pulmonary veins. Echocardiogram is
useful to exclude intra-atrial thrombus and assess ventricular function. These central tumors also often
invade surrounding structures including the venae cavae, carina, and aorta and these should be anticipated
to plan the operative strategy.
Patients with N2 or N3 disease have very poor outcomes and survival is the exception rather than the
rule. Accurate staging is therefore essential and induction therapy offered to patients with N2/3 disease.
Some authors avoid radiotherapy during induction treatment to reduce cardiac toxicity in anticipation of
atrial resection.148
The patient is anesthetized with single lung ventilation. Central venous and arterial cannulae are
placed. Intraoperative transesophageal echocardiogram facilitate assessment of extent of intra-atrial
tumor, presence of thrombus, and cardiac function during atrial clamping. It can also help guide placement
of the atrial clamp.
CPB is often not required, but it has been employed in selected cases requiring extensive atrial
resection and patch reconstruction of the atrial wall.
Combined lung and atrial resection is best approached through a posterolateral thoracotomy, and the
patient is placed in the lateral decubitus position.
TOOLS
A vascular set should be available with different sizes of side biting and straight clamps. The atriotomy is
closed with polypropylene sutures. Where required following an extensive resection, a pericardial patch
could be used to reconstruct the atrial wall defect.
TACTICS
Following the thoracotomy, the pericardium is opened and the hilum is dissected to allow assessment of
resectability of the pulmonary vein, atrium, pulmonary artery, and bronchus. Once resectability is
determined, lung resection can proceed with the final step being the left atrial resection. The interatrial
groove is dissected to create a cuff of left atrium. The lung is retracted upward and a clamp is placed on
the atrium deep to the tumor. The atrium is divided lateral to the clamp, and the divided atrial margin is
closed with continuous polypropylene sutures. Lymph node dissection is also carried out.
Following atrial closure, the pericardium should be closed with fenestrations to avoid cardiac
herniation especially following pneumonectomy and tamponade.
Arrhythmias are common after atrial resection and consideration should be given for arrhythmia
prophylaxis following surgery.149
TECHNIQUE
Filaire and colleagues150 have described in detail the technique of dissection of the interatrial groove for
lung resection, extending on Söndergaard’s description for using circumclusion sutures to closed atrial
septal defects. In brief, the dissection begins in the well-defined Söndergaard groove between the left and
right atria (Fig. 37.15). This is developed superiorly in a narrow space between the anterior wall of the
left atrium and the superior wall of the right atrium, toward a space traversed by small vessels and
interatrial muscle fibers. These are divided to reach the limits of the dissection which are the aortic root
and the limbus of the septum primum. This dissection can create a left atrial cuff of approximately 40 mm
from the pulmonary veins.
FIGURE 37.15 Left atrial resection: The left atrium is separated from the right atrium by dissecting along Sondergaard groove.
(Reprinted from Spaggiari L, D’ Aiuto M, Veronesi G, et al. Extended pneumonectomy with partial resection of the left atrium,
without cardiopulmonary bypass, for lung cancer. Ann Thorac Surg 2005;79(1):234–240. Copyright © 2005 The Society of
Thoracic Surgeons. With permission.)
FIGURE 37.16 Left atrial resection: The left atrium can be freed to allow on average 4 cm length with which to apply a clamp
at a margin from the tumor. (Reprinted from Spaggiari L, D’ Aiuto M, Veronesi G, et al. Extended pneumonectomy with partial
resection of the left atrium, without cardiopulmonary bypass, for lung cancer. Ann Thorac Surg 2005;79(1):234–240. Copyright
© 2005 The Society of Thoracic Surgeons. With permission.)
A vascular clamp such as a Satinsky is then placed across the atrial cuff leaving a margin from the
edge of the tumor (Fig. 37.16). The clamp is now left in place to allow the hemodynamic consequence to
be evaluated, and a further transesophageal echocardiogram assessment can be carried out. Once the
margin is adequate at the site of clamp placement, and the patient is hemodynamically stable, the atrium
can be divided at the clamp and the atrium closed (Fig. 37.17). Alternatively, a stapler can be used.
A left side resection is similar with the exception there is no interatrial groove, and therefore the length
of the atrial cuff that could be resected is shorter.
If a tongue of tumor extends intraluminally deep into the atrium, it is possible to apply the clamp
across, grasping the tumor. A small atriotomy is then made lateral to the clamp, the clamp briefly relaxed
and the tumor pulled out of the atrium back through clamp (Fig. 37.18). Alternatively, this could be
excised under direct vision through an atriotomy on CPB.8
The margin of the resection can be sent for intraoperative frozen section to assess completeness of
resection, however this strategy is not absolutely accurate and a number of incomplete resection remains
despite this strategy.151
TROUBLE SPOTS
Care should be taken during dissection of the interatrial groove to avoid perforating the atrium. Other
structures to be aware of are the sinoatrial nodal artery, which may arise from the circumflex artery and
traverse the roof of the interatrial septum and is at risk of damage during sharp dissection of the roof, and
Kugel artery which supplies the atrioventricular node.150 Damage to these vessels can lead to
arrhythmias.
FIGURE 37.17 Left atrial resection: The atrium is then resected en bloc with the tumor, and the atrial incision closed.
(Reprinted from Spaggiari L, D’ Aiuto M, Veronesi G, et al. Extended pneumonectomy with partial resection of the left atrium,
without cardiopulmonary bypass, for lung cancer. Ann Thorac Surg 2005;79(1):234–240. Copyright © 2005 The Society of
Most cases of atrial resection in the literature have been carried out without CPB. Indeed, up to a third
of the atrial volume can be resected without needing reconstruction.8 Critics of CPB argue that it requires
anticoagulation with its attendant risks of bleeding; is associated with complications such as stroke,
systemic inflammatory response, and leaky vessels which in the context of pneumonectomy can lead to
life threatening pulmonary edema; and could promote metastatic disease by disseminating tumor cells
systemically. Where a clamp could be placed with an adequate margin, CPB is not necessary; however,
there were instances where a positive margin was found at operation, and the lack of CPB meant further
resection could not be carried out.149 There are large series of atrial resection without the use of
CPB,8,148,151 and in one series a routine strategy was used where if resection was felt not to be possible
without CPB, the patient was offered chemoradiotherapy instead.149
If used, the cannulation and bypass strategies for extended lung resection are versatile and CPB can be
instituted through the thoracotomy or through the femoral vessels.152,153 The aorta is cross-clamped and
the left atrium opened to allow direct inspection. The tumor is excised en bloc with the lung with a margin
of at least 5 mm. The atrium is then closed primarily or repaired with a pericardial patch, deaired, and the
patient weaned off CPB.147,154 The advantages of CPB is the direct visualization afforded by the
atriotomy, which ensures adequate surgical margin as well as minimizing tumor and thrombus
embolization. It also permits excision and repair of tumors that invade the atrial septum, the right atrium,
and large tumors which require atrial patch repair. A systematic review concluded that elective or
planned use of CPB does not adversely affect long-term survival155; nevertheless, where possible, pump
suckers and autologous transfusion should be avoided.153
FIGURE 37.18 Left atrial resection: Where a tongue of tumor extends endoluminally, this could be digitally maneuvered out of
the clamp after the atriotomy. PVS, superior pulmonary vein; PVI, inferior pulmonary vein; LA, left atrium; LV, left ventricle; T,
tumor. (Reprinted from Tsuchiya R, Asamura H, Kondo H, et al. Extended resection of the left atrium, great vessels, or both for
lung cancer. Ann Thorac Surg 1994;57(4):960–965. Copyright © 1994 The Society of Thoracic Surgeons. With permission.)
CARINA
Tumors that involve the carina are a challenge to manage and operations involving the carina are
associated with high morbidity and mortality. While there were sporadic reports of carinal resection and
reconstruction in the 1950s, Hermes Grillo was credited with the systematic study of tracheal and carinal
surgery. In his series of carinal resections which spanned over 30 years, the operative mortality fell from
16.1% to 9%, which he attributed to the lessons learnt as well as improvements in anesthetic and critical
care management.156
PLAN
Assessment of the patient is as for lung cancer patients. All patients with carinal tumor should undergo
bronchoscopic assessment by the surgeon. In addition to obtaining a diagnosis, a thorough assessment is
made of the limits of resection for the intraluminal component, and biopsies taken to define any
microscopic disease extension. A CT scan is examined to assess the extent of any extraluminal
component. The combined information is used to judge whether a complete resection can be
accomplished with a tension-free anastomosis. In general, up to about 4 cm of carina resection can be
carried out for a tension-free anastomosis between the trachea and bronchus. In fact, a gap of over 4 cm is
associated with a tripling of the incidence of anastomotic problems.156 The anastomosis is facilitated by
pretracheal and hilar release maneuvers to help bring the ends together. Laryngeal release has not been
found to be helpful for carinal resections.
Accurate staging is important. Carinal resection is a highly invasive procedure with significant risks,
and patients with mediastinal nodal involvement have a very poor outcome and every effort should be
made to identify these patients before surgery.157 Mediastinoscopy should be also carried out to assess
extraluminal spread and for accurate staging, but should be reserved for the day of surgery as it facilitates
tracheal release without an intervening period when fibrosis and scarring can establish itself.
The ventilation strategy is as crucial as the operation itself. The operative and anesthetic strategy is
discussed with the anesthesiologists, covering induction, intubation, lung isolation, and intraoperative
maneuvers. Back-up strategies for eventualities are anticipated. If there is an obstructing tumor in the
airway, rigid bronchoscopy and debulking may be required prior to intubation. Although a double-lumen
tube is favored by some,158 an extra long armored tube is the most versatile and could be manipulated
easily at operation.159 Cross-field ventilation may be required and clear communication with the
anesthetic team is essential to prepare for changing over of ventilation systems and adjustment of
endotracheal tubes. High-frequency jet ventilation is another useful adjunct, but extra care should be taken
to avoid barotrauma especially when a sealed system is inadvertently created and air could not escape.
CPB is very rarely required in carinal resection, and is mainly used in unplanned emergencies.156,157
Anticoagulation from CPB risks pulmonary hemorrhage and life-threatening respiratory failure,
contraindicating its use.160 However, in recent years there has been interest in pumpless extracorporeal
systems which do not require anticoagulation.161 They allow patients who could not undergo conventional
intubation or ventilation to undergo surgery. Furthermore, it may also allow a more beneficial lung
protective ventilation strategy to be adopted with less iatrogenic barotrauma and volutrauma inflicted on
the remaining lung. This is a particularly attractive idea given that a significant proportion of patients
following sleeve pneumonectomy develops postpneumonectomy pulmonary edema, a complication which
carries a 90% mortality rate.156
Carinal resection and reconstruction can be carried out through a median sternotomy, clamshell, and
posterolateral or anterolateral thoracotomy.162 A median sternotomy provides exposure of the carina
through the posterior pericardium (Fig. 33.10), but the exposure is limited and requires retraction of the
SVC, aorta, and right pulmonary artery. A right thoracotomy provides excellent exposure of the
intrathoracic trachea, carina including the proximal left main bronchus, and the whole right lung. Exposure
of the carina through a left thoracotomy is more challenging and may require mobilization of the aortic
arch and considerable traction; therefore, a left sleeve pneumonectomy may be preferably carried out
through bilateral thoracotomies or a clamshell incision through the 3rd or 4th intercostal space.
The patient is positioned supine for mediastinoscopy, median sternotomy, and the clamshell incision,
and in the lateral decubitus position for thoracotomy. A 4th space lateral thoracotomy provides an
excellent approach to the carina.
TOOLS
The equipment and instruments are as for a conventional rigid and fiberoptic bronchoscopy and lung
resection.
Cross-field ventilation and jet ventilation may be required and a sterile armored tube or thin jet
ventilation catheter, ventilator tubing set, and connectors are set up on the surgical side.
TACTICS
The most common operation involving the carina is a right sleeve pneumonectomy. A left sleeve
pneumonectomy is much rarer as the left main bronchus is much longer and tumors rarely extend to the
carina without having already invaded vital structures in the subaortic fossa.163 Another situation which
may call for a left sleeve pneumonectomy is when there is a positive bronchial margin after a left
pneumonectomy. Tumors of limited extent confined to the carina can be excised with a carinal resection
and reconstruction which requires an additional tension-free anastomosis to be furnished, but preserves
both lungs.
A rigid bronchoscopy is carried out on the day of surgery to confirm bronchoscopic resectability and
to plan the limits of resection. An obstructing tumor could be cored out to enable an extra-long armored
endotracheal tube to be passed beyond the obstruction with bronchoscopic guidance.
A mediastinoscopy is then carried out. The pretracheal plane is developed anteriorly along the full
length of the trachea to mobilize the trachea without disrupting the lateral segmental blood supply. Any
extraluminal tumor extension is noted. Lymph nodes are sent for frozen section pathology.
Right Sleeve Pneumonectomy

A right sleeve pneumonectomy (Fig. 37.19) is most easily carried out through a right thoracotomy. An
assessment of resectability is made; in particular, the hilar tumor may invade adjacent structures including
the SVC and main pulmonary artery. The azygos vein is divided and lymph node dissection is carried out
to facilitate dissection of the hilar structures. The hilar structures are dissected out and encircled. The
trachea and left main bronchus are dissected out for a short distance above and below the tumor,
respectively, taking care not to overly devascularize them, and tapes are passed around them. Care is
taken in particular when dissecting the left main bronchus to protect the recurrent laryngeal nerve where it
loops under the aortic arch to join the tracheoesophageal groove at the left tracheobronchial angle. Once
resectability is ensured, the structures are divided. When possible, the vessels are divided first, and the
lung is then retracted laterally to expose the carina and left main bronchus for division and reconstruction.
This may not be possible depending on the individual circumstances.
FIGURE 37.19 Right sleeve pneumonectomy. (Redrawn from Mitchell JD, Mathisen DJ, Wright CD, et al. Clinical experience
with carinal resection. J Thorac Cardiovasc Surg 1999;117(1):39–52; discussion 52–53.)
Traction sutures such as 2/0 Vicryl are placed on the left main bronchus and trachea, one cartilage ring
beyond the line of division. The left main bronchus is first divided to allow cross-field ventilation. The
endotracheal tube is pulled back and the left main bronchus is intubated and ventilation is taken over. The
trachea is then divided and the specimen is removed and the bronchial margins marked for the pathologist.
Frozen section of the bronchial margins can be performed, although a positive margin need to be balanced
with the risk of anastomotic failure arising from further resection and tension on the anastomosis. Further
traction sutures are placed on the side opposite the first sutures on the trachea and left main bronchus. If a
mediastinoscopy has not been carried out, the pretracheal plane can be freed with the finger at this point,
to increase mobility of the trachea.
The next step is reconstruction with an anastomosis of the trachea to the left main bronchus stump. The
neck is flexed to bring the trachea down toward the bronchus. The traction sutures are pulled together and
the two stumps orientated. The far side anastomotic sutures are then placed. Cross-field ventilation is then
removed and the endotracheal tube is advanced into the left main bronchus to facilitate placement of the
near-side anastomotic sutures. The traction sutures are tied followed by the anastomotic sutures, and the
anastomosis is tested for air leak and buttressed.
Left Sleeve Pneumonectomy

A left sleeve pneumonectomy (Fig. 37.20) is more challenging than a right sleeve pneumonectomy due to
restriction of access and exposure by the aortic arch. The operation can be carried out through a left
thoracotomy with retraction of the aorta if only a short length of trachea and right main bronchus needs to
be resected. Alternative approaches include clamshell thoracotomy at the 4th interspace which provides
excellent access to both hemithoraces and the carina, and median sternotomy through which access to the
carina is good but requires cardiac retraction for access to the hilar vasculature which can result in
hemodynamic instability.157 One solution to this is to perform the hilar dissection and division
thoracoscopically.164 Alternatively, two stage procedures have been described using sequential bilateral
thoracotomies.165 In this strategy, a conventional left pneumonectomy is carried out with a positive
bronchial margin. The carina is then separately resected from the right side.
FIGURE 37.20 Left sleeve pneumonectomy. (Redrawn from Mitchell JD, Mathisen DJ, Wright CD, et al. Clinical experience
with carinal resection. J Thorac Cardiovasc Surg 1999;117(1):39–52; discussion 52–53.)
Resectability is assessed as described above. Through the left thoracotomy, the aortic arch is
mobilized. The vagus nerve is followed and divided inferiorly beyond the takeoff of the recurrent
laryngeal nerve. The ligamentum arteriosum is divided and a tape is passed around the arch for retraction.
The left main bronchus is then dissected proximally taking care not to injure the recurrent laryngeal nerve.
The dissection continues onto the trachea and right main bronchus, noting the proximity of the right
pulmonary artery to the right main bronchus. Tapes are passed around these two structures to retract the
carina forward. 2/0 Vicryl traction sutures are placed on the left side of the trachea and the right main
bronchus, one ring beyond the line of division. The right main bronchus is carefully divided, the
endotracheal tube is pulled back into the trachea, and the bronchus is intubated for cross-field ventilation.
The trachea is then divided. The specimen is retrieved and the bronchial margins marked for the
pathologist. Further traction sutures are placed opposite the first sutures on the trachea and right main
bronchus.
Anastomotic sutures are placed, gently retracting on the traction sutures and aorta as necessary to
facilitate exposure. Cross-field ventilation is withdrawn when most of the far side sutures are placed and
the endotracheal tube is passed into the right main bronchus to facilitate placement of the remaining near
side sutures. The neck is flexed to bring the trachea toward the bronchus. The traction sutures are tied
followed by the anastomotic sutures, and the anastomosis is tested for air leak and then buttressed.
Carinal Resection
For tumors limited to the carina, a carinal resection without lung resection may suffice. The long armored
endotracheal tube is passed beyond the tumor into the left main bronchus where possible. The most
common approach for carinal resection is through a right thoracotomy.
Resectability is assessed as described above, and the azygos vein is divided. The pulmonary ligament
is divided and a hilar release is carried out with a U- or circumferential incision on the pericardium
around the hilum to facilitate ascent of the right main bronchus toward the trachea for a tension-free
anastomosis. The right main bronchus and the distal trachea is dissected out. Tapes are passed and the
trachea is retracted outward to facilitate exposure and dissection of the left main bronchus, taking care not
to injure the recurrent laryngeal nerve. The left main bronchus is also encircled and a tape passed round.
The lines of division of each of the trachea and bronchi are determined and confirmed
bronchoscopically, mindful that a gap of over 4 cm will cause significant tension and risk anastomotic
dehiscence. The trachea and bronchi are dissected out for only short distances beyond this to preserve its
blood supply. 2/0 Vicryl traction sutures are placed one cartilage ring beyond the anticipated line of
transection.
The right main bronchus is first divided followed by withdrawal of the endotracheal tube and division
of the left main bronchus. Alternatively, if the right main bronchus was intubated, the left main bronchus is
divided first to allow cross-field ventilation to be established before withdrawing the endotracheal tube
and dividing the right main bronchus. The trachea is then transected and the margins marked for the
pathologist. The neck is then flexed to bring the trachea down for reconstruction.
There are various configurations for the reconstruction of the carina (Fig. 37.21), depending on the
mobility and length of gap between each of the airway components. The most common configuration is an
end-to-end anastomosis between the trachea and the left main bronchus, with an end-to-side anastomosis
of the right main bronchus onto the lateral tracheal wall (Fig. 37.21A). However, if the length of resection
was small, and the trachea can reach the left main bronchial margin without tension, it is possible to
recreate a neocarina by suturing the medial borders of the left and right main bronchus, and then
performing an anastomosis of the trachea to the double-barreled neocarina (Fig. 37.21B).
FIGURE 37.21 Carinal resection: Depending on the relative lengths of the trachea and bronchi resected, several constructions
may be used. The most common are: End-to-end anastomosis of left main bronchus to trachea, and end-to-side anastomosis of
right main bronchus to the lateral tracheal wall (A), construction of neocarina (B), and end-to-end anastomosis of the right main
bronchus to the trachea, and end-to-side anastomosis of the left main bronchus to the bronchus intermedius (C). (Redrawn from
Mitchell JD, Mathisen DJ, Wright CD, et al. Clinical experience with carinal resection. J Thorac Cardiovasc Surg
1999;117(1):39–52.)
In the event the resected tracheal length is too long for a tension-free anastomosis with the left main
bronchus, the trachea can be anastomosed end-to-end to the right main bronchus, and the left main
bronchus anastomosed end-to-side onto the bronchus intermedius (Fig. 37.21C).166 This is a technically
more difficult configuration due to poor exposure of the end-to-side anastomosis, size disparity between
the left main bronchus and the bronchus intermedius, and the difficulty using cross-field ventilation in this
situation.
TECHNIQUE
The blood supply to the trachea and bronchi are segmental and enter the tracheal wall from the lateral
tissue pedicles to branch into the submucosa.167 Circumferential dissection combined with division of the
trachea can lead to devascularization and necrosis of the anastomosis, which carries a 44% mortality
rate.157 Therefore, the trachea should not be dissected for more than 1 to 2 cm from the cut edge.
Great care must also be taken when performing the anastomosis as anastomotic problems are a source
of significant morbidity and mortality. In Grillo’s series of carinal resections, 17.6% patients developed
anastomotic complications and this carry a 44% risk of mortality. Various ways to perform a
tracheobronchial anastomosis has been described. The two most common methods are circumferential
interrupted sutures, or semicontinuous sutures. There is no evidence to favor one over the other. However,
absorbable sutures should be used as nonabsorbable sutures have a tendency to form granulomas.168
With the interrupted suture method, 4/0 Vicryl sutures were placed 4 mm apart and 3 to 4 mm away
from the cut edge without tying, starting from the midline posteriorly. The sutures should be carefully
placed as any air leak after completing the anastomosis may require taking down and repeating the whole
anastomosis. After half the sutures are placed, the cross-field ventilation is withdrawn and the
endotracheal tube is advanced into the distal airway. The sutures across the anterior surface can now be
placed without hindrance. The neck is flexed to bring the ends together and the traction sutures are tied.
The traction sutures can now be used to rotate the anastomosis, so the sutures to be tied point toward the
surgeon to enable them to be tied under direct vision. The disparity in size of the openings will lead to a
degree of intussusception which does not cause problems.
The alternative method involves placing a running suture of 4/0 polydioxanone (PDS) on the deepest
aspect of the anastomosis tied at each end to interrupted sutures. The remaining half of the anastomosis is
completed with interrupted 3/0 PDS or 3/0 Vicryl placed to correct for size discrepancy.157 Again, the
neck is flexed and the traction sutures tied followed by the anastomotic sutures, with those sutures at the
membranous portion tied last to avoid tears.
The end-to-side anastomosis is created with an ovoid bronchotomy at least 1 cm or two cartilage rings
away from the other anastomosis, lying entirely within the cartilaginous part of the trachea. The length of
the bronchotomy should be the same as the width of the bronchus, but the width of the bronchotomy
aperture should be slightly smaller than the anteroposterior diameter of the bronchus, in order for the
bronchus to hold open the bronchotomy. Anastomotic sutures are placed as above, starting at the anterior
midpoint of the bronchotomy and bronchus.160
TROUBLE SPOTS
Carinal resection is an invasive operation. Mortality rates have fallen with experience but still remains
7% to 10% in experienced hands. The two most feared complications are anastomotic complications and
pulmonary edema. Meticulous attention must be placed on careful dissection and construction of the
anastomosis, using lung protective ventilation and avoiding fluid overload of the patients. Dissection of
the lateral aspect of the trachea should be minimized as it risks interrupting the blood supply as well as
the left recurrent laryngeal nerve, both of which resides in the tracheoesophageal groove.
The tracheal and bronchial walls are thin and the cartilage rings are brittle and inflexible. Care must
be taken when tying the anastomotic sutures not to overtighten the sutures which may otherwise cut through
the cartilage or the thin membranous trachea. In case of small gaps in the membranous portion, the
adjacent esophagus can be used to buttress the defect.162
CONCLUSION
Great advances have been made over the recent years to enable extended resection of locally advanced
lung cancer and the long-term results are promising. As our experience gains along with improvements in
perioperative management and new surgical techniques, the risk of these procedures fall. Close
collaboration with our colleagues in other specialties, from anesthesiologists to critical care physicians,
and from neurosurgeons to plastic surgeons is essential to ensure our patients receive the most informed
opinions and best outcomes.
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38
Surgical Resection of Superior Sulcus
Lesions
Dominique Grunenwald
“The backward curve of the ribs produced a deep groove internally on either side of the vertebral column, the pulmonary
sulcus”.1
The superior sulcus of the chest is the costovertebral gutter, the superior limit of which is the first rib. It is
a typical location for Pancoast tumors that arise from pulmonary parenchyma. Neoplasms developing
peripherally in the upper lobes may also involve the second and third ribs, intercostal nerves, the lower
roots of the brachial plexus, the subclavian vessels, the stellate ganglion, and adjacent vertebral bodies,
thus producing characteristic neurological manifestations (Fig. 38.1). The clinical and radiographic
findings were reported by Pancoast in 1932,2 following a first report in 1924 of what seemed to be a new
entity among intrathoracic tumors.3 At the same period, Tobias4 suggested that this specific clinical
syndrome was generally caused by a bronchogenic carcinoma developing at the thoracic inlet.
FIGURE 38.1 Superior sulcus tumor arising from the right upper lobe: Pancoast syndrome: apical bronchogenic carcinoma,
Horner syndrome, shoulder pain.
The thoracic inlet anatomically includes three compartments (Fig. 38.2): (1) anterior, located between
the sternum and the anterior edge of anterior scalene muscle (scalenus anterior); this space includes the
jugular and subclavian veins, as well as the phrenic nerve which runs along the anterior part of scalenus
anterior muscle; (2) middle, from the anterior scalene muscle anteriorly up to posterior border of middle
scalene muscle (scalenus medius) posteriorly; this space includes the subclavian artery and its branches
as well as the trunks of brachial plexus; and (3) posterior, located behind middle scalene muscle; this
space includes the roots of brachial plexus emerging from the vertebral foramina, the stellate ganglion, the
facet joints on the transverse process of the vertebra, and the vertebral body. According to this anatomy,
only posterior superior sulcus tumors can cause a typical “Pancoast syndrome.” Nevertheless,
bronchogenic tumors arising into the thoracic inlet may also invade the middle and anterior compartments
and involve vascular structures (Fig. 38.3).
Local control as a result of the first treatment offers the best chance of survival for patients with
superior sulcus tumors.5 Presumably, the best local control for resectable tumors is achieved by surgical
operation, provided the resection can be complete while respecting oncologic principles.6,7 Indeed,
apical chest tumors are complex diseases, with a quite poor incidence, thus never studied through
randomized trials, since they represent an ideal clinical model for multimodal strategies. As described
initially, the complete “Pancoast-Tobias” syndrome included pain, Horner syndrome, destruction of bone,
and atrophy of hand muscles.2,4 Such a clinical disease translates the highest degree of anatomic tumor
extension, that is generally beyond any surgical resource. Fortunately, such symptomatology often induces
clinical investigations which lead to diagnosis at an early enough stage, where the patient can still benefit
from a surgical excision.
FIGURE 38.2 Surgical anatomy of the thoracic inlet: anterior, middle, and posterior compartments.
FIGURE 38.3 Magnetic resonance imaging of the left superior sulcus showing the left subclavian artery completely surrounded
by an apical tumor of the lung.
Treating this complex disease presents several challenges. The concept of an adequate local control
shall encompass the entirety of all involved structures: lung, pleural sheets, muscles, ribs, subclavian
vessels, phrenic nerve, brachial plexus, and, vertebrae. Complete resection sometimes requires a
multidisciplinary surgical team effort heavily relying on thoracic, neurosurgical or orthopedic, and
vascular skills. Because of the vicinity of the spinal cord, the esophagus and the brachial plexus, there are
limits for adjuvant radiation therapy. Additionally, a high incidence of distant relapses, particularly in the
brain, raises the issue of a systemic control.8
Historically, from the time of Pancoast tumor description until 1953, the disease was considered
inoperable, as well as incurable. Then, Chardack and Mac Callum9,10 reported the case of a patient who
was treated by radical resection and postoperative irradiation and who survived 5 years without
recurrence or metastasis. Subsequently, Shaw and his colleagues11 reported their experience with 18
patients who were treated by means of preoperative irradiation followed by surgical resection.
This paper was followed in 1975 by a milestone contribution, in which Paulson detailed experience
with 61 patients purportedly having primary carcinomas in the superior pulmonary sulcus treated by
combined preoperative irradiation and extended resection. It is important to note that not all patients had
pre-therapy diagnosis of cancer and some had only scar and tuberculosis on pathologic examination. In
his manuscript, Paulson12 reported 5- and 10-year survival rates of 34% and 29%, respectively. Nodal
disease status, extent of the tumor, cell type, and pathologic effects of preoperative irradiation in the
resected specimens were found to be important prognostic factors. Interestingly, Paulson also emphasized
the contraindications for this operation, which were the involvement of the vascular structures and the
extensive invasion of the brachial plexus. Typically, the surgical approach was an extended posterolateral
thoracotomy that limited the access to the supraclavicular area.
Two decades later, a technique previously described as an approach to the large cervicomediastinal
vessels by Mathey and Cormier,13 was proposed for radical resection of lung tumors invading the thoracic
inlet. The procedure was performed through an anterior transcervical-thoracic approach that included the
removal of the internal half of the clavicle, for a safe exposure and radical resection of non–small-cell
lung cancer invading the cervical structures.14 The subclavian vessels as well as the brachial plexus
could be easily dissected. However, an additional posterior thoracotomy was required for resection of
the chest wall below the second rib.14 The authors concluded this approach was “absolutely
contraindicated” for treating superior sulcus tumors with vertebral body involvement.14
A few years later, a quite different anterior approach was described, entirely sparing the clavicle: the
transmanubrial approach (Fig. 38.4).15 This technique affords an excellent access to the superior elements
of the pulmonary hilum, but also to the anterior part of the C4 to T3 vertebral bodies. With the
transmanubrial approach, a last obstacle was surmounted, when en bloc vertebrectomy for lung cancer
attached to the spine was reported using this technique.16 The development of the transmanubrial
cervicothoracic anterior approach allowed execution of the thoracic steps of extended resections, without
a conventional thoracotomy, including partial or total vertebrectomy when needed.17
CLASSIC POSTERIOR “PAULSON’S APPROACH”

An extended posterolateral thoracotomy is performed (Fig. 38.5).11 A long parascapular incision starting
above the spine of the scapula and extending around the lower tip of the scapula to the anterior axillary
line is used. The latissimus dorsi muscle is completely divided, as well as the inferior portion of the
trapezius, which upper portion preferably is spared, for functional support of the shoulder girdle. After
complete division of the anterior serratus and rhomboideus minor muscles, elevation of the shoulder
becomes possible in order to expose the apex of thoracic cage. One can either use a hook or preferably a
thoracic retractor with asymmetrical blades to spread the scapulothoracic space between the ribs and the
inferior angle of the scapula (Fig. 38.6). According to the extent of the parietal involvement, the pleural
cavity is entered through the third, fourth, or fifth intercostal space for exploration, according to the level
of chest wall invasion. The extent of the infiltration is appraised, as well as the number of ribs to be
resected and the anterior margins (Fig. 38.7). Intercostal vessels are ligated and divided as well as the
first rib so that the posterior portion of the thoracic cage to which the tumor is attached is pulled
downward. This maneuver is meant to expose the cervical structures attached to the tumor in a way to be
dissected and sacrificed when involved. This is the most difficult step of the procedure, and the actual
limit of the Paulson’s approach, making the anterior approach preferable.15 Indeed, an even cautious
dissection of the subclavian artery and its branches is risky in such an exiguous space, and the poor
visibility on the roots of the brachial plexus is not satisfactory. When the plexus has been freed,
sometimes after division of the C8 root, the musculotendinous insertions on the first rib are sharply
divided and the dissection is extended backward to the transverse process down to the lamina of the
vertebra. At this point, the posterior bony attachment has to be dislocated. The spinalis thoracis muscle is
separated from the upper ribs and transverse processes to the lamina, allowing exposure of costal
transverse process joints. Then the costal transverse joints are opened, and the ribs are disarticulated
from inferior to superior (Fig. 38.8). At each level, the intercostal nerve is ligated and divided in the
intervertebral foramen (Fig. 38.9). If necessary, the transverse processes are cut with bone shears. If it is
uninvolved, the head of the ribs are disarticulated from the vertebral articular facets. At the end, the
radiate ligaments of the head of ribs are cut thereby allowing for the infiltrated chest wall to be pulled
inside the thoracic cavity, together with the upper pulmonary lobe. A standard upper lobectomy is
performed together with a complete mediastinal lymph node dissection without separating the thoracic
wall from the lung (Fig. 38.10). Adequate pleural drainage is instituted, and, in general, the thoracic
defect is correctly covered by closure of the muscles. A subfascial Jackson–Pratt suction drainage is
sometimes needed.
FIGURE 38.4 The transmanubrial approach includes an L-shaped manubriotomy after division of the first costal cartilage. The
entire clavicle, the sternoclavicular joint, as well as the sternomastoid muscle are spared.
FIGURE 38.5 Large posterolateral incision, from the spine of the scapula and extending around the lower tip of the scapula up
to the anterior axillary line, according to the description by Shaw and colleagues. (From Shaw RR, Paulson DL, Kee JL.
Treatment of the superior sulcus tumor by irradiation followed by resection. Ann Surg 1961;154:29–40.)
FIGURE 38.6 A retractor with asymmetrical blades is placed and spread into the scapulothoracic space between the ribs and
the inferior angle of the scapula in order to expose the apex of thoracic cage. Alternatively, a hook hanged from a stake fixed on
the operating table can be used.
FIGURE 38.7 Third intercostal space incision, anterior division of the second and third ribs, exposure of the costal transverse
process joints. (Reprinted from Cuadrado DG, Grogan EL. Management of superior sulcus tumors: posterior approach. Oper
Tech Thorac Cardiovasc Surg 2011;16:154–166. Copyright © 2011 Elsevier. With permission.)
FIGURE 38.8 The costal transverse joints are opened, and the ribs are disarticulated from inferior to superior. (From Asamura’s
operative thoracic surgery. Tokyo: Kanehara & Co. Ltd.; 2011.)
FIGURE 38.9 At each level, the intercostal nerve is divided following ligation, in the intervertebral foramen. (From Asamura’s
operative thoracic surgery. Tokyo: Kanehara & Co. Ltd.; 2011.)
In the initial report by Shaw and colleagues,11 the technique was performed 1 month after completion
of preoperative irradiation with the patients receiving a dose in a range of 30 to 35 Gy administered in a
period of approximately 2 weeks. In 1975, Paulson based on his 15-year experience, stated that
supraclavicular vascular involvement and vertebral body involvement were absolute surgical
contraindications to the procedure.12 However, in this disease, the anterior vascular involvement is not
rare, in particular the invasion of the supraclavicular vein and branches; in this setting, an intraoperative
injury can be extremely difficult to manage through the Paulson’s limited access (Fig. 38.11).
A combined cervical and thoracic approach, in two stages, was proposed in the 1990s to improve the
subclavian vessel control and facilitate resection including an anterior cervical incision followed by a
posterolateral thoracotomy with exeresis of the lung.14 The cervical step of this procedure, designed in
accordance with a technique previously described for approaching cervicomediastinal vessels, included
the resection of both the medial half of the clavicle and the first rib, thus allowing a safe exposure of the
thoracic inlet and its contents (Fig. 38.12). The so-called “Dartevelle’s approach,” by removing the
anterior portion of the scapular girdle, generally leads to serious postoperative alterations of shoulder
mobility and cervical posture (Fig. 38.13).15 These disadvantages caused by the scapular instability are
worsened by the necessary division of the sternomastoid muscle, which in turn generates to deformity,
pain, and cervical spine instability. The only way to avoid such disorders is to preserve the integrity of
the sternoclavicular joint, since any attempt of clavicle reconstruction yields either sternoclavicular
pseudojoint formation or scapular rigidity (Fig. 38.14).
FIGURE 38.10 Superior sulcus tumor en bloc resection trough a posterolateral (“Paulson”) approach: see the thoracic wall
remaining attached to the upper pulmonary lobe.
FIGURE 38.11 In case of subclavian vessel involvement, a vascular injury during the dissection is difficult to cope with from a
posterior approach.
FIGURE 38.12 The transclavicular approach, including the removal of the internal half of the clavicle. (Reprinted from
Dartevelle PG, Chapelier AR, Macchiarini P, et al. Anterior transcervical-thoracic approach for radical resection of lung tumors
invading the thoracic inlet. J Thorac Cardiovasc Surg 1993;105:1025–1034. Copyright © 1993 The American Association for
Thoracic Surgery. With permission.)
FIGURE 38.13 Postoperative alterations following transclavicular approach. (Reprinted from Grunenwald D, Spaggiari L.
Transmanubrial approach to the thoracic inlet. J Thorac Cardiovasc Surg 1997;113:958–961. Copyright © 1997 The American
Association for Thoracic Surgery. With permission.)
FIGURE 38.14 Sternoclavicular dislocation after reconstruction of the clavicle, due to the division of the sternoclavicular
ligaments.
TRANSMANUBRIAL OSTEOMUSCULAR SPARING APPROACH

This technique is based on a division of the sternal manubrium through an L-shaped incision, thus
respecting the sternoclavicular joint (Fig. 38.15). The resection of the first costal cartilage allows for the
mobilization of an osteomuscular flap that is progressively elevated by suspending the manubrial “edge.”
Through this approach, after resection of the anterior part of the first rib and, if necessary, the second or
even the third rib, a standard upper lobectomy, as well as a hilar, carinal, paratracheal, and ipsilateral
supraclavicular superior mediastinal lymph node dissection, can be performed. The cervical step of the
operation allows to separate the tumor from the cervical structures, to perform vascular resection and
reconstruction if necessary, and, to divide the external chest wall. Importantly, in the cases of a planned
vertebrectomy the dissection of the anterior vertebral plane free of the posterior mediastinal organs is
performed (great vessels, aorta, and esophagus). This approach gives an excellent access to the
supraclavicular area, as well as the superior mediastinum, while sparing the entire musculature of the
neck (Fig. 38.16). This latter includes the sternomastoid muscle which is a major component of the
cervical stability, particularly, since the scalene muscles are to be disinserted from the ribs, but also and
especially the trapezius muscle, essential to the shoulder movements.
FIGURE 38.15 Principle of the transmanubrial approach.

FIGURE 38.16 Mediastinal view from the transmanubrial approach.
The patient is positioned supine with a cushion elevating the shoulder. The head is turned on the
opposite side of the planned incision. Importantly, the operative field to prepare extends from the mastoid
to the inferior part of the thorax up and down, and from the opposite anterior axillary line to the ipsilateral
middle axillary line, laterally. A table-mounted retractor is installed beyond the ipsilateral shoulder, in
order to retract the manubrial edge, later. The skin incision starts in the neck, running along the anterior
border of the sternomastoid muscle; it is then taken across the midline toward the opposite side down to
the sternal notch to return to the ipsilateral deltopectoral groove at the level of the second intercostal
space. It is important to let the skin incision at least 1.5 cm beyond the sternal notch in order to facilitate
the exposure of the sternal manubrium (Fig. 38.17). The internal part of the sternomastoid muscle is
dissected from its anterior border in order to expose the internal jugular vein (Fig. 38.18). The
sternomastoid muscle which is essential for the cervical spine stability is left undivided and attached to
both the manubrium and the internal part of the clavicle. This is particularly important in the cases where
a vertebrectomy is planned. The venous structures, subclavian and internal jugular veins are completely
dissected and mobilized, by division of all collateral branches, up to the brachiocephalic vein on the right
side, and the left innominate vein on the left. The horizontal part of the incision is then completed along
the second rib, dissecting through the pectoralis major muscle, which is also spared, in order to preserve
an important muscle for the respiratory function as well as the upper limb strength. Next, the first
intercostal space is carefully opened lateral to the internal mammary vessels. The mammary vessels will
be spared as far as possible by blunt dissection from the sternocostal edge because they protect the
phrenic nerve, immediately located behind them. At this point, the first cartilage is dissected and resected
in order to reach the strong costoclavicular ligament which is preserved. Division of the first cartilage
needs the use of strong rib shears (Collin or Gluck) (Fig. 38.19). It is now possible to free the deep
surface of the sternal manubrium by digital blunt dissection and, using an electric saw, to perform an L-
shaped manubrial division, by separating 25% of the manubrium, while respecting the sternoclavicular
joint (Fig. 38.20). An osteomuscular flap, connected to the scapula only through the acromioclavicular
joint, is then gently raised (Fig. 38.21).18 The flap is progressively retracted by means of a lace
surrounding the manubrial edge, and fixed to the table-mounted retractor (Fig. 38.22). During this
manoeuvre, one has to pay attention to the tiny collaterals of the subclavian vein, which must be
meticulously ligated (Fig. 38.23). This is a tedious but necessary step of the operation since, at this point,
it may be difficult to control a bleeding from the subclavian vein. Once the subclavian vein is completely
dissected from its collaterals up to the axillary vein, the “trapdoor” can be opened wide, affording an
outstanding approach to the anterior compartment of the thoracic inlet, but also to the upper mediastinum
and the thoracic cavity (Fig. 38.24).
FIGURE 38.17 The transmanubrial approach: The patient is installed in the supine position; the head is turned on the opposite
side of the planned incision. The skin incision turns around the sternal dimple. (Reprinted from Grunenwald D, Spaggiari L.
Transmanubrial osteomuscular sparing approach for apical chest tumors. Ann Thorac Surg 1997;63(2):563–566. Copyright ©
1997 The Society of Thoracic Surgeons. With permission.)
FIGURE 38.18 The transmanubrial approach: The internal part of the sternomastoid muscle is dissected from its anterior border
in order to isolate the internal jugular vein. The sternomastoid muscle is left attached to both the manubrium and the internal part
of the clavicle. The first intercostal space is carefully opened, outward beyond the internal mammary vessels, who appear as
ligated on this figure. But better is to spare the mammary vessels as far as possible by blunt dissection from the sternocostal
front. (Reprinted from Grunenwald D, Spaggiari L. Transmanubrial osteomuscular sparing approach for apical chest tumors. Ann
Thorac Surg 1997;63(2):563–566. Copyright © 1997 The Society of Thoracic Surgeons. With permission.)
FIGURE 38.19 The first costal cartilage is divided outward the costoclavicular ligament, with strong rib shears (left side).
FIGURE 38.20 L-shaped division of the sternal manubrium.

FIGURE 38.21 The transmanubrial approach: The osteomuscular flap is progressively elevated after division of the sternal
manubrium and the first costal cartilage, only articulated to the scapula through the acromioclavicular joint. (Reprinted from
Grunenwald D, Spaggiari L. Transmanubrial approach to the thoracic inlet. J Thorac Cardiovasc Surg 1997;113:958–961.
Copyright © 1997 The American Association for Thoracic Surgery. With permission.)
FIGURE 38.22 The flap is progressively retracted by the means of a lace surrounding the manubrial edge, and suspended to the
table-mounted retractor.
FIGURE 38.23 The tiny collaterals to the subclavian vein must be ligated cautiously.
FIGURE 38.24 The opening of the “trapdoor” gives an outstanding approach to the anterior compartment of the thoracic inlet.
(From Grunenwald D, Spaggiari L. Transmanubrial osteomuscular sparing approach for apical chest tumors. Ann Thorac Surg
1997;63:563–566. Copyright © 1997 The Society of Thoracic Surgeons. With permission.)
FIGURE 38.25 On the left side, the termination of the thoracic duct is ligated and divided, in order to approach the middle
compartment.
A thoracoscope introduced through the intercostal space allows one to verify the preoperative findings
regarding disease extension on the chest wall and the spine. Once the resectability is confirmed, the
subclavian vascular involvement has to be determined. In the event of venous infiltration by the tumor, the
subclavian vein will be sacrificed. Proximal control is usually obtained at the level of the Pirogoff’s
confluent and the innominate vein, on the right side, and the innominate vein on the left side. Distal control
is achieved simply on both the internal jugular vein and the axillary vein, since all the collaterals have
been ligated and divided. On the left side, the thoracic duct is generally divided and carefully ligated,
upstream from its confluence at the angle formed by union of left internal jugular vein and left subclavian
vein (Fig. 38.25). The phrenic nerve runs along the anterior surface of the scalenus anterior muscle on
both sides to then enter the thoracic inlet behind the subclavian vein and in front of the subclavian artery
(Fig. 38.26); at this point, it crosses in front of the internal mammary artery. If the phrenic nerve is
infiltrated by an anterior tumor, the decision to sacrifice it is made in accordance to the preoperative
assessment. If the phrenic nerve is still functional, this difficult decision must take in account the balance
between the benefits of a presumably complete resection and the risk of postoperative respiratory failure.
When there is a pre-existing obvious phrenic nerve palsy, the nerve can be divided above and below its
invasion, together with the division of the scalenus anterior muscle. This gives access to the middle
compartment of the thoracic inlet, including the subclavian artery and the brachial plexus. On the right
side, the control of the artery is obtained via careful dissection of the brachiocephalic trunk, both internal
and external carotid arteries, and, distally, the initial portion of the axillary artery (Fig. 38.27). All the
collateral branches of the subclavian artery need to be divided often beyond the tumor mass. The artery is
then reconstructed either using a prosthetic bypass, or an end-to-end anastomosis, that is generally
feasible in light of the length of the subclavian artery arch. The replacement of the subclavian vein must
be performed using a ring-reinforced polytetrafluoroethylene tube, because of the risk of kinking upon
closure of the incision (Fig. 38.28). On the left side, it will be mandatory to control both the left internal
carotid and the subclavian arteries into the thorax if needed. Distally, in the same fashion as on the right
side, the axillary artery will be dissected as far as possible, after ligation and division of the numerous
collateral branches around the tumor mass (Fig. 38.29). Obviously, the removal of all fatty tissue in this
area allows for a complete lymph node dissection. At this point, the middle scalenus muscle is separated
from the first rib, providing access to the posterior compartment of the thoracic inlet that includes the
roots of the brachial plexus and the bony structures of the vertebral column (Fig. 38.30). Upon retraction
of both the subclavian vein and artery, an outstanding view on the brachial plexus and its roots permits to
assess the actual nerve involvement and to make a final decision upon the sacrifices needed in order to
achieve a complete resection, knowing that a C8 root sacrifice will be followed by a definitive complete
ulnar paralysis. In the event of a planned partial or total vertebrectomy, this step is only exploratory, since
the division of the nervous roots will be performed afterward from the midline posterior incision. If the
foraminae are not invaded, a complete resection will require disarticulation of the ribs involved by the
tumor. Before this step, the upper lobectomy as well as a mediastinal lymph node dissection must be
performed. To this purpose, a trocar is introduced in the inferior part of the thoracic cavity. The superior
lobar arteries can be divided either through the anterior approach or the inferior trocar, using a vascular
stapler (Fig. 38.31). Likewise, the upper pulmonary vein is controlled and divided (Fig. 38.32); the hilar
part of the lobar resection is completed with the division of the upper lobar bronchus using the same
technique. Albeit difficult at times, the division of the fissures can be done through the anterior incision.
In order to identify the fissure, the lung must be reinflated, thus limiting the available room for the stapler.
Opening the fissure generally requires several firings of a linear cutting stapling device. The upper lobe is
freed from mediastinal and pulmonary attachments but remains fixed only by the chest wall involvement
(Fig. 38.33). If the tumor is small, it is frequently possible to wedge out the tumor of the upper lobe out on
safe margins; this manoeuvre allows the removal of the remaining lobe thereby greatly facilitating the
subsequent mediastinal and posterior dissection (Fig. 38.34). At this point, the actual superior sulcus
extension of the tumor will be properly addressed by an en bloc extralesional approach. The chest wall
mobilization starts from the lowest rib to resect, which is divided anteriorly at least 5 cm away from the
pleural adhesions, and, posteriorly, freed from muscles up to the costotransverse joint (Fig. 38.35). This
is made possible by the previously described removal of the major portion of the upper lobe. The anterior
resection is carried out cranially by individually ligating and dividing the intercostal vessels, and the
lateral rib arches up to the first rib where the anterior cartilage has been previously divided during the
transmanubrial part of the operation. Posteriorly, the superior border of the first rib is freed from
muscular attachments as far as the transverse process (Fig. 38.36). The anterior dislocation of the
mobilized skeletal flap allows for a blunt division of the loose tissue between the subscapularis muscle
and the chest wall reaching as far as the posterior scalene muscle, the insertions of which to the second
rib are divided using electrocautery. Afterward, the technique differs in accordance to the planned
resection. In the absence of spinal attachment, the resection will not include any vertebral body resection.
In this case the chest wall resection is performed from the front, through the thoracic cavity. The direct
frontal view from the transmanubrial approach affords the disarticulation of the resected ribs primarily
from the vertebral facets, and then from the transverse processes (Fig. 38.37). As a rule, the intercostal
nerve is cautiously ligated and divided paying attention to the intercostal vessels that could be a source of
abundant bleeding. In this case, padding using an hemostatic mesh is preferred to an uncertain attempt at
ligation. Gentle retraction of the subclavian vessels allows to easily identify the nervous roots of the
brachial plexus, emerging from the vertebral foramina, which must be spared as far as possible, if not
included in the tumor growth. Once the en bloc specimen is freed from any attachment, its retrieval is
easily done through the anterior approach. After careful final inspection for hemostasis, a chest tube is
introduced through the inferior thoracic port and the incision is closed. Generally, when the thoracic
resection includes less than five ribs, reconstruction is not needed. The manubrium osteosynthesis is
performed very simply by means of two separate steel wires (Fig. 38.38).
FIGURE 38.26 On both sides, the phrenic nerve runs along the anterior surface of the scalenus anterior muscle, enters
downward the thoracic inlet behind the subclavian vein and in front of the subclavian artery. At the level of the first intercostal
space, it is located just behind the internal mammary vessels. No injury to mammary vessels warrants phrenic nerve’s integrity at
this point.
FIGURE 38.27 Exposure of the middle compartment, after division of the anterior scalene muscle (right side).
FIGURE 38.28 Prosthetic replacement of both subclavian artery and vein.
FIGURE 38.29 Extra-anatomic bypass between the left carotid and the axillary artery.
FIGURE 38.30 The posterior compartment of the thoracic inlet includes the roots of the brachial plexus.
FIGURE 38.31 The superior lobar arteries are easy to control and can be divided through the anterior approach. See the apical
tumor remaining attached to the superior sulcus.
FIGURE 38.32 The right superior pulmonary vein is divided.
FIGURE 38.33 Hilar lobectomy and mediastinal lymphadenectomy are performed. Tumor remains attached to the chest wall.
FIGURE 38.34 The tumoral portion of the upper lobe is separated from the rest of the lobe through normal pulmonary
parenchyma. This latter’s extraction from the thoracic cavity facilitates the subsequent mediastinal and posterior dissection.
FIGURE 38.35 The chest wall mobilization starts from the lowest rib to resect.
VERTEBRAL BODY RESECTION

A tumor of any size invading a vertebral body has long been considered as unresectable.12,14 According to
the 7th and 8th editions of TNM staging system, a T4 lung tumor associated with an N0 or N1 lymph node
involvement was classified as stage IIIA.19 The potential resectability of a T4 non–small-cell lung cancer
invading a vertebral body has been recognized thanks to long survival rates reported after complete
excision in appropriately selected patients.20–25
FIGURE 38.36 The anterior border of the resection specimen is divided going up, 5 cm from the patent pleural invasion, up to
the first rib. The superior border of the first rib is freed from muscular attachments backward, up to the transverse joint. (On the
right figure, posterior view.)
FIGURE 38.37 Disarticulation of the resected ribs primarily from the vertebral facet (1), and then from the transverse process
(2).
FIGURE 38.38 The closure is performed very simply by means of two separate steel threads into the sterna manubrium.
SELECTION OF PATIENTS
In addition to the usual operability assessment valid for any major pulmonary resection, the selection
criteria include histologically proven negative N2 status, and evidence of the following: vertebral
attachment or invasion by imaging studies, no brachial plexus involvement above C7, lack of involvement
of the anterior spinal artery, no spinal canal invasion, and, no esophageal infiltration. Also, the extent of
the planned resection should not exceed three vertebral bodies. The imaging evaluation includes a three-
dimensional CT-scan of the chest, an MRI of the chest and spine, a thorough brain MRI examination, a
whole-body fluorodeoxyglucose positron emission tomography (FDG-PET), an endobronchial ultrasound
exploration (EBUS), and, if needed, a mediastinoscopy in the event of a negative EBUS. In addition, in
accordance to the CT-scan and MRI findings, an esophagoscopy, a spinal cord arteriography, and a
vertebral angiography can complete the pre-resectional assessment. Following this preoperative
evaluation, a definitive decision is made on the surgical resectability, but also on the type of resection
(total or partial vertebrectomy). A total vertebrectomy is needed when an obvious invasion of the
cancellous bone of the vertebral body itself is identified (Fig. 38.39). Otherwise, when the tumor is either
only attached to the spine (T3), with or without a hypersignal on the MRI, or again, invades slightly the
corticality of the vertebra (T4), a partial or a hemivertebrectomy is sufficient. As a matter of fact, the
vertebral invasion can be categorized into three subtypes: (a) Type 1 includes the tumors in intimate
contact with the vertebral body, but without involvement of the vertebral periosteum (Fig. 38.40); (b)
Type 2 includes tumors with invasion of the lateral aspects of the vertebra (Fig. 38.41)25; (c) Type 3
includes tumors involving the cancellous bone of the vertebral body (Fig. 38.42). In the case of type 1
tumors, actually T3 tumors, a cortical en bloc spondylectomy is proposed in order to extend the resection
margin distant to the tumor extension into the surrounding bone, as it is proposed in any case of parietal
pleural invasion by a peripheral lung cancer attached to the chest wall. The improvements of the vertebral
resection and reconstruction techniques for vertebrae yet allow to be more aggressive, with the attempt of
minimizing the risk of early local relapse. For type 2 tumors (T4 disease), it is unlikely that a limited
resection would achieve an adequate local control. These cases will be offered a partial vertebrectomy.
For type 3 tumors (T4 disease), a total en bloc vertebrectomy is required.
FIGURE 38.39 A total vertebrectomy is needed where a patent invasion is identified on the cancellous bone of the vertebral
body itself.
FIGURE 38.40 Type 1: the tumor is attached to the spine (T3), with or without a hypersignal on the MRI. A partial
vertebrectomy is needed to avoid an incomplete resection (R1).
FIGURE 38.41 Type 2 are tumors with invasion of the lateral aspects of the vertebra. (From Fadel E, Missenard G, Chapelier
A, et al. En bloc resection of non-small cell lung cancer invading the thoracic inlet and intervertebral foramina. J Thorac
Cardiovasc Surg 2002;123(4):676–685. Copyright © 2002 The American Association for Thoracic Surgery. With permission.)
FIGURE 38.42 Type 3: The tumor involves the cancellous bone of the vertebral body.
FIGURE 38.43 Partial spondylectomy, anterior approach.
TYPE 1 TUMORS. PARTIAL SPONDYLECTOMY

In some cases of direct anterior contact between the tumor and the vertebral body (Fig. 38.43), an en bloc
oblique slight cortical osteotomy can be performed from the front through the anterior approach. Then
after dislocation of the costovertebral joints, followed by the costotransverse articulations, the specimen
is freed from attachments and can be removed through the cervicothoracic approach, without needing any
posterior approach nor vertebral reconstruction.
TYPES 2 AND 3. EN BLOC VERTEBRAL RESECTIONS

First Step, Anterior Approach
Whatever the type of vertebrectomy, the surgical procedure starts in the same way. Initially, a
transmanubrial approach is performed as described above.16,17 Once the supraclavicular area has been
completely dissected, a regular lobectomy is performed from the front and a mediastinal lymph node
dissection is carried out, leaving the tumor attached to the thoracic apex. The chest wall is divided
anteriorly as already described, and the blunt extrathoracic dissection is carried out largely below the
intrathoracic tumor extension and posteriorly to the transverse processes. A linear cutting stapling device
is applied on the healthy portion of the upper lobe, in order to remove the major portion from the thorax.
In this way, it becomes possible to easily approach the posterior mediastinum, thus facilitating the
dissection and mobilization of the aorta, great vessels, esophagus, trachea, away from the anterior spinal
column (Fig. 38.44). An endoesophageal tube allows to identify the esophagus by palpation during this
blunt dissection. The finger dissection in this area is, in fact, fairly easy and nontraumatic since it is
carried out in a nonvascular plan. As a result, the vertebral body is freed from the surrounding soft tissues
by a slow and progressive dissection from the tumor side up to the contralateral hemithorax, pushing the
opposite pleura from the lateral aspect of the bodies. This dissection must be extended at least one level
above and below the planned spondylectomy. To avoid any subsequent injury of the mediastinal organs
during the blind step of the posterior approach, particularly at the time of the vertebral reconstruction, a
strong protecting prosthetic tissue (2-mm polytetrafluoroethylene patch) is inserted between the spine and
the posterior mediastinum (Fig. 38.45). Then the closure of the anterior approach is performed as
described previously, introducing a chest drainage through the inferior port and placing it posteriorly in
the chest.
FIGURE 38.44 Dissection and mobilization of the aorta, great vessels, esophagus, trachea, away from the anterior spinal
column.
Following this stage, the patient is turned upside down in the prone position, using a head holder, in
order to proceed to the posterior incision (Fig. 38.46). Intraoperative evoked potential monitoring of the
spinal function is generally used.
Second Step, Posterior Approach
Total En Bloc Vertebrectomy (Type 3 Tumors)

The incision is medial (Fig. 38.45). The spine is dissected free from muscles and fibrous tissue.
Dissection is extended bilaterally 5 to 6 cm from the midline on the ribs adjacent to the involved
vertebra(e). A bilateral complete laminectomy is performed at the level of the involved vertebra(e),
extending one level in either direction as well (Fig. 38.47).26 It is extended far laterally on the facets,
transverse processes, and pedicles on the side opposite the tumor. On the healthy side, after dislocation of
the costovertebral joints, the ribs at the level of the involved vertebra(e) and at the adjacent upper and
lower levels are transected. At that time, the cord is in the middle of the wound unprotected, the roots
emerging laterally (Fig. 38.48).26 On the tumor side, the chest wall, including the transverse processes, as
well as the pedicles and ribs, remains attached to the vertebra column at the level of the planned
vertebrectomy. Subcutaneous dissection of the ribs is extended up to the extrathoracic plane that has been
dissected during the anterior step of the procedure, and allows identification of the distal rib resection
zone, previously performed from the front. The anterior vertebral body plane, previously dissected
through the anterior approach, is identified, by finding the strong prosthetic tissue still protecting the
posterior mediastinum. Lungs and posterior mediastinum are kept aside with malleable retractors (Fig.
38.49).26 It is now possible to go around the entire vertebral body. Disks adjacent to the resection are
carefully identified and marked with intravenous needles on both sides. Spinal stabilization is performed
before spondylectomy with a unilateral posterior plate and transpedicular screws, taking two or three
vertebrae on both sides of the resection (Fig. 38.50). After division of the roots entering the lateral aspect
of the tumor and after ligation of the roots adjacent to the cord inside the canal, the spondylectomy is
performed with a Gigli saw, working from front to back (Fig. 38.51).26 Sawing is done up to the posterior
third of the vertebral body. Adjacent to the cord, the remaining bone is cut with an osteotome cold chisel
from back to front under visual control (Fig. 38.52).27 This is the best technique to incise the large
vertebral longitudinal ligament, which is anterior to the cord. Then the surgical specimen, including the
thoracic wall, the pulmonary upper lobe, the tumor itself, and the vertebral body, is translated forward,
rotated about the cord, and removed laterally en bloc (Fig. 38.53). A contralateral plate with
transpedicular screws complete fixation of the spine and stabilization of the cord. Vertebral
reconstruction is performed using an autogenous bone graft (fibula), or a massive frozen bank bone, or a
mesh cage filled with cancellous bone (Fig. 38.54). The posterior wound is easily closed. A plastic
jacket is indicated until bony fusion occurs, but early walking is possible 10 days after surgery with
protection of the jacket.
FIGURE 38.45 A polytetrafluoroethylene patch is inserted between the posterior mediastinum and the vertebral column, in
order to avoid injury by screws during the blind posterior workup of stabilization. This posterior view shows the adequate
positioning of the patch, covering largely the spine anteriorly, bilaterally, and vertically.
FIGURE 38.46 Prone position, head holder, in order to proceed to the posterior incision.
FIGURE 38.47 A bilateral complete laminectomy is performed at the level of the tumoral vertebra(e), extending one level in
either direction as well. (Reprinted from Roy-Camille R, Mazel C, Saillant G, et al. Treatment of malignant tumors of the spine
with posterior instrumentation. In: Sundaresan N, Schmidek HH, Schiller AL, et al., eds. Tumors of the Spine. Philadelphia, PA:
WB Saunders; 1990:473–487. Copyright © 1990 Elsevier. With permission.)
FIGURE 38.48 The laminectomy is extended far laterally on the facets, transverse processes, and pedicles on the side opposite
the tumor. On the healthy side, after dislocation of the costovertebral joints, the ribs are transacted. (Reprinted from Roy-Camille
R, Mazel C, Saillant G, et al. Treatment of malignant tumors of the spine with posterior instrumentation. In: Sundaresan N,
Schmidek HH, Schiller AL, et al., eds. Tumors of the Spine. Philadelphia, PA: WB Saunders; 1990:473–487. Copyright © 1990
FIGURE 38.49 Lungs and posterior mediastinum are kept aside with malleable retractors (in blue); see (in green) the
polytetrafluoroethylene patch inserted into the prevertebral plane. (Modified from Roy-Camille R, Mazel C, Saillant G, et al.
Treatment of malignant tumors of the spine with posterior instrumentation. In: Sundaresan N, Schmidek HH, Schiller AL, et al.,
eds. Tumors of the Spine. Philadelphia, PA: WB Saunders; 1990:473–487. Copyright © 1990 Elsevier. With permission.)
FIGURE 38.50 Spinal stabilization is performed before spondylectomy with a unilateral posterior plate and transpedicular
screws, taking two or three vertebrae on both sides of the resection.
FIGURE 38.51 After division of the roots entering the lateral aspect of the tumor and after ligation of the roots adjacent to the
cord inside the canal, the spondylectomy is performed with a Gigli saw, working from front to back, up to the posterior third of
the vertebral body. (Reprinted from Roy-Camille R, Mazel C, Saillant G, et al. Treatment of malignant tumors of the spine with
posterior instrumentation. In: Sundaresan N, Schmidek HH, Schiller AL, et al., eds. Tumors of the Spine. Philadelphia, PA: WB
Saunders; 1990:473–487. Copyright © 1990 Elsevier. With permission.)
FIGURE 38.52 The posterior part of the body, adjacent to the cord, is cut with a bone chisel under careful visual control. See
the spatula protecting the cord. (From Roy-Camille R, Mazel C. Vertebrectomy through an enlarged posterior approach for
tumors and malunions. In: Bridwell KH, De Wald RL, eds. The Textbook of Spinal Surgery. Philadelphia, PA: Lippincott;
1991:1243–1256.)
FIGURE 38.53 The surgical specimen, including the thoracic wall, the pulmonary upper lobe, the tumor itself, and the vertebral
body(ies), is translated forward, rotated about the cord, and removed laterally en bloc. (Reprinted from Grunenwald D, Mazel C,
Berthiot G, et al. Total vertebrectomy for en bloc resection of lung cancer invading the spine. Ann Thorac Surg 1996;61(2):723–
726. Copyright © 1996 The Society of Thoracic Surgeons. With permission.)
Partial Vertebrectomy (Type 2 Tumors)

Complete resection of the vertebral body is not necessary when the tumor is only attached to the lateral
aspects of the spine, without getting over the third of the vertebral body itself. In cases in which only the
foramina(e) and the costovertebral groove are involved, only a partial vertebrectomy or
hemivertebrectomy is necessary to achieve an extended and complete resection (Fig. 38.55). This should
provide an adequate tumor-free tissue margin, thus respecting principles of oncologic surgery. The first
step, that is, anterior approach is identical as described above. Bilateral laminectomy and rib control are
not necessary. After a bony furrow is cut from the facet joints on the tumorous side, corresponding roots
are identified and divided after proximal ligation (Fig. 38.56).28 A plate and transpedicular screws are
implanted on the opposite side of the tumor before osteotomy for stabilization, as described for complete
vertebrectomy. An oblique osteotomy of the vertebral body is then performed from the posterior to the
anterior side (Fig. 38.57).28 The osteotomy is completed on the upper and lower parts of spine by
transection of the vertebral isthmus. By this means, a variable portion of the vertebral body can be
resected, according to the obliquity of the vertical osteotomy. Reconstruction is performed with
autologous bone fixed laterally with screws on the remaining vertebral bodies before inserting a second
transpedicular posterior plate (Fig. 38.58).
FIGURE 38.54 Vertebral reconstruction is performed using an autogenous bone graft (fibula), or a massive frozen bank bone
(left), or a mesh cage filled with cancellous bone (right). (Images courtesy of Mazel C.)
FIGURE 38.55 Principle of en bloc hemivertebrectomy for lung cancer attached to the spine. (Images courtesy of Mazel C.)
Other techniques of both partial and total vertebrectomy for lung cancer invading the spine have been
described throughout the world. As an example, at the University of Texas MD Anderson Cancer Center,
the surgical philosophy is quite different from that which inspired the technique described above.20
Considering that in most cases, the epicenter of the lesion tends to be posterior in the thoracic inlet, the
author’s preference is a posterolateral approach. The patient is positioned in a precise lateral position,
and secured to avoid any rotational deformity of the spine. The classical incision is superiorly and
posteriorly extended posterolateral thoracotomy, starting at the midline of the T1 spinous process. In the
cases of tumors extending to the subclavian vessels or the brachial plexus, a combined anterior neck
dissection and posterolateral thoracotomy is preferred. For tumors that involve a significant portion of the
vertebral body, in which posterior instrumentation is required, a midline incision will be added, taking
care to ensure that the angle be as wide as possible to avoid skin necrosis (Fig. 38.59). Laminectomies
are then performed and nerve roots divided when necessary as they exit the dural sac. After anterior
division of the involved ribs, the tumor is mobilized with the chest wall. In the cases of a small tumor, this
is initially separated from the involved lobe using a linear cutting stapling device through normal
pulmonary parenchyma. This facilitates the visualization of the mediastinal structures, and the anatomical
lobectomy that is then performed if pulmonary function permits. The tumor and chest wall are removed
following disarticulation of the involved ribs from their respective transverse processes, or resected en
bloc with the transverse process using an osteotome, according to the preoperative MRI findings. The
authors consider that with the most of the tumor away from the vertebral body, a more careful assessment
of the extent of the remaining vertebral involvement can be made with optimal visualization. The osseous
elements are removed with high-speed burrs, curettes, and rongeurs. The spine is reconstructed with
expandable titanium cages that can be tailored to the patient’s particular anatomy, and can be packed with
bone chips to facilitate bony fusion. This reconstruction is completed by a posterior stabilization of the
spine using different instrumentations.
FIGURE 38.56 Hemivertebrectomy: after a bony furrow is cut from the facet joints on the tumorous side, corresponding roots
are identified and divided after proximal ligation. (From Mazel C, Grunenwald D, Laudrin P, et al. Radical excision in the
management of thoracic and cervicothoracic tumors involving the spine: results in a series of 36 cases. Spine 2003;28:782–792.)
FIGURE 38.57 An oblique osteotomy of the vertebral body is then performed from the posterior to the anterior side. (From
Mazel C, Grunenwald D, Laudrin P, et al. Radical excision in the management of thoracic and cervicothoracic tumors involving
the spine: results in a series of 36 cases. Spine 2003;28:782–792.)
FIGURE 38.58 Reconstruction is performed with autologous bone fixed laterally with screws on the remaining vertebral bodies
before inserting a second transpedicular posterior plate (A). Mesh cage and autologous iliac bone graft (B). (Images courtesy of
C. Mazel.)
FIGURE 38.59 Positioning for combined posterolateral thoracotomy and midline posterior incision, as performed at the
University of Texas MD Anderson Cancer Center. (Reprinted from Martin LW, Walsch GL. Vertebral body resection. Thorac
Surg Clin 2004;14:241–254. Copyright © 2004 Elsevier. With permission.)
CONCLUSION
The surgical strategy for superior sulcus tumors has considerably changed over the past two decades. The
surgical approach, moving from an extremely destructive extended posterolateral thoracotomy to the
transmanubrial approach, enabled surgeons to expand the indications of surgical excision of such tumors
with long-term satisfactory outcomes. In these challenging cases, the success depends on the completeness
of resection, thus on the extent of the vertebral resection. In the majority of the cases, a composite
reconstruction is performed, associating bone graft, stabilization, and/or synthetic vertebral
reconstruction.
According to the published series, the outcomes of these challenging surgical resections are
encouraging, particularly in the context of multimodality strategies, with 5-year overall survival rates
close to 50%. However, morbidity was observed in 40% of the cases in the German series, without
postoperative mortality. Thirty-eight percent of the patients from the Canadian group stayed in the
intensive care unit, after surgery following chemoradiotherapy, for a median of 15 (1 to 140) days, and in-
hospital mortality was 6%.23,24 These results confirm the absolute necessity of an experienced teamwork
to manage these extremely complex procedures.
REFERENCES
1. Kubik S. Surgical Anatomy of the Thorax. Philadelphia, PA: Saunders; 1970:1.
2. Pancoast HK. Superior pulmonary sulcus tumor: tumor characterized by pain, Horner’s syndrome, destruction of bone and atrophy of
hand muscles. JAMA 1932;99:1391–1396.
3. Pancoast HK. Importance of careful roentgen-ray investigations of apical chest tumors. JAMA 1924;83:1407–1411.
4. Tobias J. Sindrome apico-costo-vertebral doloroso por tumor apexiano: su valor diagnostic en el cancer primitivo pulmonary. Rev Med
Lat Am 1932;19:1552–1556.
5. Komaki R, Mountain CF, Holbert JM, et al. Superior sulcus tumors: treatment selection and results for 85 patients without metastasis
(M0) at presentation. Int J Radiat Oncol Biol Phys 1990;19:31–36.
6. Ginsberg RJ, Martini N, Zaman M, et al. Influence of surgical resection and brachytherapy in the management of superior sulcus tumor.
Ann Thorac Surg 1994;57:1440–1445.
7. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the
superior sulcus: initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg
2001;121:472–483.
8. Shah H, Anker CJ, Bogart J, et al. Brain: the common site of relapse in patients with Pancoast or superior sulcus tumors. J Thorac
Oncol 2006;1:1020–1022.
9. Chardack WM, MacCallum JD. Pancoast syndrome due to bronchogenic carcinoma: successful surgical removal and postoperative
irradiation; a case report. J Thorac Surg 1953;25:402–412.
10. Chardack WM, MacCallum JD. Pancoast tumor: five-year survival without recurrence or metastases following radical resection and
postoperative irradiation. J Thorac Surg 1956;31:535–542.
11. Shaw RR, Paulson DL, Kee JL. Treatment of the superior sulcus tumor by irradiation followed by resection. Ann Surg 1961;154:29–40.
12. Paulson DL. Carcinomas in the superior pulmonary sulcus. J Thorac Cardiovasc Surg 1975;70:1095–1104.
13. Mathey J, Cormier JM. Approach to the large cervico-mediastinal vessels: value of cervico-sternotomy and eventually of delto-pectoral
incision. J Chir 1960;80:585–607.
14. Dartevelle PG, Chapelier AR, Macchiarini P, et al. Anterior transcervical-thoracic approach for radical resection of lung tumors
invading the thoracic inlet. J Thorac Cardiovasc Surg 1993;105:1025–1034.
15. Grunenwald D, Spaggiari L. Transmanubrial osteomuscular sparing approach for apical chest tumors. Ann Thorac Surg 1997;63:563–
566.
16. Grunenwald D, Mazel C, Berthiot G, et al. Total vertebrectomy for en bloc resection of lung cancer invading the spine. Ann Thorac
Surg 1996;61:723–726.
17. Grunenwald DH, Mazel C, Veronesi G, et al. Radical en bloc resection for lung cancer invading the spine. J Thorac Cardiovasc Surg
2002;123:271–279.
18. Grunenwald D, Spaggiari L. Transmanubrial approach to the thoracic inlet. J Thorac Cardiovasc Surg 1997;113:958–961.
19. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage
groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:706–714.
20. Martin LW, Walsch GL. Vertebral body resection. Thorac Surg Clin 2004;14:241–254.
21. Chadeyras JB, Mazel C, Grunenwald D. Vertebral en bloc resection for lung cancer: twelve years’ experience. Ann Chir
2006;131:616–622.
22. Yokomise H, Gotoh M, Okamoto T, et al. En bloc partial vertebrectomy for lung cancer invading the spine after induction
chemoradiotherapy. Eur J Cardiothorac Surg 2007;31:788–790.
23. Schirren J, Dönges T, Melzer M, et al. En Bloc resection of non-small cell lung cancer invading the spine. Eur J Cardiothorac Surg
2011;40:647–655.
24. Collaud S, Waddell TK, Yasufuku K, et al. Long-term outcome after en bloc resection of non-small-cell lung cancer invading the
pulmonary sulcus and spine. J Thorac Oncol 2013;8:1538–1544.
25. Fadel E, Missenard G, Court C, et al. Long-term outcomes of en bloc resection of non-small cell lung cancer invading the thoracic inlet
and spine. Ann Thorac Surg 2011;92:1024–1030.
26. Roy-Camille R, Mazel C, Saillant G, et al. Treatment of malignant tumors of the spine with posterior instrumentation. In: Sundaresan N,
Schmidek HH, Schiller AL, et al, eds. Tumors of the Spine. Philadelphia, PA: WB Saunders; 1990:473–487.
27. Roy-Camille R, Mazel C. Vertebrectomy through an enlarged posterior approach for tumors and malunions. In: Bridwell KH, De Wald
RL, eds. The Textbook of Spinal Surgery. Philadelphia, PA: Lippincott; 1991:1243–1256.
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39
Management of Air Leaks and Residual
Pleural Spaces
Cameron Wright
Air leaks after lung resection are very common although not inevitable. In one prospective study air leaks
were present in 71% of patients at the end of the operation before skin closure and in 89% of the patients
between skin closure and hospital discharge.1 The mean time to the last air leak in this study was 52 hours
and the median time was 28 hours.1 Most air leaks rapidly resolve after lung resection within the first few
postoperative days. The definition of a prolonged air leak is a moving target that is arbitrary in nature. A
common current definition is an air leak beyond the fifth postoperative day and is the definition used by
the Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTDB) and the European
Society of Thoracic Surgeons Database. An alternative definition is one in which the air leak is the only
reason the patient remains in the hospital after lung resection. This is perhaps more valid in these days of
VATS resection where short stays are common and often less than 5 days. This definition is however
problematic in terms of data collection for databases and is thus not often used. The STS GTDB currently
reports a 10.5% incidence of prolonged air leak (>5 days) after lobectomy and 4.1% after wedge
resection.2
RISK FACTORS FOR PROLONGED AIR LEAK

Several studies have addressed the risk factors for a prolonged air leak. These include emphysema,
steroid use, upper lobe resections, bilobectomy, and adhesions. A recent study of 768 patients who
underwent a lobectomy reported a 13% incidence of prolonged air leak.3 The independent predictors of a
prolonged air leak were lower FEV1 and adhesions. A study by Okereke and colleagues4 reported 319
patients undergoing lobectomy by open thoracotomy. The prevalence of air leak was 58%. It occurred
less frequently after left lower lobectomy and was surgeon dependent. The 50th percentile of air leak
duration was 3 days and the 90th was 7 days. Figure 39.1 presents the duration of air leak in 186 patients
from this study.4 Air leak was associated with more complications and protracted hospital course. A study
by Liang et al. reported on 352 patients who had a variety of pulmonary resections. The prevalence of
prolonged air leak was 18%. A prolonged air leak increased the median hospital stay by 4 days.
Multivariate predictors of prolonged air leak were severe radiologic emphysema, pathologic emphysema,
FEV1 < 80%, and lobectomy. The rate of readmission in patients with a prolonged air leak was
substantially higher (25% vs. 4%). Patients with a prolonged air leak had more complications than those
without (1.3/patient vs. 0.42/patient) and the majority of these were pulmonary in nature (90%).
Reoperation is very rare to manage a prolonged air leak as most will eventually seal with conservative
management.
INTRAOPERATIVE CONSIDERATIONS
PREVENTION
Obviously the best treatment of a prolonged air leak is to prevent it. Careful surgery with meticulous
surgical techniques and delicate handling of the lung remain very important. Overzealous grasping of the
lung with clamps for manipulation and exposure can readily tear the visceral pleura and thus lead to a
leak. Blunt dissection of firm adhesions can readily tear the visceral pleura, thus sharp or cautery
dissection is best used with nonfilmy adhesions. Dissection in the fissure and hilum should be very
careful as leaks from these areas are challenging to ameliorate once injured. Only truly complete fissures
should be opened and lysed to remove a lobe of lung. The vast majority of patients have incomplete lobar
fissures that should be completed by staple application. Several studies suggest that a so-called
“fissureless lobectomy” leads to a reduced rate of prolonged air leak.5 Likewise segmentectomy is
usually best done by stapling rather than the older techniques of open dissection. Inspection of the
remaining lung after reinflation is useful to look for significant air leaks that might be ameliorated by
suture, staple, or application of a sealant. Several studies have examined the usefulness of an apical
pleural tent, especially after an upper lobectomy. A number of randomized trials have been performed and
a recent meta-analysis of these trials has been published.6 Five trials were evaluated comprising 396
patients. Use of a pleural tent was associated with a reduction in length of air leak, duration of chest drain
use, and length of hospital stay (Fig. 39.2).
SEALANTS
Many sealants are marketed to ameliorate air leaks after lung resection. The ideal sealant would be easy
to apply despite the presence of blood or an air leak, readily adheres to the lung, reliably stops air leaks
completely, is compliant, is nontoxic, resists infection, is biodegradable, and completely degrades after
several weeks. Rice and Blackstone recently reviewed the use and efficacy of sealants in pulmonary
surgery in an evidence-based fashion and concluded that as of yet there was no reliable efficacious
sealant.7 I review his overall conclusions but for those interested in the details of the individual studies
please refer to his manuscript. Fibrin-based sealants were originally designed for controlling bleeding
from raw surfaces and the indications were extended to include air leak control. To date there have been
seven randomized controlled trials of fibrin sealants which suggest there is a reduction in the occurrence
and duration of air leaks but no change in the duration of chest tube drainage or hospital stay. Synthetic
glutaraldehyde–albumin sealants have only been studied in one small (52 patients) randomized trial which
showed a small benefit of reduced rate and duration of air leaks, and a reduced duration of chest tubes (by
1 day) and hospital stay (by 1 day). Concerns have been raised though about the toxicity of
glutaraldehyde. Polyethylene glycol sealants work by forming bonds in crevices of the surface of the lung.
There have been five randomized trials of polyethylene glycol sealants. Overall, there was a small
reduction in the rate and duration of air leaks but no significant reduction in chest tube days or hospital
stay. Fibrin-coated collagen fleece was developed as a topical hemostatic but was also promoted for air
leak control. There have been five randomized trials reported for collagen fleece with mixed results.
Some studies have reported a reduction in the rate of air leaks and air leak duration without much effect
on chest tube duration and hospital stay. All of these studies used mean duration of air leak as the primary
outcome. As such it might be hypothesized that the studies were set up not to highlight where sealants
might be most useful in high-risk patients, but to reduce the rate of prolonged air leaks since most leaks
seal quickly on their own.
FIGURE 39.1 Duration of air leak among 186 patients. A: Percentage of patients with an air leak. The vertical bars are 68%
confidence limits. Numbers in parentheses represent patients with an air leak. B: Probability density function, showing
percentage of patients whose air leak ceased. (Reprinted from Okereke I, Murthy SC, Alster JM, et al. Characterization and
importance of air leak after lobectomy. Ann Thorac Surg 2005;79:1167–1173. Copyright © 2005 The Society of Thoracic
Surgeons. With permission.)
A recent meta-analysis of sealant trials examining the outcome of prolonged air leak (>7 days)
reduction was reported and suggested a modest benefit to various sealants.8 Thirteen trials were included
covering 1,335 patients. There were four trials of fibrin glue (210 patients), four trials of synthetic
sealants (500 patients), two trials of a collagen patch (354 patients), and four trials of a buttress (271
patients). The pooled effect size was 0.55 (95% CI 0.39 to 0.79) as seen in Figure 39.3.
FIGURE 39.2 Forest plots showing weighted mean difference for the duration of air leak (A), the duration of chest drain (B),
and the duration of hospital stay (C) after upper lobectomy with or without a pleural tent. The solid squares denote the mean
difference, the horizontal lines represent the 95% confidence interval (CI), and the diamond denotes the DerSimonian–Laird
(DL) weighted mean differences. (Reprinted from Uzzaman MM, Robb JD, Mhandu PC, et al. A meta-analysis assessing the
benefits of concomitant pleural tent procedure after upper lobectomy. Ann Thorac Surg 2014;97:365–372. Copyright © 2014
The Society of Thoracic Surgeons. With permission.)
FIGURE 39.3 Forest plot of the meta-analysis of the outcomes of air leak more than 7 days. CI, confidence interval; OR, odds
ratio. (Reprinted from Malapert G, Hanna HA, Pages PB, et al. Surgical sealant for the prevention of prolonged air leak after
lung resection: Meta-analysis. Ann Thorac Surg 2010;90:1779–1785. Copyright © 2010 The Society of Thoracic Surgeons. With
permission.)
STAPLE LINE BUTTRESSING

Staple line buttressing has been reported using bovine pericardium strips and PTFE strips
(polytetrafluoroethylene), primarily in patients with severe emphysema undergoing lung volume reduction
surgery (LVRS). Rice summarized the evidence in these trials in his recent report.7 Three small
randomized trials were reported of buttresses in LVRS patients with very modest benefit. A secondary
analysis of the National Emphysema Treatment Trial (NETT) reported no benefit in staple line buttressing
for reduction of air leaks.9 Two small trials of buttressing were reported after lung resection with one
showing a small benefit and the other no benefit. Bovine pericardial strips have been associated with
unusual complications including late infection, hemoptysis, and pseudotumor formation.7
CHEST DRAIN MANAGEMENT

Chest drain management is not standardized after lung resection although many thoracic surgeons have a
default position of placing the chest drain on 20 cm of suction until any air leak disappears and then
convert to water seal. This practice was never evidence based. Cerfolio and Bryant recently reviewed the
literature regarding chest drain management.10 He conducted and reported a number of helpful studies
regarding chest drain management. His studies indicated it was safe to place chest tubes to water seal in
the presence of a small to moderate air leak as long as the chest radiograph demonstrated that the lung
remained fully inflated. Patients who had their chest tubes placed to water seal had quicker resolution of
their air leak. Brunelli and colleagues have also written extensively about air leaks and reported an
interesting trial comparing water seal versus suction at night for air leaks.11 An underlying theory was that
water seal during the day facilitated mobilization. The trial indicated that suction at night facilitated
sealing of air leaks. The largest trial reported to date randomized 500 patients to 15 cm of suction versus
water seal after lung resection.12 In patients who had an anatomic lung resection, the rate of prolonged air
leak was reduced from 17% with water seal down to 10% with suction. Accordingly, it seems like water
seal in the presence of a small air leak is reasonable, but moderate or larger ones should have some
suction—whether only at night or continuous.
DIGITAL DRAINAGE DEVICES

Traditional chest drainage systems are relatively simple plastic boxes that incorporate the classic 3 bottle
principle into a disposable mass-produced inexpensive device. Older boxes had water in the suction
control chamber which led to noisy bedside devices and thus patient discomfort. More modern ones have
a dry adjustable suction control valve that is silent. The magnitude of the air leak can only be roughly
judged—continuous, expiratory only, and how large the air bolus is as it traverses the water seal chamber.
Drainage tubing can become kinked or clogged without the caregiver’s knowledge. A new digital
drainage device called Thopaz (Medela, Baar, Switzerland) is FDA approved and is being used in
Europe and the United States and seems to be a step forward in managing the evacuation of the pleural
space after lung resection. Thopaz provides a continuous digital readout of the volume of the air leak and
one can precisely see exactly when the air leak has sealed, thus facilitating chest drain removal. The
suction automatically adjusts depending on the volume of leak and fluid drainage. The device alarms if the
tubing is blocked. Several randomized trials have been conducted by evaluating this device with a
generally favorable opinion. A recent large one was reported by Brunelli’s group.13 There were 191
patients in the digital device group. The mean time to air leak cessation was 1.0 versus 2.2 days (p
<0.0001), the chest drain duration time was reduced from 4.7 to 3.6 days (p <0.0001), and the length of
stay was reduced from 5.6 to 4.6 days (p <0.0001). While the drainage collection chamber is disposable,
the device is not and is relatively expensive. Caregivers must be trained in how to use and troubleshoot
this device which is very different from traditional chest drainage systems. Some surgeons have
commented that the device would be more cost effective if it was reserved for anatomic resections and
lesser resections if the patient had emphysema.
POSTOPERATIVE PLEURODESIS
Several agents have been used for pleural sclerosis, mostly for malignant effusions. The two most
commonly used are doxycycline and talc, with talc being the more effective. Talc has also been used to
treat air leaks after secondary pneumothorax in patients with emphysema and by extension after lung
resection. Sclerosis has the advantage of usually quickly controlling the air leak allowing chest drain
removal and discharge without a chest drain. Liberman and colleagues reported a large series of lung
resections (1,393 patients) which resulted in 78 prolonged air leaks (>5 days).14 Talc sclerosis was used
in 41 patients and was successful in 40. The mean time to air leak duration after sclerosis was 2.8 days.
Talc sclerosis however can cause pleural pain, fever, and rarely a systemic inflammatory response. Blood
patches have been reported to be effective in sealing air leaks in patients after lung resection in several
small randomized trials. A recent interesting trial aimed to determine the amount of blood needed for a
blood patch in patients with a persistent leak from a secondary pneumothorax was reported.15 Patients
were divided into four groups of increasing amounts of autologous blood (and a control group): A-0.5
mL/kg, B-1 mL/kg, C-2 mL/kg, and D-1 mL/kg saline. The success rates in the groups were A-27%, B-
82%, C-82%, and D-9%. Thus 1 mL/kg seems like a reasonable amount of autologous blood to use for
pleural sclerosis.
PNEUMOPERITONEUM
Basilar air spaces are especially common after bilobectomy and can be associated with a prolonged air
leak. Since pleural space apposition seems to be important in facilitating sealing of air leaks it seems
sensible to bring the diaphragm up to reduce this space and oppose the diaphragm to the visceral pleura of
the lung. This can be accomplished intraoperatively by injecting air under the diaphragm with a syringe or
by placing a small catheter under the diaphragm. A catheter can be placed postoperatively under local
anesthesia as well. Typically about 500 cc of air is injected and a chest radiograph is obtained to observe
the result. Air can be injected daily if needed as it is gradually resorbed. Many reports have indicated this
maneuver can occasionally be a useful technique to solve a difficult problem.16 Figure 39.4 illustrates the
use of pneumoperitoneum in a patient with a sizable basilar pleural space.
ENDOBRONCHIAL VALVE IMPLANTATION

Novel one-way endobronchial valves which can be inserted by a bronchoscope have been used to treat
persistent air leaks after lung resection. Small case series have been reported with generally favorable
results. A recent report added the use of a digital air leak monitoring to determine which segmental
bronchus to place the valve in and the results of the intervention.17 Thirteen patients had identification of
an air leak endoscopically and 10 patients were judged to be responders with diminution of the air leak
from 871 mL/min to 61 mL/min after implantation of the valve. The valve can be removed by
bronchoscopy after the patient recovers from hospitalization.
REOPERATION
The need for reoperation for a prolonged alveolar air leak is quite unusual. In the study by Liberman and
colleagues14 which reported on 78 prolonged air leaks, only 1 (1.3%) required reoperation. At
reoperation if the leaking site is not obvious then typically the lung is submerged under saline and the leak
can then be readily found. Depending on the exact circumstance the area may be stapled, sutured, or
sealed with a sealant. New chest drains should be placed in optimal positions to drain the pleural space.
Consideration should be given to a talc sclerosis at the completion of the operation. If there was also a
space issue then strong consideration should be given to transposing muscle into the space to fill it and to
further encourage the leak to seal.
FIGURE 39.4 A: Chest roentgenogram showing a lung cancer located in the lingual. Emphysematous changes of the lung and
chest wall are clearly evident. The patient underwent left upper lobectomy. Intraoperatively it appeared evident that space
problems could be anticipated. B: Postoperative chest roentgenogram in the same patient shows apical and basal pleural space
with fluid level. Significant air leak was noted. C: Chest roentgenogram 4 days after instillation of intraperitoneal air. All residual
air spaces were obliterated. D: Chest roentgenogram after removal of pleural drainages. A residual pneumoperitoneum is still
present. (Reprinted from DeGiacomo T, Rendina EA, Venuta F, et al. Pneumoperitoneum for the management of pleural space
problems associated with major pulmonary resections. Ann Thorac Surg 2001;72:1716–1719. Copyright © 2001 The Society of
OUTPATIENT MANAGEMENT OF PROLONGED AIR LEAKS

There is increasing enthusiasm for sending patients home with indwelling chest tubes who have a
prolonged air leak for outpatient management of a prolonged leak.18 Patients must have a smaller leak
with a chest radiograph that shows reasonable pleural apposition and the ability to cope with a chest tube
at home. Typically, a drainage device is placed in the hospital and a short period of observation with
radiographic monitoring is done, as well as patient education. If this trial is successful the patient is
discharged and typically seen in follow-up in the office on a weekly basis until the leak seals. The chest
drain is then removed in the office. There are several valve and drainage systems available, from the
original Heimlich valve to a compact valve/small drainage container (Atrium Pneumostat) to a larger
valve/500 cc plastic container (Atrium Express) that can be worn by a sling over the shoulder. I prefer the
later as the drainage is collected and the device has the ability to readily check for an air leak.
Readmission is rare (2% to 8%) with an empyema as the most likely reason.18
RESIDUAL PLEURAL SPACES

Residual pleural spaces are not uncommon after lung resection, especially after upper lobectomy or
bilobectomy. In the absence of a prolonged air leak these are typically benign and of little clinical
consequence. Subsequent imaging usually shows that these spaces fill in with fluid and shrink over time.
There is a wide spectrum of the degree of filling of the pleural space after lung resection with the
underlying lung. Three factors are in play to minimize the size of the pleural space after lung resection:
shift of the mediastinum toward the operated side, elevation of the ipsilateral diaphragm, and
overexpansion of the remaining lung. Lung restricted by a pleural peel or interstitial lung disease will
obviously limit the amount of ipsilateral lung expansion. It is important to remember that plain
radiographs underrepresent any residual pleural space after lung resection. Although a standard portable
chest radiograph often does not show any residual pleural space of any size, a CT scan will usually show
significant air in the pleural space. If an infected loculated space is suspected after a lung resection
complicated by a prolonged air leak drainage is usually necessary. The space is typically tapped with
image guidance first—either ultrasound or CT depending on location and radiologic expertise. If infection
is confirmed than the space is usually drained by an open window thoracostomy ideally located toward
the bottom of the space. The space can be irrigated and packed or alternatively treated with a Vacuum
assisted closure (VAC) to clean up the space and encourage granulation tissue growth.19 The lung does not
collapse after an open window thoracostomy since the pleural space becomes fused over time after
prolonged chest tube drainage. The space can be closed by antibiotic irrigation/closure (Clagett
procedure), a myoplasty, and/or a thoracoplasty.20,21
REFERENCES
1. Wain JC, Kaiser LR, Johnstone DW, et al. Trial of a novel synthetic sealant in preventing air leaks after lung resection. Ann Thorac
Surg 2001;71:1623–1629.
2. www.sts.org
3. Brunelli A, Casssivi SD, Halgren L. Risk factors for prolonged air leak after pulmonary resection. Thorac Surg Clin 2010;20:359–364.
4. Okereke I, Murthy SC, Alster JM, et al. Characterization and importance of air leak after lobectomy. Ann Thorac Surg 2005;79:1167–
1173.
5. Balasara KR, Balderson SS, D’Amico TA. Surgical techniques to avoid parenchymal injury during lung resection (Fissureless
lobectomy). Thorac Surg Clin 2010;20:365–369.
6. Uzzaman MM, Robb JD, Mhandu PC, et al. A meta-analysis assessing the benefits of concomitant pleural tent procedure after upper
lobectomy. Ann Thorac Surg 2014;97:365–372.
7. Rice TW, Blackstone EH. Use of sealants and buttressing material in pulmonary surgery: An evidence based approach. Thorac Surg
Clin 2010;20:377–389.
8. Malapert G, Hanna HA, Pages PB, et al. Surgical sealant for the prevention of prolonged air leak after lung resection: Meta-analysis.
Ann Thorac Surg 2010;90:1779–1785.
9. DeCamp MM, Balckstone EH, Naunheim KS, et al. NETT research group. Patient and surgical factors influencing air leak after LVRS:
Lessons learned from the NETT trial. Ann Thorac Surg 2006;82:197–206.
10. Cerfolio RJ, Bryant AS. The management of chest tubes after pulmonary resection. Thorac Surg Clin 2010;20:399–405.
11. Brunelli A, Sabbatini A, Xiune F, et al. Alternate suction reduces prolonged air leak after pulmonary lobectomy: A randomized
comparison versus water seal. Ann Thorac Surg 2005;80:1052–1055.
12. Leo F, Duranti L, Girelli L, et al. Does external pleural suction reduce prolonged air leak after lung resection? Results from the
AirINTTrial after 500 randomized cases. Ann Thorac Surg 2013;96:1234–1239.
13. Pompilli C, Detterbeck F, Papagiannopoulous K, et al. Multicenter international randomized comparison of objective and subjective
outcomes between electronic and traditional chest drainage systems. Ann Thorac Surg 2014;98:490–497.
14. Liberman M, Muzikansky A, Wright CD, et al. Incidence and risk factors of persistent air leak after major pulmonary resection and use
of chemical pleurodesis. Ann Thorac Surg 2010;89:891–898.
15. Cao GQ, Kang J, Wang F, et al. Intrapleural instillation of autologous blood for persistent air leak in spontaneous pneumothorax in
patients with advanced chronic obstructive pulmonary disease. Ann Thorac Surg 2012;93:1652–1657.
16. DeGiacomo T, Rendina EA, Venuta F, et al. Pneumoperitoneum for the management of pleural space problems associated with major
pulmonary resections. Ann Thorac Surg 2001;72:1716–1719.
17. Firlinger I, Stubenberger E, Muller MR, et al. Endoscopic one-way valve implantation in patients with prolonged air leak and the use of
digital air leak monitoring. Ann Thorac Surg 2013;95:1243–1250.
18. Varela G, Jimenz MF, Novoa N. Portable chest drainage systems and outpatient chest tube management. Thorac Surg Clin
2010;20:421–426.
19. Aru GA, Jew NB, Tribble CG, et al. Intrathoracic vacuum-assisted management of persistent infected pleural spaces. Ann Thorac
Surg 2010;90:266–271.
20. Massera F, Robustellini M, Della Pona C, et al. Open window thoracostomy for pleural empyema complicating partial lung resection.
21. Fournier I, Krueger T, Wang Y, et al. Tailored thoracomyoplasty as a valid treatment option for chronic postlobectomy empyema. Ann
Thorac Surg 2012;94:387–393.
Section
IX
POSTOPERATIVE MANAGEMENT OF
THE GENERAL THORACIC SURGICAL
PATIENT
40
General Principles of Postoperative Care
Jason P. Shaw
Major pulmonary and esophageal procedures exert tremendous physiologic stress on patients. To obtain
the best results, perioperative care must be optimal. This begins long before the procedure starts and does
not end until long after the patient leaves the hospital.
PREOPERATIVE PREPARATION
PATIENTS’ PERCEPTIONS AND QUALITY OF LIFE

As Cykert and colleagues1 point out, patients are most concerned about their functional outcome following
a major operation such as pulmonary resection, esophagectomy, or chest wall resection. They fear being
limited in physical activity, having a bed-to-chair existence, and requiring complete assistance with
activities of daily living. They do not seem to fear postoperative atelectasis, pneumonia, 3 days of
mechanical ventilation, or even death. However, nonparticipation by the patient in rehabilitation in the
postoperative period may lead to postoperative atelectasis and pneumonia, which can then lead to
significant respiratory compromise and some of the dreaded outcomes patients want to avoid. According
to Wright and colleagues,2 the most common problems delaying discharge from the hospital include
inadequate pain control, prolonged air leak, severe nausea, fever, debility, and arrhythmias (Table 40.1).
Efforts to improve the patient’s preparation prior to the day of operation should be directed at preventing
complications that would lead to limited physical function.
Postoperative quality of life is an important outcome measure in the thoracic surgical patient. Many of
the recent developments in minimally invasive surgery have advanced this aim. Some authors have gone
so far as to suggest that quality of life after lung cancer surgery may be associated with long-term
survival.3 Postoperative care should be focused on facilitating the patient’s return to full function as soon
as possible. As patient’s expectations of the postoperative recovery period impact quality-of-life
perceptions, frank preoperative discussions are a key element of a successful postoperative course.
TABLE 40.1 Common Reasons for Delay in Discharge
Cause Percentage
Inadequate pain control 28
Prolonged air leak 19
Severe nausea 17
Fever 16
Debility 12
Atrial arrhythmia 7
Adapted from Wright CD, Wain JC, Grillo HC, et al. Pulmonary lobectomy patient care pathway: a model to control cost and maintain quality.
Ann Thorac Surg 1997;64:299–302. Copyright © 1997 The Society of Thoracic Surgeons. With permission.
PREOPERATIVE TEACHING
To achieve the best participation in patients’ postoperative care, the patient and family should be as fully
informed as possible. When both patient and family know what to expect, they are better prepared to deal
with problems as they arise. The surgeon should have frank and open discussions with the patient and
family concerning the anticipated outcome and expected postoperative problems, along with the usual
measures to combat those problems. Such discussions help the patient and family understand that the
postoperative course may not be smooth and that aggressive measures may be required to achieve ultimate
recovery.
Studies such as those by Turner and Williams4 and Hekkenberg and colleagues5 show that patients
retain only about half of what is discussed, so repeated sessions may be necessary to ensure that the
perioperative journey is fully anticipated. Included in these discussions should be planning for what
happens after hospitalization. Involvement of social services at the time of scheduling the operation will
facilitate a smooth transition from the acute care setting.
PREOPERATIVE PULMONARY EXERCISE AND TRAINING

If surgical intervention is elective, a short period of preparation (preferably 3 weeks) may be beneficial if
directed at improving the patient’s physical status and specifically at pulmonary preparation, conditioning
exercises, and nutrition. In 1979, Gracey and colleagues6 studied 157 patients about to undergo a major
operation. They administered a standard pulmonary preparation program used at that time and found that
not only were the complications significantly reduced but also that postoperative pulmonary
complications were related to the extent of the operation. They drew no specific conclusions.
In 1999, Debigare and colleagues7 studied preparation for lung volume reduction procedures. Because
many patients traveled a great distance, the investigators devised a home exercise training program that
included incentive spirometry, muscle exercises, and aerobic training. It began with detailed teaching and
follow-up and was ensured through weekly phone calls and a diary filled out by each patient. As a result,
there was a significant increase in the 6-minute walk test, quality-of-life perception, peak work rate, peak
oxygen consumption, endurance time, and muscle strength; it was therefore concluded that such training
was beneficial when time permits a delay in the timing of the operation.
SMOKING
Smoking cessation has always been considered an important issue in preparation for an operation.
However, the evidence shows that the effects of cigarette smoking linger long after cessation and that
inordinately long preoperative delays would be necessary to achieve any significant improvement. The
Lung Health Study Research Group has published many reports concerning the effects of smoking
cessation. Anthonisen and colleagues8 reported the results of one of the aforementioned group’s studies
involving individuals with documented early chronic obstructive pulmonary disease (COPD) who
stopped smoking; they experienced improvement of lung function, with the greatest benefit being noted in
the first year. No conclusions can be drawn concerning the early effects of smoking cessation, because the
investigators’ first observation point was 3 months after intervention.
In a study of rats exposed to smoking followed by cessation, Hannan and colleagues9 found that
smoking significantly decreased the fluidity of alveolar macrophages, which persisted up to 18 weeks
after cessation. Jeffery and colleagues10 studied tracheal surface epithelium and ciliary function in rats
exposed to smoke. They found an increase in the number of cilia in intraluminal mucus and in the presence
of secretory cells of types IV (i.e., merocrine) and V (i.e., apocrine). They also found that the area of
trachea covered by cilia, as determined by point counting, increased significantly.
Verra and colleagues11 studied the cilia of human individuals who were smokers, ex-smokers, or
nonsmokers. They noted that the percentage of axonemal ultrastructural abnormalities was higher in
smokers and ex-smokers than in nonsmokers or control subjects, a condition that seemed to persist long
after smoking cessation. The axonemal ultrastructural abnormalities were polymorphic, characteristic of
acquired ultrastructural changes. These results suggest that chronic smoking may induce an increased
number of abnormal cilia, which may lead to impaired clearance of mucus.
Bertram and Rogers12 noted that epithelial recovery can occur for smokers who have quit for 2 years.
Andersson and colleagues13 studied bronchoalveolar lavage fluid from former smokers and found that
Clara cell secretory protein was increased in smokers and remained elevated for up to 12 months after
smoking cessation. Despite the lack of firm evidence, it is still recommended that patients quit smoking
for as long as possible prior to operation.
Some data suggest that cessation of smoking leads to higher postoperative complications. This is based
on the fact that patients have increased secretions early after cessation. However, in 2005, Barrera and
colleagues14 studied smokers undergoing thoracotomy at Memorial Sloan-Kettering Cancer Center. They
found no difference in pulmonary complications among recent quitters versus continuing smokers. Only
patients with >60 pack-years and those with a significantly reduced diffusion capacity had higher risks of
pulmonary complications. The investigators concluded that it was safe to quit at any time before
operation.
NUTRITION
Preoperative nutritional repletion remains controversial. Preoperative assessment of nutrition cannot be
done with any one simple test. The best assessment is weight loss and adequacy of nutritional intake. In
1977, Fogliani and colleagues15 declared that they could give patients with esophageal cancer sufficient
nutrition and return them to positive nitrogen balance using a diet consisting of an average of 2,000 to
2,600 calories as carbohydrate and lipids and 12 to 14 g of nitrogen. Lim and colleagues16 used total
parenteral nutrition to achieve positive nitrogen balance but noted that this took a minimum of 4 weeks.
Despite this difference, the goal for preoperative preparation of the patient is to maintain nutrition at all
possible costs to prevent additional weight loss before operation and to schedule the procedure as soon
as the patient is prepared.
MEDICATIONS
Preoperative medications should be continued up to the time of operation. The only exceptions are
anticoagulant medications. Patients on warfarin (Coumadin), low-molecular-weight heparin,
unfractionated heparin, or clopidogrel (Plavix) should stop their medications long enough prior to the
procedure so that the effects of these drugs are minimal. Cessation of aspirin is an individual preference.
For pulmonary and esophageal surgery, there is no evidence that aspirin increases bleeding. There is also
no evidence that the addition of preoperative short-term bronchodilators changes operative outcomes.
POSTOPERATIVE MANAGEMENT
CONDUCT OF THE OPERATION

Perioperative management and the conduct of anesthesia are discussed in other chapters. However,
several points are worth emphasizing. Management of anesthesia begins with the proper preparation of
patients so that they will be able to emerge smoothly and promptly after the end of the operation.
Avoidance of long-acting narcotics and paralytics is essential to this philosophy. The anesthesiologist
should be judicious with fluids, keeping the additional crystalloid above fluid losses to 500 to 750 mL.
Pain control is extremely important to the early mobilization of patients. Regardless of approach
(epidural, continuous bupivacaine infusion, patient-controlled analgesia, or a combination), the goal is
continuous pain relief sufficient to allow the patient to participate in pulmonary rehabilitation and
experience early mobilization without significant restrictions placed by the method of analgesia.
POSTOPERATIVE IN-HOSPITAL DISPOSITION

Patients should go to a unit familiar with the management of patients who have undergone complex
thoracic surgery. The initial setting should be monitored, and the nurse–patient ratio in the early
postoperative period should be sufficiently high to permit assessment and intervention as needed as well
as sufficient staff for early mobilization. Each institution defines the staffing ratio differently, but a 1:2
nurse–patient ratio is ideal. Automatic admission to the intensive care unit is a waste of resources. Recent
efforts to utilize automated monitoring systems incorporating end-tidal capnography may provide a role in
early detection of postoperative complications.17
CHEST DRAINAGE SYSTEMS

Surgeons now have several different options for draining the chest. Although actual tube choice is beyond
the scope of this chapter, most surgeons place either one or two chest tubes to drain the pleural cavity.
The tubes are attached to a drainage system that permits one-way drainage only, with a portion of the
device set up to collect fluid. These devices use a variety of valves or liquid to establish a one-way
system. All of the collection systems are designed to provide suction on the tubes if the surgeon desires.
In the past, the manufacture of these devices was governed by a single American standard published by
the American Society for Testing and Materials18 that specified the minimal safety and performance
standards for pleural and mediastinal drainage. In 2003, this standard was withdrawn by the society and
replaced by the three standards on suction devices written by the International Standards
Organization.19–21 These new standards specify looser criteria but apply the standards worldwide.
In the past, all chest tubes were placed on suction at 20 cm H2O. In recent years, the advisability of the
ubiquitous use of suction has been questioned. Several investigators—including LoCicero,22 Cerfolio,23
and Wain24 and their respective colleagues—contend that if the lung is fully expanded with the tube on no
suction, the patient will do well. Now there is more individual preference concerning chest tube suction.
Regardless of types of chest tubes and the use of suction, the drainage tubes must be assessed at least
daily for patency, function, air leakage, and drainage. Inspection of the tube and drainage system for clots
or blockages assures patency. Obstructions are removed by “stripping” the tubing. This is accomplished
by occluding the tubing and pulling it away from the patient to produce a local suction effect. If this does
not work, a balloon-tipped catheter may be passed up the tubing to remove the clot, or a suction catheter
may be used for the same purpose.
A functioning tube is one that shows variation in the fluid within it when the patient breathes quietly.
This may be observed while talking with the patient at the bedside. Good respiratory variation indicates
proper functioning of the tube. Limited changes in the level of the fluid in those drainage systems with a
water column may indicate partial blockage, and the tubing may require further stripping. The tubing
should be placed so that it does not coil, leaving low points to collect fluid. Such collections impede fluid
flow and may cause positive pressure to build up in the tubing and back up into the patient.
Air leakage is assessed by observing the water-seal chamber on the drainage device. Air leakage
should first be assessed off suction at quiet respiration. Next, the patient is asked to cough and the
chamber is observed. Finally, the patient may be placed back on suction if suction is being employed, and
the chamber again observed. Several grading systems have been devised. In general, air leaks should be
characterized by the force necessary to produce the air leak and the amount of the air leak. The smallest
leak is an intermittent one produced on suction only, and the largest one is a continuous air leak. Newer
devices being evaluated currently display the amount of air leak digitally.
Drainage should be measured daily and during the preceding 8 hours so that an estimate can be made
concerning whether the rate of fluid drainage is increasing or decreasing. Nurses usually record the
drainage in 8-hour shifts and provide a total daily drainage for the last three shifts. Also, the character of
the drainage should be noted. Change in the character of the fluid from sanguinous to serous is usually a
good sign. Change from serous to purulent connotes potential empyema. In planning the removal of a chest
tube, the drainage must significantly decrease to levels acceptable to the surgeon. Although exact numbers
are not scientifically verified for the amount of pleural fluid produced per day while a chest tube is in
place, a convenient number is 3 mL/kg per day or 1 mL/kg every 8 hours. For the average patient, this
would amount to 240 to 300 mL per day.
Chest tubes and drainage systems are intended to keep the lung expanded and prevent the development
of a space. Once air leakage ceases and drainage has decreased to acceptable levels, the system has
performed its function and should be removed. In an age of cost containment, this could be anytime after
the operation. Wain and colleagues24 have noted that for major pulmonary resections, the average length
of time to chest tube removal was 4.5 days.
Much recent effort has been spent in an attempt to shorten hospitalization after pulmonary resection. In
an effort to reduce costs, Southey and colleagues discharged patients home with a digital chest tube; while
costs were reduced, readmission to hospital was 30%. A similar strategy demonstrated modest cost
savings among CMS patients.25 Drahush et al. suggested that an approach to pulmonary resection that
involved fissure-less technique, staple-line buttressing, and standardized approach to chest tube
management could potentially result in shorter postoperative hospitalization. Regardless of approach, the
timing of chest tube removal remains an operator-dependent variable and can still be decreased
significantly. There is no scientific proof that a chest tube must be on suction for 2 days after operation
followed by 2 days of water seal before it is removed.
MEDICATIONS
Patients are encouraged to take their medicines with the exception of warfarin up to the time of surgery.
However, most medications can be withheld safely for a few days postoperatively until normal
metabolism and bowel function have returned. There is no indication for the use of prophylactic
medications. The use of perioperative antibiotics for pulmonary or esophageal resection should be
individualized, as Mangram and colleagues26 reported in a guideline for prevention of surgical site
infection sponsored by the Centers for Disease Control and Prevention. They noted that prophylactic
antibiotics should be used for operations with an anticipated high infection rate or for those with severe
or life-threatening consequences if infection occurs and that an antimicrobial agent should be selected
based on published recommendations for a specific operation and efficacy against most common
pathogens. In fact, Luchette and colleagues27 found, in a meta-analysis, that data supporting the use of
prophylactic antibiotics for emergency thoracotomies and chest tubes were minimal; they recommended
only 24 hours of antibiotics. A survey conducted by LoCicero28 showed that few surgeons used
prophylactic antibiotics for thoracotomies. A more recent review acknowledges that there may be
evidence for the use of prophylactics in thoracic cases.29 Yet, the call for antibiotics at the time of the
“surgical pause” or “time out,” prophylactic antibiotics are necessary only for cardiac, vascular,
orthopedic, and colon procedures. There are no contemporary surveys of current surgical practice for
elective clean pulmonary operations.
Pain relief is an important part of the postoperative care of the patient undergoing a thoracotomy.
Patients deserve to be as pain-free as possible. In addition to patient comfort, one of the important
reasons for good pain management is that the patient needs to participate fully in postoperative
rehabilitation. Deep breathing, coughing, and ambulation from the time of transfer from the recovery room
all help to prevent unwanted complications. Methods of pain relief are not covered in detail here. There
is no definitive scientific study to answer the question of which pain-management strategy is best. As
Savage and colleagues30 point out, in choosing an approach to postthoracotomy pain management, the
thoracic surgeon and anesthesiologist must consider the following: the physician’s experience, familiarity,
and personal complication rate with specific techniques; the desired extent of local and systemic pain
control; the presence of contraindications to specific analgesic techniques and medications; and the
availability of appropriate facilities for patient assessment and monitoring postthoracotomy. Whatever
method of pain relief is employed, it should facilitate early participation in rehabilitation. If the pain-
control approach prevents this by limiting mobility or altering mental capacity, another approach should
be considered.
IN-HOSPITAL PULMONARY REHABILITATION

In the early postoperative course, the most significant potential complication following thoracotomy is
pneumonia. A significant risk factor for the development of pneumonia is atelectasis. This is a common
problem following thoracotomy and can be minimized only with the patient’s help. Several techniques for
the prevention of atelectasis have been tried and investigated over the years.
Stock and colleagues31 performed a trial of continuous positive airway pressure (CPAP), incentive
spirometry, and coughing/deep breathing in patients following upper abdominal operations. They found
that CPAP increased functional residual capacity faster than the other methods but was not tolerated as
well as the others. They also found that coughing/deep breathing and incentive spirometry were
equivalent techniques. Ferreyra and colleagues,32 in an intriguing meta-analysis in 2006 of CPAP for
postoperative patients after abdominal operations, found that the technique was better than “standard”
therapy, although that therapy was not carefully defined.
In 1991, Hall and colleagues33 reported on a trial of incentive spirometry or chest physiotherapy
following upper abdominal operations. They found that there was little difference between the techniques,
although they preferred chest physiotherapy. However, most hospitals have eliminated the respiratory
therapist from routine postoperative care, and the nurse is too busy to perform this function effectively. In
1998, Chumillas and colleagues34 instructed patients with significant emphysema to perform home
exercises consisting of incentive spirometry and coughing/deep breathing and, as a result, found improved
outcomes and fewer complications following operation. In 2006, Pasquina and colleagues35 reviewed the
available literature for the use of physiotherapy in abdominal surgery. They found 35 trials with few
differences. Their conclusion was that the routine use of respiratory physiotherapy after abdominal
surgery did not seem to be justified.
In 2007, Freitas and colleagues36 reviewed the data for incentive spirometry in patients who had
undergone coronary artery bypass surgery. They found only small, poorly controlled trials. Their
conclusion was that “In view of the modest number of patients studied, methodological shortcomings and
poor reporting of the included trials, these results should be interpreted cautiously. An appropriately
powered trial of high methodological rigor is needed to determine those patients who may derive benefit
from incentive spirometry.”
In-hospital pulmonary rehabilitation, including patient-initiated incentive spirometry or chest
physiotherapy, has been examined in general thoracic surgery patients in several descriptive studies.
These studies have focused on outcome parameters such as postoperative complications, length of stay,
hospital cost, and pulmonary function. In 2005, Varela and colleagues37 found that routine use of
pulmonary physiotherapy compared with incentive spirometry alone reduced postoperative complications
such as pneumonia and atelectasis and also reduced hospital costs, based on a decreased length of
hospital stay. In 1991, Weiner and colleagues38 concluded that lung function could be increased
significantly when incentive spirometry and specific inspiratory muscle training were used before and
after operation among patients with COPD. In 2000, Gosselink and colleagues39 performed a randomized
controlled trial comparing chest physiotherapy alone with chest physiotherapy plus incentive spirometry.
They found no difference in postoperative pulmonary complications, although the study may have been
underpowered.
Still, the most effective approach to the prevention of atelectasis is preoperative home exercises with
coughing/deep breathing and possibly incentive spirometry and continuation of the same exercises with
adequate pain control following operation. Because the nursing and other professional staff are stretched
thin and can provide only sporadic attention, families are encouraged to support the patient’s efforts on a
regular basis during waking hours.
POSTOPERATIVE PHYSICAL THERAPY
Simple maneuvers such as getting patients out of bed to a chair and early ambulation may help prevent
complications such as atelectasis and venous thromboembolism. In addition to pulmonary rehabilitation,
physical therapy may be crucial in preventing deconditioning, particularly in elderly patients, and may
promote mobility and independence. Early evaluation by a physical therapist may also help anticipate
special discharge needs in terms of carrying out activities of daily living after the patient leaves the
hospital.
TABLE 40.2 Common Risk Factors for the Development of Postoperative Deep
Venous Thrombosis
Age (>40 yrs)
Prolonged immobility (>4 hrs) or paralysis
Prior deep venous thrombosis or pulmonary embolism
Obesity
Hypercoagulable states
Factor V Leiden mutation
Protein S deficiency
Protein C deficiency
Antithrombin III deficiency
Antiphospholipid antibodies or lupus anticoagulant
Plasma hyperhomocystinemia
Major surgery or fractures (especially of abdominal, pelvic, lower extremities)
Malignancy
Varicose veins
Heart failure
Myocardial infarction
PREVENTION OF VENOUS THROMBOEMBOLISM

Measures to prevent postoperative venous thromboembolism should be implemented in high-risk patients
undergoing thoracic surgical procedures. Methods of prophylaxis include pneumatic calf compression
devices and low-dose fractionated or unfractionated heparin. Risk for venous thromboembolic disease
may be stratified according to patient and procedural factors, as outlined by Wain and colleagues24 and
listed in Table 40.2. The majority of patients undergoing thoracic operation fit the high-risk category, as
defined in Table 40.3. These patients have a calf thrombosis rate of 20% to 40%, a pulmonary embolus
rate of 2% to 4%, and a fatality rate of 0.4% to 1.0%. In 2006, Mason and colleagues40 found a 7.4%
incidence of postoperative venous thromboembolism among patients undergoing pneumonectomy for
malignancy. In 2007, the American Society of Clinical Oncology guidelines recommended that patients
with cancer who will have a thoracotomy or laparoscopy lasting >30 minutes should receive
pharmacologic thromboprophylaxis with either fractionated or unfractionated heparin. According to the
2015 ASCO guidelines,41 patients undergoing major cancer surgery should receive prophylaxis starting
before surgery and continuing for at least 7 to 10 days. Prophylaxis should begin preoperatively or as
early as possible in the postoperative period.
Despite recommendations from ASCO, NCCN, and ACCP, compliance with guidelines for
thromboprophylaxis in high-risk hospitalized patients remains low. A combined regimen of
pharmacologic and mechanical prophylaxis may improve efficacy among the patients at highest risk.
POSTOPERATIVE NUTRITION
During the operation, fluid management is designed to limit free water that might produce interstitial
edema and thus limit oxygen diffusion capacity. Following operation, this philosophy continues. Stable
patients should receive minimal maintenance fluids at 0.5 mL/kg per hour or less. During the first 24 to 48
hours, urine output will be lower than most nursing staff are used to seeing. One must resist the urge to
increase the fluid intake or give boluses of crystalloid. On the first postoperative day, the patient may
begin a regular diet without fluid restrictions and the maintenance fluids may be stopped. For patients
having esophageal resection, jejunal feeding should be initiated in the postanesthesia care unit with saline
at 10 mL per hour. If tolerated overnight, full-strength feedings can be substituted and increased every 8
hours until the patient’s feedings reach a calculated goal.
TABLE 40.3 Classification of Risk Levels for a Postoperative Venous Thromboembolic Event
Thromboembolic Event (%)

Risk Level Calf Vein Proximal Clinical Fatal Successful
Thrombosis Vein Pulmonary Pulmonary Prevention
Thrombosis Embolism Embolism Strategies
Low
Uncomplicated 2 0.4 0.2 0.002 No specific
minor surgery in prophylaxis;
patients aged <40 early and
yrs with no “aggressive”
clinical risk mobilization
factors
Moderate
Any surgery in 10–20 2–4 1–2 0.1–0.4 LDUH (q12h),
patients aged 40– LMWH
60 yrs with no (≤3,400 U
additional risk daily), GCS,
factors; major or IPC
surgery in patients
aged <40 yrs with
no additional risk
factors; minor
surgery in patients
with risk factors
High
Major surgery in 20–40 4–8 2–4 0.4–1.0 LDUH (q8h),
patients aged >60 LMWH
yrs without (>3,400 U
additional risk daily), or IPC
factors or patients
aged 40–60 years
with additional
risk factors;
patients with
myocardial
infarction;
medical patients
with risk factors
Highest
Major surgery in 40–80 10–20 4–10 0.2–5.0 LMWH (>3,400
patients aged >40 U daily),
yrs with prior fondaparinux,
venous oral VKAs
thromboembolism, (INR 2–3), or
malignant disease, IPC/GCS +
or LDUH/LMWH
hypercoagulable
state; patients with
elective major
lower extremity
orthopedic
surgery, hip
fracture, stroke,
multiple trauma,
or spinal cord
injury
LDUH, low-dose unfractionated heparin; LM WH, low–molecular-weight heparin; GCS, graduated compression stockings; IPC, intermittent pneumatic compression; VKA,
vitamin K antagonist.
Adapted from Geerts WH, Pineo GF, Heit JA, et al. 42 Copyright © 2004 The American College of Chest Physicians. With permission.
MYOCARDIAL INFARCTION
Postoperative cardiac arrhythmias and ischemia remain common problems after thoracotomy. Groves and
colleagues43 monitored the heart rates of 82 patients having a major thoracotomy. They discovered that the
number of patients suffering from silent myocardial ischemia doubled following thoracotomy. Patients
who had ischemia had an average postoperative resting heart rate of 93 beats per minute, as opposed to
those without ischemia, who had an average postoperative resting heart rate of 82 beats per minute. They
noted that 12% of patients developed atrial arrhythmias, none of which were associated with myocardial
ischemia.
CARDIAC ARRHYTHMIAS
Because arrhythmias are more common in postoperative cardiac surgery, most published studies and
guidelines focused on that group of patients. However, the strategies are similar for general thoracic
surgery patients. A brief review of the most commonly used medications is presented in Table 40.4. In
2006, Dunning and colleagues,44 on behalf of the European Association for Cardio-thoracic Surgery Audit
and Guidelines Committee, published guidelines and suggested a treatment algorithm that has been
adapted and presented in Figure 40.1. Because atrial arrhythmias are more common (ventricular
arrhythmias are rare after thoracotomy), their management is discussed here. The treatment of atrial
arrhythmias relies primarily on resuscitation of the hemodynamically unstable patient, as outlined in
standard Advanced Cardiac Life Support protocols. The principles of correcting electrolyte
abnormalities and ruling out myocardial ischemia should be paramount for patients demonstrating
ventricular ectopy, tachycardia, or both.
Once the diagnosis of an atrial tachyarrhythmia has been established, the first priority is to assess the
patient’s hemodynamic stability. In addition, one should maintain oxygenation, assess fluid balance, and
assess the serum potassium. If the patient experiences syncope or if the blood pressure is less than 80 mm
Hg systolic, the options are chemical conversion or synchronous electrical cardioversion. For DC
conversion, the first shock is typically delivered at 200 J, with subsequent shocks at 300 and 360 J,
respectively.
If the patient is hemodynamically stable and mentating, one should achieve control over the ventricular
rate to allow better ventricular filling and an optimal ejection fraction. Drugs including digoxin,
verapamil, diltiazem, and metoprolol all depress atrioventricular nodal conduction and are most useful
here. Many thoracic surgery patients exhibit bronchospasm, however; therefore, beta-adrenergic blocking
drugs are relatively contraindicated. For these reasons, amiodarone has become the most common agent,
followed by diltiazem, sotalol, and digoxin. Details of dosing are listed in Table 40.4. If these drugs are
not successful or if the patient’s hemodynamic condition deteriorates, synchronous cardioversion should
be undertaken immediately. Once rate control has been achieved, the medication may be changed to
equivalent doses of oral amiodarone over the next 24 hours.
During this period of time electrolytes such as potassium and magnesium should be assayed and
replaced as needed. Myocardial ischemia should be ruled out by electrocardiography. In the absence of
these factors, the natural history of postoperative atrial tachyarrhythmias is self-termination. Therefore,
usually nothing more than a day or two of rate control is required. If the patient spontaneously converts to
normal sinus rhythm over the next 24 hours, the medication can be discontinued and no further treatment is
required. If, however, the patient remains in a rate-controlled fibrillation or flutter beyond 24 hours,
cardioversion should be attempted after echocardiography is performed to exclude the presence of
intracardiac thrombus. Usually this is begun as a trial of chemical cardioversion with antiarrhythmic
medication. Unfortunately there is no single drug that demonstrates high efficacy at converting
postoperative atrial fibrillation or atrial flutter to sinus rhythm. The class I-A agents, such as
procainamide and quinidine, exhibit approximately a 30% conversion rate, similar to that of placebo. The
class I-C agents, such as flecainide and propafenone, claim a somewhat higher conversion rate (about
40% to 60%), but their use is contraindicated in patients who have had a recent myocardial infarction or
those who are known to have a depressed ejection fraction. The new class III agent ibutilide claims a
very high conversion rate of approximately 60% but is associated with both a high relapse rate and the
appearance of malignant ventricular arrhythmias such as torsades de pointes. One of the older class III
agents, D-sotalol, has been shown to be effective at converting atrial fibrillation to sinus rhythm, but the
racemic mixture of D- and L-sotalol has significant beta-blocking activity and is relatively
contraindicated in thoracic surgery patients.
Amiodarone has become the most popular drug for cardioversion, particularly since it is relatively
safe in patients with depressed ventricular function. Although amiodarone causes pulmonary fibrosis
when used chronically, postoperative atrial fibrillation is short-lived and self-limited, so that exposure to
amiodarone is limited. The usual dosing is intravenous: 5 to 7 mg/kg over 30 to 60 minutes, then 1.2 to
1.8 g/day continuous IV or divided oral doses until a total dose of 10 g has been given. The usual
maintenance dose is 100 to 400 mg per day. Its short- and long-term toxicities include bradycardia, visual
disturbances, nausea, phlebitis (if amiodarone is given IV), and constipation as well as hepatic, ocular,
pulmonary, thyroid, and neurologic toxicity. Torsades de pointes ventricular tachycardia is less common
than with dofetilide, ibutilide, or sotalol.
TABLE 40.4 Commonly Used Antiarrhythmic Agents

Drug Classa Loading Dose Maintenance Dose
Adenosine Unassigned 6–12 mg rapid IV push None

Digoxin Unassigned 1.0–1.5 mg (4 doses/12 hrs) 0.125–0.25 mg/day PO or IV
Procainamide I-A 17 mg/kg (load over 20 min) 2 mg/min IV infusion
Sotalol III 80 mg bid 120 mg bid
Ibutilide III 1 mg IV over 10 min None
Amiodarone Unassigned 150 mg IV over 10 min 1 mg/min for 6 hrs, then 0.5 mg/min for 18 hrs, convert to 800–1,600 mg/day
Diltiazem IV 0.25 mg/kg (load over 10 min) 5–10 mg/min IV infusion
a Vaughan–Williams classification.
FIGURE 40.1 Algorithm for the management of postoperative atrial arrhythmias. (Adapted from Dunning J, Treasure T,
Versteegh M, et al. Guidelines on the prevention and management of de novo atrial fibrillation after cardiac and thoracic surgery.
Eur J Cardiothorac Surg 2006;30:852–872. Reproduced by permission of European Association for Cardiothoracic Surgery.)
If the patient who has had multiple episodes of atrial arrhythmias converts to sinus rhythm, the oral
antiarrhythmic drug should be continued for at least 30 days after surgery. It may be stopped in the
outpatient setting, because the risk of relapsing into atrial fibrillation or atrial flutter is extremely low so
long after the operation. If the arrhythmia persists, however, the patient should be anticoagulated with
heparin and then maintained on warfarin. Semielective electrical cardioversion may be undertaken at this
time, with adequate serum levels of antiarrhythmic drug present as determined by echocardiographic
guidance.
Typically, if patients are discharged from the hospital in rate-controlled atrial fibrillation with
adequate anticoagulation, they will spontaneously convert to sinus rhythm as outpatients. If, however, they
remain in atrial fibrillation beyond 30 postoperative days, they should be offered outpatient electrical
cardioversion provided that they have remained therapeutically anticoagulated.
LABORATORY TESTING
Routine laboratory testing is unnecessary except for specific conditions such as blood glucose level for
diabetes mellitus or blood urea nitrogen for patients with renal insufficiency. Other tests for specific
indications might include a blood count for significant hemorrhage or serum potassium level for chronic
diuretic usage. Chest radiographs likewise should not be performed on a routine basis. It is not necessary
to obtain a radiograph every day and for each manipulation of the chest drainage system, such as the
routine cessation of the use of suction. If the immediate postoperative radiograph shows good lung
expansion, the air leakage is minimal or nonexistent, and the physical examination does not change, there
is no need to repeat the radiograph. In general, patients can average three or fewer postoperative
radiographs.
CLINICAL CARE GUIDELINES

Several institutions have initiated guidelines for all professional staff to follow in the management of
postoperative patients. Such protocols have been used successfully for the cardiac surgical patient. In
1997, Knott-Craig and colleagues45 reported that the standard use of preoperative digitalis, aggressive
perioperative pulmonary therapy, subcutaneous heparin, and veno-occlusive stockings led to a decrease in
postoperative complications in thoracotomy patients. That same year, Wright and colleagues2 used data
collected from the previous year to make changes in the management of patients. The guideline detailed
daily goals that the patient and care team were to achieve. Items detailed on a daily basis included
assessments, test ordering, physical therapy, medications, diet, oxygen therapy, patient education, social
service and case management, pain management, chest tube management, and wound care. The ideal
patient was used, and this allowed the clinically naive to rapidly gain an insight into the total care of the
patient. They noted significant decreases in length of stay and hospital costs. Zehr and colleagues46 were
able to show similar results at Johns Hopkins Hospital. Cerfolio and colleagues47 studied 500 patients
using a clinical guideline and found increased patient satisfaction.
PREVENTION OF READMISSION
The goal of postoperative management is to prevent or minimize the effects of the most common problems
that lead to a poor outcome. One surrogate measure of a poor outcome other than death is the rate of
readmission. As Handy and colleagues48 point out, the rate is much higher than most surgeons care to
admit. The aforementioned authors operated on 374 patients and had a 2.1% mortality rate. Of the 366
patients discharged, 69 (18.9%) were readmitted a total of 113 times. Table 40.5 lists the reasons for
readmission. By far the most common reason for a return to the hospital was pulmonary complications
(27%). Fifty-one percent of the patients were readmitted as inpatients; the remainder were emergency
department evaluations. No significant differences in demographics, diagnosis, extent of procedure,
postoperative complications, length of stay, or reason for readmission were identified between inpatient
and emergency department readmissions. Patients undergoing larger resections, such as pneumonectomy
and lobectomy, were admitted more frequently. Moreover, the study found that the patients undergoing
pulmonary resections who were readmitted had an increase in subsequent mortality over the 5 years of
study. Twelve (4.0%) of the 297 patients not requiring readmission died, whereas 8 (11.6%) of the 69
readmitted patients died. Based on this and the present authors’ personal experience, a number of
institutions have developed patient-care pathways to address the major causes of morbidity.
TABLE 40.5 Most Common Reasons for Readmission After Thoracotomy

Cause Percentage
Pulmonary complications 27
Wound problems 14
Cardiac complications 7
Deep venous thrombosis 3
Neurologic complications 1
Psychiatric problems 1
Urinary complications 1
Miscellaneous 16
PREPARATION FOR DISCHARGE

If postoperative care is well planned and executed, the patient should be able to go home. However,
unforeseen events may lead to having to plan for the patient to go to a rehabilitation facility prior to going
home. The exact placement of patients depends on how sick they are and how much rehabilitation they can
perform. In a short-term acute-care rehabilitation facility, the patient must be able to do at least 6 hours
per day of rehabilitation, and the length of stay is limited to 5 days. A skilled nursing facility may take
patients who can do only a few hours of rehabilitation daily, but with an average length of stay of 21 days.
Long-term acute-care facilities accept very ill patients with rehabilitation potential to return to full
activity, including those on ventilators, and are permitted an average 25-day length of stay.
After discharge from the acute care facility or one of the rehabilitation facilities, home care is often
needed. This care provides checks on the general well-being of the patient, nutritional care, respiratory
care, and wound care.
Planning far in advance of discharge will ensure a smooth and rapid transition back to home.
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39. Gosselink R, Schrever K, Cops P, et al. Incentive spirometry does not enhance recovery after thoracic surgery. Crit Care Med
2000;28:679–683.
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41
Ventilatory Support of the Thoracic
Surgical Patient
Jonathan C. Yeung ■ Lorenzo Del Sorbo ■ Shaf Keshavjee
INTRODUCTION
Remarkable developments in surgical technique, anesthetic management, and ventilator technologies have
allowed complex pulmonary operations to become commonplace. While the majority of thoracic surgical
patients are extubated immediately postoperatively, inevitably some patients will require postoperative
ventilator support. An understanding by the thoracic surgeon of ventilator support strategies and their
initiation and termination is important in obtaining the best outcome for these patients.
DEFINITIONS
Mechanical ventilation is an artificial means of life support which aims to assist or replace pulmonary
and respiratory muscle function in times of stress. Invasive mechanical ventilation refers to ventilator
support delivered below the vocal cords through an interface that stents (translaryngeal endotracheal
tube) or bypasses (tracheostomy) the upper airway. Noninvasive mechanical ventilation refers to support
delivered through an interface that requires patency of the upper airway.
The major goals of ventilator support are to protect the airway, reduce the work of breathing, and
improve gas exchange until a safe return to a normal unassisted respiratory function can be achieved.
INDICATIONS
The decision to intubate and begin mechanical ventilation is largely a clinical one. A variety of threshold
physiologic parameters derived from the literature surrounding the discontinuation of mechanical
ventilation have been proposed to support the decision for mechanical ventilation, but these values cannot
replace clinical judgment.1 For example, patients who exhibit marked tachypnea, accessory muscle use,
pursed lip or “tripod” breathing, and changes in mental status will imminently require ventilator support,
regardless of objective criteria. In contrast, a comfortable patient with chronic obstructive pulmonary
disease may meet many of those threshold physiologic parameters, but have no true need for mechanical
ventilation. Ultimately, three major scenarios dictate the need for intubation: failure of airway
maintenance or protection, failure of oxygenation or ventilation, and a deteriorating clinical course.
Failure of Airway Maintenance or Protection

A failure to protect the airway is a primary indication for intubation and mechanical ventilation.
Postoperative airway compromise can stem from a number of etiologies, including laryngeal edema,
laryngospasm, absent gag reflex, and obstruction. In general, such patients should be evaluated by a
physician with experience in managing difficult airways. In cases of pure airway obstruction, where
underlying lung function is normal, mechanical ventilation is utilized simply to mitigate the increased
airway resistance introduced by the endotracheal tube.
Failure of Oxygenation
Failure of adequate oxygenation ultimately results in tissue hypoxia. Because we do not yet have a
reliable real-time measure of tissue oxygenation, blood oxygenation is used as a surrogate marker.
Physiologically, hypoxemia can be caused by: decreased alveolar pO2, ventilation/perfusion (V/Q)
mismatch, right to left shunt, diffusion defects, and poor cardiac output.2 In the immediate postoperative
period, decreased alveolar pO2 can arise from hypoventilation due to oversedation. Mechanical
ventilation can rectify this problem by taking over control of the respiratory rate. In V/Q mismatch, there
are some areas of the lungs which are better perfused than ventilated and some areas which are better
ventilated than perfused, that is, when V/Q matching is not 1:1, there is some “wasted” ventilation or
perfusion. Without matched interaction between air and blood, the effectiveness of alveolus to capillary
oxygen diffusion is affected. While this occurs to some degree in the normal lung, when increased
significantly, it becomes pathologic. At one end on the spectrum, alveoli are ventilated, but not perfused.
This is known as dead space ventilation. At the other end of the spectrum, alveoli are perfused but not
ventilated. This is known as shunt, and it can be anatomic or physiologic. Anatomic shunts occur when
blood passes from the right side of the heart to the left without passing through the lungs. Physiologic
shunts occur when blood passes through the lungs without any oxygenation, such as in areas of complete
atelectasis. In both cases, the consequence is that deoxygenated blood will mix with oxygenated blood,
diluting and reducing the total oxygen content of the blood leaving the heart. As blood is bypassing
aerated lung, increases in FiO2 will not improve oxygenation. In the postoperative scenario, V/Q
mismatch is largely caused by loss of pulmonary functional residual capacity (FRC) from atelectasis or
pulmonary edema. Mechanical ventilation can help improve physiologic shunts and V/Q matching by
increasing the FRC by recruiting atelectatic and partially collapsed lung units with positive pressure.
Diffusion defect is the reduction in the diffusion capacity of oxygen to the blood. This could be due to an
impediment in the alveolar–blood interface such as from pre-existing pulmonary fibrosis or from the
development of pulmonary edema. Mechanical ventilation allows for the delivery of higher inspired
concentrations of oxygen, increasing the oxygen driving force across the alveolar–capillary barrier.
Failure of Ventilation
In ventilatory failure, the amount of alveolar ventilation is inadequate to eliminate the amount of CO2
produced. This results in an increased PaCO2 and a decreased blood pH. Low pH with high PaCO2
suggests an acute hypercarbia, whereas a normal pH with a high PaCO2 suggests a more chronic or
compensated hypercapnia, and is less worrisome. Patients with a coexisting metabolic acidosis may yet
have a normal or low PaCO2, but a serially decreasing pH suggests tiring and increasingly inadequate
ventilation. Hence, blood pH is also an important variable to follow.
Clinically, hypercapnia may present as dyspnea, tachypnea, diaphoresis, and/or confusion. The
underlying cause for hypoventilation stems from an imbalance between the neuromuscular capacity of the
respiratory system and the respiratory load. Postoperative examples of neuromuscular issues include
oversedation, injury to phrenic nerves, and residual paralytic agents. Poorly controlled myasthenia gravis
is another example of a muscular cause of hypoventilation which can be seen postoperatively by thoracic
surgeons. An increase of the respiratory load due to lung diseases, chest wall diseases, or cardiovascular
dysfunction may also lead to hypoventilation. Flail chest, chest wall resection, and airway obstruction are
examples of thoracic surgical issues inhibiting adequate ventilation. Finally, cardiovascular dysfunction
compromising lung perfusion and thus resulting in V/Q mismatch and increased alveolar dead space is an
etiology seen in the postoperative scenario. A significant pulmonary embolism can cause a similar effect.
Patients who are otherwise fit may be able to maintain adequate ventilation in situations of respiratory
compromise by increasing their rate of respiration and by recruiting the use of accessory muscles for
breathing. Ultimately, these patients will tire, with resulting rapid respiratory collapse. Starting
mechanical ventilation early in these patients can help avoid an unstable situation. With the mechanical
support afforded by the respiratory muscles, the body can redistribute blood flow away from the
respiratory muscles to support other vital organs. Indeed, intubation and mechanical ventilation have been
shown to decrease global oxygen consumption by 20%.3 The inverse of decreasing oxygen consumption in
patients on mechanical ventilation applies to patients upon withdrawal of mechanical ventilation, and this
should be kept in mind when patients are weaned from mechanical ventilation in the early perioperative
period.4 Mechanical ventilation can also aid ventilation by increasing the FRC, and thus the number of
ventilated lung units.
OVERVIEW OF LUNG VENTILATOR PARAMETERS

Ventilator Management
A variety of parameters allow for the control of mechanical ventilation. They include flow, tidal volume,
ratio of inspiratory to expiratory time (I:E), positive end-expiratory pressure (PEEP), respiratory rate,
and FiO2.
Flow
Flow refers to the inspiratory flow of gas. It is calculated in liters per minute and starts at the beginning of
inspiration and stops at the end of inspiration. The peak flow rate is the maximum flow delivered by the
ventilator during inspiration. Insufficient flow rates result in flow asynchrony where the patient will
exhibit discomfort and begin to use accessory respiratory muscles in an attempt to increase inspiratory
flows. Flow (L/min) is often plotted against time on the x-axis. This is referred to as a flow–time curve.
Tidal Volume
Tidal volume is the amount of gas moved with each breath. This can either be directly controlled or
indirectly controlled as a function of pressure and is further discussed below.
Inspiratory Time
Inspiratory time is the time spent on the inspiratory phase of the respiratory cycle. Inspiratory time is
directly determined in pressure-controlled ventilation modalities, or is affected by the tidal volume and
the inspiratory flow rate in volume targeted modalities. In general, longer inspiratory times improve
oxygenation by increasing the mean airway pressure and by providing time for the redistribution of gas
from more compliant alveoli to less compliant alveoli. However, longer inspiratory times are less likely
to be tolerated by the patient and usually require a deeper level of sedation.
Inspiratory to Expiratory (I:E) Ratio

The I:E ratio is the ratio of time spent in inspiration to the time spent in expiration. While inspiration is an
active process, expiration is passive and depends on lung and chest wall mechanics.
Positive End-Expiratory Pressure

PEEP is the positive pressure applied to the airways at end expiration. This helps improve oxygenation
by distending open alveoli. Physiologic levels of PEEP will prevent alveolar collapse in patients with
normal FRC. Higher levels of PEEP can be used to keep open collapsed airways and flooded alveoli in
injured lungs. Increasing PEEP has the side effect of increasing the intrathoracic pressure, leading to
reduced preload. Intrinsic PEEP, or auto-PEEP, occurs with incomplete expiration prior to the next
breath (Fig. 41.1). As the previous breath is not completely exhaled, progressive gas trapping will occur,
leading to increased alveolar pressure at end-expiration. Intrinsic PEEP should be minimized where
possible. Solutions can include decreasing tidal volume and increasing the expiratory time to allow for
complete expiration.
Respiratory Rate
The number of breaths occurring each minute determines the respiratory rate. It can be directly set on the
ventilator in controlled ventilation modalities, or it can be determined by the patient’s triggering efforts in
assisted ventilation modalities.
FiO2
The FiO2 is the amount of oxygen delivered in the ventilated gas. It can range from 21% (room air) up to
100% (pure oxygen). The lowest possible FiO2 to meet oxygenation demands should be utilized in order
to reduce absorption atelectasis and hyperoxic injury to the lung.
Ventilator Dynamics
According to the most simplistic theoretical model, the respiratory system can be simplified as the
combination of a resistive and an elastic component in series. Lungs and the chest wall are the elastic
element, whereas airways, tracheal tube, and the ventilator circuit are the resistive element.5 Therefore,
the pressure applied to the respiratory system to generate the tidal volume is determined by two
components: the pressure that overcomes the resistive load or airway resistance and the pressure that
overcomes the elastic recoil (load).
FIGURE 41.1 Flow–volume loop demonstrating air trapping and auto-PEEP. (From Waugh JB, Deshpande VM, Harwood RJ.
Rapid Interpretation of Ventilator Waveforms. Englewood Cliffs, NJ: Prentice Hall, 1999. Copyright © Jonathan B. Waugh,
Vijay M. Deshpande, Melissa K. Brown and Robert Harwood. With permission.)
The pressure that overcomes the resistive load or airway resistance is affected by the viscosity and
density of the gas, length, lumen radius, ventilator flow rate, and flow pattern. This is represented
mathematically by Poiseuille law: , where ∆P is the pressure loss, L is the length of pipe, μ is
the dynamic viscosity, Q is the volumetric flow rate, and r is the radius. Clinically, the variables of lumen
length and radius can be manipulated by minimizing the endotracheal tube length and maximizing the
diameter. Clearly, the length of the patient’s airways is constant. The viscosity and density of the gas
mixture is also largely fixed. One unique exception is Heliox, a mixture of helium and oxygen, used
because it is lighter in density than nitrogen and oxygen in air. This mixture can be used in severe airway
resistance conditions such as in asthmatics or in tracheal stenosis to aid airflow. It is, however, rarely
used in intubated patients. The more relevant variables in airway resistance are the factors of lumen
radius and flow. Lumen radius represents a key factor. As described by Poiseuille law, airway resistance
and lumen radius are related to the fourth power. Consequently, bronchoconstriction, secretion
accumulation, or other obstruction will significantly increase airway resistance. Clinical maneuvers such
as frequent suctioning and the use of bronchodilators are important to reduce airway pressure. Flow rate
is another variable open to manipulation. The flow rate should be maintained as low as possible to meet
patient demand. Whereas too low a flow rate will increase the work of breathing due to flow asynchrony,
too high a flow rate will lead to flow turbulence away from laminar flow, increasing resistance.
The elastic load of the respiratory system depends on the elastic properties of the alveoli and the chest
wall, including the diaphragm. These anatomical components determine the respiratory system elastance,
which represents the elastic resistance of the respiratory system to expand. The higher the elastance, the
higher pressure needed to achieve a certain respiratory system expansion, or tidal volume. For example,
as alveoli fill with fluid, it will resist expansion, and thus increase the lung elastance. Gastrointestinal
ileus causing increased abdominal pressure will resist the excursion of the diaphragm and will similarly
increase the chest wall elastance.
On the ventilator, measured airway pressures include the peak inspiratory pressure (PIP), which is the
highest level of airway pressure delivered to the lungs by the ventilator during inspiration, and the plateau
pressure, which represents airway pressure when there is no flow (Fig. 41.2). PIP represents the sum of
airway resistance and respiratory system compliance. In contrast, because plateau pressure is measured
when flow is reduced to zero, airway pressure and alveolar pressures will have equalized and thus
plateau pressure reflects the elastic properties of the respiratory system alone. Airway pressures should
be measured routinely to avoid causing barotrauma to the lungs. The trends in the different pressures can
hint at the cause of increased airway pressures. For example, increasing airway pressures with stable
plateau pressures suggest an increasing obstruction in the large airways or ventilator tubing.
Compliance, which is the inverse of elastance, is calculated by the change in volume divided by the
change in pressure. Similar to how airway pressure is divided into peak and plateau pressures,
compliance is divided into dynamic and static compliances. Dynamic compliance represents pulmonary
compliance during airflow. It is calculated by Vt/(PIP - PEEP). Static compliance represents pulmonary
compliance during the absence of airflow; Cstat = Vt/(Pplat - PEEP). As with airway pressures,
compliances are best measured as a trend to monitor patients. If the dynamic compliance increases but the
static compliance remains the same, the issue can be localized to the airway. Conversely, in the case of
increasing alveolar consolidation, both dynamic and static compliance will decrease. As positioning of
the patient can affect diaphragmatic excursion and chest wall compliance, in order for serial compliance
measurements to be representative, patient positioning needs to be standardized.
FIGURE 41.2 Relationship between tidal volume and airway pressure during mechanical ventilation. The plateau pressure is
measured by performing an “inspiratory hold” to allow airway pressure to reach a constant value. PEEP, positive end-expiratory
pressure. (From Tobin MJ, Danzker DR. Ventilatory support: who, when, how? In Miller TA, ed. Physiological Basis of
Modern Surgical Care. St Louis: Mosby-Year Book, 1988. Copyright © 1988 Taylor and Francis Group, LLC. Reproduced by
permission of Taylor and Francis Group, LLC, a division of Informa plc.)
COMPONENTS AND DEFINITIONS OF THE VENTILATED RESPIRATORY

CYCLE
The ventilated respiratory cycle has four major phases. Triggering is the switch from expiration to
inspiration. This can be set to be completely ventilator controlled or in response to a patient’s inspiratory
effort in assisted modalities of ventilation. Inspiration is the phase where the ventilator is inflating the
patient’s lungs. Cycling is the switch from inspiration to expiration. Parameters such as time, volume
delivered, fall in flow, or pressure can be used to trigger cycling. Exhalation is the phase where the
patient’s lungs are allowed to deflate and is largely a passive process. The different modes of ventilation
are distinguished by how they achieve these variables. There are two major modes of ventilation:
ventilation targeted to a pressure and ventilation targeted to a volume. A breath is one cycle of inspiration
and expiration. An assisted breath is one where the mechanical ventilator provides some assistance with
work of breathing. A spontaneous breath is one where the patient triggers and cycles the breath. It can be
assisted or unassisted. A mandatory breath is one where the ventilator triggers and cycles the breath.
Volume- Versus Pressure-Targeted Strategies

In the volume-targeted strategy, tidal volume is guaranteed, with airway pressure as the dependent
variable. Each breath is delivered according to a predetermined flow–time curve (waveform and peak
flow), with the area under the curve defining the volume. The output of the volume-controlled mode is
defined by four settings: inspiratory flow–time curve profile, tidal volume, respiratory rate, and time as
either an I:E ratio or inspiratory time. Clinicians set the peak flow rate, the flow profile, tidal volume,
respiratory rate, PEEP, and FiO2. Inspiration ends when the set tidal volume is delivered unless a
prespecified safety pressure limit is reached. The most common flow profile is the square wave profile
delivering a constant flow over a set time (Fig. 41.3). Other flow–time profiles with decelerating or
sinusoidal inspiratory flow waveforms have been developed in an attempt to reduce barotrauma, but no
definitive evidence has been demonstrated in favor of one waveform over another.6 Airway pressures
depend both on ventilator settings and the patient’s pulmonary mechanics. Large tidal volumes or high
peak flows can raise airway pressures, as can worsening pulmonary compliance. The major advantages
with volume-targeted ventilation include the capacity to deliver a predictable VT, the flexibility of flow
and volume adjustments, and the guarantee of a preset minute ventilation (MV).7
In the pressure-targeted strategy, airway pressure is guaranteed, with tidal volume as the dependent
variable. Clinicians set the target (maximum) inspiratory pressure level, the inspiratory time, respiratory
rate, PEEP, and FiO2. The target pressure and inspiratory time is used to determine when to terminate a
breath. Gas flows rapidly through the ventilator circuit in order to pressurize the circuit (and airways) to
a set pressure target. Rapid feedback mechanisms measuring airway pressures allow for deceleration as
the target is reached. Once the target is reached, flow is adjusted to maintain a stable or “square wave”
pressure profile over the rest of the set inspiratory time. Consequently, the flow waveform will show a
decelerating pattern. When the alveolar pressure matches the target pressure, flow will cease (Fig. 41.3).
Thus, the inspiratory time is an important factor. Too short an inspiratory time will lead to cessation of
flow prior to equilibration of alveolar and circuit pressures. Too long an inspiratory time will lead to
cessation of flow due to equilibration of alveolar and circuit pressures before the end of a breath, thereby
increasing mean airway pressure without increasing tidal volume. To assess inspiratory times, an
inspiratory hold can be performed. If equilibrium has not yet been achieved, a fall in airway pressure
below the pressure control target will be observed. If the inspiratory time is too long, observation of
flow–time curves will demonstrate a period of zero flow, and the inspiratory time can be shortened to
maximize tidal volume for a given static compliance. The patient’s pulmonary mechanics can also affect
the resultant tidal volume. Worsening pulmonary compliance will result in lower tidal volume (and thus
MV). The major advantages with pressure-targeted ventilation include the ability to better control the
mean airway pressure and better distribution of gas among alveolar units with different compliances.
FIGURE 41.3 Idealized airway pressure, alveolar pressure, and flow tracings during volume-cycled ventilation (with constant
inspiratory flow) and pressure-cycled ventilation. (From Marcy TW, Marini JJ. Control mode ventilation and assist/control
ventilation. In Stock MC, Perel A, eds. Mechanical Ventilatory Support. Philadelphia, PA: Lippincott Williams & Wilkins; 1997.
With permission.)
A variety of studies have examined whether volume-targeted or pressure-targeted ventilation is

superior. Overall, there is no distinct survival benefit to either strategy of ventilation. Some studies have
shown advantages to volume modes, including lower mean airway pressures8–10 and improved shunt.11
Other studies have shown advantages to pressure ventilation,12,13 including a study showing improved gas
distribution at end expiration, possibly due to higher peak flows obtained with pressure-targeted
ventilation.14,15 However, in settings of significant inspired volume loss due to a large air leak (e.g.,
pleurectomy), pressure-targeted strategies may be advantageous as loss of significant volume through the
air leak can lead to “continuous inspiration” without expiratory cycling.
MODES
Controlled Mechanical Ventilation
In controlled mechanical ventilation, ventilation of the patient is entirely ventilator driven and no patient
work is required. Consequently, patients cannot initiate breaths and, in patients with a respiratory drive,
ventilator dyssynchrony can occur and deep sedation or paralysis is required. The delivered tidal volume
can be either pressure-targeted or volume-targeted (Fig. 41.4).
Assist Control Ventilation
In assist control (AC) ventilation, breaths can be triggered by either the ventilator or by the patient.
Patient-triggered breaths are sensed by the ventilator from the small inspiratory efforts made by the
patient. The clinician determines the minimal MV by setting the respiratory rate and the tidal volume or
target pressure, depending on whether a volume-targeted or pressure-targeted mode is desired. Patients
can breathe above the ventilator to increase the MV and each patient-initiated breath is fully supported by
the ventilator. Because a fully supported breath is always provided, patients with high respiratory rates
are at risk of respiratory alkalosis and decreased venous return and cardiac output. Moreover, care is
needed in setting the trigger sensitivity. Too high a sensitivity can result in autocycling of the ventilator,
and too low a sensitivity can result in missed inspiratory efforts and increased work of breathing (Fig.
41.4).16
Intermittent Mandatory Ventilation

Intermittent mandatory ventilation (IMV) is similar to AC ventilation in that the clinician determines the
minimal MV and the patient is able to breathe above the set rate to increase MV.7,17 The major difference
is that the patient-initiated breaths are not fully ventilator supported, but instead are spontaneous breaths
with an option for supplemental airway pressure where needed. In these spontaneous breaths, the rate,
flow, and volume are determined by the patient’s strength, effort, and lung mechanics. Because these are
not fully supported breaths, IMV has been purported to allow the patient to exercise their respiratory
musculature while on the ventilator. However, this has not borne out to be true.18–20 To prevent a
mechanical breath from being stacked with a spontaneous breath, synchronized IMV (SIMV) was
developed to synchronize the patient’s breaths (up to the mandatory rate) with machine supported breaths.
As with the previous modes, IMV and SIMV machine breaths can be either volume or pressure targeted
(Fig. 41.4).
Pressure Support
In contrast to the previous modes of ventilation, pressure support (PS) ventilation is a completely
spontaneous mode of ventilation. The patient determines the respiratory rate, the inspiratory flow, and the
inspiratory time, that is, the patient controls both triggering and cycling. In this mode, the clinician sets the
inspiratory pressure level, the PEEP, and FiO2. When the patient triggers the ventilator, the ventilator will
deliver a rapid flow up to the preset pressure limit. The patient is free to continue this breath as long as
they wish, with the flow cycling off when a fall in flow to a predetermined percentage of peak inspiratory
flow or absolute amount of flow is reached, depending on the ventilator software. Therefore, tidal volume
will change depending on patient effort, the inspiratory pressure level, and lung characteristics. This
mode is thought to provide patients with a more natural breathing pattern on mechanical ventilation (Fig.
41.4).21,22
FIGURE 41.4 Patterns of airflow, airway pressure, and lung volume during mechanical ventilation. Gas flow (cycle Δ) is
initated by patient effort (−P) or set time cycle. Inspiratory flow ceases (limit Δ) when a preset volume, pressure, or flow is
achieved. CMV, continuous mechanical ventilation; IMV, intermittent mandatory ventilation; PCIRV, pressure-controlled inverted
ratio ventilation; PCV, pressure control ventilation; PEEP, positive end-expiratory pressure; PS, pressure support. (From Bartlett
RH. Respiratory physiology and pathophysiology. In: Bartlett RH, ed. Critical Care Physiology. Boston; Little, Brown, 1996.
Copyright © Robert H. Bartlett. With permission.)
ADVANCED VENTILATOR MODES

Airway Pressure Release Ventilation
This mode of ventilation was designed to aid the ventilation of difficult-to-oxygenate patients with acute
lung injury.23 It aims to increase mean airway pressures while minimizing increases in peak airway
pressures, that is, this mode aims to recruit collapsed alveoli. In this strategy, first described by Stock and
Downs in 1987, a high CPAP for a prolonged time is applied to recruit alveoli and to maintain adequate
lung volumes.24 This avoids the repetitive recruitment and derecruitment of the lung during more
conventional ventilation strategies. Spontaneous breathing occurs during this high pressure phase and thus
allows the patient to control their respiratory frequency, increasing comfort and synchrony. While PS can
theoretically be applied during the high pressure phase, this additional support can increase applied
airway pressure to dangerous levels and cause injurious lung distension. A time-cycled phase to a lower
airway pressure for a short period of time is utilized for ventilation. This mode is an example of inverse
ratio ventilation, where the time spent in inhalation is greater than the time spent in exhalation; that is, an
I:E ratio >1 (Fig. 41.4).
High Frequency Ventilation

This mode of ventilation combines very high respiratory rates (>1 breath/s) with tidal volumes which are
smaller than the anatomic dead space.25 Four categories of high frequency ventilation (HFV) exist: high
frequency positive pressure ventilation, high frequency oscillation (HFO), high frequency jet ventilation,
and high frequency percussive. However, HFO is the most common clinically utilized method today. In
HFO, breaths are delivered via an oscillating diaphragm. Rates are set to 200 to 900 breaths per minute
and a high mean airway pressure (also known as a constant distending pressure) is set to stent open the
alveoli. The small breaths are designed to prevent overdistension of the alveoli and the high mean airway
pressure is designed to prevent the repetitive collapse and recruitment of alveoli. Because the oscillating
diaphragm moves in both directions, exhalation is active. Tidal volume is dependent on the oscillation
frequency. As the frequency decreases, delivered tidal volume increases, because the longer respiratory
cycle allows for a larger swing of the oscillating membrane, at a given power.
Gas transport during HFV is incompletely understood.26 A variety of mechanisms have been proposed:
(1) As tidal volume is close to anatomic dead space, the leading edge of the gas front may reach proximal
alveoli and contribute to gas exchange by bulk flow. (2) The filling rate of each lung unit differs based on
its compliance and resistance. After inspiration, there is redistribution of inspired gas from filled fast-
filling units to slower-filling units, leading to regional gas movement known as pendelluft. (3) The
asymmetry in gas velocity between inspiration and expiration leads to a phenomenon known as
convective streaming. High velocity inspired gas travels centrally down the smaller airways, entraining
gas closer to the airway walls. The slower moving exhalational gas thus streams away from the alveoli
along the outer wall. (4) The beating heart can enhance gas exchange by agitating the surrounding lung
tissue. This is known as cardiogenic mixing. (5) Areas of turbulent flow allows for lateral convective
mixing. (6) Areas of laminar flow allow for lateral diffusive mixing. (7) Collateral ventilation through
nonairway connections can occur.
Two recent randomized controlled trials (RCTs) have looked at HFO in the acute respiratory distress
syndrome (ARDS) population. The OSCILLATE trial was stopped early due to a finding of increased
inhospital mortality of 12%.27 The HFO group required more vasopressors than the conventionally
ventilated group, suggesting that the higher intrathoracic pressures used in HFO caused a substantial
increase in RV afterload. Similarly, the high airway pressures used in the HFO group may have caused
further barotrauma. The OSCAR trial is a similar multicenter trial comparing HFO to usual ventilator
care.28 In this study, 30-day mortality was similar between the two groups. Interestingly, airway pressures
utilized in their HFO group were lower than the OSCILLATE trial, suggesting that barotrauma could have
contributed to the worse outcome in the OSCILLATE trial.
Neurally Adjusted Ventilatory Assist

One of the major functions of mechanical ventilation is to offload the respiratory muscles and allow for
gas exchange until improvement in the cause of respiratory failure can occur. Prolonged mechanical
support can lead to diaphragmatic atrophy and dysfunction, whereas modes which allow for
diaphragmatic effort risks patient–ventilator asynchrony. Neurally adjusted ventilatory assist (NAVA) was
designed to better synchronize ventilator support with the patient’s neural respiratory drive. Sinderby et
al.29 developed a nasogastric tube with electrodes allowing for diaphragm electromyography signal
acquisition. The diaphragmatic electrical activity is sent to the ventilator where it then assists the
spontaneous breath by delivering a pressure proportional to the electrical activity of the diaphragm.
Pressure is delivered until electrical activity decreases by 30%. As this is a new strategy, only small
studies are available. Colombo et al.30 and Patroniti et al.31 compared PS levels to matched NAVA levels
and found that NAVA averted the risk of overassistance, avoided patient–ventilator asynchrony, and
improved patient–ventilator interaction at high assist levels. This promising mode of ventilation clearly
cannot be utilized if the respiratory center, phrenic nerve, or neuromuscular junctions are disrupted.
Moreover, patients with contraindications to insertion of a nasogastric tube cannot use this mode of
ventilation.
NONINVASIVE VENTILATION
Noninvasive ventilation (NIV) refers to the administration of ventilator support without endotracheal
intubation or tracheostomy. Positive pressure NIV has become increasingly utilized since the development
of nasal CPAP for obstructive sleep apnea. The advantages of NIV include the preservation of airway
defense mechanisms, maintenance of an intact upper airway, and increased patient comfort and mobility.
A variety of interfaces have been designed for delivery of the pressurized gas to enter the airway.
Common categories of interfaces include nasal and oronasal (face mask) type systems. Leaks resulting
from a poor fit can reduce alveolar ventilation and synchrony between the patient and the machine.
Therefore, a variety of interfaces should be available in order to find one which minimizes leak.
Generally, face mask type systems are better than nasal systems, as those require the patient to keep
his/her mouth closed. However, emesis with a face mask in place does carry the risk of aspiration.
Moreover, modern mechanical ventilators specifically developed for NIV have a substantial capability of
compensating for air leaks, which solves many practical issues related to the use of NIV.
Different ventilator modes can be utilized during NIV. Continuous positive airway pressure (CPAP)
delivers a constant positive pressure during both inspiration and expiration and can recruit collapsed
alveoli, resulting in an increase in FRC. In contrast, noninvasive PS ventilation is a true ventilation mode,
requiring a ventilator. Inspiratory effort triggers the ventilator to deliver a decelerated flow in order to
meet a PS level. Once the flow falls by a certain amount, ventilatory support ceases. This setting is also
known as BiPAP as two levels of pressure are utilized: an inspiration pressure (the PS) and the expiration
pressure (the CPAP level). It is essential that the patient is cooperative with this technique as leaks can
promote significant patient–ventilator dyssynchrony leading to an increase in the work of breathing. The
choice of the right equipment, the coaching of the patient, and the constant adjustment of the ventilator
settings are essential components for success of NIV.
NIV, by reducing the work of breathing, increasing the end-expiratory lung volume and improving
oxygenation, has been studied as a promising tool to avoid endotracheal intubation after extubation
failure. However, very different results have been reported in different patient population on the efficacy
of NIV, likely due to the different pathophysiologic mechanisms leading to respiratory failure in different
clinical contexts and their response to NIV.
In the general ICU population, NIV failed in two clinical trials to show any benefit when applied in
patients experiencing postextubation respiratory failure.32,33 In contrast, in the postoperative population,
promising results from the application of NIV, and in particular of CPAP, have been reported. An
interesting study explored 96 patients recovering from coronary artery bypass grafting randomized to
receive CPAP or NIV (each one for 1 hour every 3 hours) or incentive spirometry for 20 minutes every 2
hours during the first 2 postoperative days. NIV and CPAP significantly improved oxygenation, vital
capacity (VC), and the forced expiratory volume in 1 second, but failed to show any benefit in terms of
reduction of lung atelectasis, which was similar in the three groups (12% to 15%).34 In the thoracic
surgery population, one randomized trial demonstrated the efficacy of NIV in preventing postoperative
reintubation. The study randomized 48 patients with postlung resection respiratory failure to receive NIV
or standard of care, including oxygen, physiotherapy, and bronchodilators. The need of IMV was
significantly lower in the NIV group compared to the control (21% vs. 50%). Interestingly, the mortality
rate was also lower in the NIV group as compared to the control (13% vs. 38%).35 More recently, a large
multicenter randomized clinical trial demonstrated that NIV is not inferior to high flow oxygen delivered
heated and humidified by nasal cannula in preventing or resolving postoperative acute respiratory failure
in cardiothoracic surgical patients.36
ADVERSE EFFECTS OF MECHANICAL VENTILATION

Ventilator-Induced Lung Injury
Though mechanical ventilation is often life-saving; injury to the lung by the ventilator itself, particularly in
the common situation of pre-existing lung injury, is a major concern. In the early experience of mechanical
ventilation, the sole concern was to rest the respiratory muscles and to provide gas exchange. Not shortly
thereafter, it was recognized that mechanical ventilation itself can initiate and potentiate existing lung
injury during ventilation. Broadly, two main mechanisms can explain ventilator-induced lung injury:
alveolar overdistension and the repetitive opening and closing of alveoli.37
Conceptually, alveolar overdistension is simple; one can imagine overdistension to be akin to a
balloon stretching and popping. The other injury is from the repetitive recruitment and derecruitment of
alveoli from inadequately recruited lung units. This is known as atelectrauma or cyclic atelectasis. The
repeated opening and collapse of the alveoli can cause injury via effects on surfactant function, epithelial
sloughing, and hyaline membrane formation. Physical injury however, from either mechanism, is only one
component of lung injury. Secondary propagation of the mechanical injury occurs from the secretion of
proinflammatory mediators by the lung itself, leading to further inflammation and consequences thereof
such as microvascular breakdown, bacterial translocation, and a systemic inflammatory response.
Ventilator-induced injury is perhaps most worrisome in patients with ARDS. ARDS is an acute
inflammatory lung injury, which is characterized by an increased pulmonary vascular permeability,
leading to increased lung fluid and reduced aerated tissue, that is, a proinflammatory milieu already exists
within the lung. As many different events can incite ARDS, including complications of thoracic surgery,
the appropriate support and treatment of ARDS is clinically important. ARDS is foremost a lung injury;
all patients require mechanical ventilation and it is in this population where mechanical ventilation
associated lung injury has become most apparent. It is now established that a low tidal volume ventilation
strategy is beneficial in this population of patients (Fig. 41.5). The multicenter ARMA trial randomly
assigned 861 mechanically ventilated patients with ARDS to receive either a low tidal volume ventilation
(initial tidal volume of 6 mL/kg predicted body weight) or conventional mechanical ventilation (initial
tidal volume of 12 mL/kg).38 The low tidal volume ventilation group had a lower mortality rate (31% vs.
40%) and more ventilator-free days (12 vs. 10 days). While the low tidal volume strategy was generally
well tolerated, insufficient ventilation can lead to hypercapnic respiratory acidosis. It remains unclear
what effect this has on ARDS lung injury; however, some animal studies and a post-HOC analysis of the
ARMA trial suggest that respiratory acidosis might in fact be protective against ventilator-induced lung
injury.
Although ventilator-induced lung injury has traditionally been believed to clinically occur only in
patients with ARDS, more recently the injurious effect of mechanical ventilation has also been
demonstrated in patients with healthy lungs. In a large multicenter randomized clinical trial, 400 patients
undergoing abdominal surgery were assigned to receive during anesthesia in the operative room either
conventional mechanical ventilation with tidal volumes of 10 to 12 mL/kg of predicted body weight and
zero PEEP, or a protective ventilation strategy with tidal volumes of 6 to 8 mL/kg of predicted body
weight and 6 to 8 cm H2O of PEEP and lung recruitment maneuvers every 30 minutes.39 In the 7 days
following the surgical intervention, the group of patients treated with the lung protective strategy had
significantly less pulmonary and extrapulmonary complications, as well as a shorter hospital length of
stay, as compared with the group that received higher tidal volumes.
Interestingly, protective mechanical ventilation has been shown to reduce pulmonary complications
and lung inflammation in patients undergoing thoracoscopic esophagectomy.40 During left lung ventilation,
patients were randomized to receive either low tidal volume (5 mL/kg and 5 cm H2O PEEP; n = 53) or
conventional tidal volumes (8 mL/kg; n = 48). IL-1 beta, IL-6, and IL-8 expression in alveolar lavage
fluid collected 18 hours after the surgery was significantly lower in the protective mechanical ventilation
strategy group. Moreover, this group had also a significantly lower incidence of pulmonary complications
as compared with the group treated with higher tidal volume.
Pneumonia
Every mechanically ventilated patient is at risk for a ventilator-associated pneumonia (VAP), which is
defined as a pneumonia occurring 48 hours after intubation. The risk of acquiring VAP has been reported
as 3%/day during the first week, 2%/day during the second week, and 1%/day for the subsequent weeks.41
As with all pneumonias, VAP occurs when bacteria are introduced into the sterile lower respiratory tract
and are able to overwhelm host defenses to establish an infection. For the vast majority of VAP, these
infections are caused by the aspiration of oropharyngeal bacteria into the lungs.42 Intubated patients are at
particular risk because the foreign endotracheal tube impairs the cough reflex and mucociliary clearance
important in clearing aspirated bacteria in healthy patients. The endotracheal tube cuff does not
necessarily prevent aspiration. Contaminated secretions build up above the cuff and slowly work their
way around the cuff, colonizing the trachea and forming a biofilm on the tube itself. Positive pressure
ventilation then further propels the bacteria into the lungs. Other sources of infection can include
contaminated suction catheters, direct hematologic spread from a distant infection, and aspiration of
infected material from the stomach. These sources of infection are potentiated by the immune dysfunction
of the critically ill. A variety of novel endotracheal tubes are now on the market to address many of the
above concerns. ET tubes have been designed with modified cuff shapes and materials to help prevent
microaspiration around the cuff. An ET tube with a subglottic suction port to help drain secretion buildup
above the cuff has also been designed.43,44 Finally, silver-coated ET tubes have been made to help
prevent the development of biofilms.45 In a large, randomized, multicenter study, microbiologically
proven VAP was delayed and decreased in patients who received a silver-coated ET tube.46 However, no
differences were found in either ICU or hospital length of stay. Further studies will be required to
evaluate the clinical and cost effectiveness of these new devices.
FIGURE 41.5 A: In a 70-kg patient with ARDS, conventional ventilation at a tidal volume of 12 mL/kg and a PEEP of 0 cm of
water (panel A) leads to alveolar overdistention at peak inhalation and alveolar collapse at end exhalation. In contrast, protective
ventilation at 6 mL/kg and a PEEP of 5 cm of water (panel B) limits alveolar overdistention and collapse by providing a low tidal
volume and an adequate PEEP. (From Malhotra, A. Low-Tidal-Volume Ventilation in the Acute Respiratory Distress Syndrome.
(From Malhotra, A. Low-Tidal-Volume Ventilation in the Acute Respiratory Distress Syndrome. N Engl J Med 2007;357:1113–
1120. Adapted from Tobin MJ. Advances in mechanical ventilation. N Engl J Med 2001;344:1986–1996. Copyright © 2001
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)
Heart and Circulation Effects

The lungs do not exist in isolation and neither do the effects of mechanical ventilation. Initiation of
positive pressure ventilation will cause a fall in the preload to the heart.47,48 The positive alveolar
pressure supplied by the ventilator will increase lung volumes. This will apply pressure to the heart and
increase the intramural pressure. Hence, venous return will decrease and thus reduce preload. In patients
with normal heart function, this results in falls in cardiac output and blood pressure but this can be
minimized with IV fluid, which helps restore adequate venous return and preload.
Afterload is also affected by positive pressure ventilation. Right ventricular afterload can be either
increased or decreased by mechanical ventilation. When lung volumes are below FRC, pulmonary
vascular resistance is increased. Lung recruitment by positive pressure ventilation back to FRC can
therefore reduce pulmonary vascular resistance and result in an overall reduction in right ventricle
afterload. On the other hand, when lung volumes are at or above FRC, further positive pressure
ventilation increases the hydrostatic pressure on the alveolar capillaries, thereby increasing the resistance
of the pulmonary vasculature and thus increases the afterload of the right heart. Left ventricular afterload
is generally reduced by positive pressure ventilation. As a result of the compression of the heart by the
increased intrathoracic pressure, the transmural pressure in the left ventricle increases, thereby reducing
afterload.
Therefore, depending on the cardiac performance of the patient, initiation of positive pressure
ventilation can be beneficial (e.g., in cardiogenic pulmonary edema) or detrimental (e.g., in
hypovolemia).
Diaphragmatic Dysfunction
In addition to ventilator-induced lung injury, VAP, and cardiovascular side effects, there is a growing
body of evidence suggesting that IMV may also be detrimental to the diaphragm. The inactivity and
unloading of the diaphragm caused by the application of mechanical ventilation results in diaphragmatic
weakness, atrophy, and injury that correlates with the duration of ventilatory support. The proteolysis of
the muscle fiber of the diaphragm during its inactivity plays a major role in determining diaphragmatic
atrophy and loss of force-generating capacity. This condition is defined as ventilator-induced
diaphragmatic dysfunction.49–51
WEANING FROM MECHANICAL VENTILATION

Ultimately, the goal of mechanical ventilation is to restore the lungs to good independent function. Ideally,
this occurs before common side effects of mechanical ventilation can occur. However, the decision as to
when extubation can safely occur is often difficult. In addition to adequate lung function, weaning off the
ventilator requires adequate muscular strength and an adequate drive to breathe. If respiratory strength is
weak, or the corollary, the respiratory load is too heavy, the muscles will fail. To begin the process of
weaning, it is important to understand the initial reason for starting mechanical ventilation. Only once this
process has been corrected can extubation be considered. As duration of mechanical ventilation, ICU, and
hospital length of stay are all increased after an episode of failed extubation, it is vital to accurately
predict when extubation can successfully occur.52
Three determinations are needed to assess whether a patient can be liberated from the ventilator. First,
the patient should be stable from a cardiorespiratory standpoint. Adequate oxygenation (P/F >200, PEEP
= <8), hemodynamic stability, and an improving underlying condition is necessary. Second, a trial to
demonstrate that the patient can breathe with minimal to no support from the ventilator is performed. This
is known as a spontaneous breathing trial (SBT). Finally, the patient needs to demonstrate that they can
protect their airway. Assessing the quantity of airway secretions, cough strength, and mental status all
contribute to this determination.
A variety of parameters have been utilized in an attempt to predict successful weaning. VC around 10
to 15 mL/kg and tidal volume around 5 to 8 mL/kg have been used as cutoffs. VC is often difficult to
measure as it requires significant cooperation from the patient. Consequently, studies have shown that VC
does not predict weaning outcome accurately.53 MV and maximum voluntary ventilation (MVV) are also
parameters that have been studied to predict weaning effectiveness. MVV is the volume of gas which can
be exhaled with maximum effort over 1 minute. The difference between the MV and the MVV indicates
the ventilatory reserve of the patient to maintain a normal PaCO2, if needed. An MV <10 L/min and an
ability to double this with MVV was associated with the ability to wean successfully. However, again,
this requires significant cooperation from the patient.
Muscle strength is another assessment of weaning. Respiratory muscle function can be tested by
measuring the maximal inspiratory pressure. Healthy young men can generate −120 cm H2O and women
−90 cm H2O. To measure this factor in intubated patients, a one way valve can be connected to the circuit
which allows the patient to exhale freely but inhale against a manometer. Generally, an MIP <−30 cm H2O
is associated with successful extubation and an MIP >−20 cm H2O is associated with an inability to
maintain spontaneous breathing.54 These values generally have a better negative predictive power than
positive predictive power.
FIGURE 41.6 A breath-by-breath plot of respiratory frequency and tidal volume in a patient who failed a weaning trial. The
arrow indicates the point of resuming spontaneous breathing. Rapid shallow breathing developed almost immediately after
extubation. (From Tobin MJ, Perez W, Guenther SM, et al. The pattern of breathing during successful and unsuccessful trials of
weaning from mechanical ventilation. Am Rev Respir Dis 1986;134(6):1111–1118.)
More recently, Yang and Tobin54 described the rapid shallow breathing index (RSBI). In their
experience, they found that while MV is preserved in patients who fail weaning, the components of MV,
VT, and respiratory frequency, can combine to result in inefficient gas exchange (Fig. 41.6). The RSBI is
calculated by the respiratory rate divided by the tidal volume (frequency/VT). By using a threshold of less
than 105, the f/VT ratio had a positive predictive value of 0.78 and a negative predictive value of 0.95.
This measure is easy to measure and not dependent on patient cooperation or effort.
Once a patient is felt to be ready for ventilator weaning, a trial of spontaneous ventilation, usually for
around 2 hours, is performed. One randomized trial found that SBT trials of 30 minutes or 120 minutes
were equivalent in identifying patients who could undergo extubation, but 2-hour trials remain the
standard in most SBT protocols.55 T-piece, CPAP, and PSV are different SBT strategies. The T-piece trial
is the oldest strategy. The patient is disconnected from the ventilator and connected to a flow of
oxygen/air for a set period of time. Given that the endotracheal tube remains in place, the work of
breathing is thus higher than in an extubated patient. Consequently, the use of CPAP or PSV of 5 to 8 cm
H2O to mitigate this additional resistance was thought to better predict ventilator weaning. While
Brochard et al.20 demonstrated superiority of PSV versus T-piece trials, the Spanish Lung Failure
Collaborative Group study did not demonstrate any difference.56 Automatic tube compensation is a new
ventilator technology which supports the patient with an ongoing and automatically calculated magnitude
of inspiratory pressure to compensate for the flow-dependent resistance added by the endotracheal tube.57
However, while trials of ATC in SBT have been shown to be safe, no additional advantage was
identified.58 Thus, it remains unclear what the best strategy for SBT is. Indeed, some believe that a T-
piece trial is best as the additional resistance from the ET tube simulates breathing through some upper
airway edema.59
No clear criteria exist for determining whether an SBT was successful or not. Hypercapnia or hypoxia
clearly signify failure, but other more subjective criteria such as tachycardia, agitation, anxiety, and
diaphoresis remain dependent on the clinical assessment of the physician. The Spanish Collaborative
Group have published criteria of failure in their studies (respiratory frequency of more than 35
breaths/min; arterial oxygen saturation below 90%; heart rate above 140 beats/min or a sustained
increase or decrease in the heart rate of more than 20%; systolic blood pressure above 180 mm Hg or
below 90 mm Hg; agitation; diaphoresis; and anxiety or signs of increased work of breathing [accessory
muscle use, paradoxical or asynchronous rib cage-abdominal breathing movements, intercostal
retractions, nasal flaring]) which can be helpful to the clinician.18,55,56
Weaning Protocols
To better prepare for extubation, daily screening protocols have been developed to identify patients who
are ready for extubation. Most protocols start with daily sedation interruption for optimal wakefulness for
screening. Candidates usually already have adequate oxygenation (PaO2 >60 mm Hg, FiO2 <0.5, PEEP
<8) and an RSBI <105. SBTs using either PS, CPAP, or T-piece for up to 120 minutes will be tried and
stopped if certain criteria are met. In general, these protocols can be driven by nurses or RTs rather than
physicians. Recent studies show that protocol-driven weaning is superior as physicians are often
distracted with other tasks.60 To that end, perhaps in the future, weaning from mechanical ventilation will
be computer driven. Indeed, a recent trial showed that a computerized protocol was superior to a
physician-directed weaning process.61
ADJUNCTIVE STRATEGIES OF RESPIRATORY SUPPORT

Extracorporeal Life Support
Until recently, ventilatory support of a patient has required the use of the patient’s own lungs for gas
exchange. This sets up the obligate conflict between further injury to the lungs by the ventilator and the
need for adequate oxygenation and ventilation of the patient. Therefore, removing the burden of the task of
gas exchange away from the lungs during respiratory failure may allow for improved lung recovery.62–64
With recent viral respiratory outbreaks, interest in the use of extracorporeal life support (ECLS) systems
for cardiorespiratory support has become renewed. Extracorporeal membrane oxygenation (ECMO) is
one strategy within ECLS to meet this goal. ECMO technology is similar to that of cardiopulmonary
bypass used during cardiac surgery. Blood is drained from the patient and actively pumped through a
membrane oxygenator for oxygenation of the blood and removal of CO2. In general, oxygenation is mainly
dependent on flow rate, while elimination of CO2 mainly depends on the gas flow rate. Different
configurations of ECMO circuits can be utilized for respiratory failure. For pure respiratory failure,
venovenous (VV) ECMO can be utilized where venous blood is oxygenated by the membrane oxygenator
and returned to the venous system. Recently, an engineered double lumen cannula supporting 4 to 5 L/min
of blood flow has been introduced allowing for VV ECMO solely through the right internal jugular vein.65
This facilitates the patient being able to ambulate while on ECMO, avoiding further deconditioning. For
patients with need of cardiac support in addition to respiratory failure, VA ECMO, a configuration where
blood is drained from a vein and reinfused into an artery, can be utilized.
Use of ECMO is not without risk. Bleeding is a common complication in ECMO due to need for
systemic anticoagulation and circuit induced platelet dysfunction. Thromboembolism is also a major
potential complication. Clot formation within the circuit and subsequent embolization can be dangerous in
VV ECMO and devastating in VA ECMO. Other technical difficulties can also occur during cannulation.
Use of ECMO was first established in neonates where randomized controlled studies demonstrated
benefit.66 In adults, standardized criteria for initiating ECMO have not yet been established and historical
studies demonstrated poor outcomes with the technique. The CESAR trial randomized 180 patients to
consideration for ECMO or usual care with resultant higher survival in the group considered for
ECMO.67 With the H1N1 epidemic in 2009, a variety of centers around the world have included ECMO
in their treatment. In these observational trials, patients in Australasia and Italy demonstrated survival
rates of 75% and 68%, in 68 and 60 patients, respectively.68,69 In the United Kingdom, patients who were
and were not referred for ECMO had survivals of 24% and 53%, respectively, which is in contrast to a
French study which showed no survival benefit for patients referred for ECMO.70,71 An international
randomized trial (NCT01470703) is currently recruiting patients with severe ARDS for ECMO.
Hopefully, this will better define the efficacy of ECMO for patients with refractory ARDS. ECLS remains
a nascent field, and its role will likely evolve with the inevitable technologic advancements which will
occur.
CONCLUSION
Ventilatory support of the thoracic surgical patient remains a common occurrence. Surgeons need to be
familiar with the different ventilation strategies in order to better manage postoperative care.
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54. Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. New Engl
J Med 1991;324(21):1445–1450.
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ventilation. Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med 1999;159(2):512–518.
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ventilation in critically ill adult patients. Cochrane database Syst Rev. 2014;11:CD006904.
61. Lellouche F, Mancebo J, Jolliet P, et al. A multicenter randomized trial of computer-driven protocolized weaning from mechanical
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42
Complications of Thoracic Surgical
Procedures
Benjamin D. Kozower
INTRODUCTION
The operative morbidity and mortality of thoracic surgery have markedly improved as surgical techniques
and perioperative management have evolved. In the early 1980s, the Lung Cancer Study Group reported
an operative mortality of 6.2% and 2.9% for pneumonectomy and lobectomy, respectively.1 Two decades
later, Allen and colleagues2 reported mortalities of 0% and 1.3%, respectively, in a multi-institutional
randomized trial. In another large series, 30-day and in-hospital mortality for pulmonary resection were
0.5% and 0.8%, respectively.3 These results are remarkable given the increasing complexity of patients
undergoing thoracic interventions. Mortality rates for esophagectomy patients have improved, but remain
high in comparison to other high-risk surgeries, with recent reports approximating up to 9%.4 Patients
historically deemed inoperable, such as those with marginal lung function or increased age, are now
reasonably considered for surgical management.5–7 Despite encouraging outcomes with reduced operative
mortality, postoperative complications in the thoracic surgery patient continue to be a significant
challenge. The frequency of complications remains high, with most series reporting rates of nearly 30% to
40%.2,8–10 Overall complication rates after esophagectomy also remain high, with rates of more than 50%
in both open and minimally invasive series.11–14 These complications may ultimately have a greater effect
on quality of life than the choice of technical approach.14
Reducing the risk of morbidity begins in the preoperative period with optimization of the individual’s
medications, comorbid diseases, nutrition, smoking cessation, and patient education. To reduce
postoperative complications, smoking cessation is ideally achieved 4 to 8 weeks prior to surgery to gain
the most benefit, but it remains valuable at any time.15,16 Those with borderline pulmonary function may
benefit from pulmonary rehabilitation to improve muscle strength and exercise tolerance.17,18 Nutritional
status is a significant preoperative consideration. As identified by the landmark Veterans Affairs study
and others, hypoalbuminemia correlates with malnutrition and is the strongest predictor of postoperative
morbidity and mortality.19–22 This underscores the vital importance of careful preoperative preparation to
improve patient outcomes. Expertly minimizing and managing complications frequently requires
multidisciplinary support. Such involvement and attention is critical as complications have a direct
influence on numerous outcomes such as readmission rate, resource utilization, and quality of life.14,23–26
This chapter provides an overview of common complications encountered, and their management
following thoracic surgery.
AIR LEAK (ALVEOLAR–PLEURAL FISTULA)
One of the most common postoperative complications is an alveolar–pleural fistula, or air leak, and is
defined as a communication between the pulmonary parenchyma distal to a segmental bronchus and the
pleural space.27 The presence of an air leak can prolong the patient’s hospital stay more than other
barriers to discharge, such as suboptimal pain control or nausea.28,29 Mortality rate associated with a
prolonged air leak has been reported to be as high as 12%, potentially as a result of its correlation with
other serious pulmonary complications such as atelectasis, pneumonia, and empyema.29,30 The incidence
of air leak varies with the type of surgical intervention and the postoperative day. Cerfolio and
colleagues31,32 report a 25% incidence on postoperative day 1 and 20% on day 2. The majority of minor
leaks stop spontaneously. The definition of a prolonged air leak varies somewhat according to study, but
generally may be considered to be present if the air leak persists by postoperative day 4 and beyond,
accounting for approximately 5% to 15% of cases.32,33 The Society of Thoracic Surgeons (STS) database
defines a prolonged air leak as one that exceeds the otherwise necessary length of stay. The risk of air
leak is increased with a low predicted forced expiratory volume in 1 second (FEV1), emphysema, cystic
fibrosis, poor chest tube placement, upper lobe resections, and bilobectomy compared to lobectomy.34
Novel surgical techniques may be employed to assist in the prevention of air leaks. It may be feasible to
identify an air leak intraoperatively after a parenchymal resection by submerging the area in saline, and
observing for leaks during gentle reinflation of the atelectatic lung. Pleural tents, pericardial-buttressed
staple lines, and fissureless surgery have all been shown to be beneficial.35–37 Also, fibrin sealants and
various glues have been used with varying success.
Chest tubes generally remain in place as long as an air leak persists. Small air leaks are best managed
with the patient’s chest tube to water seal (passive suction), while a new or enlarging pneumothorax
requires active suction.38 Earlier transition to water seal may enhance the resolution of parenchymal air
leaks.31,33,39 Water seal is safe even in the presence of a concomitant pneumothorax, with the recognition
that increasing hypoxia, subcutaneous emphysema, or enlarging pneumothorax are indications for
suction.40 Although some authors endorse placing the chest tube on higher suction to resolve an air leak,
we believe the data using the least amount needed (usually −10 to −20 cm H2O).34
It may be feasible to carefully adjust a malpositioned tube, and use of a blood patch or endobronchial
valve has also been described. A blood patch is attempted by administering 50 to 100 mL of the patient’s
own whole blood through the chest tube.41–43 Multiple administrations may be necessary which may then
increase the risk of empyema; nonetheless, recent literature supports the use of a blood patch as a safe and
efficacious option.34,44 Use of a one-way endobronchial valve has recently been described as a viable
treatment option for prolonged air leaks.45,46 These were initially designed and successfully used for the
treatment of emphysema and distal bronchopleural fistulas (BPFs). The broadened application of these
valves provides an additional management option. The author has increasingly used this option to reduce
hospital length of stay and have the patients follow up in clinic to test for an air leak and remove their
tubes.
Operative closure of an air leak is rarely necessary, in which case fibrin sealants and glue, suturing
with or without pledgets, and pericardial or polytetrafluoroethylene strips have all been described.47
Fortunately, most patients with a persistent air leak can be safely discharged home with an outpatient
device, such as a Heimlich valve, and removal can be accomplished in the clinic setting.33
BRONCHOPLEURAL FISTULA
A BPF is a communication between a lobar or segmental pulmonary bronchus and the pleural space.48 In
contrast to alveolar–pleural fistulas, a BPF frequently requires operative or endoscopic intervention for
resolution. The incidence of BPF varies according to the surgical procedure, with reported rates of up to
8.6% for right pneumonectomy, 2.3% for left pneumonectomy, 1% after lobectomy, and 0.3% with
segmentectomy.48 However, in some series the incidence has been reported to be as high as 20%.49,50 This
variability may be attributable to particular risk factors such as underlying lung disease (benign vs.
malignant) and the surgical technique. There are a variety of risk factors that have been identified to
increase the risk of BPF. These include preoperative radiation, chemotherapy, infectious lung disease,
immunosuppression, diabetes, surgeon inexperience, long bronchial stump, devascularization of bronchial
stump, residual tumor at bronchial resection margin, excessive tension, right pneumonectomy, and
prolonged intubation.48,51–53
A BPF may occur as an early or late complication. A new or large air leak is an early manifestation
that should elicit a high index of suspicion and further investigation.
Late presentations include fever, malaise, dyspnea, productive cough with purulent or serosanguinous
expectorant, new large air leak, new pleural loculation, or new pleural air–fluid level on chest x-ray.49
Management is largely determined by the patient’s condition, presence of empyema, location of size and
fistula. If observed early, the fistula is likely due to a technical error and surgical re-exploration is
required.49 Adequate chest tube drainage is needed to prevent or drain an empyema, as well as to prevent
contralateral contamination.54 When infectious etiologies are suspected or an empyema is present,
appropriate antimicrobial coverage is also required. In mechanically ventilated patients, reducing PEEP,
tidal volume, and respiratory rate are important measures to minimize flow through the fistula.49
Fistulas are confirmed with bronchoscopy or bronchography using 5 to 10 mL of propyliodone diluted
1:1 with saline if the defect is not endoscopically identified.55,56 Distal fistulas may require the use of
balloon catheters to systematically occlude bronchial segments to assist in recognition. CT scan may also
be useful in identifying the etiology of a BPF and potential need for surgical intervention. Multiple
adhesives, biologic glues, and coils have been described in the literature, and reported to be successful
for small fistulas.49,56 They can be applied directly to the fistula during bronchoscopy; however, there has
been no consensus to support the use of one compound over another.
Endoscopic closure has become a more attractive option as new devices and techniques are refined.
Endobronchial valves were initially designed for the treatment of emphysema, but have now found a role
in the treatment of persistent air leaks and distal BPFs.45 Amplatzer devices were originally developed
for transcatheter closure of cardiac defects and have also been demonstrated to be useful for BPFs.50 The
device consists of two nitinol mesh disks, a central connector, and polyester fabric inside the mesh to aid
in occlusion and tissue ingrowth. They have been successfully deployed in defects of varying sizes,
including mainstem bronchi.50
The mainstay of therapy has been operative intervention. When surgical management is necessary,
debridement of devascularized tissue and primary closure should be completed. The stump can be closed
with a vascularized muscle flap or omentum that can be mobilized to circumferentially reinforce the
bronchus.48,54
Empyemas can develop which are challenging to manage. Chronic open drainage or staged closure
may be required. An Eloesser procedure for cavity drainage followed by later closure with an omental
flap has been described for complicated fistulas.57
ATRIAL FIBRILLATION
Atrial fibrillation is a common complication after pulmonary resection, with an incidence of
approximately 20% according to several series.58–61 The incidence may be as high as 40% after
pneumonectomy.59,62 Most episodes occur within 3 days of surgery, with peak occurrence on
postoperative day 2, and more than 95% of cases resolve within the first week.59 Risk factors include
age, male gender, previous arrhythmia, congestive heart failure, COPD, intraoperative blood transfusions,
type of pulmonary resection (right pneumonectomy), and type of incision (clamshell).59,61,63,64
Given the associated morbidity, mortality, increased length of hospital stay, and cost, considerable
attention regarding medical prophylaxis has appeared in the literature. Evidence suggests prophylactic
magnesium, calcium channel blockers, and β-blockers reduce the risk of atrial fibrillation; however, β-
blockers may increase the risk of pulmonary edema.59,64–66 Digoxin may increase the incidence of atrial
fibrillation.59,65 For the hemodynamically stable patient that develops atrial fibrillation postoperatively,
immediate rate control can be obtained with a short-acting β-blocker (esmolol) or calcium channel
blocker (diltiazem). If the patient is hemodynamically unstable, cardioversion is necessary. In all cases,
correctable triggering factors should be addressed. These include electrolyte abnormalities, fluid balance,
catecholaminergic inotropic agents, bleeding, sepsis, and airway issues. Amiodarone is an effective
option for rate control and conversion to sinus rhythm.67 Amiodarone dosing should be closely monitored
particularly for pneumonectomy patients, as acute respiratory distress syndrome (ARDS) has been
reported with cumulative doses.66 The 2014 American Association for Thoracic Surgery (AATS)
guidelines provide further detailed information regarding atrial fibrillation prevention and management
strategies.66
The risk of thromboembolic events is greatest when atrial fibrillation has been present for longer than
48 hours. Anticoagulation should be initiated if the patient is in and out of atrial fibrillation, or
persistently in atrial fibrillation for more than 48 hours.59,68 Echocardiography confirms the presence or
absence of an atrial thrombus, as cardioversion should not be performed in the presence of a thrombus. If
there was no preoperative history of atrial fibrillation, antiarrhythmics, rate control agents, and
anticoagulation can typically be discontinued 3 months after surgery.68,69 Ventricular arrhythmias occur in
approximately 15% of thoracic surgery patients; however, sustained ventricular arrhythmias or
hemodynamic compromise are rare.59
MYOCARDIAL INFARCTION
Thoracic surgery is generally considered an intermediate-risk procedure with regard to perioperative
cardiovascular events; high-risk surgery is one that is emergent, or prolonged and associated with large
fluid shifts/blood loss.70,71 The incidence of perioperative cardiac ischemia and myocardial infarction for
thoracic surgery is 3.8% and 1.2%, respectively.59 However, the risk of myocardial infarction may be as
high as 17% for those with a history of previous infarction.59 The varying reported incidence is dependent
on the sensitivity and specificity of the method of diagnosis, in addition to the above stated risk associated
with surgery and patient factors.72 The mortality rate of perioperative myocardial infarction has been
reported to be as high as 70%.59
Abnormal preoperative exercise testing and intraoperative hypotension are strongly predictive for the
development of ischemic events.73 Other important considerations according to the Lee index are
ischemic heart disease, history of congestive heart failure or cerebrovascular disease, diabetes,
preoperative creatinine level greater than 2.0 mg/dL, as well as functional status.74–76
The influence of β-blockade to reduce overall perioperative cardiovascular morbidity and mortality
remains controversial. A recent Cochrane Review identified the conflicting results of current literature on
the topic.77 However, their role in reducing arrhythmias and acute myocardial infarction has been
established, and as such are a valuable consideration for thoracic surgery.77
The risk of myocardial infarction peaks within the first 3 postoperative days.72 This time frame
corresponds with fluid mobilization, postoperative pain, catecholamine surge, and increased thrombotic
risk.72,78 Elevated heart rate and blood pressure increase myocardial oxygen demand and create a
potential for supply/demand mismatch. Patients suspected of having a postoperative myocardial infarction
should be promptly evaluated with serial biomarkers (troponin, creatinine kinase-MB), ECG, and treated
according to advanced cardiac life support protocol. Oxygen, morphine, and aspirin should be given, as
well as an intra-aortic balloon pump (IABP), inotropic or pressor support if indicated.72 Anticoagulation
should be initiated if not otherwise contraindicated by bleeding risk.72
In the setting of ongoing ischemia, cardiac catheterization and associated interventions may be needed.
PULMONARY INSUFFICIENCY
Although thoracic surgery can be performed for patients with marginal respiratory reserve, postoperative
pulmonary insufficiency is a common complication.5,79,80 Pulmonary complications generally develop
progressively with impairment of respiratory function within the first 3 postoperative days.81 Several
series note a 20% to 30% overall pulmonary complication rate.29,82–86 Chronic obstructive lung disease
and pulmonary fibrosis have known increased rates of respiratory insufficiency after lung resections.87,88
Age older than 75, body mass index greater than 30, American Society of Anesthesiology (ASA) score
greater than 3, history of smoking, extent of resection, prolonged operative time, and need for
postoperative mechanical ventilation have also been identified as important factors.29,84,89–91 Data is
conflicting with regard to the value of preoperative spirometry in predicting postoperative pulmonary
complications.29,92–94 Considering factors such as clinical findings, predicted postoperative pulmonary
function, and exercise variables may be more helpful.5,29,92
Leo and colleagues83 developed a multifactorial score to assist in the identification of those at higher
risk of developing pulmonary complications. Severity corresponded with the patient’s chest x-ray,
dyspnea, administered oxygen, quality of bronchial secretions, cough, and auscultation.83
Insufficiency can develop as a result of atelectasis and retained secretions. If severe, reintubation may
be necessary. Patients need aggressive pulmonary toilet, ambulation, nasotracheal suction, nebulizer
treatment, as well as adequate pain control to enable appropriate cough and effort with incentive
spirometry. Patients may develop signs of respiratory distress prior to radiographic evidence of a
problematic infiltrate. Aggressive management can reduce the morbidity and mortality associated with
these complications.95
ACUTE RESPIRATORY DISTRESS SYNDROME

ARDS is characterized by the acute onset of refractory hypoxemia with a PaO2/FIO2 <200 mm Hg, and
diffuse bilateral infiltrates on chest x-ray in the absence of an elevated pulmonary capillary wedge
pressure.96,97 Acute lung injury (ALI) is defined as PaO2/FIO2 <300 mm Hg.96 This definition has recently
been augmented to identify those with ARDS for more than 72 hours as a particularly severe group with a
high proportion of diffuse alveolar damage.98 It is important to exclude other confounding diagnoses such
as cardiac insufficiency, thromboembolism, and transfusion reactions that may require other interventions.
Pathophysiology and management of ALI and ARDS are briefly reviewed here. The reader is referred to
Chapter 112 for an in-depth discussion.
The incidence of ARDS after lung resections varies, occurring in up to 15% of pneumonectomies,
approximately 3% of lobectomies, and 0.9% to 4.1% for lesser resections.99–105 The mortality rate
associated with developing ARDS following lung resection is significant.106 Kutlu and colleagues103
reported a series of 1,139 patients undergoing pulmonary resection with a frequency of ARDS/ALI of
3.9% and a 72.5% total mortality; cases of right pneumonectomy were uniformly fatal, left
pneumonectomy with a 50% mortality, and lesser resections with a 0.7% to 7.4% mortality. More recent
series report a declining mortality rate, in the range of 40% to 45%, which may be attributable to greater
attention to protective ventilation strategies and ICU management.107–109
A considerable amount of work in the literature has been devoted to identify risk factors in the
development of ARDS. Age, COPD, cardiac disease, excessive perioperative fluid administration, extent
of resection, operative time, and blood loss, have all been found to increase risk.99–105,107,110,111
Interestingly, preoperative spirometry and arterial blood gas were not predictive of ARDS.112 Kor and
colleagues113 reported a surgical lung injury prediction (SLIP-2) model in a multicenter cohort of at-risk
surgical patients. In their series, 7.5% of at-risk patients developed ARDS.113 Predictors of ARDS
identified were high-risk aortic surgery, high-risk cardiac surgery, emergency surgery, cirrhosis,
admission location other than home, increased respiratory rate, FIO2 greater than 35%, and SpO2 less than
95%.113
ARDS generates a diverse inflammatory response involving numerous cytokines and mediators.
Disappointingly, clinical trials have been unable to identify an anti-inflammatory with a survival benefit.
Prostaglandins, prostacyclin, surfactant, lisofylline, nitric oxide, ketoconazole, fish oil, N-acetylcysteine,
and corticosteroids have been unable to demonstrate a significant improvement of mortality.114,115
Treatment currently consists of supportive care and preventing further injury. Multiple studies have
identified ventilator-induced damage as a source of injury, with shear forces affecting alveolar walls and
small airways.114 Neuromuscular blocking agents have been used, but the risks and benefits of their
utilization remain controversial.114
Protective lung ventilation includes a tidal volume of 6 mL/kg of predicted body weight, maintaining
plateau pressures less than 30 cm H2O and minimizing PEEP.116 Data support this ventilation strategy
even in patients without lung injury and may reduce progression to ARDS.117,118 The hypercapnia that may
result with these ventilation parameters is permitted, and potentially beneficial in some
circumstances.119–121 Hypercapnia potentiates hypoxic pulmonary vasoconstriction, increasing local
alveolar ventilation and enhancing ventilation/perfusion (V/Q) matching.122–124
Prone ventilation has demonstrated improved outcomes in severely hypoxemic patients, reducing the
transpulmonary pressure gradient, recruiting collapsed regions without increasing airway pressure, and
improving oxygenation.125 Notably, prone ventilation is more effective in obese patients with ARDS than
nonobese patients.126 Extracorporeal membrane oxygenation (ECMO) may be needed if patients fail these
ventilation strategies. Positive results in the conventional ventilator support versus ECMO for severe
adult respiratory failure (CASAR) trial supports the use of this intervention in such patients.125 Fluid
management in ARDS is an additional consideration. An increase in pulmonary vascular resistance
occurs after pulmonary resection, with increased blood flow to the remaining lung, and may play a role in
fluid and protein flux given pulmonary lymphatic disruption after resections.127–130 Vascular and epithelial
permeability is increased in ARDS as well. Conservative fluid management reduces the number of
ventilator days, but may be challenging with a septic or hemodynamically unstable patient.131
PULMONARY EDEMA
Pulmonary edema after lung resection is a serious and potentially fatal complication, particularly for
postpneumonectomy patients. Incidence ranges between 2.5% and 4% and mortality approaches
50%.99,102,132–135 A variety of physiologic changes occur after pulmonary resection contributing to the
development of edema. Increased endothelial permeability, increased gradient across pulmonary
microcirculation, and disrupted lymphatic drainage all play a role.130,136 Repetitive collapse and
hyperinflation additionally creates an ischemia/reperfusion type of injury.130,134
Lung protective ventilation strategies and avoidance of excessive fluid administration are essential to
the prevention of pulmonary edema.132,134 In general, total positive fluid balance in the first 24 hours
should not exceed 20 mL/kg and urinary output greater than 0.5 mL/kg/hr is unnecessary.132 Diuretics can
be administered to maintain appropriate fluid balance. Fresh-frozen plasma has been associated with the
development of edema, and should be avoided if possible.135 Controversy remains regarding the potential
benefit of corticosteroids, and whether induction chemotherapy or chemoradiotherapy increases
risk.2,100,104,137–139 If the patient is not responding to routine therapy, it is important to rule out other
potential causes such as cardiac insufficiency, thromboembolism, or sepsis; as echocardiography, blood
cultures, CT scan, and placement of a Swan–Ganz catheter may be beneficial.
FIGURE 42.1 Bilateral ground glass opacities, consolidations, and pleural effusions consistent with pulmonary edema and
pneumonia status post Ivor-Lewis esophagectomy.
PNEUMONIA
Rates of pneumonia after pulmonary resection vary from 2.2% to 20%, according to the specific criteria
for diagnosis.29,91,140–142 Mortality is approximately 7.5.%.29,140,143,144 Contributory factors include extent
of resection (pneumonectomy > lobectomy), ASA status, prolonged intubation, impaired pulmonary
reserve, current smoking status, and atelectasis.29,84,145,146 Atelectasis is exacerbated by poor cough,
diaphragmatic dysfunction, chest wall instability, and inadequate pain control.147,148 This generates a V/Q
mismatch that can lead to hypoxemia, followed by impaired function of alveolar macrophages and
pneumonia as a potential result.149
The diagnosis of pneumonia may be considered when a new and persistent lung infiltrate develops
with purulent secretions, fever, leukocytosis, increasing oxygen requirements, and bronchial alveolar
lavage (BAL) culture >104 cfu/mL.29 Bronchoscopy is useful to obtain accurate sampling for culture.
Radiographic changes frequently lag other signs, as such empiric antibiotics should be selected and later
narrowed according to culture results (Fig. 42.1). Aggressive pulmonary toilet, ambulation, control of
secretions, appropriate pain management, and nebulizer therapy should be maintained throughout
treatment.150
EMPYEMA
Empyema may occur in 2% to 15% of lung resection cases, with an overall mortality of
26%.54,86,110,151–153 The risk of empyema is threefold higher with pneumonectomy as compared to lesser
lung resections.152 Empyema may develop as an early or late complication, with the majority occurring
within 4 weeks of surgery, and is frequently associated with a BPF or prolonged air leak (26.3%).154,155
Patients present with fever, malaise, productive cough with serosanguinous expectorant, or radiograph
with a new fluid level. CT scan assists in the diagnosis and potential surgical planning. Risk of
developing an empyema is increased with factors such as extent of resection (pneumonectomy and
bilobectomy > lesser resection), BPF, impaired nutritional status, immunosuppression, and infectious lung
disease.48,51–53,155,156
Treatment of an empyema includes antibiotics, drainage of the pleural space, and potentially open
pleural packing for a persistent space followed by obliteration of the space with antibiotic solution or
muscle flap. Bacterial colonization is typically with staphylococcal, streptococcal, or pneumococcal
species, and appropriate antimicrobial coverage should be chosen. Unfortunately, there is significant
morbidity associated with this process consisting of prolonged hospitalization and repeated operations.
If diagnosed in its early exudative phases, an empyema can be effectively treated with chest tube
drainage followed by irrigation with antibiotic solution.155,157,158 If a large BPF is identified, or the
empyema is organized/fibropurulent, surgical intervention is needed. Resection of a segment of rib(s)
with suturing skin flaps to the empyema cavity (open window thoracostomy) combined with repeated
dressing changes allows complete drainage.154,159,160 An open window thoracostomy is completed in the
most dependent portion of the empyema cavity as identified by CT scan, and can be an effective technique
to manage empyema complicating pulmonary resection.152,154 A median time of 5 months is needed for
obliteration of the pleural cavity and subsequent chest wall closure, which may require muscle
transposition (latissimus dorsi or pectoralis major) to complete.154
The Clagett procedure consists of open pleural drainage, closure of any identified BPF, debridement of
necrotic tissue, and secondary closure after filling with antibiotic solution.161 Pairolero and colleagues162
later reported a Clagett procedure, which includes the use of muscle transposition to close a BPF. A
bedside modified Clagett procedure has recently been described, and may be useful in appropriately
selected patients.163 Thoracotomy with debridement of necrotic tissue, chest tube povidone–iodine
irrigation until drainage fluid has a negative Gram stain, and filling of the pleural space with an antibiotic
solution with closure is an additional management option.155 If recurrence of infection occurs after an
intervention such as open window thoracostomy, more invasive procedures may be needed.
HIGH CHEST TUBE OUTPUT

Thresholds for the removal of chest tubes after thoracic surgery vary considerably, and until recently,
guidance in the literature was lacking.33,164 Commonly, tubes are left in place until drainage is less than
150 to 250 mL/day.165 Physiologic fluid filtration, which occurs at the parietal pleura, is approximately
350 mL/day.166 The pleural cavity additionally has an absorptive capacity that can reach up to 2
L/day.166,167
A “high-output” chest tube may be defined as greater than 250 mL/day.168 An important component of
chest tube management is not only the quantity of fluid drainage, but character as well. Unusual
characteristics such as blood, chyle, or cerebral spinal fluid (CSF) should prompt further
investigation.164,168 A high-output chest tube due to cerebral–arachnoid pleural fistula is rare, and usually
is associated with symptoms such as headache, nausea, and confusion.169 The presence of chyle in pleural
fluid is confirmed by obtaining a triglyceride level greater than 110 mg/dL or positive Sudan fat
stain.170,171
Cerfolio and Bryant168 reported their experience with chest tube removal in a series of 2,077 patients
following elective pulmonary resection. Chest tubes were removed with up to 450 mL/day of drainage,
provided the output was nonchylous and without air leak. Their median day of discharge was
postoperative day 4, with a 5% 60-day readmission rate, which was comparable to the rest of the patient
population. Of those that required readmission, only 0.55% was as a result of a symptomatic effusion.168
Bjerregaard and colleagues172 obtained similar results, supporting the feasibility of high-output chest tube
removal. These results suggest that removal of tubes with an output up to 400 to 450 mL/day may be safe
and appropriate although this is not practiced universally.33,168,172,173
Chest tube removal after other interventions such as pleurodesis for a malignant effusion, chylothorax,
or empyema, should be adapted to the patient’s clinical course. If there is concern for anastomotic leakage
after esophageal resection or tracheal reconstruction, tubes should be maintained and appropriate
management performed.
CHYLOTHORAX
A chylothorax is the leakage of lymphatic fluid containing chylomicrons and fats into the thoracic
cavity.174 The incidence of chylothorax after pulmonary resection has been reported to be between 0.04%
and 2% after lobectomy, and 0.7% to 1% after pneumonectomy.175–178 After esophagectomy, incidence is
approximately 3%.179,180 Associated morbidity and mortality are significant, with rates of mortality as
high as 50%.181,182 Risk of injury is increased in patients with large tumors, positive N2 nodal disease,
those who have received neoadjuvant treatment, right-sided operations, and those having mediastinal
lymphadenectomy.178,179,182,183
The course of the thoracic duct is along the vertebral bodies, entering the aortic hiatus on the right side
and decussating to the left at approximately the 5th vertebral body and ascending into the mediastinum
(Fig. 42.2). However, its course varies from this in up to 45% of cases, potentially contributing to
injury.180,184 Damage may occur during mediastinal lymph node dissection or mobilization of the lower
thoracic esophagus, frequently leaking into the right chest.
Chylothorax may be an early or late complication. Most chylothoraces require intervention (duct
ligation or embolization). Conservative management may cautiously be attempted if chest tube output is
low.175,177,178,182,185 Injury to the thoracic duct may be suspected when chest tube drainage is high or the
fluid has a milky white quality. This usually develops when tube feedings or oral intake are initiated.
Chyle consists of lymphatic fluid (lymphocytes, immunoglobulins) and lipid (chylomicrons,
triglycerides). The presence of chyle in pleural fluid is established by obtaining a triglyceride level
greater than 110 mg/dL or positive Sudan fat stain, and cell count will demonstrate a predominance of
lymphocytes.170,171,182 Chyle does not contain fibrinogen, making even small lacerations to the duct or its
tributaries troublesome as they will not seal on their own.180,182 Lymphangiogram can assist in diagnosis,
particularly if involvement of the main thoracic duct is a concern (Fig. 42.3A,B).170 If a large injury is
identified, surgical ligation of the duct and pleurodesis is the most appropriate initial management. This is
frequently required following surgical injury to the duct and should be performed early after diagnosis to
prevent the sequelae of a persistent leak.
Patients with a low output leak (less than 450 mL/day) may be treated by limiting or stopping oral
intake, and monitoring chest tube output to ensure decreasing volume. It is essential that the lung is fully
expanded and fluid is not collecting in the pleural space. Once a decreasing chest tube output is confirmed
over 48 hours (less than 450 mL/day), a low fat or medium-chain triglyceride (MCT) diet can be initiated
for 2 weeks.178,180,182 This course may be completed as an outpatient with a chest tube in place if output
remains below 450 mL/day.178 Octreotide administration (infusion or subcutaneously) may be a beneficial
adjunct but is expensive.177,178,180,186 When drainage is less than 200 to 300 mL/day, the patient is
challenged with a fatty meal.177,178,180,182 Monitoring of nutrition (albumin, prealbumin), electrolytes, and
white blood cell count should continue during this time.
Significant morbidity and mortality occurs with a chylothorax that is not appropriately identified and
treated. Persistent chylothorax can lead to neutropenia, lymphocytopenia, antibody loss, infection/sepsis,
albumin loss, and malnutrition.184,187 Mortality of persistent chylothorax has been reported to be as high
as 50%, most commonly occurring from sepsis due to lymphocyte depletion and malnutrition in an already
immunocompromised patient.180,181
FIGURE 42.2 Thoracic duct anatomy.
Immediate surgical intervention is frequently necessary when chest tube drainage is a high output
(greater than 1 L/day) or conservative management has failed.180,182,183,188 The decision for reoperation
should be made in a timely fashion as delays contribute to further increases in patient mortality. If high-
output drainage persists beyond 2 to 5 days, surgical intervention is advisable.177,182,189–191
Administration of a lipid/cream prior to surgery may assist with intraoperative identification of the leak.
At the time of reoperation, the leak can be oversewn if identified, followed by duct ligation and
pleurodesis to help obliterate the potential pleural space.180,182,183,188 Percutaneous embolization is an
additional modality that may be employed in appropriately selected patients, particularly when a thoracic
duct ligation fails to resolve the chylothorax.192
FIGURE 42.3 Lymphangiogram demonstrating lymphatic leak at the level of the carina supplied by multiple periaortic (A) and
pericaval (B) collaterals. Managed by redo right thoracotomy, duct ligation above the diaphragm, and pleurodesis.
HEMORRHAGE
Major hemorrhage following thoracotomy and pulmonary resection is infrequent, but may occur as the
result of inadequate hemostasis or unrecognized injury of chest wall vessels and bronchial arteries, or the
disruption of a previously ligated vessel.2,33,90 Allen and colleagues2 noted a rate of 2.4% for hemorrhage
requiring transfusion, and 1.5% requiring reoperation.
Since perioperative blood loss should be minimal, re-exploration should be promptly considered if
transfusion is required or if there is bloody drainage of 100 mL/hr for more than 2 hours.29 Large-volume
bloody drainage requires immediate attention to identify the bleeding source. Meticulous hemostasis
during the initial operation, with double ligation of vessels and re-examination prior to closure, reduces
later bleeding episodes. The increased use of staplers for pulmonary vessels may reduce the
postoperative bleeding risk. Special attention should be directed to the inferior pulmonary ligament,
bronchial arteries in the areas of lymph node dissection, and the subcarinal area where small feeding
vessels are located. Bleeding from the pulmonary parenchyma after resection may occur and should be
inspected prior to closure. Coagulopathy may be present and should be corrected accordingly, and
normothermia must be maintained. A hematoma that is not properly evacuated will place the patient at risk
for later empyema or lung entrapment.
ANASTOMOTIC LEAK
Anastomotic leak after esophagectomy is a serious and potentially fatal complication. A leak may be
defined as a full-thickness gastrointestinal defect that can allow the extravasation of oral secretions or
gastric fluid through the disruption in the conduit or anastomotic site.182 The incidence of leak varies with
the site of anastomosis: 12.3% in cervical as compared to 9.3% with intrathoracic anastomosis.193 Even
in high-volume centers, overall rates can approach 8% to 13%.194–197 Lower occurrence has been
reported with some variations of technique.197–200 Although rates are improving, intrathoracic leak can be
dramatic with progression to a lethal mediastinitis with a 20% to 35% mortality.201–204 Mediastinitis after
cervical anastomotic leak is unusual.
Kassis and colleagues193 identified several predictors of anastomotic leak in their detailed analysis of
the STS database. They identified obesity, heart failure, coronary disease, vascular disease, hypertension,
steroids, diabetes, renal insufficiency, tobacco use, and length of operative time greater than 5 hours as
significant factors in the development of a leak.193 Notably, poor pulmonary function, emergent or
reoperative procedures, neoadjuvant therapy, and intraoperative blood transfusion did not increase this
risk.193,205
Consideration of the blood supply after esophagectomy is an important factor in the development of
leaks. The esophagus has a segmental blood supply, with communicating branches that must extend over
long distances, making esophageal anastomotic sites at risk for poor healing and ischemic necrosis.182,205
The gastric conduit is dependent on the right gastroepiploic artery, the compromise of which may lead to
ischemia and anastomotic disruption.182 Mobilization of an appropriate conduit length to avoid tension,
and attention to minimizing trauma to the proximal site of anastomosis will help to preserve conduit
vascularization.206 By avoiding prolonged periods of hypotension, adequate perfusion to these sites can
be maintained. In addition, the lack of a serosal layer and delicate outer longitudinal muscle may play a
role with anastomotic leak rates.205,206
Esophagogastric anastomoses in the chest are subjected to negative pressure and possible reflux of
gastric fluid into the suture or staple line.182 Contamination of the pleural cavity places the patient at risk
for a robust inflammatory response, respiratory compromise, and unstable hemodynamics; a potentially
lethal combination.182 The greater curvature of the stomach may be tailored to create a tubular conduit,
with the benefit of reducing acid secreting tissue and improved mechanical positioning.182 Gastric
distension and delayed emptying may develop when the whole stomach is used, potentiating a risk of
leak.207,208 However, some authors advocate maintaining the whole stomach for an improved blood
supply and avoidance of creating an additional suture line.209,210 According to recent literature, there
seems to be no significant difference in the incidence of leak when comparing stapled esophagogastric
anastomosis versus handsewn, minimally invasive versus open esophagectomy, and anterior versus
posterior route of reconstruction.205,211 However, some conflicting data exists and the risk of leak
associated with varying anastomotic techniques continues to be debated.206,212,213
Treatment of anastomotic leaks is dependent on the site of the anastomosis and severity of the leak.
Opening the neck incision may adequately drain cervical anastomotic leaks, and a localized anastomotic
leak may be conservatively managed with dietary modification.11,182 In contrast, conduit necrosis will
require prompt operative intervention with resection and cervical diversion, followed by staged
reconstruction with colon or jejunum.11,206,214 Typically, a major leak and necrosis will present within 72
hours postoperatively with signs of sepsis and a large fluid collection or suspicious chest tube
drainage.205,206 A cervical leak characteristically presents after the fifth postoperative day with wound
erythema, drainage, and fever.205 Intrathoracic leaks have the potential to be insidious, with simply a low-
grade fever, malaise, and leukocytosis, but can deteriorate to sepsis and multisystem organ failure if
unrecognized.194,205 Other clinical features associated with leaks include perianastomotic collections, a
hematoma or seroma at the neck incision site, abscess, empyema, mediastinal air, and pneumothorax.206
Contrast esophagogram will assist in the identification and localization of a leak. CT scan and
esophagoscopy to inspect the mucosa may also be helpful (Fig. 42.4).205,214
Management of a large noncontained leak includes initiation of broad-spectrum antibiotics, fluid
resuscitation, and operative intervention. Focal necrosis may be salvageable with debridement, repair,
and buttressing with a vascularized pedicle.194,205,215 Surgical exploration is warranted for any
symptomatic, noncontained intrathoracic leak.205,215 Extensive involvement necessitates conduit take
down, debridement and resection of devitalized tissue with return of the remainder to the abdomen,
cervical diversion, and wide chest tube drainage. Continuity is re-established once the patient has
clinically improved at a later date; however, this is often a complex endeavor.205,214,215
An asymptomatic contained cervical leak may not require operative intervention; patients may be kept
on clear liquids or nothing by mouth for several additional days and typically do not require
antibiotics.216 A larger contained cervical leak with erythema and fluctuance will need evacuation, wound
packing, and antibiotics if cellulitis is present.205 Resolution typically occurs within 2 weeks; failure to
promptly respond should generate suspicion and investigation for a more serious problem such as
descending mediastinitis or distal obstruction.217 Asymptomatic contained intrathoracic leaks may be able
to be successfully managed nonoperatively.202,215 Metal, plastic, and silicone stents have all been
described in the management of contained intrathoracic leaks.218,219 Stents may be a safe and well-
tolerated option when mediastinal or pleural contamination is limited, and used with appropriate drainage
of these areas (Fig. 42.5).218 Timing of stent removal varies, but generally is left in place for several
weeks to minimize stricture development.218 Overall, the need for reoperation has become less common,
even for intrathoracic leaks.202,215,218–221 The majority of leaks are amenable to either drainage alone, or
drainage with stenting. Recognition of a true anastomotic disruption or conduit necrosis remains critical
as reoperation is clearly indicated.
FIGURE 42.4 Esophagogastric anastomotic leak demonstrated by presence of extraluminal gas.
ESOPHAGEAL STRICTURE
Those that endure an anastomotic leak are frequently at risk for stricture.194,216,222 Briel and colleagues194
identified that 47% of patients with an anastomotic leak went on to develop stricture; however, 78% of
those with known strictures had not had a previous leak. The incidence of stricture after esophagectomy
varies widely, ranging from 10% to over 50%.200,213 This range may be partially due to variations in
patients’ report of symptoms such as dysphagia as well as the lack of a specific authoritative definition.223
Dysphagia postoperatively may indicate factors other than stricture; symptoms may develop as a result
of edema, muscle or nerve injury with neck dissection, vocal cord paralysis and can potentially resolve
without a specific intervention over time.182,205,223,224 Up to 32% of patients complaining of dysphagia
may not have an anastomotic stricture.224,225 Initial evaluation for suspected stricture should include
contrast esophagogram studies or endoscopy. Stricture may be identified as dysphagia with anastomotic
narrowing observed on esophagram or esophagoscopy.194,223,226,227 The risks of developing stricture are
similar to those described above for anastomotic leak in terms of attention to blood supply and handling
of tissues. Conduit ischemia plays an important role in the development of stricture; however, not all
patients that have identifiable ischemia develop this complication.194 Data is somewhat conflicting, but
there does not seem to be a difference in the development of stricture with various anastomotic
techniques.211,223,228,229 Newer modifications may, however, demonstrate superior outcomes.197,200
FIGURE 42.5 Successful placement of esophageal stent for treatment of anastomotic leak.
Some strictures may resolve without intervention over time as the anastomotic diameter is known to
increase in size, and may potentially double, in the first 12 months after esophagectomy.198,230,231
Correspondingly, dysphagia is observed to improve during this period. The majority of anastomotic
strictures present within 2 to 6 months of esophagectomy.197,200,228 Gradual serial dilations can address
many of the persistent symptoms. Typically between two to five dilations over several sessions are
needed to achieve adequate improvement.197,200 Perforation following dilation is rare, and operative
revision of a stricture is seldom needed.194,223 The development of a stricture more than a year after
esophagectomy should raise suspicion of recurrent malignancy and should be investigated.182,223
NERVE INJURY
Recurrent Laryngeal Nerve
The incidence of recurrent laryngeal nerve (RLN) injury after lung resection is approximately 0.7.%.2
Rates of injury vary after esophagectomy, with a higher incidence in transhiatal or three-hole resection as
a result of dissection and retraction in the neck.232,233 After an Ivor-Lewis esophagectomy, injury rates are
approximately 0.9% to 4.8%, as compared with the transhiatal approach, which is in the range of 11.2%
to 14%.196,234,235 Overall incidence may be underestimated, as vocal cord function is not routinely
evaluated after surgery. During pulmonary resection, the nerve is at risk during mobilization of the left
upper lobe and dissection of level 5 lymph nodes in the aortopulmonary window.
The RLN supplies all the intrinsic muscles of the larynx, except for the cricothyroid, and is critical for
vocal cord function.236 As a result, injury may cause hoarseness, inability to cough, aspiration, and
difficulty swallowing; and bilateral involvement can be life threatening with loss of a patent airway.232,236
However, patients may also remain asymptomatic. Diagnosis is made with laryngoscopy to visualize the
vocal cords.
Although damage may not be permanent, it is associated with significant postoperative morbidity. RLN
injury correlates with higher rates of pulmonary complications (aspiration pneumonia), decreased ideal
body weight, vital capacity and functional status, as well as dysfunctional swallowing resulting in choking
and coughing.237,238 Return of function is seen in 41% of patients within 1 year of injury, and in 49%
within 2 years.238 The mean duration of speaking difficulties was 5.7 months.238 Speech therapy may be
helpful, but definitive surgical intervention may ultimately be needed.236 To prevent damage to the RLN,
neck dissection and exposure should proceed carefully, with precise placement of retractors or clamps,
and avoiding excessive cauterization to protect from the creation of a thermal injury.236 In pulmonary
resection, dissecting close to the parenchyma during a left upper lobectomy and away from the
mediastinum and level 5 nodes can reduce injury.
Early involvement by Otolaryngology is beneficial particularly with a known intraoperative injury.
Medialization laryngoplasty assists with the improvement of vocal fold closure.239 A variety of options
are available for in-office injections to accomplish medialization. Intervention is important to improve
cough to clear secretions and prevent pneumonia.
Phrenic Nerve
Phrenic nerve injury is well documented as an associated complication of cardiac surgery, but remains at
risk during other types of thoracic surgery as well.239–242
Incidence varies according to the procedure, with rates reported anywhere from 10% to 85% in
cardiac surgery.243,244 Injury to the nerve can result due to excessive traction, compression, tumor
invasion, mobilization of pulmonary adhesions, or direct trauma such as during lymph node dissection.239
The phrenic nerve is the singular supply to the diaphragm; thus injury is manifest by chest radiography
demonstrating a newly elevated hemidiaphragm. Injury can be confirmed by ultrasound or dynamic
fluoroscopy revealing paradoxical movement of the diaphragm with inspiration.245,246 As a result of the
breathing impairment associated with this paradoxical movement, phrenic nerve injury places the patient
at risk for atelectasis, pneumonia, CO2 retention, and difficulty weaning from mechanical ventilation.239
Cold phrenic nerve injury as seen during cardiac surgery generally resolves without specific
intervention; nerve injury due to other causes may also improve spontaneously but may take as long as 18
months to 3 years.239 Patients that are asymptomatic may not need further management. However, those
with respiratory distress benefit from surgical plication of the diaphragm to prevent ongoing
atelectasis.239,247 This procedure stabilizes the paralyzed diaphragm allowing the healthy side to do less
work, decrease lung compression, and improve overall lung mechanics.239 Plication allows more
effective recruitment without interfering with return of diaphragm function that may improve over time.239
CONCLUSION
Postoperative complications are best managed by minimizing known risk factors, appropriate patient
selection, and prompt recognition when they occur. Management strategies continue to evolve and
multidisciplinary care enables the reduction of morbidity and mortality.
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227. Honkoop P, Siersema PD, Tilanus HW, et al. Benign anastomotic strictures after transhiatal esophagectomy and cervical
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228. Hsu HH, Chen JS, Huang PM, et al. Comparison of manual and mechanical cervical esophagogastric anastomosis after esophageal
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2007;84(3):1029–1031.
Section
X
THE CHEST CAGE

43
Chest Wall Deformities
Charles B. Huddleston ■ Yosef Jose Greenspon
INTRODUCTION
Chest wall deformities as a whole are relatively common, produce a wide variety of differing
appearances, and although are generally benign, may produce life-threatening physiologic disturbances.
For the purposes of organization, they may be classified into the following categories: (1) pectus
excavatum, (2) pectus carinatum, (3) Poland syndrome, (4) sternal defects, and (5) miscellaneous
anomalies not easily fitting into the other four subsets.
PECTUS EXCAVATUM
Pectus excavatum is by far the most common chest wall deformity. It occurs in approximately 1 of 200
live births and generally appears soon after birth. It is characterized by posterior depression of the
inferior half of the body of the sternum along with posterior curvature of the attached costal cartilages.
There are seven or eight ribs that attach to the sternum; ribs eleven and twelve are usually “floating” and
the others fuse to the one above to account for all twelve. As the ribs curve around posteriorly from the
spine to the sternum anteriorly they are composed of bones up to the costochondral junction. At this sharp
transition point, they become and stay cartilaginous for the remaining distance to the sternum. The lower
three to four ribs are generally involved at the level of the sternum. The osseous portion of the ribs may
be deformed in older children and adults. The manubrium, upper sternum, and ribs one through three are
rarely part of the deformity. It may be asymmetric, usually more depressed on the right than the left with
rotation of the sternum toward the right in this situation. The cause of pectus excavatum is unknown
although it would seem related to an imbalance between the growth of the ribs and that of the thoracic
organs (heart and lungs). The vast majority (85% to 90%) appears soon after birth and it is much more
common in boys than girls by a four to one margin.1 It commonly occurs in children with connective tissue
disorders such as Marfan (60% incidence), Loeys–Dietz and Ehler–Danlos syndromes.2,3 Congenital
diaphragmatic problems have been implicated because of the association between pectus excavatum with
congenital diaphragmatic hernia and agenesis of the diaphragm.4,5 Prune belly syndrome is commonly
associated with pectus excavatum.6 There is also an association of pectus excavatum with scoliosis.7
There seems to be an increased incidence in some families; approximately one-third of all patients will
have another family member with a chest wall deformity.1,8
A variety of grading systems have been proposed to assess the severity of the depression.9–13 For the
most part, the Haller index is the most commonly employed assessment of severity. It is derived by
dividing the transverse chest dimension by the distance from the back of the sternum to the anterior aspect
of the spine at the deepest point of the sternal depression. This can be assessed by chest radiograph
although was originally described from measurements taken from computed tomograms (CT scans) of the
chest (Fig. 43.1). A normal value is approximately 2.5. In severe cases this can be greater than 6.0.
Asymmetry is often difficult to quantitate in expressing the severity of the deformity although there is a
system described to do just that.13 Apart from applying some degree of objectivity by assigning a number,
these indices are not used for anything else, such as indications for operation.
CLINICAL PRESENTATION
The most common reason for children to be brought to medical attention is the appearance of the
deformity itself. Symptoms usually fall into one or more of three categories—pain, exercise intolerance,
or appearance. Pain is generally located in or around the sternal depression. It is usually sharp and
fleeting, lasting no more than a few minutes. It may occur randomly or related to exercise. Exercise
intolerance is generally of a moderate degree. Often quite fit athletes note that their performance is
somewhat worse than their peers but above average. Naturally, the appearance is often concerning
because of the implications for adolescents as they go through an often troublesome period of their lives
where being “different” in any way brings unwanted attention. On the other hand, some have used this as a
method of drawing positive attention, such as appearing on late night television show segments “funny
things I can do with my body” (Fig. 43.2).
FIGURE 43.1 This is a frame from a chest CT scan. The Haller index is calculated by measuring the transverse inner chest
dimension and dividing it by the distance from the back of the sternum to the front of the spine at the most severely depressed
point. Note also in this figure the compression of the right atrium, tricuspid valve, and right ventricle by the sternum.
Physical Findings
The most obvious finding on physical exam of course is the depression in the anterior chest wall (Fig.
43.3). This usually involves the lower half of the sternum and adjacent ribs. It may extend laterally to the
mid clavicular line. The costal margins inferiorly are often flared outwardly. When there is asymmetry it
is usually more sunken on the right with rotation of the sternum from left to right. Lung sounds are usually
clear. There may be a systolic murmur. In some patients this can only be heard when sitting or standing
upright.
FIGURE 43.2 The patient depicted in this figure has found some usefulness in his chest wall deformity. He is finishing off his
breakfast by drinking the remainder of the milk from his cereal. He sacrificed this convenience to have his pectus excavatum
repaired.
FIGURE 43.3 This patient has an obvious severe pectus excavatum with symmetric depression of the anterior chest wall
involving the inferior two-thirds of the sternum and anterior costal cartilages.
PATHOPHYSIOLOGY
Many physicians (and a few insurance companies) believe that pectus excavatum produces no cardiac or
pulmonary impairment. This is contrary to the observations made by numerous surgeons who have noted
improved stamina following operation in those where that was a major complaint. Since one of the
earliest operations by Sauerbruch in 1913,14 efforts at demonstrating an objective improvement in some
measure of cardiopulmonary performance have been attempted. Sauerbruch’s patient was a 19-year-old
son of a Swiss watchmaker who could not tolerate working a full day in his father’s company. This was
likely not a particularly physically stressful job. Following recovery from repair of his pectus excavatum
he was working long days without tiring. Many studies of cardiopulmonary measurements have been
performed to prove or disprove the notion that pectus excavatum causes some objective diminution in
heart and/or lung function and that repair improves this.
Pulmonary Function Studies

Many investigators have evaluated these patients with pre- and post-repair pulmonary function
studies.15–26 There are some differences in the age of the patients studied as far as the timing for repair.
There are also differences in the choice of repair with some undergoing an “extensive” Ravitch procedure
and others a less extensive procedure. More recently the minimally invasive pectus repair, known as the
Nuss procedure, is the more common operation employed. Typically these patients have a vital capacity
on the order of 80% to 85% of predicted preoperatively; the forced expiratory volume in one second
(FEV1) is also at around that value. The post-repair pulmonary function studies demonstrate some
variability in the final vital capacity and FEV1. Interestingly, the studies in which the Nuss operation is the
primary procedure utilized for the repair tend to have some improvement in the vital capacity and FEV1
whereas those in which the Ravitch procedure was performed do not. However, the differences noted
between the pre- and postoperative pulmonary function tests are not significant regardless of the
procedure employed. Therefore, it is unlikely that the observed improvement in stamina is related to that.
One of the largest studies to date is a multicenter study by Kelly et al.,27 in which 327 total patients were
entered, 182 of which went through the complete follow-up protocol. Most of these patients underwent the
Nuss procedure although around 15% had the Ravitch operation. The pulmonary function tests were
slightly improved but did reach statistical significance. The vital capacity went from 88% of predicted to
93% and the FEV1 rose from 87% of predicted to 90%. Total lung capacity increased from 94% to 100%
of predicted. All these were statistically significant even though the actual increase was not very much. It
seems unlikely that this relatively small (albeit significant) increase would be responsible for substantial
improvement in exercise-related symptoms.
Exercise Testing
It has long been recognized that the posteriorly displaced sternum can compress the anterior wall of the
right ventricle28 (Fig. 43.1). Further, post-repair, this compression is often resolved.29 The question
remains as to how this translates to a change in cardiovascular performance. Studies on cardiac function
in pectus excavatum patients include cardiac catheterization, nuclear medicine studies, oxygen
consumption exercise studies, and echocardiography.
Three studies using exercise during cardiac catheterization consistently document a reduction in
cardiac output during upright exercise in patients with pectus excavatum chest wall deformities compared
with cardiac output in the supine position as well as controls.30–32 When supine, the cardiac output is
consistently higher at the same heart rate in all three studies. When patients were studied in a similar
fashion post-repair, the upright exercise cardiac output was similar to the normal controls. Some studies
of exercise performance used nuclear medicine technology. Peterson et al. performed radionuclide studies
at rest and during upright bicycle exercise to assess left and right ventricular volumes and function.33 They
found no difference in the left ventricular ejection fraction or cardiac index comparing the pre- and
postoperative values. They did find that there was an increase in left ventricular end diastolic volume and
stroke volume indices. The right ventricular end diastolic volume index increased significantly following
operative correction of the pectus excavatum deformity. This suggests that there might well be some
cardiac compression by the sternum that is relieved by operation. The patients studied had a subjective
improvement in exercise tolerance and improved overall exercise performance.
Because of its convenience and noninvasive nature, echocardiography has been frequently studied in
patients with pectus excavatum. It is not at all uncommon for abnormalities to be found in patients with
severe pectus excavatum. Specifically, right ventricular compression and impingement at the level of the
tricuspid valve can be seen. Right ventricular dimensions are typically abnormal (lower than normal) and
seem to increase following repair. This is the proposed mechanism by which cardiac output during
exercise increases following repair.34–38 Although some have used echocardiography to assess cardiac
output before and after repair, this has been criticized due to difficulties with calculating left ventricular
volumes pre- and postoperatively.39 Mitral valve prolapse has been a focus of some studies of the
echocardiographic appearance of the heart in patients with pectus excavatum.40–42 Some suggest a
relationship between the two with the proposition that repair may treat this entity.38,43 The role this might
play in the improved symptoms noted in those repaired is not conclusive because mitral valve prolapse
does not by itself result in any significant reduction in cardiac output; only in the presence of significant
mitral valve regurgitation would this occur. The diagnosis of mitral valve prolapse is also somewhat
subjective and operator dependent to a degree. Therefore, we would view the relation of mitral valve
prolapse and pectus excavatum with some skepticism.
Noninvasive exercise studies in patients with pectus excavatum have also been performed in an effort
to relate physiology to the anatomic abnormalities. The variables studied include VO2 max (maximum
oxygen consumption) and exercise endurance. Patients with pectus excavatum had lower values than
controls and improved to similar levels as the controls following repair.44,45
The ongoing vexing question of the physiologic impact of a pectus excavatum and whether repair offers
relief of the physiologic impact has not really changed much over the past decade. At least three sets of
investigators have performed a meta-analysis of the available literature. One of these concludes that the
cardiac function and cardiopulmonary status of patients with a pectus excavatum is impaired resulting in
diminished exercise capacity.46 One of these also offers a favorable opinion regarding the salutary effects
of surgery for pectus excavatum, but is somewhat less robust in its affirmation.47 The third concludes that
there is no benefit of repair as far as the cardiac performance is concerned.39 The authors’ view is that
there likely is some benefit to be had in those patients with symptoms suggestive of reduced exercise
tolerance and that the benefit is derived from relief of compression of the anterior wall of the right
ventricle by the back of the sternum. At least two-thirds of symptomatic patients note improvement
subjectively.
Psychological/Quality of Life Issues

There is little question that a significant pectus excavatum results in diminished quality of life for
adolescents.48–52 Boys in particular are impacted. They may avoid swimming in public or will always
cover their chest by wearing a shirt while swimming. Undressing in a school locker room or gym
becomes a stressful ordeal. Apart from these subjective complaints, scores on standardized tests
demonstrate clear problems with body image, self-esteem, and so on. Repair results in both subjective
improvements in these areas as well as higher scores on the quality of life questionnaires. Although
pectus excavatum may cause symptoms related to the cardiopulmonary impact of the chest wall deformity,
it is more common for adolescents to seek treatment because of the impact on their appearance.
Evaluation
All patients should undergo a standard history and physical examination. The association of Marfan’s
syndrome with pectus excavatum dictates that one should be suspicious of this diagnosis when evaluating
these patients. A standard chest radiograph is generally sufficient for calculating the Haller index.
Computed tomography or magnetic resonance imaging of the chest provides nice detail of the deformity
particularly when there is some asymmetry present. It allows for a more precise calculation of the Haller
index and will demonstrate whether there is cardiac compression or not. Whether this should be
considered part of the standard work up of these patients is debatable.53 Pulmonary function tests may be
instructive. Echocardiography may or may not confirm cardiac compression, as images are often difficult
to obtain due to the deformity. It will screen for any evidence of cardiac manifestations of Marfan’s
syndrome. In addition, this is a useful tool when the patient has symptoms of exercise intolerance out of
proportion to the degree of the deformity, allowing one to rule out other more malignant causes of this,
such as pulmonary hypertension or hypertrophic cardiomyopathy.
Surgical Repair
A variety of surgical procedures have been proposed over the years since the initial procedures
performed by Meyer54 and Sauerbruch.14 Ravitch, in the operative technique that currently bears his name,
repaired a pectus excavatum by resecting all of the deformed costal cartilages along with the
perichondrium, divided the xiphoid process from the sternum, and performed a transverse sternal
osteotomy; the sternum was secured anteriorly in a somewhat overcorrected position using Kirschner
wires or heavy silk sutures.55 This procedure was modified by Baronofsky56 and Welch10 emphasizing the
importance of preserving the perichondrium as well as its attachments to the sternum. This provided the
cellular mechanism for regeneration of the ribs. The final major modification in the procedure was the use
of a strut placed either through the sternum or under it to provide support while awaiting regeneration of
the ribs.57–60 The strut is generally removed 6 to 12 months following the correction. These struts have
generally been metal but more recently bioabsorbable struts,61 one of the resected costal cartilages, and
Marlex mesh62 have been used. There is no evidence to suggest the superiority of these over more
traditional metal struts. The risk over time is recurrence of the sternal depression once the material
resorbs. Long-term follow-up is necessary to compare these various strut approaches. A combination of
the basic original procedure plus these modifications is the procedure used most often when surgeons
employ the “Ravitch procedure” for repair of pectus excavatum.
Another procedure proposed for the treatment of pectus excavatum is the so-called sternal turnover. In
this operation the affected costal cartilages are divided and the sternum mobilized. The abnormal portion
of the sternum is then transected, rotated 180 degrees, and reattached to the upper sternum. In some series
the internal mammary arteries are preserved to maintain blood supply to the sternum.63–65 In other series,
the sternum is basically a bone graft.66 The advantage of these turnover procedures is that no strut is
necessary. There is some evidence that the sternum is viable in late follow-up. However, as a free graft, if
infection occurs the complications could be disastrous.
The appearance of the chest wall can be altered without dealing with the skeletal deformity as well.
Silastic molds of the defect can be fashioned and implanted under the subcutaneous space to fill the void.
This approach often has quite a favorable cosmetic result with less pain than would be associated with a
more standard repair. However, this would have no impact on the compression of the anterior wall of the
heart and whatever physiologic derangements that produces. The optimal candidate for this procedure
would be one with minimal physiologic derangements but with poor body image. Nonetheless, the silastic
molds are at risk of infection and extrusion.67,68
A nonsurgical approach to pectus excavatum has also been described. This procedure involves
application of vacuum to the affected area of the anterior chest wall using a suction cup.69,70 The suction
cup or vacuum bell is placed on the chest wall and sealed. Vacuum is applied using a hand pump. This is
left in place for a variable period of time, usually at least 30 minutes twice daily. The treatment is used
for a prolonged period of time. The overall long-term results are a bit difficult to glean from the available
literature. There seems to be good early appearance of the chest and some may even have persistent
elevation of the sternum with this treatment. However, in the report by Haeckner it appears that only 13%
had a good result after 18 months of therapy. This is an interesting approach but appears to have limited
follow-up and somewhat poor results with less than 25% deriving benefit.
Another procedure described involves the use of magnets. One is implanted into the sternum and the
other is on an external brace. The concept is that daily applications over a prolonged period of time will
result in the sternum being distracted outwardly into a more normal position.71 After completion of
therapy the magnet is removed. Both the insertion and removal are outpatient procedures. The results
reported to date are marginal at best and the procedure is presently considered experimental.
Nuss and colleagues described a “minimally invasive” approach to correction of pectus excavatum in
the 1990s.72 This procedure involves incisions on both sides of the chest at approximately the level of the
deepest point of depression. A large clamp is passed through one side, behind the sternum, and out the
other side. A preformed bar is pulled through so that the concave side is pointed outwardly. This is then
rotated 180 degrees, popping the sternum and affected ribs outward. The bar is secured on each side and
left in place for approximately 3 years. Presumably, by that time the remodeling of the ribs and anterior
chest wall is complete; the bar is removed at this point. This technique has been dubbed the “Nuss
procedure” or minimally invasive repair of pectus excavatum (MIRPE). Although there were initially
some concerns about using this technique in adults, there are multiple series describing successful Nuss
procedures in patients older than 21 years.50,73
Other operations described for pectus excavatum include the Robicsek procedure and the Leonard
procedure. Both of these are modifications of the Ravitch procedure. In the Robicsek procedure
polypropylene mesh is placed beneath the sternum and the perichondrial sheaths are sewn to this.74 In the
Leonard procedure a sheathed wire is passed under the sternum and out through the skin; it is then
attached to an external brace.75
Currently, the vast majority of operations performed for pectus excavatum are either the Nuss or
modified Ravitch procedures. Modifications of the original procedures have been made over the years
although no substantive change in the Ravitch procedure has occurred in the past two decades. There has
been less time to evaluate the impact of modifications of the original Nuss procedure. Nonetheless,
sufficient material in the literature exists for some comparison. There are certainly significant differences
between the two operations. The incisions are in different locations—either midline or inframammary for
the Ravitch and on bilateral chest walls for the Nuss. The strut stays in longer with the Nuss procedure—
3 to 4 years versus 6 to 12 months for the Ravitch. Which operation is better? A compilation of multiple
reports of these two operations has been published.76 The results are presented in Table 43.1. The
operative time clearly favors the Nuss procedure. The length of intravenous pain medication and/or
epidural anesthetics is longer with the Nuss operation and the length of stay is often longer. The
complication rate is higher with the Nuss procedure for both minor and major complications. The most
bothersome complication of the Nuss procedure has been displacement of the strut. Modifications of the
procedure have been introduced to diminish this by using “bar stabilizers” on one or both sides of the
chest. Struts used in the Ravitch procedure can also become dislodged. In general this is unusual. The
incidence reported in this compilation of studies is similar primarily because of one study in which the
incidence was 50%; most reports have an incidence of less than 5%. There are case reports of cardiac
injury during the Nuss procedure which are life threatening. The use of thoracoscopy as an adjunct to the
Nuss procedure to guide the bar placement has reduced the incidence of inadvertent injury to the heart and
lungs.77,78
In general, operations for pectus excavatum are performed on otherwise completely healthy
individuals in whom this condition poses no life-threatening risk. For that reason, operative risks must be
kept at a minimum and certainly mortality should be essentially zero. Reports in the literature have
examined complications in detail for both the Nuss and the Ravitch procedures. These are listed in Table
43.2. The major complications of the Nuss procedure were higher in the earlier experience at most
centers, in part due to the “learning curve.” Also playing a role in reducing the complications has been the
use of thoracoscopy to avoid cardiac and pericardial injury as well as the use of stabilizers on the lateral
chest wall to secure the bar to the ribs, thereby avoiding rotation or dislodgement of the bar. In
experienced hands there is little difference in the incidence of complications of the two procedures.
Length of hospital stay is nearly the same although there is quite a lot of variability between institutions.
Likewise, the pain experienced by patients is similar but pain management also varies between
institutions. Therefore, it is most instructive when these two procedures are compared when performed in
the same institution. At least three such studies exist.79,80 All show a slightly longer duration of
intravenous and epidural agents for pain control following the Nuss procedure compared to the Ravitch.
All also show a slightly longer duration of hospitalization for the Nuss procedure.
TABLE 43.1 Comparison of Nuss and Ravitch Procedures

Nuss (Pediatric) Ravitch (Pediatric) Nuss (Adult) Ravitch (Adult)
OR time (min) 86 (65–198) 166 (84–282) 94 (65–198) 191 (165–217)
Blood loss (ml) 29 (4–90) 111 (80–200)
Complication (%) 38 (4–98) 12.5 (1.3–63) 21 (0–100) 8
Strut displaced (%) 6.6 (0.8–33.3) 6.4 (0–50) 6.1 (2–25) 0
Epidural duration (days) 2.5 (0–3) 0.6 (0–1.3) 3 (2.8–3) 0
Length of stay (days) 6.1 (3.1–10) 5 (3.1–6.2) 7.3 (4–10) 2.9
Unintended reop (%) 6.3 (0–23) 5.3 (0–17) 5.3 (0–42) 3.3 (1–10)
Good/excellent (%) 95 (83–97) 96 (83–99) 88 (64–92) 91
There have been case reports of quite serious, life-threatening complications of the Nuss procedure.
Cardiac perforation has been reported on a number of occasions as mentioned above. Leonard and
colleagues reported one case of exsanguinating hemorrhage during removal of the strut when it lacerated a
pulmonary vessel. They also reported bilateral sternoclavicular dislocation.81 Cardiac tamponade
secondary to erosion of the aorta by a strut that had rotated 90 degrees has been reported.82 Acute
obstruction of the inferior vena can occur presumably as a result of tension on the pericardium anteriorly
kinking off the inferior vena cava.83 Serious hemorrhage has occurred due to erosion into the internal
mammary artery when a bar partially rotated.84
TABLE 43.2 Complications of the Ravitch and Nuss Procedures

Type Ravitch (%) Nuss (%)
Major
Cardiac perforation 0 0.5
Bar dislodgement (requiring reoperation) 1 2.5
Infection (requiring bar removal) 0 1.0
Minor
Pneumothorax 1.5 8
Pleural effusion (requiring evacuation) 1 8
Pericardial injury (without cardiac injury) 0 4
Atelectasis 2 3
Prolonged pain (requiring readmission) 0 2
Rupture of intercostal muscle 0 9
Metal allergy (requiring bar removal) 0 2
Overcorrection (“acquired carinatum”) 0 2
Late outcomes following repair have generally been quite good. Both procedures have around 90% to
95% satisfaction grade as good or excellent when the patients are queried greater than 1 year following
repair. However, recurrences do occur. The incidence is somewhat difficult to ascertain because of the
lack of truly long-term (>10 years) studies. Follow-up ranging from 2 years,82 6 years,85 and 10 years86
documents recurrence rates of between 2.7% and 7.8% following the Ravitch procedure. The
preponderance of evidence suggests that younger age (prepubertal) at repair is a risk factor for
recurrence. Patients with connective tissue disorders, such as Marfan syndrome, also have a higher risk of
recurrence. A review by Nuss et al. in 2002 of 329 patients described a recurrence rate of approximately
8%.87 Similar to the Ravitch procedure, they found that repair undertaken at age less than 6 years was
associated with a higher rate of recurrence. In addition, earlier removal of the strut, especially less than 1
year following repair, put the patients at higher risk of recurrence.
Perhaps the most troubling late complication of the Ravitch procedure is an “acquired Jeune
syndrome” or thoracic dystrophy. These patients develop a severe restrictive chest wall deformity. This
was first noted by Haller who reported three older children who had undergone early and extensive
Ravitch repair of pectus excavatum. They had poor growth of the anterior chest wall and some evidence
of overgrowth of the upper chest, an area untouched at the original operation. A band-like narrowing of
the mid-chest resulted, along with significant restrictive chest wall motion and pulmonary function tests.88
This has occurred primarily in children with an extensive rib resection performed at a relatively young
age. A restrictive chest wall deformity may occur presumably due to deranged growth of the anterior chest
wall.89 Martinez et al. demonstrated this in an animal model in which the anterior costal cartilages of 6-
week-old rabbits were resected and growth observed over the ensuing 5 months. Marked impairment in
growth was noted over this time. If the costochondral junction is left intact, there was less growth
impairment.90 Treatment of acquired asphyxiating thoracic dystrophy is very difficult. One suggested
procedure involves resection of ribs on either side, a midline sternotomy leaving the sternal halves
separated by placing permanent struts fashioned from the resected ribs.91
Some special circumstances deserve specific discussion. Patients with Marfan syndrome and similar
connective tissue disorders have perhaps the most severe chest wall deformities. Repairs with either the
Ravitch or Nuss procedures have been successful, but recurrence rates are higher than seen in otherwise
normal children.92,93 One should consider using permanent hardware to maintain chest stability or leaving
the metal struts in for extended periods of time to avoid recurrence. Oftentimes, cardiac repair and chest
wall repair are undertaken at the same setting in these patients. The Nuss procedure would not be
appropriate in this situation.
Although the early recommendations by Nuss et al. shied away from using their technique in adults,
multiple centers now do so.94 The most significant difference in the adult population is the greater rigidity
of the anterior chest wall compared to those in early teenage years.95 Some have proposed a thicker metal
bar to overcome this barrier.96 The Ravitch procedure has also been used in repair of pectus excavatum in
adults with good success.97
Recurrence of the sternal depression can occur with either procedure as mentioned above. Both the
Ravitch and Nuss procedures have been used for recurrent pectus excavatum, regardless of the initial
procedure.98 These operations are generally more difficult than the initial repair. Often more hardware is
employed to deal with ribs that are either poorly re-formed or absent altogether. Generally speaking, the
reoperations have similar risk profiles and outcomes as the initial procedure.
SURGICAL TECHNIQUE
The Ravitch procedure is depicted in Video 43.1 and Figure 43.4. The incision for boys is generally a
midline lower sternal incision and for girls a bilateral inframammary incision. One must be cautious in
girls to avoid an incision which might compromise breast growth and development.99 Dissection is
carried out to lift the pectoralis and rectus abdominis muscles off the involved ribs generally from the
midline to the mid-clavicular lines. The involved costal cartilages are then resected from the sternum to
either the costochondral junction or to the point where the ribs have a more normal contour. This is done
in a subperichondrial fashion preserving the perichondrial sheaths in their position as much as possible.
This allows regrowth of the ribs once the sternum has assumed a normal position. The xyphoid process is
removed as it generally points anteriorly. Once removed, there is easy access to the mediastinum
posterior to the sternum. This is dissected up to the level at which the sternum begins to angle posteriorly.
A closing wedge osteotomy is then performed, removing a small triangular-shaped segment of sternum,
leaving the posterior table of the sternum intact. A greenstick fracture of the posterior table is then
performed so that the sternum can rotate as if on a hinge into the normal anatomic position. In cases where
there is asymmetry to the chest wall resulting in rotation of the sternum (usually to the right), the sternum
is rotated back into position. Dissection behind the sternum from one side to the other is undertaken
around 2 cm cephalad to the distal tip of the sternum. A stainless steel strut is selected for placement at
this level to support the sternum. The strut should be long enough to lie on the ribs left in place laterally.
The strut may need to be bent slightly to accommodate the normal curvature of the anterior chest wall. The
strut is then secured to the soft tissue on either end with suture. The closing wedge osteotomy is secured
with heavy nonabsorbable suture. Time is then spent assuring hemostasis. Some surgeons place drains
into the subpectoral space prior to closure. The authors do not. Some open the right pleural space and
leave a thoracostomy tube. We have seldom found that necessary. The pectoral muscle layer is closed in
the midline, attaching it to the periosteum of the sternum.
Browser issues
Video 43.1 Ravitch procedure.
FIGURE 43.4 A: Following exposure of the anterior costal cartilages, the perichondrium is scored with electrocautery. B: The
cartilaginous portion of the rib is pealed out of the perichondrial sheath using a fine tooth hemostat going from the sternum to the
costochondral junction or to the point where the rib assumes a more normal position. C: This exposes the pearly white rib when
staying in the proper plane. Occasionally dividing the rib makes the removal easier. A Sauerbruch rib cutter is particularly useful
for dividing the rib at the distal extent of dissection. E: This leaves behind an empty perichondrial space from which a rib will
regenerate. F: A small wedge of the anterior portion of the sternum is removed at the point where the sternum angles posteriorly.
We use a standard osteotome and mallet for this. G: The xyphoid process is removed to allow access to the mediastinum just
behind the sternum. A greenstick fracture of the posterior table of the sternum is performed, bringing the lower end of the
sternum anteriorly, as if on a hinge, into the normal position. This closing wedge osteotomy is then closed with heavy suture
passed through the sternum itself. H: A strut is passed posterior to the sternum near the inferior portion so that the ends of the
struts rest on the ribs remaining in place laterally.
The Nuss procedure is shown in Figure 43.5.72 The chest is carefully inspected to identify the level of
maximal sternal depression. An anterior line is drawn traversing across the chest from the bi-midaxillary
lines crossing the point of depression. Additionally, the intercostal sites on the medial aspect of where the
depression begins are marked bilaterally as this is where the bar will enter the chest. Incisions are placed
on either side of the chest wall just anterior to the midaxillary line and bilateral subcutaneous tunnels are
made from the incisions on either side to the level of the previously marked intercostal sites. The
orientation of the incisions can either be transverse or oblique along the inframammary crease. Using the
inferior limit of the right lateral chest wall incision, a 5 mm thoracoscopic cannula is inserted into the
right chest, slightly anterior to the midaxillary line. Using thoracoscopic guidance, the pleural space is
entered and dissection behind the sternum is performed using an S-shaped instrument to develop a space
between the sternum and the pericardium. Dissection is continued using the tip of the instrument aiming in
the direction of the contralateral intercostal site. The instrument is carefully maneuvered to allow exit
through the left chest and out the left lateral chest incision. Techniques to elevate the sternum with a small
subxyphoid incision have been advocated. Once the instrument has exited the left chest incision, an
umbilical tape is attached to its tip and pulled through to the right chest. The pre-shaped bar is then passed
back through the chest behind the sternum so that it is projecting out of each side. This bar is then rotated
180 degrees, and in so doing, the sternum and anterior chest are popped into position. Stabilizers are used
to secure the bars laterally to the chest wall to prevent rotation/dislodgement of the bar. In some cases the
severe posterior angulation of the distal sternum dictates insertion of a second bar. In these cases,
stabilizers are paced on each bar but on opposite sides.
FIGURE 43.5 Nuss procedure. A: This is the preoperative appearance of the patient to undergo the Nuss procedure. It is a
symmetric deformity. B: An incision is made on each side of the chest. The preformed strut is protruding through the incisions
along with the S-shaped instrument. The strut is rotated 180 degrees using the tool that is seen attached to the right side of the
strut. This will evert the sternum and lower chest wall. C: Stabilizers are attached to the bar and then to the adjacent rib and/or
soft tissue. D: The final result chest radiograph.
All of these operations and modifications have similar postoperative management. Prophylactic
antibiotics are administered for 24 hours. Pain control is generally provided in the form of an epidural in
the first 24 to 48 hours followed by intravenous or oral narcotics depending upon the individual patient.
Drains may or may not be used. Thoracostomy tubes may or may not be used. The authors’ approach is to
employ epidural anesthesia for 48 hours followed by oral narcotics supplemented by patient-controlled
analgesia with intravenous morphine. Drains are not used.
Each procedure has its advantages and disadvantages. Patients should be informed and allowed to
participate in the decision-making process. Excellent results with minimal complications have been
achieved with both procedures with the rare exceptionally troublesome complication associated with the
Nuss procedure.
PECTUS CARINATUM
This deformity consists of anterior protrusion of the anterior chest wall, usually involving the lower half
of the sternum. The medial portions of the effected ribs protrude outwardly. There may be concavity of the
anterolateral chest wall on either side. There may be asymmetry. Within this general description pectus
carinatum has been subdivided into four anatomic types listed in Table 43.3.100 The most common of these
is the so-called chondrogladiolar. To look at these children, it appears as if the sides of the chest were
compressed inwardly forcing the anterior chest to bulge out forming a wedge or vaguely like the keel of a
boat (hence the term carinatum) (Fig. 43.6). The second and third types are effectively in the same
location, but rotated somewhat. The left parasternal area is more commonly the one bulging anteriorly.
The fourth type of pectus carinatum has been termed chondromanubrial deformity (Fig. 43.7). The lower
portion of the manubrium projects anteriorly and the lower sternum posteriorly, basically a combination
of pectus carinatum and excavatum. This is occasionally seen in Noonan syndrome.3
TABLE 43.3 Pectus Carinatum Classification

Chondrogladiolar
Unilateral asymmetric protrusion of the parasternal region
Unilateral asymmetric protrusion of the parasternal region with contralateral depression of the other side
Chondromanubrial
Etiology
As with pectus excavatum, the prevailing opinion about causation has to do with the relative overgrowth
of the costal cartilages resulting in the sternum bulging anteriorly. The relative symmetry or lack thereof
relates to unequal overgrowth of the ribs. There may be some genetic component as a positive family
history of chest wall deformities is noted in at least 25%. It is more common in boys than girls and is
associated with scoliosis and difference in the height of the shoulders. It is rarely noted soon after birth
but rather appears in the preteen years of childhood. It typically gets worse during periods of rapid
growth. The somewhat rare chondromanubrial variety, in contrast to the chondrogladiolar, appears soon
after birth. The sternum is typically very broad with early closure of the sternal growth plates.
Clinical presentation is primarily related to the appearance of the chest. The outward position of the
sternum may result in some pain. It is often difficult for these children to sleep prone and they may wake
up at night when rolling on to their stomach. Exercise intolerance is generally not associated with any
form of pectus carinatum. Conditions associated with pectus carinatum include any condition associated
with abnormal formation of bone, cartilage, or connective tissue such as Marfan syndrome, Loeys–Dietz
syndrome, and osteogenesis imperfecta.101,102 Some of the most severe sternal deformities are associated
with these conditions.
PATHOPHYSIOLOGY
This deformity does not create any substantial cardiopulmonary abnormality. Unlike pectus excavatum,
there is no compression of the anterior surface of the heart. Even the chondromanubrial form does not
have enough posterior deviation of the sternum to cause this. Likewise, pulmonary function tests are
generally normal.18 Given the relative absence of exercise-related symptoms, there is little enthusiasm for
researchers to pursue anything other than cursory evaluation of the cardiopulmonary function.
FIGURE 43.6 A: This is a typical appearance of a pectus carinatum. There is a bit of asymmetry. The lateral chest wall is
somewhat concave. B: This is the appearance of the chest 6 weeks following repair.
FIGURE 43.7 A: This is a patient with a chondromanubrial pectus carinatum. Note the anterior position of the upper sternum
and the posterior deviation of the lower sternum. B: This is the appearance of this same patient 6 weeks following repair.
TREATMENT
The indications for treatment depend entirely upon the degree to which the patient is troubled by the chest
wall appearance. This is not life threatening. The options are orthotic bracing and surgery.
Haje and Bowen introduced orthotic bracing as a legitimate form of therapy in 1992.103 Since then
many have reported their own institutional results using various braces which perform the same
underlying function—that is, to reshape the anterior chest wall to create a more symmetric, flat
appearance104–107 (Fig. 43.8). Most consider the upper age range to be 16 years for application of this
treatment. Although it works best on the symmetric form of chondrogladiolar pectus excavatum, it can also
be effective for the asymmetric varieties. The brace is fitted by a trained orthotist to provide appropriate
level of compression of the anterior protrusion with counterpressure on the back. The brace is to be worn
for nearly the entire day and it is therefore anticipated that a reddened area will appear over the skin of
the chest wall after removal of the brace. Most children can sleep without difficulty with the brace
applied. The total duration of therapy is between 1 and 2 years. When a reasonable flattening of the chest
has occurred the brace can be worn only during sleep during the maintenance phase. The most common
problem with this treatment is noncompliance which occurs in 10% to 33%. Nearly all compliant patients
will notice improvement. Recurrence or failure of therapy occurs in around 5%. Complications are rare
and mostly related to superficial skin problems which resolve with temporary discontinuation of the
brace. Pulmonary function tests are unaffected by this treatment.108 An attempt at providing objectivity to
the process of external bracing was presented by Martinez-Ferro. He evaluated the amount of pressure
required to compress the sternum to create a relatively flat chest. The stiffer the chest wall, the more
pressure required for correction. This then relates to both the pain associated with the brace and the
likelihood of compliance and ultimately of success. A brace was designed which allowed measurement of
the pressure applied.109
A variety of techniques have been employed to correct pectus carinatum. These include resection of a
portion or the entirety of the sternum,110 using the rectus muscle by transecting it and reattaching it to a
more cephalad portion of the sternum111,112 and finally subperichondrial resection of the abnormal costal
cartilages with an opening anterior transverse sternal osteotomy.113 Although metal struts have been
recommended in some repairs, these are generally not necessary.
A minimally invasive procedure has also been described. This involves placing a metal strut much as
it would be done with the Nuss procedure except that the strut goes anterior to the sternum to apply
continuous pressure to reshape the chest wall.114 This is essentially an “internal” version of external
bracing.
SURGICAL TECHNIQUE
The technique that the authors recommend and which is most commonly employed is an open repair using
modifications of the Ravitch and Welch procedures for pectus carinatum. The skin incision is as with the
excavatum repair. The effected costal cartilages are resected in a subperichondrial fashion. The xyphoid
process is removed as it often is angled posteriorly. This also allows easy access to the substernal region
to bluntly dissect it away from the mediastinum. A transverse anterior osteotomy of the sternum is
performed at the level at which the sternum angles anteriorly. A greenstick fracture of the posterior table
of the sternum is performed and the sternum is angled posteriorly as if on a hinge. The gap in the sternum
is filled with an appropriately shaped piece of one of the resected costal cartilages which is sutured into
position. The pectoral and rectus abdominis muscles are closed over the sternum, attaching the muscle to
the periosteum to help eliminate the potential space created. Some recommend the use of a metal strut
placed anterior to the sternum to hold it in place, much like the strut placed with repair of pectus
excavatum posterior to the sternum. We have not found this useful or necessary (Fig. 43.6). Although a
drain can be placed in the area between the muscular flap and the chest wall, we find that with good
hemostasis this is seldom necessary. Prophylactic antibiotic administration and pain control measures are
similar to the pectus excavatum repair, although in general, the pain following carinatum repair seems less
intense than with the excavatum repairs.
FIGURE 43.8 A and B: This patient is wearing a typical brace employed for orthotic treatment of pectus carinatum. There are
anterior and posterior pads to provide steady pressure on the sternum. C: This is a custom-made device for a patient with an
asymmetric carinatum deformity.
When asymmetry is present, it is necessary to rotate the sternum to attain an appropriate position. If the
asymmetry includes depression of the contralateral side of the chest, the use of a sternal strut is
recommended. For patients with the chondromanubrial type of pectus carinatum a more extensive repair is
necessary. Generally more ribs are resected (up to the second rib superiorly). Two sternal osteotomies
are necessary—one superiorly to account for the anterior protrusion of the upper sternum and one more
inferiorly to account for the posterior deviation of the lower sternum. These osteotomies are handled
according to the carinatum and excavatum techniques described previously. These allow alignment of the
upper and lower portions of the sternum. It is necessary to support the lower end with a metal strut (Fig.
43.7).
FIGURE 43.9 A: This patient has Poland syndrome. The breast on the right is completely absent along with most of the right
anterior chest wall musculature. B: This axial view of a CT scan of a patient with Poland syndrome shows absence of the
anterior chest wall musculature as well as some deficiency of underlying ribs.
The short- and long-term results with repair of pectus carinatum are very good.113 The hospital length
of stay is around 3 days and the complication rate is low, approximately 4%; pneumothorax accounts for
most of these and seldom requires thoracostomy tube. Recurrence is also quite uncommon, particularly
when operation is undertaken in children in their mid-teenage years. Caution should be exercised in
patients with congenital abnormalities of bone, cartilage, and connective tissue, however. In these
patients, permanent metal support to the chest wall should be considered.
POLAND SYNDROME
In 1841 the description of a patient with absence of the anterior chest wall muscles appeared in the
English medical literature.115 Alfred Poland was a medical student at Guy’s Hospital of London at the
time he submitted this for publication. The syndrome consists of variable absence of the structures of one
side of the chest wall (usually the right) accompanied by syndactyly on the same side. The syndrome
actually was described earlier by Froriep116 in the German literature, wherein he described a female with
absence of the breast, ribs three and four, the pectoralis major and minor muscles, and portions of the
serratus muscle. The name “Poland syndrome” stuck when Clarkson (also of Guy’s Hospital) applied the
term to his collection of similar patients in the same journal as Poland’s publication.117 Such is how
immortality is occasionally obtained. This syndrome is quite rare, occurring in approximately 1 in
30,000.118,119 The syndrome may consist of abnormalities of the breasts, hypoplasia of the sternal head of
the pectoralis major and minor muscles to complete absence of the anterior portions of the second to fifth
ribs and costal cartilages. Breast involvement is nearly universal ranging from hypoplasia to complete
absence of the breast and nipple (Fig. 43.9). A reasonable approach to categorizing this spectrum of
deformities is into simple and complex forms (Table 43.4). Although the chest deformities are troubling,
the associated upper extremity anomalies are more disabling. This occurs in approximately two-thirds of
all cases.120 The hand deformities include hypoplasia and fused fingers, usually involving the central
three digits (Fig. 43.10). It may also be associated with Mobius’ syndrome, which is bilateral or
unilateral facial palsy and abducens oculi palsy.121 The etiology of Poland syndrome is unknown. Some
have suggested that maternal smoking increases the likelihood twofold.122 It is estimated to be three times
as common in men than women, but women more commonly seek medical attention due to the breast
involvement.123
The indications for surgical correction depend upon the degree of chest wall involvement. In the
“simple” form where the chest wall deficiency consists of breast and pectoralis muscle involvement
alone surgical therapy is cosmetic and consists of placement of myocutaneous flaps, fat transfer, and
prosthetics. When there is absence of ribs a structural repair is required along with myocutaneous flaps,
and so on. In either case, in general it is recommended that repair be delayed until completion of growth.
The one exception to this recommendation is in the setting of lung herniation causing respiratory
embarrassment.124,125 Careful imaging with CT or MRI will provide details of the chest wall deficiency
as well as any coexisting deficiency of ipsilateral muscle that might be used for the repair. One should
exercise caution in using myocutaneous flaps involving the latissimus dorsi muscle as this will create
some degree of disability from the loss of function of this muscle.
TABLE 43.4 Poland Syndrome

Type Breast Muscle Chest Wall Arm
Simple Smaller Pect major/minor absent Chest hair absent Mild shortening
Nipple/areola displaced upward, lighter Serratus may be deficient Ribs intact Possible syndactyly
color
Complex Rudimentary or absent Pectoralis and serratus muscles Hemithorax Smaller
absent smaller
Ribs 2–6 absent Brachysyndactyly
FIGURE 43.10 This is a picture of the hand of the patient originally described by Poland. Despite the obvious weathered
appearance of the hand, there is obvious syndactyly involving the second and third digits.
STERNAL DEFECTS
These chest wall deformities are rare, but extraordinarily dramatic in presentation. They are the result of
failure of ventral fusion of the sternum. They can be roughly divided into four groups: cleft sternum,
thoracic ectopia cordis, thoracoabdominal ectopia cordis, and cervical ectopia cordis.
CLEFT STERNUM
The heart is generally structurally normal and in a normal position. The upper portions of the hemi-sternal
halves are not fused but the skin is intact over the chest wall. Rarely the cleft may involve the lower
sternum only with the manubrium intact.126 These children are functionally normal and rarely have any
other congenital anomalies with the possible exception of cervicofacial hemangiomas. The most common
clinical presentation is bulging of the skin with crying. This is often very dramatic, but seldom of clinical
significance. The repair can usually be accomplished with primary re-approximation of the sternal halves.
The flexibility of the infant sternum and chest wall allows for the ease of this without compression of the
lungs or heart. When there is wide separation of the sternum or in older infants and children where the
chest is not so flexible, sliding or relaxing lateral chondrotomies may be helpful in getting the sternum to
come together. Prosthetic mesh material or muscle flaps have also been used to fill in the defect. Another
technique described is to raise the periosteum off the sternal halves laterally to medially, flip it over, and
sew it together in the midline. This is then strengthened by placing chondral grafts in this bed.127 By far it
is simpler to repair this in infancy when primary repair is generally uncomplicated and prosthetic
material is unnecessary.
ECTOPIA CORDIS
This is literally translated to mean malposition or displacement of the heart. The term is an unusual
combination of Greek (ectopia) and Latin (cordis) that occasionally merge into an entity in medicine.
Although technically this could describe any malposition of the heart, the term is applied to cases where
some or all of the heart is outside the thoracic cage and may or may not be encased in skin. The heart is
covered by skin in around 20% of cases, the other 80% having some or all of the heart exposed by nothing
more than a very thin membrane. This is clearly one of the more dramatic events that can be noted in the
delivery room, that is, to have the naked beating heart exposed to all present. The etiology is unknown but
perhaps related to disruption of the amnion and possibly disruption of the chorionic layer or yolk sac.128
The timing of this event is around the third or fourth week of gestation, corresponding to the time of
cardiac chamber formation, perhaps accounting for the high incidence of cardiac malformations
associated with this. The diagnosis is easily made prenatally by ultrasound. There are three forms, as
mentioned above.
THORACIC ECTOPIA CORDIS

These infants are severely deficient in midline tissues that would ordinarily cover the heart. The
pericardium is absent as well. The heart is rotated around anteriorly. Congenital cardiac anomalies are
present in the vast majority with tetralogy of Fallot being the most common, although many others also
occur (Table 43.5). An abdominal defect is often present. As a consequence of the external location of the
heart or a portion thereof during prenatal development, the total intrathoracic volume is reduced.129 For
that reason, simple reduction of the heart and primary closure of the skin defect almost always result in
failure due to compression of the heart and impairment of venous return. The overall plan is to stabilize
these patients, cover the heart, recreate a thoracic cage to encase the heart, and finally repair the cardiac
defect itself. This may occur over many stages.130,131 The first component of therapy is to cover the heart
with moist, sterile gauze sponges and then proceed soon after birth with a more definitive coverage.
Polytetrafluoroethylene (PTFE) material is suitable for a fascial substitute although there is risk of
erosion and exposure of this. On some occasions it may be possible to mobilize skin flaps sufficiently to
close over the PTFE patch. Split thickness skin graft or cadaveric skin graft can be used if necessary.
Otherwise, more complex myocutaneous flaps may be necessary.132 Rib cartilage grafts may be necessary
to recreate the deficient bony thoracic cage. The timing of the cardiac repair depends upon the specific
anomaly and the clinical presentation. In reality, the mortality is extremely high for these infants.
However, there are isolated case reports of successful treatment, even in a single stage.133
TABLE 43.5 Congenital Cardiac Lesions Associated With Ectopia Cordis
Thoracic (N = 58) Thoracoabdominal (N = 100)
Tetralogy of Fallot 13 13
Diverticulum of left ventricle 0 29
With tetralogy of Fallot 1
With VSD ± ASD 13
TGA with pulmonary stenosis or atresia or VSD 5 4
Patent ductus arteriosus 6 0
VSD ± ASD 13 14
VSD with pulmonary stenosis 0 2
Truncus arteriosus 3 4
Coarctation of the aorta ± ASD 3 0
Single ventricular anomalies 6 8
Cor biloculare 3 4
Cor triatriatum 2 0
Double-outlet left ventricle 2 2
Double-outlet right ventricle 1 2
Aortic stenosis, VSD 0 1
Eisenmenger complex 0 1
Aberrant right subclavian artery 1 0
Bilateral superior venae cavae 1 1
Normal 2 4
ASD, atrial septal defect; TGA, transposition of the great arteries; VSD, ventricular septal defect.
THORACOABDOMINAL ECTOPIA CORDIS

There are four differences between this and thoracic ectopia cordis: (1) the heart is covered by a thin
membrane, (2) the heart is not rotated anteriorly, (3) there is a large abdominal wall defect, and (4) there
is a diaphragm defect. This “thin membrane” covering the heart is probably pigmented skin, but is so thin
as to be transparent. The pentalogy of Cantrell is lumped in with this and is a constellation of five
congenital anomalies: (1) deficiency of the anterior diaphragm, (2) midline upper abdominal wall defect,
(3) a defect in the anterior pericardium, (4) congenital cardiac malformation, and (5) a defect in the lower
sternum. The abdominal wall defect is usually an omphalocele; other types include gastroschisis,
diastasis recti, or a ventral hernia. As with thoracic ectopia cordis, associated cardiac anomalies are
common and similar. However, there is an unusually high incidence of left ventricular diverticulum (Table
43.5). In many cases this is the only portion of the heart that is external. The importance of the
diverticulum to the overall ventricular size and function is unclear. There is a temptation to simply excise
this and cover the remaining exposed heart with skin flaps. Unfortunately this diverticulum is important to
the circulation on occasion. Therefore, one should be very cautious about this approach. Occasionally, the
heart can be located entirely within the abdominal cavity with the great vessels penetrating through the
diaphragm to reach the appropriate destinations.
Successful repair and long-term survival are more commonly achieved in thoracoabdominal ectopia
cordis than in thoracic ectopia cordis. As with thoracic ectopia cordis, the repair must first focus on
closure of the skin defects over the heart and abdominal cavity and consists of repair of the omphalocele
and the diaphragmatic defect and coverage of the heart. Repair of the congenital cardiac lesion is
generally undertaken at a separate time although there are successful case reports of single stage repair of
the congenital cardiac defect with repair of the chest and abdominal wall defects.134,135
Cervical Ectopia Cordis

This is the most rare of the types of ectopia cordis, occurring in perhaps 3% of all cases. It may occur
with a completely intact sternum and skin. This is almost universally fatal.
ASPHYXIATING THORACIC DYSTROPHY (JEUNE SYNDROME)

In 1954 Jeune et al. published a case report of a newborn with a narrow, rigid chest with multiple
cartilage anomalies. This infant died soon after birth due to respiratory insufficiency.136 The most
prominent feature is a narrow, bell-shaped thorax and protuberant abdomen. The chest is narrow in both
the transverse and sagittal planes. The ribs are short, wide, and oriented in a more horizontal plane, rather
than the typical oblique position (Fig. 43.11). This presumably limits the motion of the ribs with
respiration. Microscopic examination of the costochondral junction demonstrates disordered and poorly
progressing endochondral ossification, resulting in decreased rib length. Other skeletal involvement is
common and includes short extremities, elevated clavicles in a fixed position, and small pelvis with
hypoplastic square iliac bones. The primary issue is poor lung growth137 with restrictive chest wall
motion resulting in pulmonary impairment. Most infants die early as described by Jeune; however, others
have shown that longer term survival is possible.138 It is inherited as an autosomal recessive pattern and
is associated with a specific gene mutation on chromosome 7.139
FIGURE 43.11 This is a classic chest x-ray appearance of a patient with Jeune syndrome. Note the very horizontal orientation
of the very wide ribs and the long narrow thorax.
FIGURE 43.12 The patient depicted in these chest films has Jarcho–Levin syndrome. The vertebral bodies are very abnormal
with almost no intervertebral spaces. The ribs are very close to one another and the lung volumes are obviously quite small.
Surgery has recently been advocated for those more severely affected individuals who have survived
infancy. The overall goal with these procedures is to expand the thoracic cavity and allow for adequate
lung expansion. The techniques employed include sternotomy with separation of the sternal halves,140
lateral thoracic expansion,141 and vertical expandable titanium rib (VEPTR) procedure.142,143 Although
there have been some survivors of these procedures, the mortality remains high. The expansion of the
chest does not account for the lack of sufficient lung buds, which is an underlying problem with these
patients, but may allow for palliation until further growth occurs. Most of the infants undergoing
successful operation have survived early infancy already; thus these series are a somewhat select group of
patients. Nonetheless, operative intervention does provide some hope for improved life expectancy and
quality of life.
FIGURE 43.13 This patient with congenital scoliosis along with Jarcho–Levin was treated with VEPTR in an effort to
straighten the spine, expand the intercostal spaces, and thereby increase the thoracic cavity.
As mentioned above, there is an “acquired” form of asphyxiating thoracic dystrophy related to early
and extensive pectus excavatum repair using the Ravitch technique. This is usually associated with some
degree of recurrence of the deformity in addition to a restrictive chest. Operations to correct this include
redoing the original pectus repair with overcorrection using an anteriorly angled modified splint.88
Another procedure advocated is similar to that described for congenital Jeune syndrome. A median
sternotomy is performed with placement of multiple rib grafts between the sternal halves to separate them
and increase the overall chest diameter.144,145
JARCHO–LEVIN SYNDROME
This anomaly was first described by Jarcho and Levin in 1938 and consists of multiple alternating
hemivertebrae that are very small and near to one another in most or the entire thoracic and lumbar
spine.146 The ribs of necessity are very close to one another and the rib spaces are very small (Fig.
43.12). The lungs do not develop appropriately resulting in a restrictive chest wall deformity and small
lungs. This is inherited as an autosomal recessive disorder with evidence of a mutation in gene MESP2 on
chromosome 15. The disorder is more common in people of Puerto Rican descent.147 This rare disorder
has been classified into two subtypes—spondylothoracic dysostosis (STD) and spondylocostal dysostosis
(SCD).148 Those with STD have vertebral anomalies and severely deformed and fused ribs. They have a
worse prognosis due to a more restrictive chest than those with the SCD variety where there are varied
patterns of rib hypoplasia and vertebral anomalies. In children surviving through infancy the calculated
lung volume by CT scan is around 28% of normal.149 Many of these children not surviving through infancy
likely have even smaller lung capacity. Efforts to treat this have generally involved using VEPTR devices,
although this is considered somewhat controversial142 (Fig. 43.13). These devices allow for periodic
expansion to allow for growth.
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44
Hernias of the Chest Wall
Nigel E. Drury ■ Pala Babu Rajesh
First described by Roland in 14991 and classified by Morel-Lavallée in 1845,2 lung herniation is defined
as displacement of lung parenchyma outside the thoracic cavity through a defect in the chest wall,
diaphragm, mediastinum, or thoracic outlet.3 In the literature, there have been fewer than 400 reported
cases of chest wall hernias, the majority of which concern herniation through an intercostal space. The
current classification divides lung hernias according to their etiology into congenital or acquired, with the
latter comprising traumatic, spontaneous, or pathologic herniation (Table 44.1). Of the acquired hernias,
those secondary to blunt chest trauma are now the most common.
ETIOLOGY OF LUNG HERNIATION
CONGENITAL HERNIAS
Congenital hernias of the chest wall are rare with knowledge limited to case reports and small series.4
They are found either at the thoracic inlet or, less frequently, through an intercostal space. Supraclavicular
herniation results from attenuation or absence of the conical fibrous dome of endothoracic fascia as it
blends with the deep cervical fascia (Sibson fascia).3 The herniated lung passes into the neck between the
scalene and sternocleidomastoid muscles. On the other hand, congenital intercostal lung herniation may
occur either anteriorly, at one of the costochondral junctions, or laterally due to the lack of development
of an intercostal muscle in combination with weakness of the endothoracic fascia.
TRAUMATIC HERNIAS
Blunt Trauma
Nonpenetrating injuries to the thoracic cage may result in multiple rib fractures with interruption of the
endothoracic fascia, intercostal muscles, and costal cartilages to produce a defect through which acute or
chronic lung herniation may occur. The major cause of traumatic lung herniation today is a compression
injury sustained during a motor vehicle crash, particularly in those passengers restrained by a 3-point
shoulder harness.5 This common etiology has led it to be included as a potential component of the
“seatbelt syndrome.”6 The shoulder strap passes diagonally across the chest in either direction, depending
on the occupant’s position within the vehicle. Injuries occur along the path of the strap and chest wall
hernias are most commonly parasternal, through a defect can be created by costochondral separation at
multiple levels (Fig. 44.1).6,7 Associated injuries include fractures of the sternum, clavicle, and ribs
including such complications as a flail segment, pneumothorax, pulmonary contusion, lung laceration, and
hepatosplenic injury.8 The elderly are at increased risk of chest wall injury and its complications due to
their diminished muscle mass, reduced chest wall compliance, limited cardiopulmonary reserve,
osteopenia, and other comorbidities.9 However, the introduction of advanced safety features such as
collision airbags and restraints that regulate energy transmission to the occupant, through pretensioners
and load-limiters,10 are likely to reduce the overall incidence of chest wall injuries. Rear seat passengers
and those in older vehicles will lack these modern features and remain at greater risk.
TABLE 44.1 Classification of Lung Hernias of the Chest Wall

Congenital
Supraclavicular
Intercostal
Acquired
Traumatic
Blunt trauma
Penetrating trauma
Spontaneous
Pathologic
Modified from Morel-Lavallée A. Hernie du poumon. Bull Soc Chir Paris 1845–1847;1:75–195.
FIGURE 44.1 CT of the chest showing right parasternal lung herniation, rib fracture, and hemothorax related to seat belt
restraint in a high-speed motor vehicle crash. (Reprinted from Rice D, Bikkasani N, Espada R, et al. Seat belt-related
chondrosternal disruption with lung herniation. Ann Thorac Surg 2002;73:1950–1951. Copyright © 2002 The Society of Thoracic
Surgeons. With permission.)
Penetrating Trauma
Intercostal hernias may develop at the site of stab or gunshot wounds to the chest but more often result
from surgical incisions with a thoracotomy or thoracoscopy. Overall, postoperative lung herniation occurs
in a tiny percentage of patients who undergo a thoracic surgical incision and results from failure to
adequately close the incision with secure approximation of the ribs to seal off the intercostal space.4
When this is not achieved, or when the closure breaks down due to infection, delayed wound healing or
pericostal suture rupture, the lung may herniate through the resulting defect (Fig. 44.2).11 In the largest
reported experience of chest wall hernias, Seder and colleagues12 at the Mayo Clinic identified obesity,
chronic obstructive pulmonary disease (COPD), oral steroid use, and diabetes mellitus as potential risk
factors for poor tissue healing leading to postthoracotomy dehiscence and herniation through the chest
wall. Early or late failure of primary chest wall surgery may result in chronic hernia development, such as
following chest wall reconstruction or correction of pectus excavatum.13
Counterintuitively, herniation is more common after thoracoscopy14,15 or mini-thoracotomy16 rather
than formal posterolateral thoracotomy, perhaps due to less meticulous closure of the defect (Fig. 44.3).4
Several groups have reported lung hernias occurring after an anterior mini-thoracotomy for minimally
invasive cardiac surgery17,18 with left internal mammary artery (LIMA) harvesting predisposing to local
ischemia and poor wound healing19 and fracture or avulsion of the costal cartilages resulting in chest wall
instability.20 In addition, lung herniation has also been reported in a patient with a chronic cough
following LIMA harvest via a sternotomy due to intercostal muscle weakness, atrophy, and delayed
rupture.21
FIGURE 44.2 CT of the chest demonstrating lung parenchyma protruding through a defect in the anterior chest wall following
anterior thoracotomy. (From Athanassiadi K, Bagaev E, Simon A, et al. Lung herniation: a rare complication of minimally
invasive cardiothoracic surgery. Eur J Cardiothorac Surg 2008;33:774–776. Reproduced by permission of European
Association for Cardiothoracic Surgery.)
FIGURE 44.3 CT of the chest revealing herniation of the lingula through a chest wall defect at the site of a previous
thoracoscopy port. (Reprinted from Temes RT, Talbot WA, Green DP, et al. Herniation of the lung after video-assisted thoracic
surgery. Ann Thorac Surg 2001;72:606–607. Copyright © 2001 The Society of Thoracic Surgeons. With permission.)
SPONTANEOUS HERNIAS
A spontaneous lung hernia occurs at a site of localized weakness in the thoracic cage without an
antecedent injury and is prompted by a sudden rise in intrathoracic pressure such as coughing, sneezing,
singing, heavy lifting, or blowing into a musical instrument.3,22 These hernias almost invariably occurring
anteriorly, medial to the costochondral junction where there is only a single layer of intercostal muscle,
most commonly involve the lower rib cage and are usually associated with a fracture of the rib or
cartilage.22,23 In their review of the literature, Brock and Heitmiller found that spontaneous anterior lung
hernias occur with equal frequency on both sides of the chest and seem to follow an episode of coughing,
sneezing, or abnormal motion. Patients described in the literature are exclusively male, usually older
smokers with a history of underlying pulmonary disease and may be obese.22 Weissberg and Refaely4
reported one case of a spontaneous supraclavicular lung hernia in a middle-aged woman with COPD but
it is unknown whether this was a truly spontaneous hernia or the late presentation of a congenital hernia.
PATHOLOGIC HERNIAS
Any condition that results in destruction of a localized area of the chest wall may lead to subsequent lung
herniation. Munnell3 described a number of such pathologies including abscess of the chest wall or
breast, empyema necessitatis, primary or secondary malignant tumors invading the chest wall, and
tuberculosis osteitis. However, these conditions are commonly treated with surgery or radiotherapy early
in the disease process such that progression to chest wall destruction and herniation is mostly limited to
geographic areas where access to healthcare is inadequate.
CLINICAL PRESENTATION AND MANAGEMENT
The presentation of lung hernias of the chest wall is variable, often according to the etiology, from the
acute onset of severe symptoms to a late presentation many years after an initial injury. Some congenital
hernias may actually present for the first time in adulthood.4 The diagnosis can often be made on the
history and physical examination alone although imaging is essential for preoperative confirmation and
surgical assessment.
SYMPTOMS AND SIGNS

Clinically, lung herniation may or may not be symptomatic but most often presents as a tender,
subcutaneous soft tissue mass that enlarges when intrathoracic pressure is raised. Symptoms include pain
and/or tenderness (50% to 85% of cases), dyspnea, cough, and an intermittent bulging at the site of
herniation.4,12 The onset may be insidious or it may immediately follow an acute episode of coughing,
sneezing, or constipation.22 Although lung incarceration is very uncommon, when it occurs it typically
presents with severe pain and respiratory compromise.24 Patients may have a recent or past history of
trauma or previous thoracic surgery, chronic lung disease, obesity, diabetes mellitus, smoking, steroid
use, chronic infection, or malignancy.3,12 Rare patients will have no identifiable comorbidities. Unusual
symptoms include dysphagia or neuralgic arm pain due to nerve root compression with supraclavicular
herniation.25
Signs of chest wall herniation include bulging on coughing or straining, often with an impulse or a
palpable defect in the thoracic cage (Fig. 44.4). The presence of an overlying thoracic surgical scar may
also provide a clue to the underlying diagnosis. Following recent or acute trauma, there may be localizing
signs of injury including the thoracic “seatbelt sign,” a linear ecchymosis of the skin across the chest in
the line of a restraint.6 There may be an associated ipsilateral pneumothorax, surgical subcutaneous
emphysema, hemothorax, or pleural effusion resulting in reduced air entry on auscultation.
FIGURE 44.4 Bulging of the chest wall resulting from an underlying lung hernia following removal of a pleural drain for the
treatment of empyema. (Reprinted from Weissberg D, Refaely Y. Hernia of the lung. Ann Thorac Surg 2002;74:1963–1966.
FIGURE 44.5 Coronal CT reconstruction demonstrating traumatic right lung herniation. (Reprinted from Wiens S, Hunt I,
Mahood J, et al. Novel fixation technique for the surgical repair of lung hernias. Ann Thorac Surg 2009;88:1034–1035.
INVESTIGATIONS
The diagnosis of a chest wall hernia should be confirmed by radiologic examination. Standard and
oblique plain radiographs remain valuable to identify separation of the ribs during postoperative follow-
up.11 However, computed tomography (CT) is the investigation of choice: rapid image acquisition while
the patient performs a Valsalva maneuver is considered the gold standard.14 Herniation is diagnosed by
the presence of a portion of the lung parenchyma protruding beyond the thoracic cage through a defect. CT
provides valuable information for operative planning, particularly with multiplanar image reconstructions
(Fig. 44.5), to delineate the size and location of the chest wall defect, the extent of lung herniation, the
presence of associated injuries, and exclude possible complications such as strangulation. Other
modalities such as fluoroscopy and ultrasound can also be used to diagnose lung herniation; the latter may
be particularly useful in the emergency room when a patient with major chest trauma is too unstable to be
transported to the CT scanner.26
TREATMENT
Management of a lung hernia is determined by symptoms, location, and size. Asymptomatic hernias,
particularly supraclavicular hernias in the thoracic inlet, require no intervention. Pain, increasing size,
and signs of impending incarceration, such as difficulty in reducing the hernia, are the main indications for
surgery.4 The risk of incarceration is increased in small, rigid defects and should prompt early
intervention. Surgery for cosmesis may also be justified.
FIGURE 44.6 Intraoperative photographs of the identification of the chest wall defect (A) shown in Figure 44.2, and fixation of
a Vicryl patch to the rib margins with interrupted sutures (B). (From Athanassiadi K, Bagaev E, Simon A, et al. Lung herniation:
a rare complication of minimally invasive cardiothoracic surgery. Eur J Cardiothorac Surg 2008;33:774–776. Reproduced by
permission of European Association for Cardiothoracic Surgery.)
Most supraclavicular lung hernias remain asymptomatic but occasionally, symptoms may occur and
repair should be performed. A transthoracic approach is preferred as the risk of recurrence is lower than
with a transcervical approach27 and may be amenable to thoracoscopic repair.28 If the endothoracic
(Sibson) fascia is intact, a hernia sac is present which must be dissected free prior to repair of the defect;
if not, only closure of the defect after reduction of the hernia is indicated. Both direct suture repair28 and
bovine pericardium patch reinforced with biologic glue have been reported.25
In contrast, repair is indicated in almost all intercostal lung hernias, including congenital hernias that
present during adulthood.4 Conservative management should only be considered in patients with chronic
herniation and multiple comorbidities, including advanced lung disease and morbid obesity, or who
decline surgery. A binder may provide symptomatic relief but most will continue to enlarge over time and
should remain under clinical and radiographic follow-up.
Many techniques have been described for the repair of chest wall hernias, using open,3
thoracoscopic,29 or a combination of both approaches.30 At initial assessment, the portion of herniated
lung parenchyma should be inspected to identify whether it has been strangulated and become necrotic; if
nonviable, the affected tissue should be resected as a wedge using a stapler device. Small chest wall
defects can usually be closed by direct suture and fixation of the adjacent ribs with pericostal or
intracostal sutures.4,11 Larger defects require the use of autologous tissue or synthetic mesh to close the
hernia orifice. Munnell3 advocated the use of musculofascial tissue flaps developed from the intercostal
neurovascular bundle, perhaps with elevation of periosteal flaps or even mobilization of adjacent ribs.
While this approach has the advantage of avoiding foreign material and potentially reducing the risk of
infection, often the surrounding tissues have also been traumatized and may be of insufficient quality or
mobility to aid repair. Current practice in chest wall hernia repair, as in abdominal hernia surgery, often
includes the use of a synthetic mesh, bridging the intercostal space and fixed around the margin of the
defect (Fig. 44.6).31 A variety of materials have been reported including high density polyethylene
(Marlex), polyglactin (Vicryl), polypropylene (Prolene), polyethylene terephthalate (Dacron),
polytetrafluoroethylene (PTFE, Teflon), and expanded PTFE (Gore-Tex). Composite materials have also
been used such as a sandwich of Marlex mesh filled with methyl methacrylate cement.19 During wound
closure, muscle and subcutaneous tissue may need to be mobilized over the mesh to provide protection for
the repair. In their series, Seder and colleagues12 performed primary repair in 18 patients and prosthetic
mesh repair in 9 patients, finding no difference in perioperative complications between groups. Indeed, as
the mesh leads to the formation of a fibrous capsule, if it were to become infected and require late
removal, the remaining capsule would usually be sufficient to prevent recurrence of the hernia. More
recently, extracellular matrix patches have been used to repair chest wall defects including hernias; these
provide a scaffold for infiltration by recipient cells, leading to incorporation within the repair.32 Other
techniques have been reported, including the use of stainless steel wires6 or titanium bars, plates, and
screws33,34 but the advantages of rigid fixation over flexible mesh repair is not established and the use of
such devices is likely to be more expensive than simpler alternatives.12
In summary, hernias of the chest wall are classified according to etiology into congenital, traumatic,
spontaneous, and pathologic. Pain is the prevailing symptom and should precipitate surgical repair, most
commonly using a synthetic mesh.
ACKNOWLEDGMENT
We thank the late Thomas W. Shields whose chapter on lung hernias in the 7th edition of his book formed
the basis of this chapter.
REFERENCES
1. Roland. De pulmonis sanarpot, Liber III (cap) XXV. In: de Chavliae G. Cyrurgia. 1499:144.
2. Morel-Lavallée A. Hernie du poumon. Bull Soc Chir Paris 1845–1847;1:75–195.
3. Munnell ER. Herniation of the lung. Ann Thorac Surg 1968;5:204–212.
4. Weissberg D, Refaely Y. Hernia of the lung. Ann Thorac Surg 2002;74:1963–1966.
5. Kiraly L, Schreiber M. Management of the crushed chest. Crit Care Med 2010;38(Suppl):S469–S477.
6. May AK, Chan B, Daniel T, et al. Anterior lung herniation: another aspect of the seatbelt syndrome. J Trauma 1995;38:587–589.
7. Rice D, Bikkasani N, Espada R, et al. Seat belt-related chondrosternal disruption with lung herniation. Ann Thorac Surg 2002;73:1950–
1951.
8. Arajärvi E, Santavirta S. Chest injuries sustained in severe traffic accidents by seatbelt wearers. J Trauma 1989;29:37–41.
9. Martinez R, Sharieff G, Hooper J. Three-point restraints as a risk factor for chest injury in the elderly. J Trauma 1994;37:980–984.
10. Walz M. NCAP test improvements with pretensioners and load limiters. Traffic Inj Prev 2004;5:18–25.
11. Sanders LH, Newman MA. Use of intracostal sutures reduces thoracotomy pain with possible risk of lung hernia: another measure for
prevention of pain. Ann Thorac Surg 2005;79:750; author reply 750.
12. Seder CW, Allen MS, Nichols FC, et al. Primary and prosthetic repair of acquired chest wall hernias: a 20-year experience. Ann
Thorac Surg 2014;98:484–489.
13. Jaroszewski D, Johnson K, Lackey J, et al. Complex repair of pectus excavatum recurrence and massive chest wall defect and lung
herniation after prior open repair. Ann Thorac Surg 2013;96:e29–e31.
14. Hauser M, Weder W, Largiadèr F, et al. Lung herniation through a postthoracotomy chest wall defect. Demonstration with spiral CT.
Chest 1997;112:558–560.
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607.
16. Athanassiadi K, Bagaev E, Simon A, et al. Lung herniation: a rare complication in minimally invasive cardiothoracic surgery. Eur J
17. Bhamidipati CM, Iyalla KI, Seymour KA, et al. Lung hernia following robotic-assisted mitral valve repair. J Card Surg 2012;27:460–
463.
18. Gouda H, Multz AS, Khan A, et al. Lung hernia as a sequela to limited-access mitral valve surgery. Tex Heart Inst J 2002;29:203–205.
19. Deeik RK, Memon MA, Sugimoto JT. Lung herniation secondary to minimally invasive direct coronary artery bypass grafting. Ann
Thorac Surg 1998;65:1772–1774.
20. Ng PC, Chua AN, Swanson MS, et al. Anterior thoracotomy wound complications in minimally invasive direct coronary artery bypass.
Ann Thorac Surg 2000;69:1338–1341.
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1995;59:1579–1580.
22. Brock MV, Heitmiller RF. Spontaneous anterior thoracic lung hernias. J Thorac Cardiovasc Surg 2000;119:1046–1047.
23. Montgomery JG, Lutz H. Hernia of the lung. Ann Surg 1925;82:220–231.
24. Sloth-Nielsen J, Jurik AG. Spontaneous intercostal pulmonary hernia with subsegmental incarceration. Eur J Cardiothorac Surg
1989;3:562–564.
25. Rahman M, Buchan KG, Mandana KM, et al. Bilateral cervical lung hernia with T1 nerve compression. Ann Thorac Surg
2006;81:716–718.
26. Marlow S, Campbell T, Davis A, et al. Emergency ultrasound in the diagnosis of traumatic extrathoracic lung herniation. Am J Emerg
Med 2013;31:633.e1–633.e2.
27. Victor S, Muthurajan S, Sekhar TG, et al. Giant cervical herniation of an apical pulmonary bulla. J Thorac Cardiovasc Surg
1987;93:141–142.
28. Jheon S, Lee EB, Cho JY, et al. Thoracoscopic repair of cervical lung hernia. J Thorac Cardiovasc Surg 2002;124:1030–1031.
29. Reardon MJ, Fabré J, Reardon PR, et al. Video-assisted repair of a traumatic intercostal pulmonary hernia. Ann Thorac Surg
1998;65:1155–1157.
30. Khalil MW, Masala N, Waller DA, et al. Surgical repair of post-traumatic lung hernia using a video-assisted open technique. Interact
31. Szentkereszty Z, Boros M, Sápy P, et al. Surgical treatment of intercostal hernia with implantation of polypropylene mesh. Hernia
2006;10:354–356.
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chest wall reconstruction in thoracic surgery. Interact Cardiovasc Thorac Surg 2014;18:335–339.
33. Wiens S, Hunt I, Mahood J, et al. Novel fixation technique for the surgical repair of lung hernias. Ann Thorac Surg 2009;88:1034–1035.
34. Billè A, Okiror L, Karenovics W, et al. Experience with titanium devices for rib fixation and coverage of chest wall defects. Interact
45
Infections of the Chest Wall
Edward J. Bergeron ■ Robert A. Meguid ■ John D. Mitchell
INTRODUCTION
Chest wall infections necessitating surgical consultation are relatively rare. They may result from direct
inoculation of the chest wall or, secondarily, as a result of contiguous spread from infected tissue,
hematogenous spread, previous chest wall trauma, or instrumentation. Chest wall infections may occur in
soft tissue, cartilage, and bone. Infectious pathogens may be bacterial, fungal, or viral. Common pathogens
responsible for chest wall infections are presented in Table 45.1. Chest wall infections may or may not be
necrotizing. Diagnosis of chest wall infections can be difficult due to subtle, nonspecific signs, symptoms,
and presentations, and due to their clinical rarity. They may present as a discrete mass, superficial
infection, or draining sinus. Effective management of chest wall infections ranges from antibiotic
administration to wide surgical resection of all devitalized tissue and subsequent coverage with well-
vascularized soft tissue. This depends upon the type, magnitude, and location of the infection. Prompt
timing in diagnosis and treatment is important to minimize associated morbidity. The authors present a
systematic review of these infections, and their associated workup and management.
NECROTIZING CHEST WALL INFECTIONS

Necrotizing chest wall infections are typically aggressive infections warranting early antibiotic therapy
and aggressive surgical debridement. The majority of these infections, typified by extensive tissue
necrosis and associated gas production, occur postoperatively or subsequent to chest wall trauma.
Occurrence of necrotizing chest wall infections has been reported following tube thoracostomy for the
drainage of empyema, surgical treatment of Boerhaave syndrome with pleural contamination, and gastric
herniation following laparoscopic fundoplication.1 Common organisms responsible for necrotizing chest
wall infections are included in Table 45.1. The overall mortality has been reported to be as high as 73%.2
Necrotizing infections can violate tissue planes as they are not contained by the usual host defense
mechanisms. This subset of infections is more frequently encountered and considered serious when they
involve the abdomen, perineum, and lower extremities. However, necrotizing infections can occur
anywhere on or in the body, including the chest. Necrotizing chest wall infections have the unique
potential of extension into the pleural space. This can lead to impairment of respiratory mechanics,
resulting in an associated mortality of 59% to 89%, which is approximately double that of necrotizing soft
tissue infections occurring in other anatomic locations.3–5
Immunocompromised patients, including diabetics, have the highest incidence of necrotizing infections.
Presentation is commonly “pain out of proportion” to the wound’s bedside appearance. Physical
examination may demonstrate skin erythema, blistering, crepitus, swelling, and induration, and may be
accompanied by watery exudate. If the infection has spread systemically, fever, chills, hypotension,
tachycardia, and changes in mental status may be observed. Prompt recognition and subsequent treatment
is essential to prevent patient demise.
Necrotizing chest wall infections can be caused by single organisms, such as Streptococcus or
Clostridium perfringens species. However, single organism infections make up the minority of
necrotizing chest wall infections. Polymicrobial infections consisting of both aerobic and anaerobic
bacteria are more common and account for approximately two-thirds of reported cases.6 These bacteria
interact synergistically to create fulminant infection and necrosis. Most reported cases spread along tissue
planes from adjacent regions, including the abdominal wall, neck, and extremities.
TABLE 45.1 Common Pathogens Responsible for Chest Wall Infections

Necrotizing Bacterial Chest Wall Nonnecrotizing Bacterial Chest Wall Fungal Parasitic Infections
Infections Infections Infections
Bacteroides spp. Actinomyces spp. Aspergiullus Cordylobia
spp. anthropophaga
Clostridium spp. Brucella spp. Mucor spp. Echinococcus spp.
Enterobacteriacae family Haemophilus influenzae Phycomyces Leishmania spp.
spp.
Fusobacterium spp. Mycobacerium spp. Rhizopus spp.
Peptostreptococcus spp. Propionibacterium spp.
Staphylococcus aureus Pseudomonas aeruginosa
Staphylococcus epidermidis
Streptococcus pyogenes
FIGURE 45.1 Chest wall infection with gas formation involving the soft tissue surrounding the right fourth and fifth ribs and the
cartilage, and adjacent empyema, in a 68-year-old diabetic man whose chest wall was inoculated while gardening. Note the gas
bubbles, complex fluid collection, soft tissue swelling and extension into the right pleural space. This was treated with serial wide
debridement, and pectoralis major advancement flap with subsequent skin grafting.
Chest radiographs of necrotizing soft tissue infections of the chest may reveal subcutaneous
emphysema, but more commonly will appear normal. Noncontrast computed tomography (CT) imaging is
useful for delineating associated subcutaneous gas and fluid collections, and ruling out pleural cavity
involvement (Fig. 45.1). T2-weighted magnetic resonance imaging (MRI) may demonstrate edematous
soft tissue or fluid collections associated with the infection. Clinical suspicion for necrotizing soft tissue
infections of the chest wall should be heightened on the basis of presenting symptoms and physical
examination. Management should not be delayed due to unimpressive findings on radiographic imaging.
Crepitant anaerobic cellulitis typically presents with skin erythema, blistering, crepitus, and can
progress to rapid clinical deterioration into septic systemic shock. Crepitus, in particular, is associated
with anaerobic infections, including Bacteroides and Peptostreptococcus. Infections will present with
abundant gas in infected, poorly vascularized tissues. Patients will commonly complain of severe pain
with minimal movement or manipulation, helping to distinguish this necrotizing cellulitis from necrotizing
fasciitis. Treatment mandates appropriate systemic antibiotic administration and, often, surgical
debridement.
Necrotizing chest wall cellulitis in immunocompromised patients may be caused by fungal infections.
Specifically, Aspergillus species and Phycomyces may result in invasion of blood vessels, with
subsequent vessel thrombosis. Treatment should be administered in the same manner as that for
necrotizing bacterial infections, including wide resection to viable tissue and the use of appropriate
antifungal agents, typically azole-based therapy (i.e., itraconazole, voriconazole) or amphotericin B,
depending on severity.
Myonecrosis is typically a mix of aerobic and anaerobic infections. It may involve a Clostridial
species. Although it is classically found in the lower extremities and perirectal areas, it has been reported
to occur in the chest wall.7
Necrotizing fasciitis of the chest wall is infrequent, but often lethal. Necrosis associated with the
infection involves both the superficial and deep fascia. Thrombosis of the associated blood vessels may
also be present. Systemic toxicity may be present and mandates prompt resuscitation, antibiotic
administration, and aggressive surgical debridement.
All necrotizing soft tissue infections warrant similar, aggressive therapy regardless of location. Early
administration of broad-spectrum systemic antibiotics, aggressive surgical debridement to viable tissue,
and goal-directed resuscitation, often requiring invasive hemodynamic monitoring to maintain end-organ
perfusion, should be anticipated. Regular operative debridement, occurring at daily to every other day
intervals, is often required to obtain infectious source control. Frozen pathologic examination can confirm
resection beyond necrosis to uninvolved tissue.
Following complete debridement of all devitalized tissue and when the patient has become
hemodynamically stable, reconstruction of the chest wall may be required. The defects created by repeat
debridement tend to be large and may be full thickness in nature. In addition, chest wall structural integrity
often needs to be reestablished to aid respiratory mechanics. In classic wound healing, fibrosis may aid in
structural integrity. However, in necrotizing infections, the rapid onset of the infection does not allow for
underlying fibrosis development. The use of a prosthetic mesh for structural integrity is usually
contraindicated due to the infectious risk. Thus, cadaveric and other biologic matrices have become an
attractive option for skeletal reconstruction, although they lack the mechanics of their prosthetic
counterparts. After skeletal reconstruction has been achieved, vascularized soft tissue coverage is
mandated. This soft tissue coverage is also difficult, not only due to the large size of the defects requiring
repair but also due to the infectious involvement of the chest wall muscles, which are commonly used for
tissue flaps in the more classical chest wall reconstructions. Reconstruction methods and alternatives are
discussed later in this chapter.
NONNECROTIZING INFECTIONS
Nonnecrotizing infections of the chest wall are more common and associated with lower morbidity than
their necrotizing counterparts. They often respond to nonsurgical management, but knowledge of their
presentation and management is important to thoracic surgeons. A discussion of nonnecrotizing chest wall
infections, both common and rare, follows.
ABSCESSES
Soft tissue abscesses may occur anywhere on the body. Specific to the chest wall are subpectoral and
subscapular abscesses. These present due to their large potential spaces. While these may be primary
infections, they more commonly occur as a secondary infection associated with thoracotomy. Localized
pain, fever, and leukocytosis are common presenting symptoms. Chest radiography will typically appear
normal. Intravenous-contrast CT imaging is useful for delineating the abscess, demonstrating rim
enhancement. Prompt, complete surgical drainage with institution of culture-directed antibiotics are the
mainstay therapies. Surgical drainage and debridement of devitalized tissue are undertaken at the first
operation. Subsequently, the authors use a succession of wet-to-dry dressing changes two to three times
daily, using Dakin’s solution or a dilute chlorine derivative solution initially, followed by saline as the
wound becomes clean. Alternately, a negative-pressure wound therapy dressing changed every other day
under gradually weaned pain control or sedation can be used for management of wounds without evidence
of ongoing infection.
Chest Wall Actinomycosis

Actinomycosis of the chest wall is a rare thoracic infection.8 Actinomyces is a gram-positive anaerobic
bacteria commonly found in healthy human and animal oral flora. Actinomycosis is a chronic disease
characterized by granulomas or abscesses which eventually progress to draining sinuses discharging
bacterial microcolonies with the appearance of “sulfur granules.” There are three major forms of
actinomycosis: (i) cervicofacial (most common, 65%), (ii) abdominal (20%), and (iii) thoracic (15%).
The thoracic form usually results from aspiration by a patient with poor oral hygiene. Thoracic
Actinomyces infection subsequently develops within the lung parenchyma and can progress through the
pleura, necessitating drainage out of the chest wall. Thoracic actinomycosis may be complicated by
hemoptysis, systemic spread, a chronic draining sinus, or empyema.9
Hematogenous spread of actinomycosis is rare, but when it occurs, it typically has a thoracic origin.
This disseminated form of the disease may result in distant abscesses, including the brain. Localized chest
wall infections caused by Actinomyces, without pulmonary involvement, are rare and often misidentified
as locally advanced primary chest wall tumors.
Actinomycotic chest wall infections can be diagnosed by isolating Actinomyces in culture. However,
the organism is difficult to grow in culture medium; therefore, this may result in false-negative cultures. A
surgical biopsy is commonly necessary to provide tissue for histopathologic confirmation of the presence
of pathognomonic grainy microcolonies, or “sulfur granules.” Actinomycosis of the chest wall is treated
with incision, drainage, and debridement of the affected areas and long-term penicillin therapy.10
Tubercular Abscesses
Extrapulmonary tubercular infections account for a minority of tuberculosis infections. Tuberculosis
infections of the chest wall account for only 10% of extrapulmonary tuberculosis infections.11 However, a
resurgence of tuberculosis in recent decades, largely as a result of proliferation of immunosuppressive
conditions combined with immigration of people from developing nations to North America, has resulted
in this being a more common entity.12
Tubercular abscesses of the chest wall have a strong predilection for the sternal margins. However,
they may additionally involve ribs, costochondral junctions, costovertebral joints, and the vertebrae.
Predilection to the sternal margin has been suggested to be the result from internal mammary lymph node
infections secondary to primary pulmonary involvement. The infected lymph nodes then caseate, erode
through the chest wall, and result in visible “swelling.” Subpleural collections of this caseating material
from the infected, necrosed lymph nodes are known as “cold abscesses.” Bone erosion by tuberculosis
results from pressure necrosis caused by the granulation tissue, or contiguous spread resulting in bone
infection.
Multidrug systemic therapy is the mainstay for tuberculosis infections. However, treatment of cold
abscesses includes the addition of aggressive surgical debridement and wide excision of the bone and
infected soft tissue to prevent recurrence.11,13 Muscle flap reconstruction of the sternum typically follows,
as described further.
FIGURE 45.2 CT Scan Imaging of Empyema Necessitans. A right loculated empyema (noted by arrow, →) with direct
communication of the chest wall (asterisk, *) consistent with empyema necessitans.
Empyema Necessitans
Empyema necessitans results from an undrained, underlying pleural infection. This infection is commonly
polymicrobial and is the direct extension of an untreated empyema that extends through the chest wall into
the superficial tissue of the chest. Physical examination and axial radiographic imaging of the chest (e.g.,
chest CT imaging) will elucidate the diagnosis (Fig. 45.2). Definitive treatment includes antibiotic
administration, surgical drainage of the empyema, and debridement of devitalized tissue from the site of
necessitans through the chest wall. Spontaneous drainage of the empyema necessitans is typically
inadequate treatment.
FUNGAL INFECTIONS
Fungal infections of the chest wall may occur. As discussed earlier, infections caused by Aspergillus
species and Phycomyces may result in soft tissue necrosis as they can invade blood vessels, thus resulting
in thrombosis. Aspergillus chest wall infections may result from primary direct infection or from a
disseminated infection. These typically present as an indurated plaque progressing to a necrotic ulcer of
the skin. On histologic evaluation, Aspergillus chest wall infections are characterized by branching
septate hyphae. Phycomyces histologically appear as broad-based nonseptate hyphae. Other organisms
associated with chest wall infections include Mucor or Rhizopus species. Treatment requires surgical
debridement to normal-appearing, granuloma-free tissue on frozen pathologic examination, with
concurrent and prolonged antifungal chemotherapy.
PARASITIC INFECTIONS
Parasitic infections may involve the chest wall. Although these are rarely encountered in North America,
they may be encountered in patients living in, or those who have traveled from, endemic areas. A few
different parasites are notable for chest wall involvement, and are discussed below.
Leishmaniasis, caused by the protozoan parasite Leishmania, is transmitted by the bite of the
Phlebotomine sand fly. It is endemic in parts of the Arabian Peninsula, Asia, Africa, South America,
Central America, and southern Europe. Infection can manifest as a cutaneous ulcer developing weeks to
months after the bite occurred. Diagnosis is based on clinical history, including travel exposure, and
physical examination. It can be treated with medications such as fluconazole, miltefosine, or pentamidine.
Specific medical treatment is dependent on the species of Leishmania acquired, the type of infection, and
the location where the disease was acquired. Surgery is typically reserved for cosmetic treatment of
cutaneous lesions.14
Infection of soft tissue by parasitic larvae of myiatic flies can involve the chest wall. Myiasis is
parasitic infestation of the living flesh. An example of this is infection by the Cordylobia anthropophaga
(the tumbu fly or mango fly) species of the myiatic blow fly, which is endemic in central and east
Africa.15 Diagnosis is based on clinical history, including travel exposure, and physical examination.
Treatment of this dramatic infection is elimination of the parasitic larvae by incision and debridement or
extraction, with subsequent treatment with antiparasitic agents, such as ivermectin.16
Echinococcosis, or hydatid cyst formation by the larvae of the Echinococcus species of tapeworms,
may occur in ribs. Echinococcus species are endemic in some areas of Africa, South America, and Asia.
Although typically infesting the liver and lungs, bone involvement may rarely occur. Rib involvement
accounts for 8% of bone hydatidosis.17 The eggs of the Echinococcus species are ingested by humans as
an accidental host. These eggs penetrate the small bowel wall and disseminate hematogenously, typically
to the liver and lungs but rarely to the chest wall. The eggs release embryos, which grow into cysts. These
cysts typically grow 5 to 10 cm in size per year, and can survive in hosts for many years. Within cysts
develop daughter cysts and protoscolices. Multiloculated pleural swelling is present and the disease can
progress to destruction of cancellous bone and spread to the vertebral bodies.
Diagnosis of echinococcosis is based on clinical history, including travel exposure, and physical
examination. Imaging modalities to visualize the hydatid cysts include ultrasound, CT, and MRI,
demonstrating presence of the fluid-filled cyst. Confirmation of diagnosis is achieved with serologic
testing including enzyme-linked immunosorbent assay (ELISA) and indirect hemagglutination assay.
Needle biopsy of the cyst may result in dissemination of the daughter cysts and protoscolices and is,
therefore, contraindicated. Treatment is en bloc surgical resection of cystic lesions with negative margins,
as well as sterilization of other sites of hydatidosis, such as the liver or lungs, either surgically or
chemically. Rupture of the cysts during diagnosis or surgery may result in dissemination of the disease.
Pre- and posttreatment chemotherapy is administered with albendazole or mebendazole, continued for 1 to
6 months after surgery.18
COSTOCHONDRAL INFECTIONS
Infections of the costal cartilage, spanning the bony rib to the sternum, occur due to inoculation of the
tissue by bacteria or, less commonly, fungi. The majority of costochondral infections result from surgical
intervention, but may occur subsequent to penetrating trauma or via hematogenous spread from other
sources of infection within the body. Of surgical etiology, the majority of costochondral infections follow
median sternotomy for cardiac surgery. In addition, thoracotomy and tube thoracostomy have been
identified as inciting surgical trauma resulting in costochondral infections. Of note, infection of the
cartilage of the xiphoid may result in bilateral spread of infection to the chest wall and costal cartilages.
Costochondral infections typically present as progressive discomfort or pain of the anterior chest wall,
accompanied by localized tenderness on palpation, low-grade fever, leukocytosis, overlying erythema,
and, rarely, a draining sinus. In situations where the patient has undergone prior surgery or trauma to the
area, instability due to nonunion of involved ribs may be present beyond what is a reasonably expected
time required for healing. With wounds healing via secondary intention, the infected cartilage may remain
exposed in the bed of a narrow, granulating wound. As the overlying soft tissue and skin granulates, the
chronically infected cartilage will develop a draining sinus.
Diagnosis of costochondral infection is made through a combination of clinical suspicion due to a
compelling history and physical examination plus imaging to guide local therapy. Upon interview of the
patient, one can often elicit a history of discreet chest wall trauma such as surgery. This is often followed
by a prodromal period of chest wall pain on exertion, progressing to pain with minimal activity and
respiration. Accompanying fevers, if any, are often low grade. Physical examination demonstrates
tenderness over the chest wall adjacent to the nearby infection. Laboratory workup may be notable for
mildly elevated leukocytosis and elevated erythrocyte sedimentation rate (ESR) and C-reactive protein
(CRP). MRI is the imaging modality of choice as it may demonstrate tissue edema not well visualized on
CT scan.
Treatment of costochondral infection is a combination of use of targeted antibiotics and surgical
resection of infected tissue. Given the difficulty in identification of causative pathogens of most
costochondral infections, broad-spectrum antibiotics targeted at gram-positive bacteria (e.g.,
Staphylococcus aureus and S. epidermidis) should be instituted. Surgery is indicated when symptoms
persist, or findings on physical examination or radiographic imaging are compelling of infection
refractory to antibiotics alone. Surgical treatment involves resection of the infected cartilage and
surrounding infected soft tissue. As the seventh through tenth costal cartilages are contiguous, infection
involving any part of this costal cartilage typically requires resection of the entire costal arch unilaterally
to achieve control. Samples of infected tissue should be sent for Gram stain and culture at the time of
debridement.
Management of chest wall defects resulting from wide resection of costochondral infection depends on
the extent of the defect. In the authors’ experience, most defects resulting from treatment of costochondral
infections are not full thickness with most skin, intercostal muscle, and perichondrium preserved. These
usually can be managed with local soft tissue transposition, wet-to-dry dressings, or negative-pressure
dressings with ongoing antibiotic administration.
OSTEOMYELITIS OF THE CHEST WALL

Primary chest wall osteomyelitis is most frequently associated with intravenous drug abuse in the
community and traumatic inoculation. Secondary sternal osteomyelitis is associated with complications of
cardiothoracic surgery. Patients typically present with localized chest wall pain, with or without low-
grade fever. On physical examination, they may have localized chest wall tenderness, erythema, swollen
soft tissue, and, occasionally, sinus tract formation overlying the infected bone (Fig. 45.3A). Laboratory
studies may demonstrate mild leukocytosis, or no elevation in white cell count at all, and elevated ESR
and CRP.
Osteomyelitis and associated changes to tissue surrounding the infected bone can be visualized on
plain radiograph, ultrasonography, CT scan, MRI, or nuclear medicine bone scan. Imaging from CT scan
and noncontrast MRI are most useful for guiding treatment and planning surgery. Imaging may reveal fluid
collections, edema, or air surrounding the infected bone, and changes to the bone consistent with
osteomyelitis (Fig. 45.3B,C).
FIGURE 45.3 (A) Chronic sinus tract following sternotomy for cardiac surgery with underlying osteomyelitis of the manubrium
and clavicular heads; (B) Sagittal T1-weighted image from MRI demonstrating low signal with enhancement of the manubrium
and abnormal enhancement of T1 hypointensity extending posterior to the sternum into the anterior mediastinum at the level of
the sternomanubrial articulation; (C) Axial T2-weighted image from MRI demonstrating high enhancement of manubrium; and
(D) Complete surgical excision of involved bone and the overlying soft tissue was performed. (Figures courtesy of R. Meguid.)
Bone biopsies and concomitant blood cultures should be obtained prior to institution of antibiotics, if
possible. Bone biopsies can be achieved via needle biopsy or open, surgical biopsy. However, negative
cultures should not supersede clinical suspicion of infection. A recent review of image-guided
percutaneous biopsies for osteomyelitis demonstrated a low probability of identifying specific microbes.
Less than 10% of biopsies resulted in additional information for the identification of the pathologic
microorganism present and treatment modification.19 The successful treatment of chronic sternal
osteomyelitis entails administration of targeted antibiotics, extensive surgical debridement of infected and
devascularized tissue, followed with myocutaneous reconstruction (Fig. 45.3D). Examples of common
chest wall infections are discussed below.
OSTEOMYELITIS OF THE STERNUM

Primary sternal osteomyelitis is associated with intravenous drug abuse, whereas secondary sternal
osteomyelitis occurs in 1% to 3% of patients following sternotomy. The most significant risk factor for
secondary sternal osteomyelitis is reoperation for excessive postoperative bleeding following cardiac
surgery. Other risk factors for postoperative sternal infections include diabetes mellitus, low cardiac
output, and the use of bilateral internal mammary artery grafts during coronary artery bypass grafting.20
FIGURE 45.4 (A) Chronic sinus tract from underlying rib osteomyelitis following prolonged tube thoracostomy presenting 9
years after right thoracoscopic pleurodesis for spontaneous pneumothorax, followed by two subsequent thoracotomies and
exploration and decortication for recurrent hematoma and empyema in the right chest of a patient with hemophilia; and (B)
sinogram of sinus tract. This patient was treated surgically with excision of the underlying infected rib and debridement of the
associated overlying soft tissue with local tissue advancement flap coverage and a prolonged course of culture-directed
antibiotics. (Figures courtesy of R. Meguid.)
Joint effusions at the sternomanubrial joint may be present. In the setting of a prior sternotomy, patients
may have an unstable sternum with serosanguineous drainage. Findings on imaging may include malunion
of the sternotomy, and broken or avulsed sternal wires or closure devices.21 Bilateral pectoralis muscle
flap advancement is most commonly used for soft tissue coverage of poststernotomy osteomyelitis when
available.22
OSTEOMYELITIS OF THE RIBS

Osteomyelitis of the ribs is less commonly encountered than that of the sternum. It is usually diagnosed
due to local pain, tenderness, and inflammation, with or without a chronic, persistent draining sinus.
Osteomyelitis of the ribs is most commonly due to traumatic inoculation by S. aureus, secondary to either
trauma or surgery. On imaging, any intrapleural nidus of infection perpetuating a persistent draining sinus
should be identified (Fig. 45.4A,B). In the setting of osteomyelitis of the ribs, we have encountered
parenchyma–pleural fistulas and foreign materials such as nonabsorbable braided sutures resulting in
chronic infection. Excision of all infected bone, treatment of the cause of a fistula, and local soft tissue
coverage, followed by prolonged antibiotic administration, is typically required for eradication of
osteomyelitis of the ribs.
OSTEOMYELITIS OF THE STERNOCLAVICULAR JOINT

The sternoclavicular joint consists of the lateral notch of the manubrium, the medial inferior head of the
clavicle, and the costocartilage of the first rib. It is a gliding synovial joint and has minimal soft tissue
coverage. Infections of the sternoclavicular joint only represent 2% of pyogenic arthritis. However, 20%
of patients with sternoclavicular infections may develop a sternoclavicular joint-related abscess as a
result of the joint capsule’s inability to distend.23 Intravenous drug use, immunosuppression including
diabetes and long-term steroid use, chronic hemodialysis, subclavian venous catheters, and local trauma,
including surgery, are all predisposing factors for sternoclavicular joint infections.24 Tracheostomy in
patients with short necks, or those created low down on the manubrium, are predisposed to development
of osteomyelitis of the manubrium and sternoclavicular joint (Fig. 45.5A). Women who have undergone
breast irradiation for breast cancer may also have a late presentation of sternoclavicular joint septic
arthritis decades following their radiation treatments. Radiation-induced skin changes and associated
upper extremity motion limitations are thought to contribute to the development of infection.25 Infectious
seeding of the sternoclavicular joint is typically via the hematogenous route. However, direct contiguous
spread of infection may result in a septic sternoclavicular joint. S. aureus is the predominant organism
present in the general population. Pseudomonas aeruginosa historically is reported as being more typical
in intravenous drug users.26 However, recent evidence suggests S. aureus is still the major pathogen for
the general population and intravenous drug abusers.27 The thoracic surgeon plays a central role in the
management of sternoclavicular joint infections due to their proximity to the pleural space, mediastinum,
and brachiocephalic structures.
FIGURE 45.5 Appearance of osteomyelitis of the medial right clavicle and adjacent manubrium, with inflammation of
surrounding tissue, in a 70-year-old man with a long indwelling tracheostomy appliance, (A) on edge-enhanced nuclear medicine
scan; (B) on T1-weighted postcontrast MRI, demonstrating confluent T1 hypointense enhancing signal involving the medial third
of the right clavicle and an effusion within the right sternoclavicular joint with associated prominent capsular and synovial
enhancement—note the differential enhancement of the right medial clavicular head versus the left; (C) on T2-weighted
precontrast MRI, demonstrating T2 hyperintense, enhancing signal within the bone marrow of the right clavicular head; and (D)
on axial CT scan image demonstrating sclerosis of the bone but lack of clear indications of osteomyelitis. This patient underwent
resection of the medial third of the right clavicle and adjacent manubrium, and debridement of the adjacent soft tissue, with
delayed secondary closure using negative-pressure wound therapy. Concurrently, he was treated with a prolonged course of
culture-directed antibiotics.
The vast majority (95%) of pyogenic sternoclavicular joint infections are unilateral. Occurrence on the
right side is slightly greater than on the left. Patient presentation includes sternoclavicular joint pain with
or without shoulder pain, and 65% may have associated fever. Physical findings include focal tenderness
with joint swelling, skin erythema, and associated induration, depending on the extent of infection.27
Imaging of sternoclavicular joint infections can be troublesome. Plain radiograph and ultrasound are
unreliable in the early phase of the infection. CT scan is the preferred diagnostic imaging to help the
thoracic surgeon determine the spatial relationship of the sternoclavicular joint infection to the remaining
chest wall and pleural space. CT scan also images sternoclavicular joint-related bone erosion and
sclerosis in patients presenting subacutely, and potentially new bone formation from more chronic
infections. However, bone scan and MRI may better demonstrate signs of osteomyelitis (Fig. 45.5A–D).
Ultrasound is useful for joint effusions, enlargement of the joint synovium, and associated soft tissue
collections.28 Patients who have an unexplained cause of sternoclavicular joint infection should undergo
echocardiogram to determine whether valve vegetations are present, seeding the bloodstream with
bacteria.
The management of pyogenic septic arthritis is partially dependent on the extent of the infection.
Sternoclavicular joint infections without extracapsular fluid collections or bony destruction can be
managed medically with administration of broad-spectrum antibiotics and removal of potential seeding
sources (i.e., central venous catheters).27 Incision and drainage may suffice for joints with limited
infection or when a histopathologic specimen is needed for diagnosis and to guide antibiotic therapy.
However, simple incision and drainage is unlikely to resolve the infection.24,29 Surgical debridement is
typically required for adequate treatment. Wide en bloc resection of the joint and involved soft tissue or
piecemeal debridement of all nonviable tissue and associated structures is commonly required when
periarticular fluid, abscess, bone destruction, or persistent infection following extended courses of
antibiotic administration are present.
Resection of an infected sternoclavicular joint proceeds as follows: (i) A hockey-stick incision is
made extending laterally over the medial half of the clavicle, and inferiorly down the manubrium to the
first intercostal space to allow access to the sternoclavicular joint; (ii) All involved tissue is widely
debrided and viable pectoralis and sternocleidomastoid muscle fibers are resected away from areas of
phlegmon; (iii) The clavicle lateral to the area of osteomyelitis is circumferentially exposed, with care to
protect the underlying subclavian vein and artery; (iv) The clavicle is divided 2 cm lateral to the
inflammatory mass using an oscillating saw and the clavicular head is resected; (v) The remaining
involved soft tissue, sternoclavicular joint, and adjacent manubrium is debrided with rongeurs and/or
curettes. Soft tissue and bone is sent for microbiologic assessment and culture. Limiting the manubrial
resection to half of the manubrium is important to maintain chest wall stability. The costal cartilage and
medial portion of the first rib can be divided with rib shears if involved, although this is rare.24,29
Serial debridement of sternoclavicular infections is occasionally required to ensure all devitalized and
infected material is removed. A temporary negative-pressure dressing or wet-to-dry dressings using
Dakin’s solution is useful between episodes of debridement. The exposed divided clavicle and
manubrium can be covered with locally advanced soft tissue, including the strap muscles of the neck or
the superior part of the pectoralis major muscle, and allowed to heal by secondary intention. The majority
of resulting wounds respond well to negative-pressure dressings. Occasionally, the resulting defect is
large and requires more complex soft tissue coverage for closure. An ipsilateral pectoralis muscle
advancement flap is well situated to cover the defect. Simultaneously and following debridement, long-
term antibiotics are administered. Despite the aggressive nature of debridement of infected
sternoclavicular joints, postoperative shoulder function is usually well preserved, and the majority of
patients report long-term normal upper extremity performance.
In a series of 26 patients with sternoclavicular joint infection, patients reported pain as the most
common symptom, followed by swelling over the infected sternoclavicular joint.29 Five of the patients
had a history of trauma, and half of the patients reported ongoing or recent infections. Patients were
treated with antibiotics for a median of 42 days following surgical drainage. Four patients had undergone
previous incision and drainage, and wound cultures were positive in the majority of patients. Unilateral
debridement was the treatment most commonly used, allowing for the eventual use of an ipsilateral
pectoralis muscle flap for coverage and closure.
Atypical infections of the sternoclavicular joints may also occur. Extraspinal tubercular arthritis may
occur at the sternoclavicular joint.30 Tuberculous infections of the sternoclavicular joint may have
characteristic radiologic findings including an inflammatory mass, abscess wall calcification, and
absence of new bone formation. Compression of the subclavian vessels by this inflammatory mass may
also be found. Microbiologic and histologic studies are necessary to make a definitive diagnosis.
Treatment is as described for more commonly occurring sternoclavicular joint infections, with use of
prolonged chemotherapy targeted to tuberculosis.
Brucella sternoclavicular arthritis is rare, but has been reported.31 Brucella are gram-negative,
facultative anaerobes found in domesticated animals. It is endemic in parts of Central America, the
Mediterranean, Middle East, and Asia. Human infections may result from consumption of infected meat
and milk. Musculoskeletal involvement is the common human manifestation. The infection is systemic.
Sternoclavicular joint infection occurs in the minority of cases (2% to 5%).32 Definitive diagnosis
requires microbiologic organism confirmation, or antibody serology. Treatment is 6 to 12 weeks of
streptomycin and doxycycline or tetracycline to eradicate the organism from the bone. Surgical
debridement is seldom necessary.
SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis) is an important differential
diagnosis for pyogenic sternoclavicular joint infections. It is a complex set of musculoskeletal disorders
and associated skin conditions defined by joint and skin inflammatory processes in the absence of
infection.33 SAPHO is a noninfectious sternoclavicular joint inflammation, and the resulting associated
osteitis is a result of sterile inflammatory infiltrates. The sternoclavicular joint is the most common site of
skeletal involvement (63% to 90% of cases) in SAPHO syndrome. Typical SAPHO syndrome presents in
otherwise healthy adolescents and young adults with a prolonged relapsing course. Bone pain is the
classic symptom manifested from osteitis and hyperostosis. CT scan and MRI do little to differentiate
SAPHO syndrome from its infectious pyogenic arthritis counterpart. Bone scan, and more recently
positron emission tomography-CT (PET-CT), are particularly useful modalities for the diagnosis of
typical SAPHO with the classic pattern of sternoclavicular joint, sacroiliac joint, and spine inflammation.
These are confirmed with negative cultures of involved joint aspiration and bone biopsies.34
Treatment of SAPHO syndrome is based upon nonsteroidal anti-inflammatory drug (NSAID) therapy.
Antimicrobial therapy for Propionibacterium acnes may be added in some cases. If patients experience
persistent symptoms following 1 month of NSAID therapy, a trial of bisphosphonates and more aggressive
anti-inflammatory agents are added. Surgery is only indicated when bone mechanics are adversely
effected by the inflammation, which is more common with spine and long-bone involvement than the
sternoclavicular joint.35
MANAGEMENT OF SURGICAL WOUNDS RESULTING FROM CHEST WALL

INFECTIONS
NEGATIVE-PRESSURE WOUND THERAPY

The widespread adoption of negative-pressure wound therapy, or vacuum-assisted closure technology, to
complex wounds and more specifically, chest wounds has proven effective.36 These negative-pressure
dressings accelerate wound healing and ultimately wound closure by continuously providing a wound bed
environment with increased blood flow, drainage of excess fluid and resulting decrease is tissue edema,
while removing bacteria. The degree and schedule of subatmospheric pressure can be varied depending
on the device.37 Negative-pressure wound therapy provided by these devices has been shown to alter
wound bed cell cytoskeleton and trigger intracellular cascades increasing cell division, formation of
granulation tissue, and ultimately promote wound healing.38 This technique is employed for small wounds
with exposed soft tissue only, which do not enter the pleural space. Occasionally, there is the use of
negative-pressure wound therapy to stabilize and temporize an open sternum after debridement of sternal
wound infections (Fig. 45.6). In the latter, the authors find the negative-pressure wound dressing promotes
granulation tissue formation providing a bed for subsequent reconstruction with soft tissue flaps.
The wide and ever-increasing availability of negative-pressure wound dressings combined with their
few contraindications, low rate of complications, and relative portability have made them a mainstay of
modern wound care. They are routinely managed in the outpatient setting, and ideal for subacute and
chronic wounds. This outpatient management allows the patient to resume activities of daily living and for
the elective scheduling of any subsequent surgical reconstruction. Negative-pressure wound dressing use
in the chest has been shown to lessen inpatient hospital stays, decrease the number of required operative
debridements, decreased rates of subsequent wound infection, and increase rates of primary wound
closure.39 Negative-pressure wound dressing application to thoracotomy incisions, including intrapleural
application and even in direct contact with the heart has proven safe.40 The wide range and success of
negative-pressure wound dressing makes it an increasingly used tool in contemporary chest wall wound
management.
BIOLOGIC CHEST WALL RECONSTRUCTION

Large and varying-thickness soft tissue defects in the chest wall may result from surgical debridement of
chest wall infections, as noted above. Resulting defects can pose challenges to wound reconstruction,
closure, and management. One strives to cover large and full thickness chest wall defects resulting from
treatment of infections with autologous tissue, minimizing foreign material which may themselves become
nidus for infections. While in-depth review of chest wall reconstruction is beyond the scope of this
chapter, soft tissue reconstruction can be performed using a combination of myocutaneous, muscle and
omental flaps, skin grafts and free bone grafts. Muscles such as the latissimus dorsi and serratus anterior
can be used to cover exposed lung and mediastinal structures, as can omentum brought up into the chest
through the diaphragm. Autologous ribs from a sterile, contralateral site can be used as a free graft for
large defects, in lieu of metallic prosthetics. The preference is to use pectoralis major advancement and
rotational flaps for anterior defects, with bilateral pectoralis major advancement flaps covering and
stabilizing sternal defects. For lateral and posterior defects, the latissimus dorsi and serratus anterior
muscles are usually reasonably large and mobile to provide coverage. These muscle flaps can then accept
skin grafts when necessary. Delayed reconstruction with prosthetic tissue such as titanium, Gore-Tex (W.
L. Gore & Associates, Inc., Newark, Delaware, USA), or polypropylene mesh (Marlex, Chevron Phillips
Chemical Company LLC, The Woodlands, Texas, USA) is possible once the infection has been
convincingly cleared.
FIGURE 45.6 An example of negative-pressure wound therapy after sternal dehiscence and development of osteomyelitis
following cardiac surgery via median sternotomy. This modality is commonly used in the modern management of chest wall
infections. (Figures courtesy of A Babu.)
SUMMARY
Chest wall infections involve a spectrum of presentations from extensive cellulitis to draining sinuses to
discrete masses. Causes are broad, but include direct chest wall trauma, chest wall inoculation from
systemic infection, and surgical intervention of the chest wall. Outcomes are affected by the rapidity of
diagnosis and onset of definitive treatment, the causative organism, extent of the infection, and degree of
immunosuppression. The potential for infectious spread into the pleural space and mediastinum can have
devastating consequences, making chest wall infections more severe than other anatomic regional
wounds. As cardiothoracic surgery in evermore complex patients continues, especially in the
immunosuppressed, chest wall infections are an entity with which the practicing cardiothoracic surgeon
must be familiar.
The mainstay of therapy is surgical debridement of devitalized and infected tissue with appropriate
antibiotic administration. Based upon extent of tissue resection, deleterious effects on respiratory
mechanics may result. The remaining wound bed requires well-vascularized soft tissue coverage if
native, healthy tissue is no longer present. Wound management can be achieved via negative-pressure
wound therapy or chest wall reconstruction, careful to prevent further spread of infection.
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46
Thoracic Outlet Syndrome
Dean M. Donahue ■ Asishana Osho
INTRODUCTION
Thoracic outlet syndrome (TOS) is a spectrum of symptoms resulting from compression of at least one of
these structures: the brachial plexus, subclavian vein, or artery. While they may coexist, nerve
compression and vascular compression produce different clinical scenarios. The anatomic regions within
the thoracic outlet that often produce compression are the interscalene triangle, the costoclavicular space,
and the subcoracoid space. Because of the lack of established objective criteria to diagnose neurogenic
TOS (NTOS), the exact incidence is unknown. It has been estimated that in the United States, cases of
TOS occur from 3 to 80 per 1,000 people.1 Primary subclavian vein thrombosis has an estimated
incidence of between 1/50,000 and 1/100,000 people per year.2 Arterial TOS is the least common form of
this condition. Its incidence in published series of TOS ranges from 1% to 6%.3–5 There are multiple
potential etiologic factors that can lead to the development of TOS (Table 46.1).
HISTORY OF THORACIC OUTLET SYNDROME

Surgical treatment of the condition now known as TOS began in 1861 in London where Mr. Holmes
Coote6 resected a cervical rib to treat a painful upper extremity. With the development of radiographs in
the early 1900s additional imaging for “cervical rib syndrome” became available. The concept of TOS in
the absence of a cervical rib was reported in a study by T. Wingate Todd7 in 1912. Due to the technical
difficulty in performing cervical rib resection, Adson and Coffey8 proposed the use of scalenectomy in the
treatment of patients with symptomatic cervical ribs. The popularity of scalenectomy led to the term
“scalenus syndrome” in patients previously labeled as “cervical rib syndrome” in the absence of cervical
ribs.9 The term TOS is credited to Peet in 1956. The role that 1st thoracic rib resection played in the
treatment of TOS was reintroduced by Clagett10 in 1962 when he described a posterior approach to 1st
rib resection. An alternative surgical approach was proposed by Dr. David Roos11 when he reported 15
patients undergoing 1st rib resection through a transaxillary approach. Roos12 subsequently described a
variety of “bands” and “fibers” that he had observed during the course of his dissections potentially
contributing to the development of symptoms. These structures were later reclassified by Makhoul13
based on embryologic data.
ANATOMY
Understanding the anatomic complexity of the thoracic outlet region is critical in the management of these
patients. While this region needs to be considered in its entirety, there are three distinct regions where
compression may potentially occur. From medial to lateral they are: the scalene triangle, the
costoclavicular space, and the subcoracoid space. The space between the anterior and middle scalene
muscles, called the scalene triangle is occasionally a misnomer. Abnormal communicating muscle bands
between these two scalene muscles are common, and result from the fact that the scalene muscle starts in
early embryologic development as a common muscle mass. This muscle mass originates on the transverse
processes of the C3 through C7 vertebrae, then inserts broadly on the 1st rib and the posterior lateral
aspect of the 2nd rib. This common scalene muscle mass is subsequently separated into different muscles
as the neurovascular bundle is pulled outward from the trunk as the forequarter develops. There is
frequently incomplete separation of these muscles, with communicating bands of muscle and fascia
remaining between them potentially contributing to compression or irritation of the trunks of the brachial
plexus.13,14
TABLE 46.1 Etiologic Factors in Thoracic Outlet Syndrome

Anatomic
Potential sites of neurovascular compression
Interscalene triangle
Costoclavicular space
Subcoracoid arca
Congenital
Cervical rib and its fascial remnants
Rudimentary 1st thoracic rib
Scalenus muscles
Anterior
Middle
Minimus
Adventitious fibrous bands
Bifid clavicle
Exostosis of first thoracic rib
Enlarged transverse process of C7
Omohyoid muscle
Anomalous course of transverse cervical artery
Brachial plexus posterior fixation
Flat clavicle
Traumatic
Fracture of clavicle
Dislocation of head of humerus
Crushing injury to upper thorax
Sudden, unaccustomed muscular effort involving shoulder girdle muscles
Cervical spondylosis and injuries to cervical spine
Atherosclerosis
Bone abnormalities of the C7 vertebrae, including cervical ribs and elongated transverse processes,
occupy space within the thoracic outlet and may contribute to compression of the neurovascular structures
as they traverse this space. In addition to the bone anomalies, fibrous and muscular attachments between
these structures and the underlying 1st thoracic rib may also contribute to compression. An analysis of
multiple studies show that the prevalence of cervical ribs range from 0% to 3%, with the prevalence of an
elongated C7 transverse process ranging from 2.2% to 21%.15
Knowledge of the anatomy of the phrenic nerve is required for any surgical intervention on the thoracic
outlet. This nerve follows a similar course on the right and left sides, and is located on the anterior aspect
of the anterior scalene muscle running from the lateral edge to the medial edge. It passes medial to the
insertion of the anterior scalene onto the 1st rib. As the nerve exits the thoracic inlet and enters the
superior mediastinum it is found anterior to the subclavian artery and posterior to the confluence of the
subclavian and internal jugular veins.
Abnormalities, such as distorted healing from a prior clavicle fracture, may cause compression of the
costoclavicular space. This seems to play more of a role in the development of venous TOS, although
NTOS can also develop in this setting. The subclavian vein in this location is surrounded by the clavicle
and 1st rib, as well as the costoclavicular ligament, subclavius muscle, and anterior scalene muscle. The
subcoracoid space is deep to the coracoid process of the scapula. The pectoralis minor muscle originates
on the anterior chest wall from ribs 3, 4, and 5 and inserts on the coracoid process. Anomalies between
this muscle, the latissimus dorsi and the pectoralis major muscles may contribute to the development of an
axillary arch. This anatomic anomaly may further contribute to irritation of the brachial plexus as it passes
through the subcoracoid space.16
PRESENTING SYMPTOMS
NEUROGENIC THORACIC OUTLET SYNDROME

NTOS results from compression and/or irritation of the brachial plexus. NTOS is the most common cause
of TOS, occurring in approximately 90% of patients presenting for an evaluation. Pain is the most
common presenting symptom. It is typically located in the posterolateral neck and upper trapezius region,
and may involve the area adjacent to the clavicle, the area medial to the scapula, the upper pectoral
region, and axilla. Pain may also radiate down the upper extremity. This may be generalized, but
frequently localizes to the medial or occasionally the lateral aspect of the arm and hand. Occipital
headaches are occasionally seen, as is pain radiating up to the face or ear.
The majority of patients will note symptoms of altered sensation including paresthesia involving the
arm and hand. These may be generalized, but more frequently localize to the medial aspect of the upper
extremity, particularly the 4th and 5th digits of the hand. Numbness in this region may also occur in a
similar distribution as the paresthesia. Motor symptoms may be present including vague weakness or
fatigue of the upper extremity and diminished coordination of the hand. A minority of patients exhibit signs
of vasomotor instability including skin discoloration and temperature discrepancy of the upper extremity.
A patient’s symptoms are frequently exacerbated with arm activities, particularly those that require
repetitive motion or arm elevation.
VENOUS THORACIC OUTLET SYNDROME

Venous TOS (VTOS) is also referred to as spontaneous thrombosis of the subclavian vein or Paget–
Schroetter syndrome. This results from thrombosis of an injured subclavian vein created by compression
within the costoclavicular space. This frequently occurs as a result of repetitive use of the arm,
particularly with overhead activities. These patients present with upper-extremity swelling and skin
discoloration, and often complain of a heavy sensation in the arm. Pain is not a common component, but
when present it may be described as a generalized ache or heaviness in the arm. Visible subcutaneous
collateral veins are often seen in the pectoral region, shoulder, and proximal upper extremity.
ARTERIAL THORACIC OUTLET SYNDROME
Arterial TOS results from damage to the subclavian artery, typically from a bone anomaly such as a
cervical rib or elongated transverse process of the C7 vertebrae. This arterial damage begins as
compression, then progresses to any combination of poststenotic dilation, aneurysm formation, ulceration
combo mural thrombus formation, and distal embolization to the upper extremity.
EVALUATION
NEUROGENIC THORACIC OUTLET SYNDROME

An evaluation for NTOS begins with a detailed history and physical examination. There are no
established criteria regarding the diagnosis of this condition, and a long list of potential differential
diagnoses must be considered (Table 46.2). A patient’s symptoms and physical findings merely suggest
that NTOS may exist, and one must remember that they could also be produced by other conditions. Given
that, an inexperienced practitioner may be best advised to approach this diagnosis slowly, and let the
clinical picture become clearer over time. The differential diagnosis for NTOS is broad, and a thorough
evaluation for other conditions involving the cervical spine, shoulder, or chest wall must be
performed.17,18
TABLE 46.2 Differential Diagnosis of Nerve Compression

Cervical spine
Ruptured intervertebral disk
Degenerative disease
Osteoarthritis
Spinal cord tumors
Brachial plexus
Superior sulcus tumors
Trauma (postural palsy)
Peripheral nerves
Entrapment neuropathy
Carpal tunnel (median nerve)
Ulnar nerve (elbow)
Radial nerve
Suprascapular nerve
Medical neuropathies
Trauma
Tumor
Physical findings suggestive of possible NTOS include tenderness to palpation over the
supraclavicular, infraclavicular, and/or subcoracoid space. Testing for a Tinel sign is performed over the
brachial plexus in the supraclavicular and infraclavicular regions.
A thorough sensory and motor evaluation of the upper extremity is mandatory. Weakness of the nerve-
innervated intrinsic hand muscles, particularly the adductor digiti minimize may be present. Positional
testing of the arms, including an upper extremity tension test is performed to determine the patient’s
symptomatic response. A variety of upper-extremity positional tests have also been utilized to evaluate
for pulse ablation with the arms in a “stressed” position. However, pulse ablation has been found in one
of three asymptomatic volunteers, which limits its utility as a diagnostic tool.19
There is no consensus regarding the role of diagnostic testing beyond the history and physical
examination, but the authors’ program frequently employs a multiphase contract-enhanced CT scan with a
TOS-specific protocol. High-resolution MRI with multiplanar reformat is helpful in some patients. While
not thoroughly studied in a randomized, controlled fashion, ultrasound-guided injections into the anterior
scalene and pectoralis minor muscles with botulinum toxin A has provided symptomatic relief in a
majority of selected patients in our program. Nerve conduction studies have occasionally been reported
as helpful in the diagnosis of TOS. There are reports that reduced nerve conduction velocities, and
abnormalities of the medial antebrachial cutaneous nerve are indicators of NTOS.20,21 This finding has not
been reproduced in our program, and these studies often play a greater role in evaluating for other
potential causes of a patient’s symptoms.
VENOUS THORACIC OUTLET SYNDROME

Noninvasive Doppler studies of the subclavian vein may be performed in patients with suspected
subclavian vein thrombosis, but both false-negative and false-positive results can occur. The definitive
evaluation is a contrast venogram, which also allows the use of catheter-directed lytic therapy. After
thrombolytic treatment, a repeat venogram is performed to evaluate for persistent subclavian vein
stenosis. Aggressive balloon venoplasty at this point may result in further damage to the vein by
compressing its walls between the balloon and the surrounding clavicle and 1st rib. With a persistent
high-grade stenosis, temporary flow could be re-established with a minimal ( 6 mm) balloon dilation.
VTOS can also result from a disorder of coagulation, and in the absence of a clear stenosis, an evaluation
for thrombophilia should be performed. Other potential causes of vascular compression are listed in
Table 46.3.
INITIAL TREATMENT OF NEUROGENIC THORACIC OUTLET SYNDROME

Physical therapy (PT) is the first-line of treatment for the overwhelming majority of NTOS patients.
While there is no standardized approach with consistently effective results, common treatment goals
include addressing the adaptive shortening of the scalene muscles. Weakness of the cervical flexor and
upper thoracic extensor muscles as well as the segmental stabilizers is also typically addressed. PT can
also address poor diaphragmatic breathing which can increase scalene muscle activity. Often, several
months may be required of dedicated PT before a patient notices symptomatic improvement.
TABLE 46.3 Differential Diagnosis of Vascular Compression
Arterial
Arteriosclerosis
Aneurysm
Occlusive disease
Thromboangiitis obliterans
Embolism
Functional
Raynaud phenomenon
Reflex vasomotor dystrophy
Causalgia: vasculitis, collagen disease, panniculitis
Venous thrombophlebitis
Mediastinal venous obstruction
Malignant
Benign
The decision for operative intervention in NTOS is difficult, and no consensus exists regarding
surgical indications. There is no established algorithm to follow, and the decision to operate is made for
each individual patient based on the collective results of their evaluation and the progress made in
nonsurgical treatment. Anatomic abnormalities identified on imaging, such as cervical ribs or elongated
C7 transverse processes, do not represent an absolute indication for surgery even in the presence of
symptoms. Up to 25% of these patients will improve with proper PT. Imaging may identify compression
of the scalene artery or narrowing of the costoclavicular space with the arm in a neutral position. Patients
with these findings frequently are good surgical candidates if they fail to improve with sustained PT.
Our program has used ultrasound-guided injections with botulinum toxin A into the anterior scalene
and pectoralis minor muscles.22 Approximately 70% of patients selected for these injections will have
symptomatic improvement. During this “window” of symptomatic improvement, patients can participate
more actively in their PT program. If the patient is making symptomatic progress, the injections can be
repeated at 3-month intervals. Patients with symptomatic improvement following botulinum toxin A
injections, that subsequently develop recurrent symptoms after aggressive PT, will frequently have a
successful surgical outcome. For NTOS, a successful surgical outcome depends upon a combination of an
accurate diagnosis and technical precision during aggressive decompression of the thoracic outlet.
TREATMENT OF VENOUS THORACIC OUTLET SYNDROME

Persistent stenosis following subclavian vein thrombolysis is frequently an indication for surgery. An
attempt at balloon dilation of this stenosis is not recommended in order to avoid creating further damage
of the vein. The use of intravascular stents for this condition should be strictly avoided.
The exact timing of surgery has not been established. The author’s recommendation is early, but not
immediate, surgical intervention in patients with persistent vein stenosis. Other strategies have included
approximately 3 months of oral anticoagulation followed by surgical decompression, although there
seems to be no distinct advantage for this delay. Patients with minimal residual stenosis following lytic
therapy, who remain asymptomatic, may be closely observed for the development of symptoms of venous
congestion of the upper extremity.
ARTERIAL THORACIC OUTLET SYNDROME

Arterial TOS (ATOS), a rare occurrence, represents subclavian artery thrombosis or aneurysm formation
within the thoracic outlet. This is almost exclusively seen in patients with bone abnormalities such as a
cervical rib or elongated transverse process of the C7 vertebrae. Although technically not falling into the
category of TOS, injury to the axillary artery can also occur in throwing athletes secondary to forward
compression of the artery from the head of the humerus. ATOS presenting with damage to the subclavian
artery is an indication for surgery. This includes resection of the C7 bone abnormality, the 1st rib, and
subclavian artery resection and graft reconstruction.
SURGICAL TREATMENT
The decision for surgical intervention in TOS can be difficult. The clinical experience of the diagnostic
physician should be balanced with the overall suspicion that the diagnosis of TOS is correct. An
aggressive attempt at nonsurgical treatment should be attempted in all but the most clear-cut cases.
Thoracic outlet decompression can be performed through a transaxillary or supraclavicular incision,
with the latter being the author’s preference. In cases of VTOS, some surgeons employ an infraclavicular
incision alone. More complex VTOS cases, occasionally requiring vein reconstruction, or cases of
ATOS, typically require a combined supraclavicular and infraclavicular incision. Historically,
reoperations for recurrent NTOS were performed through a posterior approach, but this approach has
largely been abandoned.
Supraclavicular Approach to Thoracic Outlet Decompression

Surgical decompression of the thoracic outlet for NTOS can occasionally involve removing the anterior
scalene muscle alone.23,24 It is difficult to select patients for this less aggressive approach, and therefore
the author’s recommendation is for a complete decompression with rib resection, scalenectomy, and
dissection of the brachial plexus. Larger anomalous bone structures such as cervical ribs or an elongated
transverse process of C7 are also resected along with the 1st thoracic rib. The supraclavicular approach
allows exposure to accomplish all of these operative goals.
The patient is placed in a modified semi-Fowler position with the operative side shoulder elevated on
folded towels to open the costoclavicular space (Fig. 46.1). The anesthesiologist should use only a single
dose of a short-acting neuromuscular blocking agent during induction, then avoid it for the remainder of
the procedure. This allows for the use of an electrical nerve stimulator to assist in identifying nerve
structures and confirming their function at the end of the procedure. An approximately 4 to 5 cm
supraclavicular incision is made beginning at the lateral border of the sternocleidomastoid muscle.
During mobilization of the scalene fat pad, the suprascapular and transverse cervical arteries are
preserved. The anterior scalene muscle is identified, and the phrenic nerve is carefully mobilized off of
this muscle with sharp dissection and bipolar cautery (Fig. 46.2). This muscle is nearly completely
resected from the scalene tubercle to the region above the upper trunk of the brachial plexus.
Communicating muscular bands between the anterior and middle scalene muscles are commonly
identified at surgery. These often surround the subclavian artery and the trunks of the brachial plexus, and
should be removed along with the anterior scalene muscle. Removal of this muscle facilitates exposure to
the brachial plexus and posterior aspect of the 1st rib. Chronic compression in the thoracic outlet may
result in scar formation around the brachial plexus trunks. In this situation, a neurolysis may be required.
This should be done with great care, and under magnification to avoid disrupting the epineurium which
could devascularize the nerve trunks. Mobilizing the nerve trunks, particularly the middle and lower
trunk, allows improved access to the posterior and lateral aspects of the 1st rib. If the upper trunk is
mobilized, attention must be paid to the dorsal scapular nerve (originating from the C5 spinal nerve) and
the suprascapular nerve. During mobilization of the lower trunk, the T1 spinal nerve is observed
originating from underneath the 1st rib, then merging with the C8 spinal nerve. Working between the trunks
of the brachial plexus, the middle scalene muscle is divided immediately above the 1st rib using bipolar
cautery (Fig. 46.3). A small amount of this muscle is left on the rib to avoid a subperiosteal resection.
Resecting too much of the middle scalene muscle posteriorly risks injury to the long thoracic or dorsal
scapular nerves. The pleura is bluntly dissected from the undersurface of the 1st rib (Fig. 46.4). The rib is
then separated from the transverse process by dividing the costotransverse ligaments with bipolar cautery.
The rib is divided at its neck, medial to the transverse process, with a Kerrison rongeur (Fig. 46.5).
Anteriorly, the rib is then divided medial to the scalene tubercle. The remaining soft tissue attachments,
including IC muscle and fibers of the serratus anterior muscle are carefully divided with bipolar cautery.
The rib is then removed intact. For patients with VTOS, a circumferential dissection to remove scar tissue
around the subclavian vein is then performed.
FIGURE 46.1 Modified semi-Fowler position with shoulder raised on folded towels to open costoclavicular space. (Reprinted
from Donahue DM. Supraclavicular First Rib Resection. Oper Tech Thorac Cardiovasc Surg 2011;16(4):252–266. Copyright ©
FIGURE 46.2 The phrenic nerve is identified on the anterior surface of the anterior scalene muscle. With bipolar cautery this is
gently mobilized medially. (Reprinted from Donahue DM. Supraclavicular First Rib Resection. Oper Tech Thorac Cardiovasc
Surg 2011;16(4):252–266. Copyright © 2011 Elsevier. With permission.)
A closed suction drain is placed, which is frequently removed on the first or second postoperative day.
Most patients are admitted for one or two nights, and early ambulation and range-of-motion exercises of
the neck and arm are begun immediately. Resistance work of the neck and upper-extremity musculature
should be avoided for the first 6 to 8 weeks.
For the patient’s with VTOS, anticoagulation is typically begun on the second postoperative day and
continued for a total of 3 months. Occasionally, a repeat venogram is performed at approximately 1 month
postoperatively. Any remaining scar tissue within the vein can be easily addressed with a balloon
angioplasty if necessary.
Transaxillary Approach to Thoracic Outlet Decompression

In some centers, the transaxillary approach is the primary surgical technique employed for thoracic outlet
decompression in patients with VTOS, and in patients who have inadequate improvement in symptoms of
neurogenic TOS following attempts at nonoperative management. Purported benefits of this approach over
the supraclavicular approach are two-fold. First is superior cosmesis, as the scar is conveniently hidden
in the axilla. The second rationale is increased safety, as 1st rib resection can be performed without
significant retraction of the brachial plexus and axillary-subclavian vessels.3,25,26 On the other hand, the
decreased access to the neurovascular structures via this technique may contribute to incomplete
decompression of the thoracic outlet, and in the authors’ practice, may result in eventual treatment failure
and recurrence of symptoms. Furthermore, the surgical wound tends to be deeper in this technique
requiring higher quality lighting and magnification in the operating room.26
FIGURE 46.3 Division of middle scalene muscle fibers off of the anterior and upper surfaces of the 1st rib posteriorly. Gentle
retraction of the upper and middle trunks of the brachial plexus provides this exposure. (Reprinted from Donahue DM.
Supraclavicular First Rib Resection. Oper Tech Thorac Cardiovasc Surg 2011;16(4):252–266. Copyright © 2011 Elsevier. With
permission.)
FIGURE 46.4 The suprapleural membrane (Sibson fascia) is bluntly peeled off of the underside of the first rib. (Reprinted from
Donahue DM. Supraclavicular First Rib Resection. Oper Tech Thorac Cardiovasc Surg 2011;16(4):252–266. Copyright © 2011
Intubation may be performed with a double lumen tube, allowing for collapse of the ipsilateral lung if
needed, thus minimizing the likelihood of lung injury during the procedure. The procedure is performed
with the patient in the lateral decubitus position with a contralateral axillary roll to provide additional
anchoring. The forearm on the operative side is abducted to 90 degrees using a traction apparatus.
Weights of 0.5 to 1 kg are required to maintain abduction with care taken to avoid hyperextension or hyper
abduction at the shoulder. Arm holders keep the arm secure in the desired position. The apparatus is set
up in a way that allows ease of access to anesthesia or a circulating assistant so that adjustments may be
made throughout the case to optimize exposure and to provide intermittent relaxation of the arm as
necessary.26
FIGURE 46.5 Working between the trunks of the brachial plexus, the posterior 1st rib is divided medial to the transverse
process of the T1 vertebrae. (Reprinted from Donahue DM. Supraclavicular First Rib Resection. Oper Tech Thorac
Cardiovasc Surg 2011;16(4):252–266. Copyright © 2011 Elsevier. With permission.)
FIGURE 46.6 Incision: The incision is transaxillary below the hairline and transverse between the pectoralis major muscle
anteriorly and the latissimus dorsi muscle posteriorly (inset). The incision is carried directly to the chest wall without angling up
toward the 1st rib. When the chest wall is encountered, the dissection is carried superiorly to the 1st rib, identifying the intercostal
brachial nerve, which exits between the 1st and 2nd ribs. It is preserved by retracting it anteriorly or posteriorly. (Division
produces 6 months to 1 year of paresthesia on the inner surface of the upper arm.) The 1st rib is dissected subperiosteally with a
Shaw–Paulson periosteal elevator and the scalenus anticus muscle is identified. A right-angle clamp is placed behind the muscle,
with care not to injure the subclavian artery or vein. The scalenus muscle is divided near its insertion on the 1st rib. (This
prevents injury to the phrenic nerve, which courses away from the muscle at this level.) (V, vein; SA, scalenus anticus muscle;
A, artery; BP, brachial plexus; SM, scalenus muscle.)
The procedure begins with a transverse incision just caudal to the axillary hairline between the
latissimus dorsi muscle and the pectoralis major muscle (Fig. 46.6). The incision is continued
perpendicular to the chest wall down to the level of the external IC muscles. During this initial dissection,
care is taken to avoid damaging the intercostobrachial nerve as it emerges between the 1st and 2nd ribs
and travels to the subcutaneous tissue near the surgical incision. This nerve may be carefully retracted
anteriorly or posteriorly to avoid injury (palsy of the nerve is associated with 6 to 12 months of numbness
over the inner surface of the upper arm). At the level of the chest wall, the dissection is then directed
cephalad toward the 1st rib along the external thoracic fascia. Exposure is optimized using a narrow
Deaver and a lighted right-angled breast retractor. Additional illumination and magnification may be
obtained using a video thoracoscope. Dissection is continued carefully beyond the 1st rib to outline the
anatomy of the neurovascular bundle and the scalene muscles in relation to the rib. Using a periosteal
elevator, the 1st rib is separated from the underlying pleura and exposed at its mid-portion to clearly
establish the insertion point of the anterior scalene muscle. With a right angle clamp placed posteriorly to
protect the subclavian vessels, the anterior scalene muscle is then divided off the 1st rib and carefully
resected into the neck to prevent reattachment to Sibson fascia. Division of the anterior scalene muscle
should be performed on the 1st rib to prevent injury to the phrenic nerve which travels along with the
muscle but begins to course away from it at the level of the 1st rib.
Following division of the anterior scalene muscle, the 1st rib is divided along its avascular mid-
portion using a rib cutter (Fig. 46.7). A triangular piece of rib is resected with the vertex of the triangle at
the scalene tubercle to avoid vascular injury. The costoclavicular ligament is then divided with
subsequent resection of the rib back to the costochondral junction. Careful attention is paid to ensure
complete decompression of the vein by removing adhesions that may be encountered at this point. If a
cervical rib is present, resection of its anterior attachment to the 1st rib is performed at the time of
division of the middle portion of the 1st rib. (The remainder of the cervical rib is removed following
resection of the posterior aspect of the 1st rib.) Attention is then turned to the posterior portion of the rib,
which is dissected posteriorly toward the transverse process (Fig. 46.8). The long thoracic nerve runs
along the posterior border of the middle scalene muscle and should be preserved as this muscle is
carefully stripped (not cut) off the 1st rib. Following dissection, the posterior segment of the rib is
divided at its articulation with the transverse process. Complete resection of the head and neck of the rib
is imperative to minimize the likelihood of treatment failure secondary to irritation of neurovascular
structures by regenerated fibrocartilage (Fig. 46.9). This is performed using rongeurs, with care taken to
avoid damage to the C8 and T1 nerve roots. Neurolysis of these nerve roots (including C7) and the
brachial plexus is then performed prior to closure.
FIGURE 46.7 Dissection: After the scalenus muscle has been divided, the 1st rib is dissected free subperiosteally and separated
from the pleura. A triangular piece of the rib is removed in the avascular area. The vertex of the triangle removed is at the
scalene tubercle. The anterior part of the rib is removed by dividing the costoclavicular ligament and resecting the rib
subperiosteally back to the costal cartilage of the sternum.
FIGURE 46.8 Posterior rib dissection: The posterior part of the rib is dissected subperiosteally to the transverse process, where
it is divided using a pair of rib shears. The rib may be resected posteriorly using an Urschel–Leksell reinforced rongeur. Care is
taken to avoid injury to the C8 and T1 nerve roots as the scalenus medius muscle is dissected from the rib.
FIGURE 46.9 Head and neck rib portion removal: After the transverse process articulation is visualized, the head and neck of
the rib are removed using an Urschel reinforced pituitary rongeur. It is important to remove the complete head and neck of the
rib so as to minimize regeneration. Care is taken not to injure the T1 nerve root below or the C8 nerve root above. Following
complete removal of the 1st rib, neurolysis of the C7, C8, and T1 nerve roots as well as the middle and lower trunks of the
brachial plexus is performed. A video thoracoscope is used for this purpose because of its magnification and light. The scalenus
medius and scalenus anticus muscles are resected up into the neck so that they will not reattach to Sibson fascia or the pleura.
In patients with upper-extremity pain syndromes including reflex sympathetic dystrophy, a dorsal
sympathectomy has been performed concurrently through the same incision, although its role is
controversial and remains unproven.26 When performed, this is initiated by separating the pleura from the
vertebrae to identify the sympathetic trunk. Following clipping of the sympathetic chain above the T1
ganglion and below the T3 ganglion (and also clipping of the gray and white ramus communicans to each
IC nerve root), the ganglion is divided sharply at T1 and T3 to remove the sympathetic chain. Frozen
sections confirm the presence of ganglion cells in resected tissue. A chest tube is placed for drainage with
subsequent closure of the subcutaneous tissue and skin (no division of major muscle groups during the
procedure). Postoperative hospital stay is 2 to 3 days with 3-month abstinence from heavy lifting as the
only activity restriction imposed upon discharge.
VATS AND ROBOTIC OPTIONS FOR THORACIC OUTLET

DECOMPRESSION
The principles of management of TOS via thoracoscopy and robotic surgery are essentially identical to
those governing treatment via the open approach. Resection of the entire 1st rib and adequate
decompression of the scalene muscles are imperative with care taken to avoid inadvertent damage to key
neurovascular structures. The initial VATS technique described by Ohtsuka et al.27 involved intubation
with a dual-lumen tube (for single lung ventilation) with subsequent placement of the patient in the lateral
decubitus position. Both surgeons were positioned anterior to the patient. Access was transthoracic with
placement of three ports: two working ports in the anterior 3rd and lateral 5th IC space, and a camera port
in the lateral 6th IC space. There have been several modifications to this initial technique, including
surgeon positioning (some surgeons now favor having the first assistant stand posterior to the patient)28
and port site selection (some surgeons use a single 4 to 6 cm transaxillary incision without additional
ports).28,29 Upon camera insertion, key structures including the subclavian vessels, the brachial plexus, the
internal mammary artery, and the sympathetic chain should be identified for proper orientation and
maximization of safety.
The surgical technique involves using a harmonic scalpel to dissect the parietal pleura and IC muscles
off the 1st rib.27 Next, the rib is freed of all critical structures including the subclavian vein anteriorly, the
subclavian artery, and then brachial plexus posteriorly. Thoracoscopic versions of periosteal elevators
are used to perform circumferential rib isolation followed by division of the rib in its mid-portion using
an endoscopic bone cutter.30 Division along its mid-point allows for manipulation of the rib in a trap door
configuration around its medial and lateral attachments. Protection of key structures during this initial
phase is imperative and this is achieved by starting the dissection anterior to the vein with division of
additional scalene attachments after rib transection and, by placing an elevator behind the rib during
cutting.31 Following division, the anterior and posterior portions of the rib are removed through one of the
ports sites. A thoracoscopic rongeur is then used to remove any remaining 1st rib anteriorly to the sternum
and posteriorly to the costochondral junction. In the transthoracic VATS approaches, a chest tube is placed
prior to closure.
With the increasing expansion of the application of robotic surgical technology, some centers are now
performing surgery for TOS using robotic techniques.32 The positioning, access, and approach mirror the
thoracoscopic method with slight variations in trochar placement.32 The camera is placed in the lowest
port at the 5th IC space. Placement of hooked cautery and a grasper is done through the medial and lateral
ports, respectively, both in the 4th IC space. A fourth, smaller incision may be made one rib space caudal
to the camera port for placement of a lung retractor if needed. Dissection is performed in a cranial
direction with special attention paid to the area between the subclavian artery and vein which is often the
thinnest portion of the 1st rib and most suitable for division.32 Following dissection, the robotic arms are
withdrawn to allow for thoracoscopic rib division using a bone cutter. The robotic arms are then
reintroduced with exchange of the grasper for another hooked cautery device. The two arms alternate
between inferior retraction and dissection of connective tissue and scalene muscles over the cephalad
aspect of the rib. The medial aspect of the rib is removed first from its sternal attachment followed by
dissection of scalene muscles from the lateral aspect of the rib with subsequent dislocation from
costocervical attachments. The specimen is removed from one of the robotic ports. A chest tube is placed
(with or without a tunneled pain catheter) prior to wound closure.32
Advocates of the VATS and robotic techniques argue that these approaches allow for better
visualization without dissection of the brachial plexus and subclavian vessels that travel just cephalad to
the 1st rib. Outcomes thus far in small series have reportedly been comparable to those in cohorts of
patients undergoing open repair.33 An additional purported benefit of the robotic technique over the open
and VATS approaches includes better maneuverability within a limited operating field. The authors
believe, however, that access to the neurovascular bundle is important to minimize the likelihood of
failure and this access is unfortunately limited through the current robotic and VATS approaches. Robotic
TOS surgery has thus far been predominantly applied in patients with venous disease and it may not be as
successful in other subsets of TOS. Furthermore, the cost of robotic surgery may not yet be offset by the
potential benefits in terms of visualization and maneuverability.
REFERENCES
1. Huang JH, Zager EL. Thoracic outlet syndrome. Neurosurgery 2004;55(4):897–902, 903.
http://www.ncbi.nlm.nih.gov/pubmed/15458598. Accessed November 9, 2016.
2. Lindblad B, Tengborn L, Bergqvist D. Deep vein thrombosis of the axillary-subclavian veins: epidemiologic data, effects of different
types of treatment and late sequelae. Eur J Vasc Surg 1988;2(3):161–165. http://www.ncbi.nlm.nih.gov/pubmed/3410064. Accessed
November 9, 2016.
3. Urschel HC, Kourlis H, Kourlis H, Jr. Thoracic outlet syndrome: a 50-year experience at Baylor University Medical Center. Proc (Bayl
Univ Med Cent) 2007;20(2):125–135. http://www.ncbi.nlm.nih.gov/pubmed/17431445. Accessed November 4, 2016.
4. Cormier JM, Amrane M, Ward A, et al. Arterial complications of the thoracic outlet syndrome: fifty-five operative cases. J Vasc Surg
1989;9(6):778–787. http://www.ncbi.nlm.nih.gov/pubmed/2657121. Accessed November 9, 2016.
5. Nehler MR, Taylor LM, Moneta GL, et al. Upper extremity ischemia from subclavian artery aneurysm caused by bony abnormalities of
the thoracic outlet. Arch Surg 1997;132(5):527–532. http://www.ncbi.nlm.nih.gov/pubmed/9161397. Accessed November 9, 2016.
6. Coote H. Exostosis of the left transverse process of the seventh cervical vertebrae, surrounded by blood vessels and nerves, successful
removal. Lancet 1861;i:350–351.
7. Todd T. The descent of the shoulder after birth. Its significance in the production of pressure symptoms on the lowest brachial trunk.
Anat Anz 1912;41:385–395.
8. Adson AW, Coffey JR. Cervical rib: a method of anterior approach for relief of symptoms by division of the scalenus anticus. Ann Surg
9. Naffziger HC, Grant WT. Neuritis of the brachial plexus plexus, mechanical in origin: the scalenus syndrome. J Surg Gynecol Obstet
1938;67:722–730.
10. Clagett OT. Research and prosearch. J Thorac Cardiovasc Surg 1962;44:153–166. http://www.ncbi.nlm.nih.gov/pubmed/13879636.
Accessed November 9, 2016.
11. Roos DB. Transaxillary approach for first rib resection to relieve thoracic outlet syndrome. Ann Surg 1966;163(3):354–358.
12. Roos DB. Congenital anomalies associated with thoracic outlet syndrome. Anatomy, symptoms, diagnosis, and treatment. Am J Surg
13. Makhoul RG, Machleder HI. Developmental anomalies at the thoracic outlet: an analysis of 200 consecutive cases. J Vasc Surg
14. Redenbach DM, Nelems B. A comparative study of structures comprising the thoracic outlet in 250 human cadavers and 72 surgical
cases of thoracic outlet syndrome. Eur J Cardiothorac Surg 1998;13(4):353–360. http://www.ncbi.nlm.nih.gov/pubmed/9641331.
Accessed November 9, 2016.
15. Tague RG. Sacralization is not associated with elongated cervical costal process and cervical rib. Clin Anat 2011;24(2):209–217.
16. Rizk E, Harbaugh K. The muscular axillary arch: an anatomic study and clinical considerations. Neurosurgery 2008;63(4 Suppl 2):316–
17. Jordan SE, Ahn SS, Gelabert HA. Differentiation of thoracic outlet syndrome from treatment-resistant cervical brachial pain syndromes:
development and utilization of a questionnaire, clinical examination and ultrasound evaluation. Pain Physician 2007;10(3):441–452.
18. Jordan S. Differential diagnosis in patients with possible NTOS. In: Illig K, Thompson R, Freischlag J, eds. Thoracic Outlet Syndrome.
London: Springer-Verlag; 2013:49–60.
19. Rayan GM, Jensen C. Thoracic outlet syndrome: provocative examination maneuvers in a typical population. J Shoulder Elb Surg
20. Machanic BI, Sanders RJ. Medial antebrachial cutaneous nerve measurements to diagnose neurogenic thoracic outlet syndrome. Ann
Vasc Surg 2008;22(2):248–254.
21. Seror P. Medial antebrachial cutaneous nerve conduction study, a new tool to demonstrate mild lower brachial plexus lesions. A report
of 16 cases. Clin Neurophysiol 2004;115(10):2316–2322.
22. Torriani M, Gupta R, Donahue DM. Botulinum toxin injection in neurogenic thoracic outlet syndrome: results and experience using a
ultrasound-guided approach. Skeletal Radiol 2010;39(10):973–980.
23. Donahue D. Supraclavicular 1st rib resection. Oper Tech Thorac Cardiovasc Surg 2011;16(4):252–266.
24. Thompson RW, Petrinec D, Toursarkissian B. Surgical treatment of thoracic outlet compression syndromes. II. Supraclavicular
exploration and vascular reconstruction. Ann Vasc Surg 1997;11(4):442–451.
25. Urschel HC, Razzuk MA. Neurovascular compression in the thoracic outlet: changing management over 50 years. Ann Surg
26. Urschel HC, Patel AN. Surgical technique: Transaxillary first-rib resection (with Dorsal Sympathectomy). In: Kaiser LR, Krohn IL,
Spray TL, eds. Mastery of Cardiothoracic Surgery. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:214–215.
27. Ohtsuka T, Wolf RK, Dunsker SB. Port-access first-rib resection. Surg Endosc 1999;13(9):940–942.
http://www.ncbi.nlm.nih.gov/pubmed/10449860. Accessed October 30, 2016.
28. Kara HV, Balderson SS, Tong BC, et al. Video assisted transaxillary first rib resection in treatment of thoracic outlet syndrome (TOS).
Ann Cardiothorac Surg 2016;5(1):67–69.
29. Chan YC, Gelabert HA. High-definition video-assisted transaxillary first rib resection for thoracic outlet syndrome. J Vasc Surg
2013;57(4):1155–1158.
30. George RS, Milton R, Chaudhuri N, et al. Totally endoscopic (VATS) first rib resection for thoracic outlet syndrome. Ann Thorac Surg
2017;103(1):241–245.
31. Urschel HC. Dorsal sympathectomy and management of thoracic outlet syndrome with VATS. Ann Thorac Surg 1993;56(3):717–720.
http://www.ncbi.nlm.nih.gov/pubmed/8379779. Accessed October 30, 2016.
32. Gharagozloo F, Meyer M, Tempesta BJ, et al. Robotic en bloc first-rib resection for Paget-Schroetter disease, a form of thoracic outlet
syndrome: technique and initial results. Innovations (Phila) 7(1):39–44.
33. Soukiasian HJ, Shouhed D, Serna-Gallgos D, et al. A video-assisted thoracoscopic approach to transaxillary first rib resection.
Innovations (Phila) 10(1):21–26.
47
Transthoracic Approaches to the Spine
Christopher W. Seder ■ Michael J. Liptay
INTRODUCTION
Surgical access to the spine can be achieved from an anterior or posterior approach. Combined anterior
and posterior approaches can be performed in a staged or sequential fashion based on the location of the
lesion, condition of the patient, and surgeon preference. The anterior transthoracic approach was first
reported in 1956 for the radical treatment of Pott’s disease.1 The following year, the use of a median
sternotomy to access the C7 to T4 corpuses was described.2 Over the next 50 years, numerous
publications reported the benefits of an anterior transthoracic approach, establishing it as an accepted
technique to access the lower cervical, thoracic, and upper lumbar spine. Approaching anterior spinal
pathology from a posterior midline incision with laminectomy can result in damage to posterior
ligamentous structures and put segmental nerves at risk.
Transthoracic approaches are commonly used in the treatment of thoracic disk disease, osteomyelitis,
vertebral body tumors, vertebral fractures, and major spinal deformities. Neurosurgeons and orthopedic
surgeons commonly enlist the assistance of thoracic surgeons to provide anterior exposure to the thoracic
spine. A thorough understanding of the spinal anatomy and its relation to intra-thoracic structures is
necessary to safely provide access to the thoracic spine. Preoperative assessment in conjunction with the
spine surgeon is necessary to establish cardiopulmonary fitness for surgery and determine the approach
that will provide optimal exposure.
In 1993, video-assisted thoracic surgery (VATS) was first described as an alternative to thoracotomy
for achieving anterior access to the spine.3 Since that time, technologic advances in endoscopic equipment
and increasing experience with minimally invasive surgery have led to the rapid acceptance of VATS for
spine surgery. A VATS approach allows clear visualization from T1 to T12, resulting in reduced tissue
trauma, less postoperative pain, improved postoperative pulmonary function, shorter hospital length of
stay, and reduced complications compared to thoracotomy.4–7
INDICATION FOR ANTERIOR APPROACH TO THE SPINE

Indications for an anterior transthoracic approach to the spine include pain relief, reduction and
stabilization of deformities, cosmesis, drainage of infection, and decompression of the spinal cord to
relieve neurologic symptoms. The spectrum of diseases encountered varies from adults to children (Table
47.1). Spinal deformities are more frequently observed in children, whereas degenerative diseases, both
infectious and malignant, are more common in adults. Spinal deformities can be the result of congenital
diseases, neuromuscular disorders, hemivertebral fractures, pseudoarthritis, Scheuermann’s disease, or
tumors. In contrast, in adults, the indications for an anterior approach most commonly include the
presence of herniated nucleus pulposa (30%), metastatic disease to the spine (27%), infection (22%),
spinal deformities (12%), fracture (6%), and primary tumors of the spine (3%).8
Primary tumors from the lung, kidney, breast, pancreas, or thyroid commonly metastasize to the
spine.9,10 Less often, direct invasion of the vertebral body from adjacent malignancies, such as lung
cancer (primarily superior sulcus tumors), neurogenic tumors (neuroblastomas, ganglioneuroblastomas,
neurofibromas), Wilm’s tumors, or sarcomas (liposarcomas, chondrosarcomas), is seen. Primary tumors
of the spine are rare and include osteosarcomas, plasmacytomas, and chondrosarcomas, among others.
Traumatic injury with destabilization of the spine leading to current or impending neurologic compromise
is also an indication for an anterior approach to the lower cervical, thoracic, and thoracolumbar spine.11
PREOPERATIVE CONSIDERATIONS
The general thoracic surgeon is well equipped to risk-stratify patients prior to a transthoracic approach to
the spine. Obtaining a complete history and physical is the initial step in the preoperative evaluation.
Basic laboratory studies should include a complete blood count, serum electrolytes, albumin, and
transferrin levels. This will give an estimation of the patient’s nutritional status, which may be poor in
patients with cancer, and could affect postoperative wound healing and risk of infection. In addition,
hypercalcemia may be present in patients with destructive metastatic spinal lesions, predisposing them to
perioperative cardiac arrhythmias. Such abnormalities should be corrected prior to surgery. Evaluation
with pulmonary function tests and blood gas analysis is essential, as most complications following an
anterior approach to the thoracic spine are pulmonary in nature.10,12 Likewise, a thorough evaluation of
cardiac status may help to prevent postoperative complications.
TABLE 47.1 Etiologies of Spinal Disorders That Indicate Anterior Thoracic

Approaches
Destructive disorders of vertebral body or disc
Infection
Tuberculosis
Pyogenic infection
Parasitic infestation
Malignancy
Metastatic disease
Involvement by adjacent primary tumors
Primary tumor of vertebral body
Degenerative disk disease: herniated nucleus pulposus
Trauma
Fracture dislocation
Compression fracture
Spinal deformities
Scoliosis
Kyphosis
Lordosis
In cases of hypervascular metastatic tumors to the spine, such as renal cell or thyroid cancer, some
authors recommend preoperative embolization.13,14 The risk of life-threatening intraoperative hemorrhage
must be weighed against the potential for complications with embolization, such as aortic dissection or
occlusion of major spinal arteries resulting in neurologic compromise.10
Anesthesia
General anesthesia with a single lumen endotracheal tube is acceptable for patients undergoing a
transcervical approach (C7 to T2). However, if an open or VATS transthoracic approach is required (T2
to L2), single-lung ventilation with a double-lumen endotracheal tube or bronchial blocker is preferred.
This allows adequate visualization of the spine, without interference from the ipsilateral lung.
Alternatively, the lung must be retracted throughout the case. If an anterior approach is followed by a
posterior approach, the double-lumen tube should be replaced with a single lumen tube prior to prone
repositioning, as facial and tracheal edema often occur while in the prone position. Adequate large bore
intravenous access is required as blood loss can be substantial during some spinal procedures. If a large
amount of blood loss is expected, a cell preservation device should be available to minimize transfusion
requirements.
Positioning
As in all of thoracic surgery, proper patient positioning is essential. Intraoperative fluoroscopy is often
required; therefore, a radiolucent operative table should be used. Both the thoracic and spine surgeon
should be present during patient positioning. For a cervical or trans-manubrial approach to C7 to T2, the
patient should be placed in the supine position, with his/her arms tucked to the side. The head should be
rotated gently away from the side of the surgery and stabilized with a foam ring. If a thoracotomy or VATS
approach is used to access T2 to T12, the patient should be positioned in the lateral decubitus position,
with their shoulders and hips perpendicular to the floor. This is required for spinal imaging and
stabilization in correct anatomic alignment. The break in the table may be placed at the vertebral level of
interest, as this allows flexing of the table to open up disk spaces, if deemed necessary. Appropriate
padding of all pressure points is essential to avoid injury while the patient is anesthetized. This includes
the use of an axillary roll to protect the brachial plexus. The patient should be secured in place using
beanbags or similar rolls and taped to the table to avoid intraoperative shifting. The lower leg can remain
straight, while the upper leg should be flexed at the hip and knee to relax the psoas muscle. The arms
should be suspended in an anatomic position to minimize the risk of orthopedic or neural injury. For a low
thoracic or thoracolumbar approach to T12 to L3, the patient is placed in the prone position with his/her
hips parallel to the table and a roll under one hemithorax to allow access to the retroperitoneum, if
needed.
Intraoperative monitoring of somatosensory-evoked potentials is used, as deemed necessary.15 In cases
of preoperative neurologic compromise, the leads should be placed prior to positioning to ensure no
injury is caused during patient manipulation on the operating room table. Somatosensory-evoked
potentials can be used by the thoracic surgeon to guide the ligation of segmental vessels when providing
spinal exposure.16
SURGICAL ANATOMY
A thoracic surgeon providing spinal exposure must have a thorough understanding of the relevant anatomy.
Each rib head has two facets that articulate with the vertebral body of the same level and the vertebral
body above. With the exception of the 1st, 11th, and 12th ribs, the rib head covers the disk
posterolaterally and a portion of the neural foramen (Fig. 47.1). The sympathetic chain lies against the
neck of the ribs in the upper thorax and along the lateral border of the vertebral bodies in the lower
thorax. During the operation, it can often be mobilized dorsally, away from the vertebral bodies.
The aortic arch is usually at about the level of T4 and the descending aorta travels along the left side of
the vertebral bodies. Although variable, the thoracic duct is most commonly found just medial to the aorta
and anterior to the vertebral body. It can be injured from either a right- or left-sided approach to the spine.
The surgeon will encounter the azygous system along the anterolateral aspect of the vertebral body in the
right chest.
The lower cervical spine is supplied by the radicular branches of the vertebral, thyrocervical, and
costocervical arteries. In the thoracic and lumbar regions, paired segmental arteries arise at regular
intervals from the posterior aspect of the descending aorta (Fig. 47.2). These arteries run horizontally
along the ventral aspect of the vertebral body and upon reaching the intervertebral foramen, each artery
gives off a dorsal branch that travels alongside of the posterior ramus of the spinal nerve. Spinal branches
then arise from the dorsal arteries, which coalesce to create the three spinal arteries that descend on the
surface of the cord: the anterior spinal artery and paired posterior spinal arteries. The anterior spinal
artery supplies two-thirds of the cross-sectional area of the cord; therefore, compromise of this vessel or
its major feeding braches can have disastrous consequences.
When exposing the thoracic spine, the segmental arteries should be ligated close to the aorta and at as
few segmental levels as possible, so that the collateral blood supply from the intercostals arteries to the
spinal cord remains intact, preventing ischemia. The collateral supply to the spinal cord is redundant in
the cervical and lumbar regions compared with T4 to T9, which has poor collateral supply and represents
the narrowest area of the spinal cord.17 This is called the “critical vascular zone of the spinal cord,” and
interference with its vascular supply may result in paraplegia. The artery of Adamkiewicz is the largest
feeder to the anterior and posterior spinal artery in the lumbar area. It arises on the left side in 75% to
80% of patients between T7 and L4, most often at the level of T8 to T10. Selective angiography or
magnetic resonance angiography with avoidance of the artery may be helpful in deciding on the surgical
approach and preventing paraplegia.18 There is controversy as to whether this vessel must be visualized
by preoperative angiography before operation on the lower thoracic spine, but many surgeons believe it is
unnecessary.19
FIGURE 47.1 Relationship of the rib heads to the vertebral bodies. (Courtesy of Gary W. Chmielewski, MD.)
FIGURE 47.2 Arterial blood supply to the vertebral column and spinal cord.
The venous blood from the spinal cord, vertebrae, and surrounding tissues drains into a venous plexus
that runs both within the vertebral canal and on the surface of the vertebral body (Fig. 47.3). This network
eventually drains into the caval and azygous systems through connections with the intercostals and lumbar
veins. The thoracic surgeon will regularly encounter the anterior venous plexus when exposing the
vertebral column. Due to its extensive collateral network, these veins can usually be cauterized as needed
without untoward effects.
The costal attachments of the diaphragm arise from the medial aspect of the 7th and 8th rib anteriorly
and the 9th through 11th ribs posterolaterally. Posteriorly, the diaphragm forms the medial and lateral
arcuate ligaments, which span the psoas and quadratus lumborum muscles, respectively. The crura of the
diaphragm extend along the anterolateral lumbar spine, extending to L2 on the left and L3 on the right (Fig.
47.4).
SURGICAL APPROACHES
The decision to use an anterior, posterior, or combined approach is generally made by the spine surgeon.
It is usually based on surgeon training, experience, disease process being addressed, body habitus, and
comorbidities. An anterior approach allows access to all aspects of the spine except the contralateral
pedicle and posterior elements. There are several reported advantages provided by an anterior approach,
including less surgical bleeding, a lower risk of infection, and the need for shorter segment fixation
devices, compared to a posterior approach.20 Many spine surgeons prefer an anterior approach for
surgical repair of thoracic disk herniations below T4, as it allows for safe and complete spinal cord
decompression.21 Likewise, an anterior approach has been shown to have a lower rate of recurrence
following repair of vertebral fractures.22 In addition, an anterior approach is often preferred to address
metastatic tumors to the spine, as they most often occur in the vertebral body. A posterior approach with
laminectomy may be able to access vertebral body tumors; however, it necessitates removal of supporting
elements of the spinal column, potentially leading to instability.10 In such cases, a posterior approach
would only be considered in patients who are not expected to tolerate the morbidity of a transthoracic
approach.23 An additional disadvantage of the transthoracic approach is if a cerebrospinal fluid leak into
the pleural space occurs, it can be difficult to manage.24
Most transthoracic approaches are performed through a standard posterolateral thoracotomy. The rib-
spreading and muscle dissection required to perform a posterolateral thoracotomy has prompted
alternative techniques including exposure via an anterolateral thoracotomy.25 This “French window” often
requires an osteotomy but no rib-spreading, which decreases the stress on the costal articulations and
pressure on the intercostal bundles (Fig. 47.5).26 A VATS approach is probably most beneficial when
access to multiple vertebrae and intervertebral discs is necessary, such as in the treatment of scoliosis.
Multiple ports in the lateral chest wall can provide “in-line” access to the thoracic vertebrae and
intervertebral spaces from T4 to L1. When the pathology is localized to one or two vertebrae, an open or
VATS procedure can be considered.
FIGURE 47.3 Venous blood from the vertebral column and spinal cord.
The choice of approach is also dictated by the level and length of spinal involvement. In treating
scoliosis and other deformities, the choice of laterality should favor the side toward which the apex of the
curve is pointed.27 The thoracic incision is placed over the rib that leads to the apex of the curve or the
rib corresponding to the level of involvement. The rib may be excised as a free graft or left as a pedicled
graft, if desired. The aorta can be visualized easily and, unless a concomitant aneurysm is present, it
should not be a problem. The presence of the liver on the right and a spinal lesion at T10 to T12 on the
right may make exposure difficult.
FIGURE 47.4 Anatomy of the diaphragm. (Courtesy of Gary W. Chmielewski, MD.)
Once a thoracotomy or VATS ports are placed and the lung is isolated, the mediastinal pleura overlying
the appropriate vertebral body is opened with cautery and segmental arteries are exposed. The segmental
arteries are ligated proximally and distally close to the aorta to prevent injury to the anterior spinal artery,
which is supplied by collaterals from the intercostal arteries. It is important to be sure the distal end of
the artery does not retract into the spinal canal forming a hematoma. Bipolar electrocautery must be used
when operating near the neural foramen to avoid infarction of the anterior spinal artery and injury to the
spinal cord. Attention should be directed to the lumbar area because of the potential injury to the lumbar
veins that may occur with mobilization. If exposure from T12 to L3 is required, it is generally necessary
to detach the diaphragm. The diaphragm should be divided 1 to 2 cm from its costal margin, avoiding
significant denervation of the muscle. Placement of marking sutures facilitates re-approximation at the
completion of the case using interrupted 1 silk or polypropylene sutures. The peritoneum is then pushed
anteriorly with care taken to avoid injury to the ureter and other retroperitoneal contents.
FIGURE 47.5 The “French window” thoracotomy.
Lesions from C7 to T2 are best approached through a combined cervical incision and sternal split to
the level of the fourth intercostal space; lesions from T2 to T6, through a right thoracotomy incision;
lesions from T6 to T12 through a left thoracotomy; and lesions from T12 to L4 through a left
thoracoabdominal approach with takedown of the diaphragm.
C7 to T2 Exposure
Lesions from C7 to T2 are best approached by a neck incision paralleling the anterior border of the
sternocleidomastoid muscle combined with an upper sternotomy to T4 (Fig. 47.6). The combined cervical
and sternal approach is executed by creating an incision along the anterior border of the
sternocleidomastoid muscle with an upper sternotomy to T4. A pediatric Finochietto retractor can be used
to distract the edges of the sternum. C7 and T1 may be accessed without sternotomy in many cases. The
head of the sternocleidomastoid muscle is divided and the carotid sheath is retracted laterally. The
innominate artery is encircled and retracted inferiorly. The pharynx, thyroid, and esophagus are retracted
medially with gentle pressure. Placement of a nasogastric tube can aid in the identification of the
esophagus. No metal retractors are used near the tracheoesophageal groove to avoid injury to the
recurrent laryngeal nerve. A left-sided neck incision is used unless contraindicated by the laterality of the
disease process because there is a lower likelihood of injury to the contralateral recurrent laryngeal nerve
by retraction of the trachea and esophagus. In patients with kyphotic deformity, the left innominate vein
crosses the field and can be divided with minimal consequence. A drain is left at the completion of the
case and the layers are closed with normal anatomic alignment.
An alternative approach to the upper thoracic spine is via a high posterior thoracotomy. The incision
extends from the level of C7 to the scapular tip, coursing half way between the spine and scapula. All
overlying muscles, including the latissimus, trapezius, rhomboids, and both teres, are divided with
electrocautery. The scapula can then be elevated with a scapular retractor, exposing the thoracic cage.
The chest can be entered through the second intercostal space. To provide more exposure, the second or
third ribs can be divided or resected. Progressively opening the retractor over time will allow the
operative field to be widely exposed. The lung can then be packed out of the way and the mediastinal
pleural overlying the vertebral body opened with electrocautery. From the right, the esophagus and
azygous vein can be mobilized anteriorly with blunt and electrocautery dissection. Venous tributaries of
the azygous must be ligated and divided. Mattress sutures in the pleura anteriorly can help retract the
azygous and esophagus away from the spine.
Large cervicothoracic tumors involving the vertebral column may require a “hemi-clamshell”
approach. Although this technique requires working in a relatively deep field, it has been shown to have
an acceptable morbidity and mortality profile for accessing C4 to T3.28
T2 to T6 Exposure
Lesions from T2 to T6 are best approached through a right posterolateral thoracotomy, entering above the
rib corresponding to the level of spinal pathology. For example, a disk at the level of T4 would be
approached through an incision at the right fourth intercostal space. Exposure is obtained by isolation of
the lung and medial retraction. A left-sided approach may be used if the disease process is primarily left-
sided, if there is involvement of the left lung or other structure, with scoliosis if the rib spaces are wider
on the left, or if a previous right-sided operation has been performed. The pleura should be opened at
least one vertebral level above and one below the target area. As with all approaches, a spinal needle can
be used with fluoroscopy to confirm the vertebral level of interest. Division of the appropriate segmental
arteries close to the vertebral bodies, in the manner previously described, reduces the risk of
compromising the anterior spinal artery. At the completion of the spinal procedure, closure is preceded by
placement of one 24 French chest tube, which is removed using standard criteria.
FIGURE 47.6 Surgical exposure of C7-T2 via a lower cervical incision and mini-sternotomy.
T6 to T12 Exposure
Lesions from T6 to T12 are best approached through a left posterolateral thoracotomy at the level of
spinal pathology. If a rib graft is needed, it is obtained at the time of entry; resection of the 10th rib
provides excellent exposure to the thoracolumbar spine. On entering the thoracic cavity, the lung is
isolated, the inferior pulmonary ligament is taken down, and the mediastinal pleura is opened from the left
mainstem bronchus down to the inferior pulmonary vein, allowing the lung to be mobilized anteriorly. If
mobilization of the aorta is required, this can be easily done. Intercostal arteries should only be divided if
necessary because of the potential resultant morbidity. If the thoracic pathology involves a substantial
number of spinal segments below T6, a spinal angiogram can be performed to visualize the artery of
Adamkiewicz. An atraumatic clamp can be used to occlude segmental vessels in this region while
monitoring for changes in SSEPs. The diaphragm obscures exposure of the spine at this level and has to
be retracted with a sponge stick or horizontal mattress stay suture. A Bookwalter retraction system
(Codman, Raynham, MA) and damp laparotomy pads can be used to retract the ribs, lung, diaphragm, or
retroperitoneal structures. Once the spinal procedure is complete, standard closure is performed, leaving
a 24 French chest tube.
T12 to L4 Exposure
Lesions of the lower thoracic and lumbar spine extending to L3 or L4 are best approached through a left
thoracoabdominal incision with takedown of the diaphragm. In deformities such as scoliosis or
kyphoscoliosis, the convex side is chosen. Otherwise, a left-sided approach avoids mobilizing the liver
and inferior vena cava. The patient is positioned in a 45-degree oblique chest position with the hips and
abdomen parallel to the table. An incision is made from the posterior axillary line to the lateral aspect of
the rectus sheath. The chest is entered through the bed of the resected 10th rib. If access is only required
to L1, the diaphragm can be stripped anterolaterally to access the retroperitoneum. If exposure of L2 to L4
is required, the diaphragm is divided 1 to 2 cm from the periphery in a circumferential fashion starting
with the crus posteriorly and advancing anteriorly to avoid entering the peritoneum. Lateral fibers of
external and internal oblique as well as transversus abdominis muscles are divided. The peritoneum and
retroperitoneal structures are mobilized medially and retracted with particular attention directed to the
location of the ureter. Once exposure is obtained, segmental arteries can be divided and excellent
exposure provided.
VATS APPROACH TO THE SPINE

Video-assisted thoracoscopic surgery (VATS) has been increasingly used for the treatment of a variety of
spinal conditions. The indications for a VATS approach are the same as any open anterior approach,
including scoliosis, fractures, vertebral infections, and malignancies. The treatment of scoliosis is
particularly well suited to a thoracoscopic approach, as there is a need to access multiple vertebral
levels. The only absolute contraindication to VATS is the inability to tolerate single-lung ventilation.
Advantages provided by VATS relate to the reduced injury of surrounding non-pathologic structures. This
results in reduced respiratory complications, pain, blood loss, shorter recovery time, and hospital length
of stay.29,30 In addition, areas of the thoracic spine that are difficult to approach through a traditional
thoracotomy, including the highest and lowest thoracic vertebrae, can be visualized. In addition to the
trans-pleural VATS approach, authors have described extrapleural and paraspinal VATS spinal
approaches.31,32
After a general anesthetic is administered, the patient is placed in the lateral decubitus position with
appropriate padding, and single-lung ventilation is initiated. A right-sided approach is generally
preferred, as the heart occupies less of the right hemithorax and the aorta does not overlie the spine. A
roll can be placed under the patient at the level of interest to open the contralateral intervertebral spaces.
Similar to many VATS pulmonary surgeries, the surgeon stands anterior to the patient. The camera port is
placed in the posterior axillary line, in the seventh intercostal space. A 30-degree camera is preferred
because it allows visualization of the spine from multiple angles. Care should be taken when entering the
pleural cavity, as underlying structures are easily damaged. The remaining ports are placed under direct
visualization. The number and location of the additional ports varies according to surgeon preference and
procedure being performed. Working ports are most commonly placed in the anterior axillary line.
Trendelenburg and reverse Trendelenburg positioning can be used to facilitate exposure. Similar to an
open approach, the pleura overlying the vertebrae is opened with electrocautery. Overlying vessels
should be sparingly divided to minimize the risk of cord ischemia. All vessels must be well cauterized or
clipped with hemostatic agent used to control minor bleeding. A relatively bloodless field is essential for
adequate thoracoscopic visualization. A thoracotomy tray should always be available for the rare
occurrence of uncontrolled bleeding. At the conclusion of the spinal procedure, a 24 French chest tube is
left in place.33
Complications of VATS spinal surgeries are the same as any open anterior approach. Issues specific to
VATS are rare and include trocar injuries or intercostal neuritis from port placement.34 Dural tears must
be immediately identified and addressed. Large tears may necessitate thoracotomy for repair.
MORBIDITY AND MORTALITY

The mortality rate after anterior exposure of the spine varies from 0% to 8.2%.10,35 These rates depend
primarily on the disease process present, patient selection, and the age group undergoing surgery. Patients
with malignancies and those with osteomyelitis have the highest incidence of postoperative
mortality.10,11,16 Mortality rates up to 25%, increased complication rate, and prolonged hospital length of
stay have been associated with an anterior approach for osteomyelitis.11,16 In general, however, the
anterior approach to the spine is regarded as a safe and effective approach. In a series of 1,223 patients
who underwent anterior spinal fusion, only 4 deaths (0.33%) and 2 cases (0.16%) of complete paraplegia
were reported.36 Both patients had undergone anterior corpectomy with strut grafting and a strut graft was
dislodged posteriorly before the posterior procedure could be performed.
Postoperative morbidity following an anterior approach ranges from 9.8% to 42.7% and is primarily
respiratory in nature.16,35 Pulmonary dysfunction, retained secretions, atelectasis, pulmonary edema, adult
respiratory distress syndrome, effusion, and pneumothorax can be observed following surgery.
Aggressive postoperative pulmonary hygiene protocols, including early mobilization (unless
contraindicated by the spine team), coughing, deep breathing, and incentive spirometry, are mandatory.
Adequate pain control is essential to promote these activities. Thus, many surgeons advocate for the use
of paravertebral intercostal nerve blocks and nonsteroidal anti-inflammatory drugs (NSAIDs) to minimize
narcotic requirement.16
Cardiac complications comprise of dysrhythmias, myocardial infarction, and congestive failure.
Careful ligation of intercostal vessels, avoidance of injury to the thoracic duct, and orientation of the
spine surgeon to the relations of the aorta and esophagus to the vertebral bodies decrease the incidence of
vascular complications, chylothorax, and esophageal injuries. Urinary tract infection, cerebrovascular
accident, gastrointestinal complications (primarily ileus), wound infection, and dehiscence are reported
in a varying number of patients. The ureter can be injured during anterior and posterior exposures of the
lumbar spine. It is usually adherent to the posterior peritoneum and is swept forward in retroperitoneal
exposures.
Various nerves are at risk for injury in retroperitoneal operations. Running along the lateral aspect of
the spine, the number of ganglia in the lumbar sympathetic chain varies considerably. Division of the
sympathetic trunk results in a transiently warmer upper or lower extremities. This complication should be
avoidable with care. The iliohypogastric and ilioinguinal somatic nerves—divisions of the first lumbar
nerve, which appears between the first and second lumbar vertebrae—course along the lateral aspect of
the psoas muscle toward the crest of the ileum. The genitofemoral nerve emerges onto the midportion of
the ventral surface of the medial groin and external genitalia and its damage in anterior spine operations
has been noted.
REFERENCES
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paraplegia. Br J Surg 1956;44:266–275.
2. Cauchoix J, Binet J. Anterior surgical approaches to the spine. Ann R Coll Surg Engl 1957;27:237–243.
3. Mack MJ, Regan JJ, Bobechko WP, et al. Application of thoracoscopy for diseases of the spine. Ann Thorac Surg 1993;56:736–738.
4. Newton PO, Marks M, Faro F, et al. Use of video-assisted thoracoscopic surgery to reduce perioperative morbidity in scoliosis surgery.
Spine 2003;28:S249–S254.
5. Newton P, White K, Faro F, et al. The success of thoracoscopic anterior fusion in a consecutive series of 112 pediatric spinal deformity
cases. Spine 2005;30:392–398.
6. Picetti G, Ertl J, Bueff U. Endoscopic instrumentation, correction, and fusion of idiopathic scoliosis. Spine 2001;1:190–197.
7. Kan P, Schmidt MH. Minimally-invasive thoracoscopic approach for anterior spine decompression and stabilization of metastatic spine
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8. Anderson TM, Mansour KA, Miller JI Jr. Thoracic approaches to anterior spinal operations: anterior thoracic approaches. Ann Thorac
Surg 1993;55(6):1447–1451.
9. McAfee PC, Zdeblick TA. Tumors of the thoracic and lumbar spine: surgical treatment via the anterior approach. J Spinal Disord
1989;2:145–154.
10. Walsh GL, Gokaslan ZL, McCutcheon IE, et al. Anterior approaches to the thoracic spine in patients with cancer: indications and
results. Ann Thorac Surg 1997;64:1611–1618.
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13. Giehl JP, Kluba T. Metastatic spine disease in renal cell carcinoma-indication and results of surgery. Anticancer Res 1999;19:1619–
1623.
14. Olerud C, Jonsson H Jr, Lofberg AM, et al. Embolization of spinal metastases reduces perioperative blood loss. 21 patients operated on
for renal cell carcinoma. Acta Orthop Scand 1993;64:9–12.
15. Jacobson GP, Tew JM. Intraoperative evoked potential monitoring. J Clin Neurophysiol 1987;4:145.
16. Pettiford BL, Schuchert MJ, Jeyabalan G, et al. Technical challenges and utility of anterior exposure for thoracic spine pathology. Ann
Thorac Surg 2008;86:1762–1768.
17. Dommisse GF. The blood supply of the spinal cord. J Bone Joint Surg Br 1974;56B:225–235.
18. Nijenhuis RJ, Jacobs MJ, Schurink GW, et al. Magnetic resonance angiography and neuromonitoring to assess spinal cord blood supply
in thoracic and thoracoabdominal aortic aneurysm surgery. J Vasc Surg 2007;45:71–78.
19. Anderson TM, Mansour KA, Miller JI Jr. Thoracic approaches to anterior spinal operations: anterior thoracic approaches [discussion].
Ann Thorac Surg 1993;55:1447–1451.
20. Gokaslan ZL, York JE, Walsh GL, et al. Transthoracic vertebrectomy for metastatic spinal tumors. J Neurosurg 1998;89:599–609.
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608.
22. Nadir A. Anterior approaches to thoracic and thoracolumbar spine. In Chung KJ, ed. Spine Surgery. InTech; 2012.
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24. Volmer DG, Simmons NE. Transthoracic approaches to thoracic disc herniations. Neurosurg Focus 2000;9(4):E8.
25. David EA, Gaffey AC, Mason RB, et al. Modified French-window thoracotomy for exposure of the anterior thoracic spine. Interact
26. Marshall MB, Carter YM. Modified French window as an alternative to thoracotomy for complex intrathoracic pathology. Ann Thorac
Surg 2009;88:685–687.
27. McElvein RB, Nasca RJ, Dunham WK, et al. Transthoracic exposure for anterior spinal surgery. Ann Thorac Surg 1988;45:278.
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1998;115:286–295.
29. Dickman CA, Detweiler PW, Porter RW. Endoscopic spine surgery. Clin Neurosurg 2000;46:526–553.
30. Escobar E, Transfeldt E, Garvey T, et al. Video-assisted versus open anterior lumbar spine fusion surgery: a comparison of four
techniques and complications in 135 patients. Spine 2003;28(7):729–732.
31. Islam S, Hresko MT, Fishman SJ. Extrapleural thoracoscopic anterior spinal fusion: a modified video-assisted thoracoscopic surgery
approach to the pediatric spine. JSLS 2001;5:187–189.
32. Rocco G, Serra L, Mehrabi-Kermani F, et al. Video-assisted paraspinal approach for the stabilization of the complex spine. Interact
33. Longo UG, Papapietro N, Maffulli N, et al. Thoracoscopy for minimally invasive thoracic spine surgery. Orthop Clin N Am
2009;40:459–464.
34. McAfee PC, Regan JJ, Zdeblick T, et al. The incidence of complications in endoscopic anterior thoracolumbar spinal reconstructive
surgery. A prospective multicenter study comprising the first 100 consecutive cases. Spine 1995;20:1624–1632.
35. Janik JS, Burrington JD, Janik JE, et al. Anterior exposure of spinal deformities and tumors: a 20-year experience. J Pediatr Surg
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36. Faciszewski T, Winter RB, Lonstein JE, et al. The surgical and medical perioperative complications of anterior spinal fusion surgery in
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48
Chest Wall Tumors
Daniel G. Nicastri ■ Gunturu N. Swati ■ Elbert E. Williams ■ Raja M. Flores, with
contributions from David R. Jones
Chest wall tumors originate and present in many different ways from primary tumors, to local extension of
adjacent tumors (lung, mediastinum, pleura, or breast), to metastatic tumors, to infectious and
inflammatory conditions. Chest wall neoplasms, both primary and metastatic, can arise from or involve
any portion of the thoracic skeleton, including the ribs, sternum, scapulae, and clavicles.
INCIDENCE AND LOCATION

Primary chest wall tumors are relatively uncommon, representing approximately 5% of all thoracic
neoplasms and 1% to 2% of all primary tumors.1
In the largest series of resected chest wall tumors, two of which are from Memorial Sloan Kettering
Cancer Center, 40% of chest wall tumors resulted from direct invasion from lung cancer (Fig. 48.1), 10%
to 20% were from breast cancer, and 30% were primary tumors of the chest wall2–4 (Table 48.1).
Primary chest wall tumors account for only 0.04% of all new cancers diagnosed and 5% of all thoracic
neoplasms.5 Approximately half of these are benign, and half are malignant.6
Of the primary chest wall tumors, benign tumors range from 21% to 67%. The most frequently
encountered benign lesions are osteochondroma, chondroma, and fibrous dysplasia.2,4,7–10 However, in
the series from the Mayo Clinic, where desmoids are considered benign, the most common benign lesions
were neurilemoma, desmoid tumor, and chondroma.10 However, desmoids are often considered low-
grade malignancies based on their high local recurrence rates, particularly in the chest wall. Across
various series, the most common primary malignant lesions are malignant fibrous histiocytoma,
chondrosarcoma, rhadomyosarcoma, and liposarcoma.4,7–10
Chest wall neoplasms can arise from, or involve, any portion of the thoracic skeleton, including the
ribs, sternum, scapulae, and clavicles. Table 48.2 shows the classification of primary chest wall tumors.
Of all chest wall tumors resected, primary bony and cartilaginous tumors account for approximately 55%,
with 45% being from the soft tissue.11 The most common site of involvement for all chest wall lesions is
the rib cage. Primary lesions of the sternum, scapulae, and clavicles are uncommon, but nearly all are
malignant. Malignant primary chest wall neoplasms can also originate in a previously irradiated field,
although this is a relatively uncommon event. Schwarz and Burt showed that 6% of patients (21 of 351)
with primary chest wall malignancies had received prior irradiation.12
FIGURE 48.1 Invasion from adjacent malignancies or metastases are more common than primary malignant chest wall tumors.
This is a lung squamous cell carcinoma invading the 5th and 6th ribs in a 63-year-old woman.
TABLE 48.1 Largest Series on Chest Wall Tumors and Resections

Authors Year Total Patients With Lung Patients With Patients With Patients With
Patients Cancer, No. (%) Breast Cancer, No. Primary Tumors, No. Metastatic Tumors,
(%) (%) No. (%)
Martini et 1987 317 127 (40) 36 (11) 83 (26) 71 (22)
al.
Mansour et 2002 187 75 (38) 43 (22) 53 (27) 16 (8)
al.
Weyant et 2005 304 99 (38) 26 (10) 79 (30) 100 (38)
al.
TABLE 48.2 Classification of Primary Chest Wall Tumors
Origin Benign Malignant
Bone
Bone Osteoblastoma, osteoid osteoma Ewing sarcoma, osteosarcoma
Cartilage Chondroma (enchondroma), chondroblastoma, Chondrosarcoma
osteochondroma
Fibrous Fibrous dysplasia
Marrow Eosinophilic granuloma Solitary plasmacytoma
Osteoclast Aneurysmal bone cyst, giant cell tumor
Other Mesenchymal hematoma
Soft tissue
Adipose Lipoma Liposarcoma
Fibrous Desmoid (fibroma) Fibrosarcoma, MFH
Muscle Leiomyoma, rhabdomyoma Leiomyosarcoma, rhabdomyosarcoma,
Nerve Neurofibroma, schwannoma (neurilemoma) Askin tumor (PNET), malignant schwannoma, neurofibrosarcoma,
neuroblastoma
Vascular Hemangioma, lymphangioma Hemangiosarcoma
Others — Lymphoma
Tumor location can offer a clue for diagnosis. For example, chondromas and chondrosarcomas
frequently occur at the anterior costochondral junctions. Primitive neuroectodermal tumors (PNETs), or
Askin tumors, and hemangiopericytomas occur more commonly posteriorly adjacent to the vertebral
column.
DIAGNOSIS AND EVALUATION
GENERAL CONSIDERATIONS IN EVALUATION AND MANAGEMENT

The average age of the patient at presentation for benign tumors is 26 years and for malignant tumors is 40
years. The male-to-female ratio is approximately 2:1 for most tumors except for desmoid tumors where it
is 1:2 male-to-female preponderance.13
The most common presentation of chest wall tumors is a palpable mass. Primary malignant chest wall
neoplasms typically manifest as large, palpable, rapidly growing symptomatic masses. Benign chest wall
neoplasms are more likely to be asymptomatic and incidentally detected. Pain is at first generalized and
the patient is frequently treated for musculoskeletal complaint or neuritis. Soft tissue masses are often
painless, whereas both benign and malignant bony lesions are typically painful due to periosteal damage.
Burt and colleagues showed that pain with or without a mass occurred in 49% of patients with
chondrosarcoma, in 95% with Ewing sarcoma, and in 78% with osteosarcoma.11
Paresthesia and weakness may be present if neurologic structures, such as the spinal cord or brachial
plexus are involved. Systemic symptoms of fever, malaise, fatigue, diaphoresis, and weight loss, in
addition to suggesting infection or metastasis, are also seen in eosinophilic granuloma, Ewing sarcoma,
and lymphomas.
Although patients commonly present with mass and/or pain, Sabanathan and colleagues recorded that
>20% of chest wall tumors were found incidentally on routine chest x-rays and, likely, more are found
today incidentally on computed tomography (CT) scan.14
Initial evaluation begins with a complete history and physical examination, with particular attention
given to history of malignancy, exposure to radiation, and presence of familial conditions such as Gardner
syndrome or von Recklinghausen disease. In patients with prior radiation to the chest wall, necrotic
ulceration is a common finding.
Chest radiograph may show bony erosion, lytic lesions, mediastinal lymphadenopathy, and the
presence of large pulmonary metastasis. Old images are valuable in determining growth rate but CT of the
chest is the single best radiographic modality to localize and characterize most chest wall tumors in order
to generate differential diagnosis along with extent of bone, soft tissue, pleural and/or mediastinal
involvement, and pulmonary metastasis. Magnetic resonance imaging (MRI) can help delineate the extent
of muscular invasion, relationship to nearby vessels, and/or spinal involvement by the chest wall lesions.
However, for the assessment of calcifications and lung pathology, a CT is still superior to MRI. Positron
emission tomography (PET) scanning or combination PET-CT scanning is very sensitive in detecting
primary tumors, especially sarcomas (100%), nodal involvement (95%), and bony manifestations. PET
staging is superior to conventional CT and/or MRI.15
BIOPSY
Following history, physical examination, and imaging, a well-planned biopsy with minimal trauma to the
surrounding tissue is very important for the diagnosis of chest wall tumors. There are three options:
needle/core biopsy, incisional biopsy, and excisional biopsy.
Needle Biopsy
Whenever possible, the authors advocate needle or core biopsy. The benefits of needle biopsy include
minimal soft tissue injury, ease of performance, and low complication rate in an outpatient setting. Fine-
needle aspiration (FNA) is done in patients who are suspected of having a metastasis from a prior
documented malignancy. However, for primary bony or cartilaginous chest wall tumor, where a larger
amount of tissue is required for pathologic diagnosis, FNA is not recommended. Percutaneous core needle
biopsy is a viable option for the diagnosis of primary chest wall tumors and is a well-accepted technique
for biopsy of primary bone tumors. An accurate diagnostic rate approaching 90% can be expected in
large-volume institutions.16,17
Incisional Biopsy
Incisional biopsy should be performed when a needle biopsy is nondiagnostic or for primary lesions >5
cm. It is important to orient the skin incision to facilitate its excision at the time of definitive resection and
to promote optimal wound healing, avoiding ulceration and infection that might delay therapy. Skin flaps
should not be raised, and the deep plane of the tumor, in particular the pleural space, should be left intact
to prevent dissemination of tumor cells.
Excisional Biopsy
Smaller lesions (<5 cm) may be diagnosed by excisional biopsy for the following reasons: removal of
entire mass; adequate tissue sampling to establish the tumor’s histology; and earlier administration of
adjuvant therapy, if necessary. Excisional biopsy with minimal margins (1–2 cm) should be employed for
small (<5 cm) primary neoplasms. The operation should be planned with the possibility of a completion
resection to follow, should larger margins be necessary. Tissue planes should be minimally disrupted as
well to preserve potential musculocutaneous flap options. Closure of the chest wall usually can be
performed primarily without reconstruction. If the lesion is benign or best treated with nonsurgical
therapy (chemotherapy, radiation, or both), no further operation is required. If the lesion is a primary
malignant neoplasm, the patient should undergo reoperation with radical excision with wide margins (>4
cm) and appropriate reconstruction.17 Excessive dissection and manipulation of the tissues may alter
subsequent wide excision.
A complete medical evaluation includes consideration of previous operations that may affect approaches
for resection or reconstruction. Patients who have had preoperative radiation therapy commonly have
fibrotic changes in the skin and soft tissues that can limit the utility of local flaps for reconstruction.
Abdominal or thoracic scars may indicate violated or disrupted pedicles for local flaps. For example, the
use of a standard latissimus dorsi flap may not be possible if the patient had an ipsilateral lumpectomy
with adjuvant radiation therapy or nodal dissection. Evaluation of thoracodorsal and long thoracic nerve
function is also helpful to ensure the integrity of the pedicle vessels for the latissimus dorsi and serratus
anterior muscles, respectively.
A multidisciplinary approach is essential for the treatment of many chest wall tumors. This is best
accomplished in the setting of a pretherapy multidisciplinary conference. If a chest wall resection will be
required, preoperative pulmonary function tests should be performed. For osteosarcoma,
rhabdomyosarcoma, Ewing sarcoma, and other small cell sarcomas, evaluation by a medical oncologist,
for possible induction chemotherapy, should be strongly considered. Patients with solitary plasmacytoma
warrant radiation therapy. At the time of resection, communication with pathologists is of paramount
importance to accurately assess resection margins and to determine the malignant potential and grade of
the lesion. Depending on the extent of the resection and the planned reconstruction, involvement of plastic
surgery and neurosurgery may be warranted.
SURGICAL MANAGEMENT
The primary surgical principle in the resection of chest wall tumors is to ensure pathologic (R0)
resection. For high-grade malignancies, 4-cm margins should be obtained, whereas low-grade
malignancies can be treated with 1- to 2-cm margins. Desmoid tumors are not technically malignant, but
their behavior is so aggressive that one should attempt to obtain 4-cm margins whenever possible.
Aggressive malignancies may require that the entire rib be resected, with costal articulations either
posteriorly or anteriorly, depending on tumor location. With rib lesions, the excision should generally
incorporate resection of all or most of the rib involved, a portion of any adjacent ribs, and en bloc
resection of any attached structures, including portions of the pleura, lung, pericardium, thymus, or
diaphragm.
PRIMARY BONE TUMORS
Primary bone neoplasms of the chest wall are uncommon. Dahlin and Unni’s summary18 of a series of
6,034 bone tumors, revealed 355 (5.9%) occurring in either the ribs (85%) or the sternum (15%). Nearly
all were malignant (89%), with sternal tumors slightly more likely to be malignant than rib tumors (96%
vs. 88%). The most common benign bone lesions are osteochondromas, chondromas, and fibrous
dysplasia. The most common primary malignant bone tumors are chondrosarcoma, Ewing sarcoma, and
osteosarcoma.2,10,11
The differential diagnoses for primary chest wall tumors are broad, and these tumors are best
classified according to their tissue of origin—that is, bone or soft tissue—and whether they are benign or
malignant (Table 48.2). Primary tumors of the rib account for 5% to 7% of all primary bone
neoplasms19,20 but make up 50% of bony malignant tumors and the majority of benign bony tumors of the
chest wall. Tumors of the rib arise from bone, cartilage, bone marrow, or vascular or neural structures.
Osteochondroma and fibrous dysplasia are the most common benign rib lesions,19 whereas
chondrosarcoma and osteosarcoma are the most common malignant lesions.21 Ewing sarcoma is the most
common malignant rib lesion in the pediatric population.20
BENIGN BONE TUMORS

The most common benign bony tumors of the chest wall are osteochondroma (30% to 50%), fibrous
dysplasia (30% to 50%), chondroma (10% to 25%), aneurysmal bone cyst (10% to 25%), and
eosinophilic granuloma. Characteristics and treatment, by tumor type, are summarized in Table 48.3.
Osteochondroma
Although osteochondroma is overall an uncommon tumor, it is the most common benign bone neoplasm,
constituting nearly 50% of all benign tumors and 2.7% to 8.5% of all primary rib tumors.22 It arises from
the bony cortex in the metaphyseal region of a rib and develops as a stalked mass. The tumor begins in
childhood and continues to grow until skeletal maturity is achieved, affecting males three times more than
females. The lesion may grow inward, remaining asymptomatic or outward producing a palpable mass. In
the chest, like chondromas and chondrosarcomas, they are typically found at the costochondral joint.
Usually, they can be diagnosed with imaging alone. On CT, there will be punctuate or flocculent
calcification with a mineralized hyaline cartilage cap. The cortex and medullary space blend into
underlying bone, which is how a definitive diagnosis is made on CT or MRI (Fig. 48.2).23 Multiple
lesions can indicate familial osteochondromatosis. Histologically, they have a cartilaginous cap that
ossifies toward the stalk or base of the process like an epiphysis.1 Concerning signs and symptoms of
malignant transformation are pain, erosion of bone, irregular calcifications, or thickening of cartilage cap
more than 2 cm in adults and 3 cm in children.23–25
TABLE 48.3 Treatment of Benign Chest Wall Tumors of Bone Origin
Tumor % Peak Common Location Treatment Malignant
Incidence Degeneration
Osteochondroma 30–50 2nd decade Costochondral junction Resection Yes
Fibrous dysplasia 30–50 2nd/3rd Lateral or posterior rib Resection only if symptomatic or Unusual
decade need diagnosis
Chondroma 10–25 2nd/3rd Anterior rib Resection with 2-cm margin Yes
decade
Eosinophilic 10–25 — Diffuse Radiation No
granuloma
Aneurysmal bone 5 First 2 Posterior spine, Resection for symptomatic lesions No
cyst decades posterior/lateral ribs
Osteomas — First 2 Posterior spine Radiofrequency ablation No
decades
Because osteochondromas have such a typical imaging appearance, resection is not recommended,
unless they are symptomatic or growing. Surveillance of these lesions since an increase in the
cartilaginous cap could indicate a malignant transformation. The risk of malignant degeneration to
chondrosarcoma is related to the thickness of the cartilaginous cap, with caps greater than 2 cm in
thickness being suspicious for carcinoma.19,23 When symptomatic or growing, treatment includes surgical
resection with negative margins to ensure diagnosis. Surgical resection allows complete pathologic
evaluation and symptomatic relief and minimizes the risk of malignant transformation.26 Recurrence after
surgical resection has not been reported.
Fibrous Dysplasia
Fibrous dysplasia is a developmental skeletal disorder in which normal bone marrow and cancellous
bone are replaced by fibrous stroma and immature bone. It accounts for up to 30% of all benign chest
wall tumors. It typically appears in the lateral or posterior ribs18 and occurs most commonly in the second
and third decades of life, with equal frequency in both sexes. Most cases (70% to 80%) involve only one
rib19; however, multiple lesions can occur in Albright syndrome (multiple bone cysts, skin pigmentation,
and precocious sexual maturity in females).
These lesions are slow growing and remain asymptomatic unless they become large enough to cause
symptoms through local compression or pathologic fracture. The radiographic findings are typical: a
trabeculated, expansile lesion with soap bubble or ground glass center and thinning cortex (Figs. 48.3 and
48.4). Amorphous or irregular calcifications may be seen as well.19 Histologically, the lesion consists of
irregularly shaped spicules of bone showing a characteristic fish-hook configuration of the trabeculae and
lack of transformation of the coarse bony fibers to lamellar bone and, occasionally, calcifications that
have been termed “Chinese characters” due to their shape.27 Malignant degeneration is unusual, and these
lesions do not require resection unless symptomatic or if the diagnosis is uncertain.
Chondroma
Chondromas represent 15% of all benign rib neoplasms and most commonly occur in the second and third
decades of life affecting both sexes equally.22 Plain film radiographs demonstrate a slow-growing, well-
demarcated, osteolytic lesion with mild expansion and well-defined sclerotic margins. In the chest, they
are typically found at the costochondral junction (e.g., osteochondromas) and anterior portions of the rib.
Punctate calcifications of the matrix and scalloping of the cortex are often seen, especially on CT and
MRI (Fig. 48.5). Microscopically, they have nodules of hyaline cartilage with chondrocytes containing
small, condensed nuclei. Chondromas can be difficult to differentiate from low-grade chondrosarcomas,
even microscopically. Therefore, when possible, all suspected chondromas are treated as malignant
lesions, and initial wide excision with 2-cm margins is recommended.24
FIGURE 48.2 A: CT scan of the chest. The letter (A) labels the atrium and arrow shows the dense calcification of the tumor.
B: Axial T2-weighted MR image showing cartilaginous apical cap (arrow). (Adapted with permission from Tateishi U, Gladish
GW, Kusumoto M, et al. Chest wall tumors: radiologic findings and pathologic correlation: part 1. Malignant tumors.
Radiographics 2003;23:1491–1508.)
FIGURE 48.3 Typical-appearing fibrous dysplasia as expansile lesion. (Arrow points to lesion.)
Aneurysmal Bone Cyst

These lesions are benign yet locally aggressive, expansile, cystic osteolytic lesions and make up
approximately 5% of all primary rib lesions.28 Most (75%) present before the second decade of life.
Aneurysmal bone cysts most commonly involve the spine, as well as the posterior or lateral aspects of the
ribs.22 In early stages, they are confined to the cortex. However, they can progress to erode through the
bone, with soft tissue extension, often making them difficult to differentiate from sarcomas. MRI may
show multiseptated hemorrhagic cysts with fluid–fluid levels within the tumor. These fluid levels also can
be seen with simple bone cysts, giant cell tumors, and chondroblastomas. Microscopically, these tumors
have blood-filled spaces without endothelial cell linings. Open biopsy may be necessary to confirm
diagnosis, as needle biopsies are often nondiagnostic. Complete excision is recommended only for
symptomatic lesions.
Eosinophilic Granuloma/Langerhans Cell Histiocytosis

Eosinophilic granuloma, also termed Langerhans cell histiocytosis, is a less common tumor in the anterior
chest wall. It is not a neoplasm but a subset of a spectrum of diseases of the reticuloendothelial system
that fall under the umbrella of “histiocytosis X,” including Letterer–Siwe disease (infants) and Hans–
Schüller–Christian disease (children). These masses present with systemic signs and symptoms such as
fever, malaise, weight loss, and lymphadenopathy, as well as local symptoms of chest pain and an
isolated tender mass that has a typical lytic appearance on imaging. Radiographic characteristics include
an expansile lesion with periosteal new bone formation and uneven destruction of the cortex, which
produces endosteal scalloping. The skull is most commonly involved, but 10% to 20% of patients have
rib lesions.29,30 Microscopically, they have nodules of hyaline cartilage, with chondrocytes containing
small condensed nuclei. Diagnosis is made with core needle or open biopsy by identifying Birbeck
granules on electron microscopy. Conversely, excisional biopsy can be performed for diagnosis and is
curative in patients with solitary eosinophilic granuloma. Patients with multiple lesions can be treated
with low-dose radiation therapy.31
Osteoid Osteoma and Osteoblastoma

Osteoid osteomas are benign osteoblastic tumors. They typically present in the first two decades of life
and mostly occur in the spine. The most defining symptom is night pain that responds to both nonsteroidal
anti-inflammatories and salicylates.
Radiographically, CT demonstrates a small (<1-cm) radiolucent lesion, termed a nidus, with a thick
sclerotic margin of reactive bone.1 These tumors have increased uptake on bone scintigraphy and show
soft tissue edema on MR. Pathologically, the nidus contains osteoids at its center, with maturation into
bone trabeculae in a fibrovascular stroma.
FIGURE 48.4 A 45-year-old man with fibrous dysplasia of the left 5th and 6th ribs. A: Note the expansile and amorphous
nature on CT. B: Gross image of resected specimen demonstrates extension into soft tissue. (Image courtesy of Dr. Robert
Jones.)
FIGURE 48.5 A 61-year-old man with chondroma involving the left anterior rib. A: On CT, calcification within the mass is
appreciated. B,C: A left hemiclamshell incision was used to excise the mass with ribs above and below. (Image courtesy of Dr.
Robert Jones.)
Osteoblastomas are rare, benign osteoblastic tumors thought to be on the continuum of osteoid
osteomas. They typically affect the posterolateral shaft of the rib. Imaging reveals a well-defined
osteolytic lesion (>2 cm) with slight expansion but with a sharp sclerotic rim. Histologically,
osteoblastomas are characterized by interconnected trabeculae of bone in a fibrovascular stroma.
Treatment for both types of lesions is usually with radiofrequency ablation. Surgical resection is rarely
necessary.
MALIGNANT RIB TUMORS

Characteristics and treatment of malignant rib lesions, along with their prognostic factors, are summarized
in Table 48.4.
Chondrosarcoma
Chondrosarcomas are the most common malignant bony tumors of the chest wall, accounting for 30% of
primary malignant bone tumors, and are most commonly found on the anterior chest wall.32 Although most
chondrosarcomas are thought to develop de novo, these tumors may also represent a malignant
degeneration of benign chondromas, as both tumors have similar clinical presentations—painful, hard,
slow-growing, fixed masses on the anterior chest wall.5 These tumors usually present in the third or fourth
decade of life,23 with a slight predominance in males.30 Synchronous or metachronous lung metastases are
seen in 10% of patients at the time of presentation.24 Radiographically (Fig. 48.6), CT often demonstrates
a lobulated mass of soft tissue attenuation with dense calcification.23
TABLE 48.4 Treatment of Malignant Chest Wall Tumors of Bone Origin and Prognostic Factors
Tumor % Peak Common Surgery Chemotherapy Radiation Survival Progno
Incidence Location (% ) Factors
Chondrosarcoma 30 3rd–4th Anterior Resection with Ineffective Reserved for 58–96a Margin,
decade chest 2-cm margin positive metasta
wall for low grade, margins or recurre
4-cm margin unresectable age, tu
for high-grade grade a
Osteosarcoma 10–15 2nd decade Rib, Resection after Neoadjuvant Ineffective, 15–27b Margin, r
scapula, chemotherapy reserved for to
clavicle inadequate chemo
resection tumor b
metasta
Ewing sarcoma 5–10 2nd decade — Resection after Neoadjuvant — >60b Response
chemotherapy chemo
metasta
Solitary — — — No role Ineffective Sole modality 40–60b Developm
plasmacytoma multiple
myelom
a10-year overall survival.
b5-year overall survival.
FIGURE 48.6 Computed tomography demonstrating anterior chest wall chondrosarcoma. Note the prominent chondroid matrix
mineralization with mottled calcification (arrows). (Adapted with permission from Rascoe PA, et al.33)
Definitive diagnosis can only be made pathologically, and this often requires abundant tissue in order
to distinguish a well-differentiated chondrosarcoma from a chondroma. Pathologic findings can range
from normal cartilage to obvious malignant changes with plump, atypical, multiple nuclei. These may be
more apparent in the periphery of the tumor. The tumor demonstrates a chondroid matrix with increased
cellularity, with the degree of cellularity, mitoses, and cytologic atypia determining tumor grade.
Resection is the mainstay of treatment, and chemotherapy is largely ineffective. Low-grade tumors can
be resected with 2-cm margins, whereas high-grade tumors should be resected with 4-cm margins (Fig.
48.7). Radiation is reserved for patients who are unresectable or who have positive resection margins,
but it is largely ineffective. Margin status is the most significant predictor of local recurrence: recurrence
among patients with negative margins is 4%, whereas recurrence among patients with positive margins is
73% (10-year survival, 47% and 92%, respectively).34 Other factors associated with prolonged survival
are lack of metastases, lack of recurrence, age <50 years,35 and tumor grade.36,37 The largest series of
resected chondrosarcomas, along with their outcomes and prognostic factors, are summarized in Table
48.5.
Osteosarcoma
Osteosarcomas make up 10% to 15% of malignant chest wall tumors and commonly occur in the rib,
scapula, and clavicles.24 The peak incidence is in the second decade of life. Reported risk factors include
environmental triggers, such as high fluoride exposure and residence on a farm, as well as genetic
predisposition (family history of malignancy, younger age at puberty, association with other
musculoskeletal anomalies, and multiple birth defects).38 In addition, retinoblastoma (RB1 mutation on
chromosome 13q14) carries a 500- to 1,000-fold increased risk of developing osteosarcoma, compared
with the general population. The Li–Fraumeni syndrome (p53 mutation) carries a 15-fold increased risk.
Chest radiographs often demonstrate a characteristic sunburst appearance showing calcifications at
right angles to the bony cortex and bone destruction with tumor merging aggressively with indistinct
borders into normal bone. There is typically a large, heterogeneous mass with areas of bony destruction
on CT (Fig. 48.8). Triangular elevation of the periosteum secondary to reactive new bone formation also
may be evident on a radiograph and is known as the Codman triangle sign. Pathologic fractures are rare.
The tumors generally are lobulated and extend through the cortical bone into the adjacent soft tissue.
Under the microscope, the predominant component may be bony, cartilaginous, or fibrous. Tumor cells are
spindle-shaped, epithelioid, or small and round with osteoid matrix calcification.25
FIGURE 48.7 A 31-year-old woman with chondrosarcoma involving the left anterior chest wall and sternum. A: Dense
calcification within the mass is appreciated on CT. B: Intraoperative imaging demonstrates the mass involving the chest wall,
which was dissected off the underlying structures. (Image courtesy of Dr. Robert Jones.)
TABLE 48.5 Chondrosarcomas: Postresection Outcomes and Prognostic Factors

Authors Year Total Survival (%) Prognostic Factors
Patients
McAfee et 1985 96 96a (wide excision), 65a (local Survival: tumor grade, tumor diameter
al.
excision), 14a (palliative excision)
Burt et al. 1992 88 64b Survival: metastasis, age >50, incomplete resection, local
recurrence
Widhe et 2009 106 92a (wide margin), 47a (intralesional Local recurrence: margin and histologic grade; Metastasis:
al. resection) histologic grade, tumor size, local recurrence
Marulli et 2014 89 70c, 67.1b , 52d , 57.8a Survival: negative margin, tumor grade, age ≤55 yrs, diameter
al. ≤6 cm
a 10-year overall survival.
b 5-year overall survival.
c5-year disease-free survival.
d 10-year disease-free survival.
Because this is a rare tumor, there is no standard consensus to the sequence for therapies. In
osteosarcomas of the extremities, due to the high rates of synchronous metastases, neoadjuvant therapy is
often employed prior to resection. However, in chest wall tumors, it is not as clear. Treatment should
involve some combination of wide resection and chemotherapy.30,39 As with other sarcomas, R0 resection
is associated with improved survival. Osteosarcomas are not radiosensitive, but radiation therapy has
been used following an incomplete resection. Overall survival, even with induction therapy, is 15% to
27% at 5 years, compared with 65% to 75% for extremity osteosarcomas.40 Many patients have
metastases at initial presentation, and radiologic imaging of lungs, bone, and liver is required. Metastases
in the lung historically portended a dismal prognosis with close to 0% 5-year survival.2 More recently,
with adjuvant and neoadjuvant therapy, prognosis in patients with osteosarcoma approaches a 5-year
survival of 15% to 20%. Survival may approach 50% in patients with no evidence of metastases.11,24
Tumor burden, the presence of metastases and response to chemotherapy are most predictive of overall
survival.24
FIGURE 48.8 CT image of a 58-year-old woman with osteosarcoma involving the sternum. (Image courtesy of Dr. Manjit
Bains.)
Ewing Sarcoma
Ewing sarcomas, along with primitive neuroectodermal tumors (PNETs, also known as Askin tumors),
represent highly malignant, small, round cell-type tumors that share a common (t11;22) (q24;q12)
translocation.41 Ewing sarcomas and PNETs represent a clinicopathologic spectrum of the same
neoplastic entity, with PNETs demonstrating more neural differentiation. Approximately 15% of Ewing
sarcomas30 and 50% of PNETs arise in the chest wall.42 They represent 5% to 10% of malignant chest
wall tumors and frequently occur in the second decade of life.43 Their radiographic features can mimic
osteogenic sarcoma, osteomyelitis, or other bone tumors. Mottled destruction, containing lytic and blastic
areas, and elevation of the periosteum and multiple layers of subperiosteal new bone formation can cause
an onion-skin appearance of the bony surface (Fig. 48.9). Magnetic resonance images of Ewing sarcomas
usually demonstrate increased signal intensity on T1-weighted and intermediate intensity on T2-weighted
images.23 Diagnosis is made with incisional biopsy, which demonstrates small, round, blue cells, with
scanty clear cytoplasm and positive staining on periodic acid Schiff. Rosettes, oval nuclei with
neurofibrillary cores, are found only in PNETs and are thus used to distinguish them from Ewing
sarcomas.44
Induction chemotherapy is typically given, followed by wide local excision. Resection should include
the extent of disease identified at pretreatment, and a failure to respond well to chemotherapy is
predictive of local recurrence. Five-year survival in patients treated with chemotherapy and surgery is
>60%.45 For patients with local disease at presentation, metastases reduce 5-year survival from 100% to
30%.24 Bilateral whole-lung radiation has been suggested to improve event-free survival in patients with
lung, bone, or bone marrow metastases.46
Solitary Plasmacytoma/Myeloma
Solitary plasmacytoma in a rib is uncommon. In one series, it represented 6% of all primary chest wall
malignancies and 3% of all plasmacytomas seen.47 It is considered a “medical tumor” and is a solitary
version of disseminated multiple myeloma. Myeloma, overall, is most common in the fifth through seventh
decades of life. Two-thirds of those afflicted are male. Solitary plasmacytoma tends to occur in younger
patients than the disseminated version. Pain is the most common symptom, often without an associated
mass. Radiographically, myeloma appears as an osteolytic lesion with cortical thinning and paracostal
opacities are frequently present. Pathologic fracture is common. To confirm it is localized, an extensive
workup may include bone marrow aspiration and urinary and blood immunoelectrophoresis.
Histologically, they appear as sheets of plasma cells with prominent nucleoli with a characteristic
pinwheel appearance.48
FIGURE 48.9 Ewing sarcoma invading 3rd and 4th ribs in a 34-year-old man.
As in Ewing sarcoma, the primary role of the surgeon is to establish a diagnosis either by core needle,
incisional, or excisional biopsy. The standard primary treatment modality for solitary plasmacytoma is
extensive radiotherapy.49 When refractory to radiotherapy, more extensive surgical resection may be
done, particularly in the case of palliation for pain. The major prognostic factor for survival is the
development of multiple myeloma.
TUMORS OF THE STERNUM, SCAPULA, AND CLAVICLE

Primary chest wall tumors and metastatic lesions can involve the manubrium and sternum. Typical benign
lesions that involve the sternum include chondromas, bone cysts, and hemangiomas. In the Memorial
Sloan Kettering Cancer Center series of primary malignant lesions involving the sternum,
chondrosarcoma was the most common histologic type, followed by osteosarcoma, plasmacytoma, and
lymphoma.35 These represented 14% of bony and cartilaginous tumors. Metastatic tumors involving the
sternum usually originate from the breast, thyroid, or kidney. Treatment of sternal tumors entails complete
surgical resection via partial (<50%), subtotal, or total sternectomy,50 with overall survival related to the
tumor’s histologic type and grade. In our recent report of 78 cases of sternal resections, R0 resection was
an independent prognostic factor.51
The scapula is a common site for primary bone tumors. In the Memorial Sloan Kettering Cancer Center
series, the scapula was the site of origin for malignant bony and cartilaginous lesions in 31% of cases,35
with chondrosarcoma, Ewing sarcoma, and osteosarcoma being the most common. Wide surgical
resection is the treatment of choice. Among scapular lesions, one benign tumor warrants mention. The
benign soft tissue tumor that is classically found at the inferior angle of the scapula deep to the serratus
anterior muscle is elastofibroma dorsi. Elastofibroma dorsi tumors typically occur in elderly women, are
slow-growing, and have a right-sided predominance, although up to 66% are bilateral.52 Patients often
present after developing symptoms, including pain and restriction of movement. Complete surgical
resection is recommended for symptomatic relief or if diagnosis is unclear. This lesion is not known to
have malignant potential.
PRIMARY SOFT TISSUE TUMORS

Primary soft tissue tumors may arise from any cell type of the thorax and may be benign or malignant. The
predominant benign tumors involving the chest wall include fibromas, lipomas, giant cell tumors,
neurogenic tumors, vascular tumors (hemangiomas), and connective tissue tumors (Table 48.2).
Neurogenic tumors involving the bony thorax include neurilemomas and neurofibromas. Neurofibromas
can occur as isolated lesions or in association with von Recklinghausen disease (neurofibromatosis).
Neurilemomas usually occur as solitary tumors that resemble neurofibromas but are not associated with
neurofibromatosis. Although sarcomatous degeneration may occur in neurofibromas and, to a lesser
extent, in neurilemomas, malignant degeneration of benign lesions overall is uncommon, and all can be
treated by local excision.
Malignant soft tissue lesions and, in particular, soft tissue sarcomas account for approximately 50% of
all primary malignant chest wall tumors. Preoperative differentiation between the various neoplasms,
however, can be difficult. When in doubt, as with bony lesions, wide resection of tumor with surrounding
structures is the preferred treatment.
BENIGN SOFT TISSUE LESIONS

The predominant benign soft tissue tumors involving the chest wall are fibromas, lipomas, giant cell
tumors, neurogenic tumors, vascular tumors (hemangiomas), and connective tissue tumors. Benign
peripheral nerve sheath tumors consist of neurofibromas and schwannomas, also referred to as
neurilemomas and neurinomas. Neurofibromas originate from peripheral nerves; in up to 60% of cases,
they can be associated with neurofibromatosis type I, multiple plexiform neurofibromas, or multiple
endocrine neoplasia.42 Although sarcomatous degeneration may occur in neurofibromas and
neurilemomas, malignant degeneration of these benign soft tissue lesions overall is uncommon, and all can
be treated by local excision. Preoperative differentiation between the various benign and malignant
neoplasms can be difficult. As such, when in doubt, wide resection of the tumor, including the surrounding
structures, is the preferred treatment.
One benign tumor that deserves special mention is the elastofibroma dorsi. It is a benign slow-growing
lesion. It presents as an ill-defined fibrotic appearing mass in the subscapular region. Although rare, it is
more common in middle-aged women.53 It may cause pain, and has a typical diagnostic appearance on CT
scan and MRI (Fig. 48.10). CT-guided biopsy and resection of symptomatic lesions is recommended.
FIGURE 48.10 Left-sided elastofibroma in a 45-year-old woman who presented with a left shoulder mass.
MALIGNANT SOFT TISSUE LESIONS

Treatment of malignant soft tissue lesions, along with their prognostic factors, is summarized in Table
48.6. Soft tissue sarcomas of the chest have a wide range of histologic profiles, including malignant
fibrous histiocytoma, angiosarcoma, leiomyosarcoma, synovial cell sarcoma, spindle cell sarcoma,
rhabdomyosarcoma, fibrosarcoma, liposarcoma, and undifferentiated sarcomas. The mainstay of therapy
for soft tissue sarcomas is surgical resection with wide margins. A 2-cm margin is recommended for low-
grade sarcomas, whereas a 4-cm margin with resection of a rib above and below the tumor is
recommended for high-grade sarcomas.17 Desmoid tumors, although benign, are included in this section,
as their clinical behavior may be aggressive.
Desmoid Tumors
Desmoid tumors, also known as fibromas, arise from musculoaponeurotic structures and are considered
myofibroblastic or fibroblastic in origin. Only 10% to 28% arise in the chest wall.43 Their histologic
profile is benign, but because of their tendency to grow into nearby structures and cause compressive
symptoms, they are often treated as though they are malignant. The peak incidence is in the second and
third decades of life. Desmoid tumors can be found in patients with familial adenomatous polyposis,
related to a mutation in the APC gene.
FIGURE 48.11 CT image of a 21-year-old woman with a locally recurrent desmoid tumor involving the left chest wall. (Image
courtesy of Dr. Manjit Bains.)
Most desmoid tumors occur in the abdominal wall, but the chest wall and shoulder girdle are common
sites for extra-abdominal disease.44 The tumor originates in muscle and fascia, extending along tissue
planes and displacing and often encasing surrounding structures, including vessels.54 Initially
asymptomatic, desmoids involving the thoracic inlet can cause paraesthesia, hyperesthesia, and motor
weakness, with progressive neural encasement.
On CT (Fig. 48.11), desmoid tumors have a variable nondescript appearance, depending on the amount
of collagen content, but generally they have similar enhancement to muscle.55 MRI (Fig. 48.12) is strongly
recommended to visualize surrounding infiltration.56
Histologically, there is a spreading pattern of uniform, well-differentiated fibroblasts and fibrocytes
without mitosis or necrosis. Finger-like projections of tumor infiltrating the surrounding tissue well
beyond the gross extent are frequently observed. Based on these microscopic findings and because
desmoids do not tend to metastasize, some authors consider them to be benign fibromatoses.57,58
Surgical resection, when technically feasible, is the standard first-line treatment. However,
observation is a very acceptable strategy for stable, asymptomatic desmoids.59 Recurrence rates for
desmoid tumors are high. Abbas et al. reported a 5-year recurrence rate of 37%, with the rate increasing
to 89% in patients with positive surgical margins.60 Recurrence can be treated with repeat resection, and
patients with multiple recurrences should be considered for adjuvant radiotherapy or targeted therapies.
Radiation therapy is typically used for unresectable disease, for locally recurrent disease, or to treat
patients with positive margins, but its effectiveness remains uncertain.61 Intraoperative brachytherapy has
been used when resection was limited by the tumor’s proximity to vital structures. Tamoxifen, given in
doses equivalent to those used for patients with breast cancer, has been shown to have efficacy against
desmoid tumors and can be used in patients for whom systemic therapy is indicated.62 Imatinib, a
selective tyrosine kinase inhibitor, has also shown promise in treating desmoid tumors, with progression-
free survival of 66% at 1 year in one study63 and 95% at 2 years in another.64 Given the prolonged natural
history of desmoids, longer follow-up is necessary to determine the true efficacy of imatinib.
TABLE 48.6 Treatment of Malignant Chest Wall Tumors of Soft Tissue Origin and
Prognostic Factors
Tumor Surgery Chemotherapy Radiation 5-year Overall Prognostic
Survival (%) Factors
Desmoid tumor Resection with 4- Adjuvant Reserved for unresectable, local 93 Margin
cm margin (doxorubicin) recurrence, or positive margins
MFH Resection Ineffective Ineffective 38 —
Synovial sarcoma Resection Adjuvant 50 —
Rhabdomyosarcoma Resection after Neoadjuvant and Neoadjuvant and adjuvant 60–75 Metastasis
chemoradiation adjuvant
Fibrosarcoma Resection after Neoadjuvant For positive margins 55 —
chemotherapy
Liposarcoma Resection Ineffective Ineffective 60 Margin,
tumor
grade
MFH, malignant fibrous histiocytoma.
FIGURE 48.12 A: CT axial view of left chest desmoid tumor. B: Magnetic resonance imaging non–contrast-enhanced T1 axial
view. (Figures adapted from Povoski SP, Marsh WL, Spigos DG, et al. World J Surg Oncology 2006;4:32.)
Soft Tissue Sarcoma

Soft tissue sarcomas of the chest wall are relatively uncommon. They include fibrosarcoma, liposarcoma,
malignant fibrous histocytoma, rhabdomyosarcoma, dermatofibroma protuberans, and angiosarcoma. Burt
and colleagues reported that primary chest wall sarcomas represented only 6% of all soft tissue sarcomas
seen over a 40-year period.11 Men are affected twice as often as women. The majority of primary chest
wall sarcomas occur in adult life; the exception is rhabdomyosarcoma, which is seen most frequently in
children and young adults <45 years of age. They are often asymptomatic and more commonly found on
the anterior chest wall with a wide range of histologies (Table 48.2).
Malignant Fibrous Histiocytoma

Malignant fibrous histiocytoma occurs in patients between the ages of 50 and 70 and has a bimodal
distribution, with the other peak between the second and third decades of life. There are four histologic
subtypes: pleomorphic, giant cell, myxoid, and inflammatory, with the myxoid subtype having the best
prognosis.65 Treatment is wide excision, as radiation and chemotherapy are ineffective. Five-year
survival is 38%.66 With wide local excision, local recurrence rates are higher than 30%.67 Metastatic
lesions are found in 30% to 50% of patients at diagnosis.66
Synovial Sarcoma
Synovial sarcomas of the chest wall are uncommon but when present occur in adolescence to early
adulthood. Radiographically, these heterogeneous masses demonstrate well-defined margins, cortical
bone destruction, tumor calcifications, and tumor infiltration of the chest wall musculature. They often
demonstrate fluid levels on MRI, owing to hemorrhage and necrosis within their cystic components.
Synovial sarcoma is composed of two morphologically different types of cells: epithelial cells and
fibrosarcoma-like spindle cells. Given the rarity of this tumor, the choice of treatment is controversial.
One approach is surgical resection followed by adjuvant radiation, although radiation can also be used
preoperatively. Another approach is to use definitive chemotherapy, as 50% of synovial sarcomas are
chemosensitive.68 Five-year survival is approximately 50%.42 Known positive prognostic factors include
young age, Her-2 expression, R0 resection, and response to chemotherapy.69,70
Rhabdomyosarcoma
Rhabdomyosarcoma is the second most common malignant chest wall tumor in children. Histologic
subtypes include embryonal, alveolar, and pleomorphic. Treatment entails wide resection followed by
radiation and chemotherapy, although only 10% of rhabdomyosarcomas present with potentially
resectable disease.42 Induction chemotherapy and radiotherapy are sometimes used. The alveolar subtype
was previously thought to be a negative prognostic factor71; however, recent evidence has shown that
overall survival is not affected by histologic subtype, completeness of surgical resection, or size of
tumor.72 Five-year survival is 60% to 75%.72,73
Fibrosarcoma
Fibrosarcomas occur in adults as heterogeneous masses on imaging, owing to necrosis and hemorrhage.
These lesions have a tendency to both recur locally and metastasize. Neurofibrosarcomas, also known as
malignant schwannomas or malignant peripheral nerve sheath tumors, are often associated with
neurofibromatosis (in one-third of patients with neurofibromatosis37) and present with a painful mass,
usually in the third to fourth decades of life. Treatment entails induction chemotherapy followed by
resection, with postoperative radiation used in patients with positive margins.37 Five-year survival is
55%.
Liposarcoma
Liposarcomas are most common in men aged 40 to 60. Treatment comprises wide local excision, and 5-
year survival is 60%.66 Local recurrence rates are high, and there is a minimal role for chemotherapy and
radiation therapy. Margin status, tumor grade, and histologic profile have all been shown to be associated
with survival.74,75
RADIATION-ASSOCIATED MALIGNANT TUMORS

The most common postirradiation tumor of the chest wall occurs in patients who received radiation for
breast carcinoma. It is a rare occurrence and is diminishing with better radiation techniques. Currently, it
represents between 4.8% and 6% of all primary chest wall sarcomas, respectively.12,76 The second most
common indication for radiation that may later result in a chest wall sarcoma is lymphoma. The median
latency period between irradiation and development of a primary chest wall sarcoma ranges from 7 to 12
years.12,77 Histologies of postradiation tumors include osteosarcoma, leiomyosarcoma, malignant fibrous
histiocytoma, as well as undifferentiated sarcomas. The precise mechanism of carcinogenesis for
postirradiation sarcoma is not known. The results of treatment of lesions arising in a previously irradiated
field were comparable to their de novo counterparts, with similar survival rates following wide surgical
resection. Long-term survival seems to be most dependent on the ability to perform a complete surgical
resection.78 Thus, these patients should be treated in a manner commensurate with that typically employed
for the de novo pathologic tumor type.
METASTATIC DISEASE AND RECURRENT BREAST CARCINOMA

The role of surgical resection for metastatic disease to the chest wall, or locally recurrent breast
carcinoma is controversial, because the former reflects disseminated disease and the latter portends it. As
previously mentioned, metastatic or locally invasive disease (from breast or lung) accounts for most chest
wall neoplasms and can occur within the bony thorax or the soft tissues surrounding the ribs, sternum,
scapulae, or clavicle. Although cure is unlikely in these circumstances, most would argue that in select
circumstances, when patients are symptomatic or have ulcerating lesions, palliation can be optimally
achieved.79,80
Anderson and coauthors proposed the following criteria for curative resection: (1) The chest wall is
the only site of disease, (2) locoregional disease is controlled, and (3) complete resection with negative
margins is possible.81 However, a 5-year survival may be as low as 20% for chest wall metastasectomy
or 41% at a median follow-up of 31.5 months in the series by Pairolero and Arnold.7,9 As reviewed by
Incarbone and Pastorino, a number of small series show 5-year survival rates that range from 35% to
58% following curative resection.82 Aggressive treatment of local failure, in select circumstances, in
addition to the potential curative benefit, may result in palliation of pain, remove a potentially unsightly
wound, and achieves optimal local control of disease. However, other options including radiation may be
more appropriate in some circumstances.
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49
Chest Wall Reconstruction
Kei Suzuki ■ Leila Jazayeri ■ Babak J. Mehrara ■ David R. Jones
HISTORY OF CHEST WALL RECONSTRUCTION

The first reported successful chest wall resection was performed in 1878: a partial sternectomy by
Holden. Then, in 1898, Parham performed a resection of the chest wall en bloc with a pulmonary tumor.1
With the advent of endotracheal intubation, closed-chest drainage, and better antibiotics, the success rate
for chest wall resections was further enhanced. During World War II, advances were made in stabilizing
techniques to manage chest wall trauma. This new knowledge was then transferred and applied to chest
wall stabilization after resection of malignancies. Bisgard and Swenson were the first to use rib grafts in
reconstruction after sternal resection.2 In addition, Watson and James used fascia lata grafts to close
skeletal defects.3
The first muscle flap for soft tissue reconstruction of the chest was introduced in 1906, when Tansini
described the use of the latissimus dorsi muscle flap for coverage of the anterior chest wall after radical
mastectomy.4 During the post–World War II era, additional advancements in soft tissue reconstruction of
the chest wall were also made. Pickrell et al. developed techniques and treatment for recurrent breast
cancer,5 and Maier described closure of large thoracic defects with local cutaneous flaps.6 In 1950,
Campbell used a pedicled latissimus dorsi muscle flap to reconstruct a full-thickness anterior chest
wound, covering the muscle with a split-thickness skin graft.7 Additionally, Kiricuta was the first to
describe transposition of the greater omentum for reconstruction of chest wall defects.8,9
These flap options, however, were not largely adopted until the 1970s, when extensive work
performed by Mathes and Nahai defined the blood supply to several muscle and myocutaneous flaps.
Once this was accomplished, coverage of increasingly complex chest wounds became possible,
permitting thoracic surgeons to perform more aggressive resections in the treatment of chest wall tumors.
Accordingly, reports by McCormack and colleagues.10 and Larson and colleagues,11 as well as by Arnold
and Pairolero,12–19 defined aggressive resection of chest wall tumors with immediate reconstruction as
the standard of care. Recently, other synthetic and biologic materials have become available, further
expanding the surgeon’s armamentarium in chest wall reconstruction.
RECONSTRUCTIVE APPROACH
The main goals in chest wall reconstruction are (1) obliteration of dead space, (2) restoration of skeletal
rigidity, (3) prevention of lung herniation and scapula impaction, (4) protection of underlying organs, and
(5) maintenance of cosmesis.20 The general reconstructive approach to the chest wall should consider
three major areas: the pleural cavity, skeletal support, and the overlying soft tissue. Chest wall defects
can generally be divided into partial-thickness or full-thickness defects. Partial-thickness defects maintain
the pleural cavity and skeletal support but lack some component of the overlying soft tissue. When
possible, these defects should be closed primarily with no tension. If the partial defect is too large for
primary closure but the exposed defect has a healthy vascularized bed, skin grafting is an acceptable
method of reconstruction. However, skin grafting of large partial-thickness defects may result in poor
aesthetic outcomes, owing to contour deformities and poor color match. In addition, skin-grafted wounds
have a higher risk of complications when postoperative radiation therapy is used. In these situations,
consideration should be given to local cutaneous advancement flaps or musculocutaneous flaps. If full-
thickness reconstruction is required, one must decide whether the reconstruction involves skeletal
structures alone or in conjunction with the overlying myocutaneous component.
Chest wall reconstruction will be discussed in three separate components: (1) pleural cavity, (2)
skeletal support, and (3) soft tissue coverage.
MANAGEMENT OF THE PLEURAL CAVITY

The goal of restoring the pleural cavity often involves the restoration of an airtight seal to generate
sufficient negative pressure for respiration. A secondary goal is to obliterate postpneumonectomy dead
space, in an effort to prevent accumulation of fluid or development of an empyema. Vascularized tissue is
often required to close off bronchopleural or tracheoesophageal fistulas to create an airtight seal.
Vascularized tissue is also used to fill intrathoracic dead space. Excellent local flap options include
extrathoracic muscles such as the latissimus dorsi, serratus anterior, and pectoralis major.16 In addition,
pedicled omental flaps21 can be passed to the thoracic cavity, either by segmental rib resection or via a
tunnel created through the diaphragm in patients treated with a pneumonectomy. These defects are then
closed over chest tubes for drainage, with appropriate antibiotic coverage. Airtight seal and skeletal
support are necessary for maintaining the chest wall mechanics. If operating for pleural cavity infections,
the success rate is higher if treatment is initiated before maturation of the empyema cavity. Thoracoplasty
or total collapse of the chest wall with obliteration of the remaining pleural cavities is reserved as a last
resort for chronic empyema.
MANAGEMENT OF THE SKELETON

In general, all full-thickness skeletal defects that have the potential for paradox should be reconstructed.
For small defects (<5 cm) or those located posteriorly under the scapula, above the fourth rib, the defect
can be closed with only soft tissues. For patients with large chest wall defects (≥5 cm) or defects
involving more than three ribs, rigid reconstruction is recommended. In deciding which materials to use,
two factors should be considered: (1) location: anterior, lateral, or posterior (if posterior, covered or
uncovered by scapula), and (2) size of the defect to be reconstructed. In essence, reconstruction requires a
prosthesis for stabilization and coverage.22,23
A variety of materials are available for reconstructing the skeletal framework of the chest wall. In
choosing among the abundance of materials, one must think of the qualities that make for the ideal
prosthesis, as determined by Le Roux and Shama24: (1) rigidity to protect underlying organs and prevent
paradoxical movement, (2) inertness to allow in-growth of fibrous tissues and decrease infection, (3)
malleability such that it can be conformed to the desired shape, and (4) radiolucency to provide reference
during follow-up. Although there is no standard for either the method of reconstruction or the material to
be used, Figure 49.1 shows the authors’ general algorithm for reconstruction of full-thickness chest wall
defects.
Meshes and Patches

Meshes offer the advantages of easy handling, long-lasting tolerability, and in-growth of regenerative
tissues. Their permeability prevents occurrence of seroma. They do not, however, provide sufficient
strength and cannot be shaped to the exact shape of the chest wall. Both synthetic and biologic meshes
have been described for use in chest wall reconstruction.
Available meshes and patches include polypropylene (Marlex, Davol & Bard, Cranston, RI, and
Prolene, Ethicon, Somerville, NJ), polyester (Mersilene, Ethicon), and polytetrafluoroethylene (PTFE)
soft tissue patches (Gore-Tex & Gore-Dualmesh, W.L. Gore & Associates, Flagstaff, AZ) and knitted
meshes (Gore-Tex, W.L. Gore & Associates). Vicryl (polyglactin-910) mesh (Ethicon) is an inert,
nonantigenic, biocompatible, and slowly absorbing material, the last quality being the main rationale for
its use in patients at risk of infection.25 Marlex mesh is rigid in one direction and distensible in the other.
It is well incorporated into the chest wall, as it permits tissue in-growth, and it has a low cost. PTFE has
the advantage of preventing fluid and air movement across the reconstructed chest wall.
FIGURE 49.1 Algorithm for full-thickness chest wall defect management. Decision-making is based on the extent of resection,
the location, and the need for skeletal reconstruction and soft tissue coverage. STSG, split-thickness skin graft.
According to a recent study performed by Wiegmann et al.,26 although prosthetic mesh materials are
more tear-resistant, more compliant, and have lower rates of bacterial adhesion, these materials are more
cytotoxic, compared with biologic mesh material. Although these findings are interesting, the clinical
relevance of this study is limited, as the analysis was performed in vitro and changes in tissue
incorporation or biologic modification cannot be fully evaluated. It is commonly accepted, however, that
synthetic mesh may increase complication rates when placed directly over viscera, when the operative
site has been radiated, or if there is evidence of bacterial contamination. For these reasons, synthetic
mesh is contraindicated for contaminated wounds.27 If prosthesis is required in these situations, biologic
mesh may be a better alternative, especially in patients who will have prolonged dependence on a
ventilator.
Biologic meshes, such as bovine pericardium (Tutomesh, Tutogen Medical, Alachua, FL), porcine
dermis (Strattice, LifeCell Corp, Bridgewater, NJ), and acellular dermal matrix (AlloDerm, LifeCell
Corp) have good tensile strength and elasticity. Because they eventually become incorporated into native
tissues,28 these materials are thought to be more resistant to infections in the long-term, compared with
synthetic mesh materials. On the basis of this concept, several studies have suggested that these options
may be useful in cases with increased risk of skin dehiscence and mesh exposure.29–32 However, the
degree of incorporation into native tissues is variable, and biologic mesh material may stretch over time,
resulting in laxity and loss of chest wall stability. In addition, although there is a fair amount of literature
on these materials for abdominal wall reconstructions, their use and the analysis of their use for chest
wall reconstructions have been more limited.
Methyl Methacrylate
When rigid reconstruction is necessary, methyl methacrylate (Simplex P, Stryker Howmedica Osteonics,
Mahwah, NJ) is useful. The so-called “Marlex sandwich” technique was introduced in the 1980s and has
gained popularity since.10,33 In this technique, methyl methacrylate is sandwiched between two layers of
Marlex mesh and conformed to the shape or contour of the defect; the sandwich is secured to the chest
wall with Prolene sutures (Fig. 49.2). Methyl methacrylate provides rigidity and allows customization of
shape to reconstruct different contours and sizes of chest wall defects. The disadvantages of methyl
methacrylate are that (1) the rigidity may actually hinder physiologic movement of the rib cage and (2)
methyl methacrylate may promote seroma formation in the surrounding soft tissues, increasing the risk of
infection. For the latter reason, we recommend leaving some space within the methyl methacrylate, rather
than making a thick sheet, to allow some tissue in-growth.
FIGURE 49.2 Intraoperative images of anterior chest wall defect, using polymethylmethacrylate. A: A large anterior chest wall
defect in the left anterior chest wall through a left hemiclamshell incision. B: Prolene sutures are placed in the surrounding ribs
and skeletal structures. C: Using the “sandwich” technique, polymethylmethacrylate is applied between two layers of Marlex
mesh. D: Sutures are tied down, and the excess mesh is excised.
Another option is the construction of neo-ribs.34 In a technique described by Dahan et al., Kirschner
wires are inserted into the ribs, over which silicone molds are threaded and secured with ties. Methyl
methacrylate is then injected in the silicone mold to form the neo-rib. The use of titanium as neo-ribs has
also been described.35 We have also constructed neo-ribs with the use of Steinmann pins, which are
subsequently covered with Penrose drains and injected with methyl methacrylate (Fig. 49.3).36 We do still
recommend placing a mesh or patch over the neo-rib: first, to prevent lung herniation, and second, to
allow tissue in-growth. The advantage of neo-ribs is that they provide the necessary rigidity while
reducing the amount of methyl methacrylate needed, thus allowing more physiologic chest cage movement,
compared with the sandwich technique, while also minimizing complications related to seroma formation.
In the authors experience at Memorial Sloan Kettering Cancer Center, in 262 patients undergoing chest
wall resection and reconstruction, the type of reconstruction (rigid vs. nonrigid) was not associated with
postoperative morbidity.37
Osteosynthesis Systems/Titanium Plates

Osteosynthesis systems are useful in multistage rib bridging or anterior chest wall stabilization. This
system includes a set of rib staples with straight and angular connectors. Stratos (MedXpert, Heitersheim,
Germany) is one such system that utilizes titanium.35 Synthes Titanium Sternal Fixation System (Synthes,
Solothurn, Switzerland) is another system that offers moldable, titanium, multiholed plates, which
accommodate screws of different lengths to be drilled into the ribs or the sternum.38,39
Titanium offers the advantage of having the highest strength to weight ratio of any metal, it has the
ability to integrate with bone, and it is resistant to infection. Its pliability also more closely mimics
physiologic rib movement.40 Its nonferromagnetic properties allow patients to be examined by MRI
postoperatively. In general, additional materials (i.e., mesh and patch) are applied for visceral coverage
and structural support (Fig. 49.4).
Sternal Reconstruction
Sternal reconstruction provides yet another challenge to the thoracic surgeon. For partial sternectomies
(<50% of sternum), mesh or patch reconstruction without rigid reconstruction should provide sufficient
results while offering the simplest solution. For subtotal or total sternectomies, rigid prosthetic
reconstruction is recommended. Traditionally, sternal reconstruction has been performed with mesh and
patch, with the addition of methyl methacrylate when rigidity is necessary. More recently, new materials
and surgical techniques have been developed, showing promising results.
FIGURE 49.3 A: A large defect in the anterior chest wall is demonstrated after resection of the tumor, measuring
approximately 11 cm in width by 9 cm in height. A Steinmann pin is conformed to the desired shape. B: A Penrose drain is cut to
a length shorter than the Steinmann pin, and the pin is placed through the Penrose. The Steinmann pin with the Penrose is placed
in the patient after holes are drilled on each side. C: Methyl methacrylate is injected into the Penrose. D: The Penrose is
removed, and the construction of the neo-rib is complete. Marlex mesh is secured to the superior native rib. The mesh is
wrapped around the neo-rib and sutured to itself with Prolene stitches.
Fabre et al. observed no perioperative deaths and only one case of wound infection (4%) in their
series of 24 patients undergoing sternectomy followed by reconstruction using the Stratos system.41 In
another series that used the Stratos system, similarly low rates of infection were reported,42,43 highlighting
one of the important merits of titanium prosthesis.
Another recent development for sternal reconstruction is the Ley prosthesis, which is a 0.5-mm-thick
titanium alloy plate shaped like a stepladder. It is flexible and adapts to the sternal contour. Its successful
use in three patients after resection of sternal chondrosarcoma was recently demonstrated by Pedersen et
al.44
Recently, a promising custom-made titanium implant designed by the use of sophisticated software was
described by Turna et al.45 In this technique, the implant model is digitally designed from CT images
using software (3-matic [version 8.0] and Magic RP [version 17.02], Materialise Medical, Leuven,
Belgium).
Girotti et al. reported their innovative approach for reconstructing the sternal defect using a method
they call the “rib-like technique.”46 In this technique, polyester multifilament knitted mesh (Surgimesh Pet,
Aspide Medical, La Talaudière, France) is stretched over an aluminum chest cast. A radiopaque acrylic
resin (Mendec Cranio, Tecres Medical, Verona, Italy) is then modeled over the mesh, filling the
sternocostal tracks of the cast, which is further reinforced by methyl methacrylate resin (Cranioplastic
Type 1-Slow Set, DePuy Synthes, Blackpool, UK). The custom-made prosthesis is fixed to the costal
stumps. The authors reviewed their 29-year experience with 101 consecutive patients who underwent
sternectomy, comparing their techniques as they evolved over time. In their first 14 years of experience
(1980 to 1993), 52 patients underwent reconstruction with mesh prosthesis. In the next 10 years (1994 to
2003), 27 patients underwent rigid reconstruction with various materials. Most recently, 22 patients had
sternal reconstruction using the rib-like technique. Major complication rates were similar across the three
groups (21%, 22%, and 27% for the mesh, rigid, and rib-like groups, respectively). Infectious or
displacement complications leading to prosthesis removal occurred in 8% of the mesh group, 11% of the
rigid group, and 0% of the rib-like group.
FIGURE 49.4 A: A large anterior chest wall defect is noted after resection of a chondrosarcoma. The head of the patient is
toward the top. B: Gore-Tex mesh is used to reconstruct the pericardium. C: Titanium plates are used to provide rigid
reconstruction. Marlex mesh is then used to provide further coverage.
Cryopreserved allografts offer another promising reconstructive material.47 First described by Marulli
et al., this technique utilizes an allograft that is treated with antibiotic solution for 72 hours and
cryopreserved at −80°C. No signs of rejection or infection were noted during the 9-month follow-up
period. In a more recent series of four patients, Dell’Amore et al. observed no operative mortality, no
respiratory complications, and no infectious complications with cryopreserved allografts.48 Major
advantages of this technique include reduced immunogenicity and improved incorporation. The graft acts
as a scaffold for new bone formation and allows recruitment of undifferentiated mesenchymal cells from
adjacent tissue, with subsequent differentiation into osteoprogenitor cells.49
Watanabe et al. reported the use of a sternal ceramic prosthesis composed of hydroxyapatite and
tricalcium phosphate (Ceratite, NGK Spark Plug Co, Aichi, Japan).50 It consists of a customized
prosthetic bone that can be tailored to the anterior chest wall defect by cutting slots and holes in the
Ceratite prosthesis for use as fasteners. This concept is original, and the component material has several
advantages, such as the ability to provide the appropriate template for bone formation, strength, and
biocompatibility. Its main disadvantage is its cost.
As these materials and techniques have been developed only recently, long-term results are lacking.
However, the short-term complication rates have been promising, with fewer infectious complications
than with the traditional techniques.
MANAGEMENT OF SOFT TISSUE
Muscle Transposition
After the skeletal structure is reconstructed, one needs to assess whether there is adequate soft tissue
coverage. In situations where soft tissue coverage is needed, local muscle flaps are utilized as the tissue
of choice. Local muscle flaps are generally safe, require less operative time than free flaps, can be taken
as muscle only or with an overlying skin paddle, and can be combined to create large flaps when needed.
Omental flaps are reserved for partial-thickness coverage or as an alternative in situations where local
muscle flaps have failed or are not available.
Latissimus Dorsi
The latissimus dorsi is the largest muscle in the body. Measuring up to 20 by 40 cm, this large, flat muscle
is a workhorse of chest wall reconstruction. It provides mobility and bulk and reaches the majority of
anterior, lateral, and posterior sectors of the chest. The latissimus is also easily placed into the chest to
address intrathoracic dead space.51 It is, however, not optimal for defects that cross the midline sternum.
The latissimus originates on the iliac crest inferiorly and the thoracolumbar fascia near the midline. It
inserts on the humerus at the intertubercular groove. The muscle has two arcs of rotation based on two
major vascular pedicles: the thoracodorsal artery and the segmental lumbar and thoracic arteries. Its
dominant blood supply is the thoracodorsal artery, which originates from the subscapular artery. The
thoracodorsal artery enters the undersurface of the muscle 5 cm from the posterior axillary fold.52 In the
substance of the muscle, the artery divides into a transverse and a longitudinal branch. Given this
anatomy, the muscle can be divided and taken as a partial latissimus flap on the transverse branch alone.
Partial latissimus flaps spare donor site morbidity and can be useful for smaller intrathoracic defects;
however, this option is rarely feasible and can be associated with increased rates of partial or total flap
loss. In most cases, the latissimus flap is based on the thoracodorsal artery and vein, which have a
pedicle length of 6 to 8 cm. Complete dissection of the latissimus and distal disinsertion provide a wide
arc of rotation, enabling coverage of ipsilateral posterior, lateral, and anterolateral chest wall defects.
However, although the distal portions of the flap may reach the sternum, the blood supply in this area is
somewhat variable and unreliable. This is problematic if too much tension is placed on the pedicle,
particularly if the muscle is disinserted from the humerus.
Alternatively, the latissimus muscle can be transferred on the basis of its secondary blood supply,
which arises by perforating vessels originating from the thoracic and lumbar artery or veins. In this case,
the flap is turned over on itself and can be used to cover defects in the upper midline of the back, after
transection of the primary pedicle. In practice, this option is rarely useful since the lumbar and thoracic
perforators are short and fragile, thereby decreasing the arc of rotation of the flap.
Donor Site Morbidity/Flap Limitations

The donor site morbidity of the latissimus flap may include contour defects, obliteration of the posterior
axillary fold, and the need for skin grafting if a large skin paddle is taken with the muscle. Mild to
moderate shoulder weakness and some loss of motion can also occur early on; this usually improves over
the course of several months.53 In some cases, postoperative physical therapy is necessary to restore
range of motion of the upper extremity. In cases where the dominant blood supply has been compromised
from previous trauma, radiation, or surgery, the muscle can be transposed on the basis of the branch to the
serratus muscle.54 A previous non–muscle-sparing posterolateral thoracotomy also limits the amount of
muscle available for rotation. This procedure divides the muscle and interrupts the choke vessels between
the thoracodorsal artery and the lumbar and thoracic arteries. However, even in cases in which the muscle
has been transected by a previous thoracotomy, the proximal (i.e., intact and vascularized) portion of the
muscle can still be harvested on the basis of the thoracodorsal artery and vein. In some patients, this
approach can provide a substantial flap that may be useful for covering moderate surface or intrathoracic
chest wall defects.
Pectoralis Major
The pectoralis major flap is a particularly useful option for upper sternal defects. It is the second largest
flat muscle of the chest wall and can be used for reconstructing the anterior and lateral chest wall, in
addition to the manubrium and the superior two-thirds of the sternum.
The fan-shaped muscle originates broadly from the sternum, the sternal half of the clavicle, and as low
down as the costal cartilage of the sixth or seventh rib. The muscle converges toward its tendinous
insertion lateral to the bicipital groove of the humerus. Its dominant blood supply is the thoracoacromial
trunk, which enters the undersurface of the muscle at the junction of the lateral and middle-third of the
muscle. It also receives segmental blood supply from the internal mammary perforators.
The flap is most commonly based on the thoracoacromial artery and rotated toward the midline. The
insertion of the humerus can be divided to extend the flap’s reach. With extended reach the muscle can be
advanced into debrided sternal and mediastinal wounds. For sternal wounds without a dead space,
bilateral pectoralis major muscles can be advanced and sutured to each other. On the basis of the
thoracoacromial pedicle, the flap can cover the upper two-thirds of the sternum. The muscle can also be
placed into the chest with resection of the second, third, or fourth rib. The pectoralis major can also be
based on the internal mammary perforators as a turnover flap, enabling coverage of the upper or lower
sternum. Before using the muscle as a turnover flap, the internal mammary vessels and their perforators
should be evaluated with imaging or Doppler ultrasound to ensure patency, especially in the setting of
mediastinitis, wide debridements, and coronary artery bypass.

The pectoralis major can be harvested either as a muscle flap or as a musculocutaneous flap to provide
healthy vascularized skin. The use of myocutaneous flaps in female patients may result in breast distortion
and loss of the anterior axillary fold. In addition, because the pectoralis major muscle is a large muscle
that is responsible for adduction and internal rotation of the upper extremity, harvest or disinsertion of this
muscle may result in decreased strength and range of motion (particularly if both the clavicular and
sternal heads of the muscle are harvested).55
Rectus Abdominus
The rectus abdominis is a long, flat muscle that can easily cover sternal and anterior chest wall defects. In
addition, because the muscle can be harvested with its overlying skin, the bulk of the flap can be used to
fill dead space within the mediastinum. Flap harvest is technically simple and does not require
repositioning, making it a good option when other options, such as the pectoralis flap or the latissimus
dorsi flap, either are not available or are not suitable for reconstructive needs.
The paired rectus muscles provide abdominal flexion and support to the medial abdominal wall. The
muscle originates at the pubic symphysis and inserts on the fifth to seventh costal cartilages. The muscle
can be up to 30 cm long and 10 cm wide. It has two dominant pedicles, the superior and inferior
epigastric arteries. For chest wall reconstruction, pedicled rectus abdominis flaps are based on the
superior epigastric artery, a continuation of the inferior mesenteric artery (IMA). A skin paddle can be
harvested with the muscle oriented vertically over the muscle (VRAM; vertical rectus abdominis flap) or
transversely if extra volume or skin is needed (TRAM; transverse rectus abdominis flap) (Fig. 49.5).56 A
vertically oriented skin paddle is more reliable, given that its perforators are oriented along the entire
length of the muscle. In cases where the IMA has been harvested, the flap can still be harvested on the
eighth intercostal vessels; however, this approach does limit the arc of rotation of the muscle and
increases the risk of partial or total flap loss.

The main drawback of the rectus flap is donor site morbidity. With harvest of the overlying fascia, there is
risk of herniation, especially below the arcuate line, where the posterior rectus sheath does not reinforce
the integrity of the abdominal wall. To avoid herniation, fascia-sparing techniques can be employed, if
possible, and at times mesh reinforcement of the abdominal wall may be necessary. Imaging can also be
obtained for patients with sternal wounds or previous abdominal surgery, to investigate the patency of the
internal mammary vessels, the superior pedicle, and skin perforators.
FIGURE 49.5 In this case, the left internal mammary artery was sacrificed as part of the chest wall resection. A: A right rectus
abdominis flap was used to provide soft tissue and skin coverage for this chest wall defect. B: The flap, pedicled off the right
superior epigastric artery, is rotated upward. C: The rotational flap provides excellent results for this patient.
Serratus Anterior
The small, flat serratus anterior muscle is particularly useful for intrathoracic coverage in chest wall
reconstruction. It is located in the midaxillary line between the latissimus dorsi and the pectoralis major
muscles and can thus be harvested with either of these muscles to augment the amount of muscle or skin
used with either flap.57
The muscle originates from the first through eighth or ninth ribs and inserts on the ventral medial
border of the scapula; it is innervated by the long thoracic nerve. It has two dominant pedicles: the
serratus branch of the thoracodorsal artery and the lateral thoracic artery. The superior slips of the
serratus are supplied by the lateral thoracic artery, whereas the inferior slips are supplied by the serratus
branch of the thoracodorsal artery. Because of this dual blood supply, the inferior slips can be taken
independently, preserving the superior five or six digitations.

Donor site morbidity is related to winging of the scapula and can be avoided by preserving the superior
five or six digitations.
Omentum
The pedicled omental flap is composed of visceral fat, with large feeding arteries and draining veins.
This highly vascular flap molds well onto irregular surfaces, making it an ideal choice for large irradiated
chest wall wounds that result in irregular surfaces of exposed bone, cartilage, or irradiation fibrosis.58
The flap primarily functions as a vascularized base for skin grafts to address large, partial-thickness chest
wall defects on the anterior, lateral, and posterior chest wall. It is also frequently used to cover sternal
defects when the pectoralis and rectus flaps are compromised or are not available. Because the omentum
lacks structural stability, it is often combined with skeletal reconstructions to provide vascularized
coverage.
The omentum possesses a rich arterial arcade derived from dominant vessels descending from the
gastroepiploic artery along the greater curvature of the stomach. The flap can be based on either the left or
the right gastroepiploic artery or vein (although the right is usually dominant and easier to harvest). The
internal arcade can be further divided to increase the length of the pedicle. The pedicle’s length allows
for great flap mobility and reach, making the omental flap a versatile flap for mediastinal defects or
partial-thickness chest wall wounds. The flap is mobilized into the mediastinum or onto the chest through
an incision in the right diaphragm (allowing for the liver to help prevent diaphragmatic hernia) or through
the superior abdominal wall (Figs. 49.6 and 49.7). Once inset, the flap can be immediately skin grafted,
or 48 hours can be used to observe the flap viability prior to final skin grafting.

The omentum is harvested through an upper midline laparotomy incision, thereby increasing the risk of
adhesions and abdominal wall hernias. In addition, tunneling the flap from one cavity to the other leaves
an implicit source for diaphragmatic or upper abdominal hernia. In patients who have undergone previous
abdominal surgery, the omentum can be scarred and adherent to the intra-abdominal contents, which
therefore precludes its use.55 In cancer patients with poor nutrition, the flap may also be scant, without the
expected or desired surface area.
FIGURE 49.6 A: Patient is a 63-year-old male with metastatic breast cancer to the chest wall. B: Preoperative CT scan
demonstrated the lesion overlying the sternum. C, D: Resection of lesion resulted in a large defect in the anterior chest wall.
Free Tissue Transfer

The thoracic trunk is well suited for reconstruction with local flaps, given the availability of many local
muscle flaps (e.g., latissimus dorsi, pectoralis major, rectus abdominis) as well as the omentum.
However, in some cases, local options are inadequate or unavailable. Therefore, microvascular tissue
transfer may be necessary.59 In general, advancements in microsurgical techniques have improved
outcomes with free flaps, while, at the same time, increasing efficiency and decreasing operating room
times. However, these procedures are by definition more complex than those involving local flaps, and in
most cases they require longer operative times and recovery.
Common soft tissue free flaps used in chest wall reconstruction include the tensor fascia lata flap
(TFL), the anterolateral thigh flap (ALT), and the rectus muscle with various orientations of overlying
skin. The TFL flap provides vascularized fascia that can be used for semirigid fixation in full-thickness
defects or in place of semirigid constructs. The ALT flap is a versatile perforator flap that can be
harvested from the patient’s thigh, in supine position, with minimal donor site morbidity. The flap is
extremely versatile, as it can be harvested as a fasciocutaneous flap, as a fascia only flap, or as a
musculocutaneous flap—making it useful for reconstruction of a variety of chest wall defects, ranging
from skin defects, to complex defects with exposed intrathoracic structures, to skeletal defects (Figs. 49.6
and 49.7). In addition, the flap is highly vascularized, enabling harvest of massive skin paddles suitable
for reconstruction in patients with large resections or wide field injury from previous radiation therapy.
Less commonly used free flaps in chest wall reconstruction include the parascapular and thoracodorsal
artery perforator flaps.17,60–62
CHALLENGING SITUATIONS
Infected Field
The reported incidence of infection after rigid reconstruction of the chest wall is 5% to 23%.22 Rigid
chest wall reconstruction in the presence of surgical site infection poses a special challenge to thoracic
surgeons. Both primary chest wall infection and infection from a previous prosthesis result in significant
morbidity and mortality, ranging from 9% to 47%.63 When operating in an infected field, conventional
treatment includes the removal or the nonuse of prosthetic material. However, this approach places the
patient in a critical respiratory situation and often leads to long-term major functional after-effects. The
availability of rib osteosynthesis systems made of titanium has modified the conventional management;
they allow the preservation or use of these implants in a one-step surgical procedure despite deep
infection in the operative site.64
FIGURE 49.7 A: The rigid reconstruction was performed with titanium bars. B: Titanium bars were then overlaid by Marlex
mesh. C: A pedicled omental flap was used to provide soft tissue coverage. D: Additional soft tissue and skin coverage was
provided by a free anterolateral thigh flap.
To avoid local wound complications, the use of new materials such as titanium, cryopreserved grafts,
and acellular collagen may be advocated to reduce the possible need for removal in infected areas. At
least in challenging cases, such as redo operations after complex chest wall reconstructions, the use of
new materials and vacuum-assisted closure have resulted in a lower rate of prosthesis removal,
compared with conventional materials (5.8% for new materials vs. 20% for conventional materials).65
CONCLUSION
Chest wall tumors represent an extremely heterogenous profile and present many challenges to the
thoracic surgeon. Primary tumors of the chest wall are best thought of according to their tissue of origin
(bone or soft tissue) and whether they are benign or malignant. While surgical resection is the mainstay of
treatment for many patients, management is extremely variable, depending on the histologic profile of the
defect, as demonstrated in this chapter. It becomes imperative for the thoracic surgeon to understand this
wide spectrum and the different treatment options available and to involve the appropriate
multidisciplinary colleagues. When surgical resection is planned, communication with pathologists is
critical for determining the appropriate surgical margins. Reconstruction of the chest wall provides yet
another challenge and must be planned in concordance with resection. Thoracic surgeons must have
knowledge of and comfort with the abundance of available reconstructive materials and methods. As is
the case with the initial management and resection of the tumor, reconstruction must take a
multidisciplinary approach and involve plastic surgeons and neurosurgeons when necessary.
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Section
XI
THE DIAPHRAGM
50
Embryology and Anatomy of the
Diaphragm
Thomas W. Shields
This chapter written by Dr. Shields is an example of his classic style. It remains as relevant today as it
did at the time he wrote it. It is included posthumously here in honor of him.
The diaphragm serves as the anatomic division between the thoracic and the abdominal cavities; as such,
it is a muscular structure that is dealt with by both abdominal and thoracic surgeons. The surgical
correction of acquired and congenital abnormalities of the diaphragm may be made from either abdominal
or thoracic approaches, depending on the nature of the lesion, the location of the lesion, other
abnormalities of the chest or abdomen, and the particular training and experience of the involved surgeon.
The diaphragm exists as an anatomic barrier but is not a surgical barrier; a competent surgeon should be
able to handle any surgical problem involving the diaphragm and therefore should be versatile enough to
approach diaphragmatic lesions from either above or below.
EMBRYOLOGY
The diaphragm originates from an unpaired ventral portion (septum transversum), from paired dorsal
lateral portions (pleuroperitoneal folds), and from an irregular medial dorsal portion (dorsal mesentery)
(Fig. 50.1). The septum transversum, formed during the third week of gestation, separates the pericardial
region from the rest of the body cavity. This part of the diaphragm grows dorsad from the ventral body
wall and moves caudad with the other contributors to the diaphragm to reach the normal position of the
diaphragm at about 8 weeks. The pleuroperitoneal folds arise on the lateral body walls, at the level
where the cardinal veins swing around to enter the sinus venosus of the heart. These folds extend medially
and somewhat caudad to join with the septum transversum and the dorsal mesentery to complete the
development of the diaphragm at about the seventh week; the right pleuroperitoneal canal closes
somewhat earlier than the left. Muscle fibers migrate from the third, fourth, and fifth cervical myotomes,
carrying along their innervation, and grow between the two membranes to complete the structures of the
diaphragm. During the 10th week, the intestines return from the yolk sac to the abdominal cavity and, at
about 12 weeks, rotation and fixation of the intestines occur. A delay or variation in the described
timetable may result in a variety of congenital hernias with or without a hernial sac or may even result in
a congenital eventration of a hemidiaphragm. Early return of the intestines to the abdomen before closure
of the pleuroperitoneal membrane results in a hernia through this opening (a so-called foramen of
Bochdalek hernia). A sac is not usually present, but if it is, the return of the intestines may have occurred
after the closure of the pleuroperitoneal membrane but before the migration of the cervical myotomes
between the membranes. Foramen of Morgagni hernias occur anteriorly, almost always have a sac, and
therefore probably result from lack of ingrowth of the cervical myotomes. A congenital short esophagus is
related to late closure of the diaphragm and early return of the intestine to the abdomen. Congenital
eventration may be a total error of ingrowth of cervical myotomes in one or both hemidiaphragms and
therefore is actually a large congenital diaphragmatic hernia and not an eventration. An absent diaphragm
probably represents an error of growth of the septum transversum and other embryologic elements.
Duplication of a hemidiaphragm can occur. The fusion and formation timetable variations may also
involve defects in the diaphragm in association with certain vascular anomalies of the lungs and heart.
FIGURE 50.1 Embryologic components of the diaphragm. (From Shields TW. The diaphragm. In: Nora P, ed. Operative
Surgery: Principles and Techniques. Philadelphia, PA: Lea & Febiger, 1972.)
ANATOMY
GROSS FEATURES
The diaphragm is a dome-shaped structure of muscular fibers radiating out from either side of an
irregularly shaped central tendon; it consists of the right and left hemidiaphragms. In structure and
function, the diaphragm differs from any other muscle in the body. It is a muscular septum between the
abdominal and thoracic cavities, serving as the major muscle of respiration. Its domelike shape allows
important abdominal structures, such as the liver and the spleen, to have the protection of the lower ribs
and the chest wall. The dome of the right hemidiaphragmatic leaf is normally at a higher level than is that
of the left. It has been generally thought that this is the result of the liver mass beneath the right leaf.
However, this view has been brought into question by the studies of Reddy and colleagues.1 Rather than
the former hypothesis, their observations support the concept that the cardiac mass is responsible for the
lower portion of the left hemidiaphragm.
Voluntary muscular fibers originate from the xiphisternum, from the lateral lower six ribs on each side,
and from the external and internal arcuate ligaments that arise from the upper three lumbar vertebrae.
Bilaterally, the muscle fibers insert into the central tendon of the diaphragm. The muscle mass of the
diaphragm is considered by De Troyer and colleagues2 and Rochester3 as comprising two distinct parts: a
thin costal muscle mass and a thicker crural portion. Although both muscle masses are innervated by the
phrenic nerves, their activity on stimulation is different. The differences that result in diaphragmatic and
lower chest wall movement are discussed in Chapter 52. Suffice it to mention that the movement of the
crural portion has lesser effect on ventilatory exchange.
The central tendon is a thin aponeurosis of closely interwoven fascial fibers in the form of a three-leaf
clover. The two lateral leaves form the dome of the diaphragm, and the third (anterior) leaf is fused with
the diaphragmatic surface of the pericardium.
Major interest in the muscular portion of the diaphragm centers on the two crura, which play varying
roles in the formation of the esophageal hiatus. The right crus arises from the bodies of the first and
second lumbar vertebrae, and the fibers divide as they pass to the left, normally overlapping in front and
behind to form the entire esophageal hiatus. Collis and colleagues,4 however, found this arrangement in
only a little more than half of their subjects. In the others, the left crus contributed to a varying degree to
the makeup of the hiatus, and in about 2%, the left crus made up the major portion of the esophageal
hiatus.
FIGURE 50.2 Thoracoscopy revealed a tiny hole about 3 mm in diameter in the right hemidiaphragm. Adjacent spots were
made up of endometrial tissue. (Adapted from Sato M, Kase K. Catamenial pneumothorax with diaphragmatic endometriosis: a
case report. J Jpn Assoc Chest Surg 1997;11:583. With permission from Japanese Association for Chest Surgery.)
The hiatal opening is situated at the level of the 10th thoracic vertebra just to the left of the midline and
just ventral to where the aorta passes into the abdomen. The inferior vena cava passes through the
tendinous portion of the right side of the diaphragm between the anterior leaf and the right lateral leaf at
the level of the eighth thoracic vertebra. The other normal openings are the parasternal foramina (i.e., the
foramina of Morgagni) through which the internal mammary arteries pass into the abdomen to become the
superior epigastric arteries. Evidence suggests that, in some subjects, a variable number of fenestrations
or pores are present or are potentially so in either hemidiaphragmatic leaf. These are more commonly
observed on the right than on the left and are located posteriorly when present. These fenestrations are of
no importance normally but may become the route of fluid or air to traverse from the peritoneal cavity into
the pleural space, as demonstrated by the studies of Park and Pham5 and Urhahn and Gunther6 (Fig. 50.2).
The thoracic side of the diaphragm is covered with the parietal pleura and the abdominal surface with
peritoneum except at the naturally occurring openings, and the bare area is occupied by a portion of the
liver.
BLOOD SUPPLY
The principal blood supply of the diaphragm is derived directly from the aorta or from its most superior
abdominal branches (Fig. 50.3); its venous drainage empties into the inferior vena cava. Both the arterial
supply and the venous drainage (the right and left inferior phrenic veins) are found on the undersurface of
the diaphragm (Fig. 50.4). The inferior phrenic artery usually bifurcates posteriorly near the dome of the
diaphragm, and the branches course along the margins of the central tendon. The smaller posterior
division courses laterally above the dorsal and lumbocostal origin of the diaphragm, where it has
collateral anastomoses with the lower five intercostal arteries. The larger anterior division runs
anterosuperiorly to the edge of the central tendon, where it anastomoses freely with the
pericardiacophrenic artery. The venous pattern is similar except that the veins generally course along the
posterior aspect of the central tendon to join the inferior vena cava. Veins on the inferior surface of the
diaphragm communicate with the hepatic veins through the left triangular and coronary ligaments of the
liver.
FIGURE 50.3 The arterial supply of the diaphragm from the abdominal aorta with variations in the origin of the inferior phrenic
arteries. (Redrawn from Anson FJ, McVay C. Surgical Anatomy. 5th ed. Philadelphia, PA: Saunders, 1971.)
NERVE DISTRIBUTION
The right and left phrenic nerves arise from their respective third, fourth, and fifth cervical nerve roots
and constitute the total nerve supply for the ipsilateral hemidiaphragm. The distribution of each nerve is
important in reference to incisions into the diaphragm. The course of each has been described by
Merendino and colleagues.7 The right phrenic nerve reaches the diaphragm just lateral to the inferior vena
cava and the left is just lateral to the left border of the heart. Generally the nerves divide, either just
above or at the level of the diaphragm, into several terminal branches. Some are distributed to the pleural
and peritoneal surfaces, but the great bulk of each nerve passes into or through the diaphragm and most
often divides into four major rami to supply the various muscular portions. Usually, two of the rami share
a common trunk for a varying distance so that three muscular branches arise from each phrenic nerve: one
anteromedially, one laterally, and the remaining one posteriorly (Fig. 50.5). Injury to any of these
branches causes paralysis of the supplied portion of the hemidiaphragm.
FIGURE 50.4 The arterial and venous distribution on the undersurface of the diaphragm. (Redrawn from Anson FJ, McVay C.
Surgical Anatomy. 5th ed. Philadelphia, PA: Saunders, 1971.)
FIGURE 50.5 Distribution of the phrenic nerves as seen from above. (Reprinted from Merendino KA, Johnson RJ, Skinner SH,
et al. The intradiaphragmatic distribution of the phrenic nerve with particular reference to the placement of diaphragmatic
incisions and controlled segmental paralysis. Surgery 1956;39:189. Copyright © 1956 Elsevier. With permission.)
DIAPHRAGMATIC LYMPH NODES

Lymph nodes of the diaphragm are divided into three groups. The first is the anterior (prepericardiac)
group located behind the xiphoid and to the right and left of the pericardium and belongs to the anterior
parietal group of nodes of the mediastinum. The second group of lymph nodes is located in proximity to
the phrenic nerves bilaterally as the nerves meet the respective hemidiaphragm and is known as the
middle or juxtaphrenic group. The third group is the posterior or retrocrural lymph nodes, which lie
behind the left and right crura. These lymph nodes are in continuity with the posterior parietal group of the
paravertebral sulcus.
SURGICAL INCISIONS
Incisions into the diaphragm must be made to avoid injury to the major branches of the phrenic nerves.
Incision through the central tendon rarely causes diaphragmatic paralysis (Fig. 50.6A,B), but this
approach provides only minimal exposure of the adjacent compartment. A more satisfactory access is
provided by a circumferential incision at the periphery of the diaphragm, which permits excellent
exposure of the upper abdominal contents from the thorax and vice versa, with little or no possibility of
injury to any major branch of the ipsilateral phrenic nerve (Fig. 50.6C). On the left, the incision may be
started at the esophageal hiatus and carried from behind forward circumferentially 2.5 to 3.0 cm away
from the attachment of the diaphragm to the chest wall. The crural or posterior branch of the phrenic nerve
is divided, but this division is of little consequence. The main branch of the left inferior phrenic artery is
usually encountered with this incision and requires division and ligation. Alternatively, the incision may
be started anteriorly, just lateral to the pericardium, and extended circumferentially as far posteriorly as
necessary. The ipsilateral hemidiaphragm may then be raised as a trapdoor and retracted medially for
exposure. Closure of the incision is accomplished readily by approximating the cut edges of the
hemidiaphragm with multiple interrupted simple or mattress sutures of 0-0 or 2-0 nonabsorbable material
of the surgeon’s choice. A similar incision may also be carried out on the right.
FIGURE 50.6 Safe areas for incision into the diaphragm. (Redrawn from Merendino KA, Johnson RJ, Skinner SH, et al. The
intradiaphragmatic distribution of the phrenic nerve with particular reference to the placement of diaphragmatic incisions and
controlled segmental paralysis. Surgery 1956;39:189, with permission.)
When a combined abdominothoracic approach is used, the incision in the diaphragm may be extended
medially between the pericardial attachment to the diaphragm and the entrance of the phrenic nerve into
the diaphragm, with severance of only the small sternal division of the nerve (Fig. 50.6D). The incision is
then carried to the apex of the esophageal hiatus. To ensure adequate exposure, the phrenic nerve and
pericardiacophrenic vessels must be freed from the pericardium proximally and retracted laterally. Care
must be exercised to prevent injury to these structures during this retraction. This incision is closed the
same as a circumferential incision. Sicular8 reported the use of this latter incision with the 90 GIA
stapling instrument in more than 50 patients with no compromise of exposure. Moreover, he reported no
clinical evidence of phrenic nerve injury postoperatively. Incisions in the diaphragm other than a
circumferential or a very medial one must be avoided because the anterolateral and posterolateral
branches of the nerve are likely to be divided.
DIAPHRAGMATIC PORES
SIGNIFICANCE OF PORES IN THE DIAPHRAGM

Kirschner9 has globally categorized the clinical occurrence of peritoneopleural transphrenic passage of
fluids or gases through either congenital or acquired pores in the diaphragm as porous diaphragm
syndromes. The numerous clinical entities are listed in Table 50.1. Kirschner9 has described these in
detail, but only a few of the more important ones are discussed briefly here. The diaphragmatic pores
permit the egress of ascitic fluid from the abdomen in some cirrhotic patients into the ipsilateral
hemithoracic pleural space, resulting in a cirrhotic hydrothorax. Hydrothorax also may occur during
peritoneal dialysis when these pores are present, and Nomoto and colleagues10 reported an incidence of
1.6% of this complication. When identified, closure of the pore is curative, as reported by Lieberman and
Peters11 and Mouroux and colleagues.12 Temes13 and Tsunezuka14 and their colleagues reported successful
video-assisted thoracic surgery (VATS) resection of the diaphragmatic defect and closure thereof in the
treatment of hepatic hydrothorax and hydrothorax following ambulatory peritoneal dialysis, respectively.
Both groups suggest this approach to be the procedure of choice in the management of such patients.
TABLE 50.1 Porous Diaphragm Syndromes According to Substance Traversing the
Diaphragm
Fluids
Spontaneous ascites
Cirrhosis of the livera
Meigs syndrome
Pancreatic ascitesa
Chylous ascitesa
Iatrogenic ascites
Peritoneal dialysisa
Hemoperitoneum
Abdominal or tubal pregnancy
Ruptured spleen
Ruptured aortic aneurysm
Operative hemorrhage
Endometriosisa
Gases
Pneumoperitoneum
Catamenial pneumothoraxa
Therapeutic pneumoperitoneuma
Spontaneous pneumoperitoneuma
Laparoscopic pneumoperitoneuma
Diagnostic pneumoperitoneuma
Tissue
Endometriosis
Catamenial pneumothoraxa
Pleural endometriosisa
Exudates or secretion
Subphrenic abscessa
Liver abscessa
Pancreatic pseudocysta
Bilothoraxa
Intestinal contents
Perforated peptic ulcera
a Defect observed.
From Kirschner PA. Porous diaphragm syndromes. Chest Surg Clin North Am 1998;8:449, with permission.
The role of diaphragmatic pores in the etiology of catamenial pneumothorax is questioned by many, but
these pores have been found in more than one-third of the cases; in some reports, such as that of Stern and
colleagues,15 all explored patients were found to have these pores, whereas Lillington and colleagues16
identified only 3 of 18 patients as having these diaphragmatic fenestrations. One of the arguments against
their role in the development of catamenial pneumothorax has been the failure to identify air in the
abdomen. However, Downey and colleagues17 reported the presence of a pneumoperitoneum associated
with a catamenial pneumothorax in a patient on three separate occasions, a finding that tends to refute the
aforementioned argument. However, Sato and Kasi18 noted that, in the presence of endometriosis of the
diaphragm, closure of the diaphragmatic pores is not always successful. In one of their patients with
repeated catamenial pneumothoraces, excision and closure of an identified defect associated with
endometriosis of the diaphragm was carried out. However, the patient had a recurrent pneumothorax
shortly after the surgical repair. They suggested that those patients who suffer this disease be placed on
hormonal treatment in addition to undergoing the surgical procedure. Slabbynck19 and Espaulella20 and
their colleagues suggest the use of a gonadotropin-releasing hormone analog as the medication of choice.
Finally, the occurrence of a tension pneumothorax during the course of laparoscopy is to be noted. This
event may be life-threatening and has been reported by Heddle and Platt,21 Whiston and colleagues,22 and
Childers and Caplinger.23 It must be differentiated from other anesthetic complications presenting with
similar clinical features.
REFERENCES
1. Reddy V, Sharma S, Cobanoglu A. What dictates the position of the diaphragm—the heart or the liver? A review of sixty-five cases. J
Thorac Cardiovasc Surg 1994;108:687.
2. De Troyer A, Sampson M, Sigrist S, et al. Action of costal and crural parts of the diaphragm on the rib cage in dogs. J Appl Physiol
1982;53:30.
3. Rochester DF. The diaphragm: contractile properties and fatigue. J Clin Invest 1985;75:1397.
4. Collis JL, Kelly TD, Wiley AM. Anatomy of the crura of the diaphragm and the surgery of hiatus hernia. Thorax 1954;9:175.
5. Park CH, Pham CD. Hepatic hydrothorax. Scintigraphic confirmation. Clin Nucl Med 1995;20:278.
6. Urhahn R, Gunther RW. Transdiaphragmatic leakage of ascites in cirrhotic patients: evaluation with ultrafast gradient echo MR imaging
and intraperitoneal enhancement. Magn Reson Imaging 1993;11:1067.
7. Merendino KA, Johnson RJ, Skinner HH, et al. The intradiaphragmatic distribution of the phrenic nerve with particular reference to the
placement of diaphragmatic incisions and controlled segmental paralysis. Surgery 1956;39:189.
8. Sicular A. Direct septum transversum incision to replace circumferential diaphragmatic incisions in operations on the cardia. Am J Surg
1992;164:167.
9. Kirschner PA. Porous diaphragm syndromes. Chest Surg Clin North Am 1998;8:449.
10. Nomoto Y, Suga T, Nakajima K, et al. Acute hydrothorax in continuous ambulatory peritoneal dialysis: a collaborative study of 161
centers. Am J Nephrol 1989;9:363.
11. Lieberman FL, Peters RL. Cirrhotic hydrothorax. Further evidence that an acquired diaphragmatic defect is at fault. Arch Intern Med
1970;125:114.
12. Mouroux J, Perrin C, Venissac N, et al. Management of pleural effusion of cirrhotic origin. Chest 1996;109:1093.
13. Temes RT, Davis MS, Follis FM, et al. Videothoracoscopic treatment of hepatic hydrothorax. Ann Surg 1997;64:1468.
14. Tsunezuka Y, Hatakeyama S, Iwase T, et al. Video-assisted thoracoscopic treatment for pleuroperitoneal communication in peritoneal
dialysis. Eur J Cardiothorac Surg 2001;20:205.
15. Stern H, Toole AL, Merino M. Catamenial pneumothorax. Chest 1980;78:480.
16. Lillington GA, Mitchell SP, Wood GA. Catamenial pneumothorax. JAMA 1972;219:1328.
17. Downey DB, Towers MJ, Poon PY, et al. Pneumoperitoneum with catamenial pneumothorax. AJR Am J Roentgenol 1990;155:29.
18. Sato M, Kasi K. Catamenial pneumothorax with diaphragmatic endometriosis: a case report. J Jpn Assoc Chest Surg 1997;11:583.
19. Slabbynck H, Laureys M, Impens N, et al. Recurring catamenial pneumothorax treated with a gn-RH agonist. Chest 1991;100:851.
20. Espaulella J, Armengol J, Bella F, et al. Pulmonary endometriosis: conservative treatment with GnRH agonists. Obstet Gynecol
1991;79:535.
21. Heddle RM, Platt AJ. Tension pneumothorax during laparoscopic cholecystectomy. Br J Surg 1984;79:374.
22. Whiston RJ, Eggers KA, Morris RW, et al. Tension pneumothorax during laparoscopic cholecystectomy. Br J Surg 1991;78:1325.
23. Childers JM, Caplinger P. Spontaneous pneumothorax during operative laparoscopy secondary to congenital diaphragmatic defects: a
case report. J Reprod Med 1995;40:151.
51
Physiology of the Diaphragm and Surgical
Approaches to the Paralyzed Diaphragm
Raymond P. Onders
This chapter will outline the physiology of the diaphragm and what conditions lead to loss of control of
the diaphragm or a paralyzed diaphragm. Surgical options for a paralyzed or dysfunctional diaphragm
will be reviewed which include diaphragm plication, phrenic nerve pacing and either permanent or
temporary intramuscular diaphragm pacing.
PHYSIOLOGY
The diaphragm is the dome-shaped muscle that separates the abdominal and thoracic cavities. There are
two portions that comprise the muscle, the costal, which is the domed portion extending from the ribs to
the central tendon and the crural, which is posterior, thicker, and attaches to the vertebrae. During
inspiration, the diaphragm muscle contracts, the dome portion flattens along with the central tendon,
which increases lung volume, decreasing pressures in the thoracic cavity allowing air flow into the lungs.
The diaphragm has no antagonistic muscles; instead, exhalation is passive but partly affected by elastic
recoil of the thoracic walls and abdominal muscles.1–3 Optimal diaphragm function requires both the right
and left sides to work in synchrony. The diaphragm contraction accounts for approximately 70%
inspiratory volume change during normal quiet breathing moving downward about 1.5 cm during each
breath. Diaphragm contraction makes up 60% of minute ventilation when in the supine position. A
unilateral diaphragm paralysis will decrease a patient’s vital capacity by 20% in an upright position and
up to 40% in the supine position which leads to significant sleep dysfunction. The diaphragm is essential
during REM sleep. During REM, sleep-associated atonia of the intercostal muscles results in decreased
chest wall compliance and leaves the diaphragm as the sole respiratory muscle.4 Paralysis of the
diaphragm can lead to significant respiratory compromise.
The diaphragm is generally under involuntary control of the central nervous system but there is the
ability to voluntarily control the diaphragm through the cerebral cortex. The neural control of breathing is
still not completely understood and active research is ongoing. The diaphragm is innervated by the
phrenic nerve that arises from the roots of C3-5. These cervical phrenic motor neurons can be controlled
involuntarily by upper motor neurons (UMNs) in the respiratory control center in the brain stem or by the
cerebral cortex UMN. There are numerous etiologies that can affect this system that will cause contraction
abnormalities of the diaphragm resulting in respiratory compromise ranging from mild shortness of breath
to the need for invasive mechanical ventilation (MV).
The brainstem network that controls breathing has intrinsic rhythmic activity that is dependent on
various inputs that will be briefly described. The pre-Bötzinger complex, part of the ventral respiratory
group (VRG), is responsible for respiratory drive and is the only drive during sleep. Loss of pre-
Bötzinger complex neurons may affect respiratory rate and lead to central apneas. Congenital central
hypoventilation syndrome (CCHS or Ondine’s Curse) is an isolated genetic loss of this center leading to
the need for MV during sleep in infancy and throughout their life. During quite breathing, a few inspiratory
neurons fire sending signals to the phrenic motor neurons in C3-5 which in turn send signals down the
phrenic nerve to cause diaphragm muscle fibers to begin contracting. The firing of the inspiratory neurons
recruits other inspiratory neurons to fire in a positive feedback loop so that along the previous pathways
more diaphragm muscle contracts. This is what leads to the ramping up of the diaphragm contraction for a
smooth breath. At the end of inspiration there is an abrupt stopping of firing and the diaphragm relaxes
with passive expiration.
There is input from chemoreceptors that modify the rhythmicity of respiration. Carbon dioxide is the
primary stimulus for change in ventilation with a central chemoreceptor on the ventral surface of the
medulla close to the respiratory control group. When plasma CO2 rises, the central chemoreceptors
respond strongly by increasing ventilation. When there is a decrease in plasma CO2, such as during
hyperventilation, there is a decreased drive for ventilation with subsequent accumulation of CO2 in the
alveoli. Eventually there is a rise in arterial CO2 and the central control of ventilation resumes.
Oxygenation plays a lesser role through the peripheral chemoreceptors in the carotid and aortic bodies.
These peripheral chemoreceptors only respond to dramatic changes in arterial PO2 through sensory
neurons to the brainstem respiratory group. This peripheral system becomes a more important control of
ventilation for patients with chronic lung diseases with retained PCO2 when the central control of
respiration has adapted to the elevated PCO2 and no longer drives respiration. If these patients are given
too much supplemental oxygen, they may lose their ventilator drive and stop breathing because their
peripheral stimulation for ventilation is eliminated.
The phrenic nerve is an important part of the physiology of the diaphragm such that if the nerve is
damaged, or does not conduct the respiratory stimulus from the brainstem, diaphragm dysfunction occurs.
If the phrenic nerve is completely severed there is permanent paralysis of the diaphragm muscle. Without
the feedback from a nerve, a muscle will convert to only fibrotic tissues, with no muscle tissue. An
injured nerve can recover. A single axon in a nerve can have hundreds of Schwann cells along its length,
leaving tiny gaps called the nodes of Ranvier between the myelin insulated segments. These nodes are
important in the transmission of the electrical signal along the axon. The Schwann cells also can also
secret neurotrophic factors that can help stimulate regrowth of axons. For a long nerve, like the phrenic
nerve, regrowth can take significant time. This is important to take into consideration before a permanent
diaphragm plication is performed after a phrenic nerve injury. Muscle activity in the form of physical
therapy including electrical stimulation, can also help in the recovery of an injured nerve.
The diaphragm is composed of both slow and fast twitch muscle fibers with up to 55% being slow
twitch type I fatigue resistant fibers. The diaphragm atrophies and converts to fast twitch type IIb muscle
fibers faster than any other muscle group with disuse. MV has been the primary therapy for respiratory
failure and a fundamental treatment in intensive care units (ICUs). MV is usually a time-limited therapy
that when withdrawn, has no untoward sequelae. When the diaphragm is not contracting, there is a
decrease in ventilation that adversely affects normal respiratory physiology, that can lead to hypercarbia
from decreased minute ventilation or hypoxia from increased dead space. Research in animals and
humans has shown that short exposure to MV leads to decreases in protein synthesis and increased
proteolysis, which is histopathologically manifested as diaphragm muscle atrophy, with up to 50% of the
diaphragm muscle atrophying and conversion to the nonfunctional, fast-twitch, type-IIb muscle fibers in
less than 1 day.5 The severity of this muscle atrophy increases with increased time of MV exposure. This
condition is called ventilator-induced diaphragm dysfunction (VIDD).
CONDITIONS LEADING TO DYSFUNCTIONAL DIAPHRAGM AND

DIAGNOSTIC TESTING OF THE DIAPHRAGM
Diaphragm paralysis is characterized by progressive muscle atrophy and diaphragm elevation. In
unilateral diaphragm paralysis, there is paradoxical motion of the diaphragm, all of which impact function
and ventilation. Diaphragm paralysis can result from either injury to the muscle or to the phrenic nerve
and can be unilateral or bilateral. Etiology of diaphragm paralysis generally falls into one of five major
categories: trauma/surgery, neuropathies, inflammatory, compression or idiopathic.6,7 Examples of
trauma/surgery which lead to diaphragm paralysis are shoulder surgeries, lung transplant, and open-heart
surgery. Between 25% and 20% of cardiac surgery patients experience diaphragm paralysis.8 Any blunt
trauma to the neck can lead to diaphragm paralysis including neck manipulations, trauma during birth, and
placement of central venous catheters. Other specific examples of diaphragm paralysis include diabetic
neuropathy, amyotrophy neuralgia, polio, mediastinal tumors with invasion of the phrenic nerve, radiation
therapy, and pneumonia. Patients with amyotrophic lateral sclerosis (ALS or Lou Gerhig’s disease) can
also develop either unilateral or bilateral diaphragm dysfunction, either through loss of central control
(UMN) that can be treated or loss of lower motor neurons in the cervical spine that cannot be treated.
Patients with bilateral diaphragm paralysis are very symptomatic and can present with dyspnea,
orthopnea, hypercarbia, headaches, difficulty sleeping, anxiety, and increase in atelectasis and
pneumonias. Unilateral diaphragm paralysis however, is asymptomatic in 50% of patients. In 25% of
patients, patients can experience mild dyspnea, fatigue, and exercise limitations.1 One of the more
common causes of bilateral diaphragm paralysis is spinal cord injury (SCI). In this group of patients,
there is no longer a functional connection between the respiratory or volitional control of breathing
(UMN) and the phrenic motor neurons in the cervical spinal cord. In the cervical SCI population, 51% of
all patients are discharged on temporary MV. Ultimately 4% of the 12,000 SCI patients per year in the
United States require chronic long-term MV. Respiratory complications are the leading cause of death in
SCI, with pneumonia being the leading cause of death in those on MV. Patients with the same level of
injury have significantly shorter life spans. Chronic long-term MV is associated with increased anxiety
for both patient and caregiver. It alters speech patterns, decreases sense of smell, adds bulk and weight to
wheelchairs, impedes mobility, and noise and tubing attracts unwanted attention. The presence of a
tracheostomy increases secretions and may cause tracheomalacia.
The diagnosis of diaphragm paralysis is made through neuroradiologic testing. In unilateral diaphragm
paralysis, elevation of the affected hemidiaphragm is noted on chest x-ray. Diaphragm eventration,
increased abdominal pressure, hepatosplenomegaly, obesity, lung resections, atelectasis, and pulmonary
fibrosis can also cause diaphragm elevation. Identification of unilateral diaphragmatic dysfunction on
chest x-ray can be highly sensitive (85%); however, in bilateral paralysis, both hemidiaphragms are
elevated which mimics normal exhalation making the diagnosis of paralysis via x-ray difficult.9 A study
by Kharma10 showed only 21% of patients with bilateral diaphragm dysfunction had abnormal chest x-ray.
Fluoroscopy of the diaphragm, sniff test, is a functional exam that can identify motion or confirm
paralysis. With this test, using fluoroscopy, the patient is instructed to breathe in and out and then taking
large deep “sniff” inspirations. Diaphragms should move symmetrically, downward at least 1 rib space or
approximately 1 cm with normal inspiration. With deep inspiration, the diaphragm can move up to 10
cm.11 With unilateral paralysis, there can be cephalic movement of the affected diaphragm creating a
paradoxical motion and with bilateral paralysis there is no true diaphragm movement. Fluoroscopy is
88% accurate in diagnosing patients with unilateral diaphragm paralysis.10 Utilizing ultrasound to
diagnosis diaphragm dysfunction is gaining favor. Under ultrasound a paralyzed diaphragm fails to
increase in thickness during inspiration compared to the functional diaphragm. Ultrasound can also
determine degree of atrophy although this is operator dependent.
To be effective in recruiting diaphragm muscle and provide ventilatory support, the phrenic nerve must
be able to provide conduction pathways through the muscle. Therefore, the lower motor neurons in the
spinal cord and the phrenic nerve must be intact to avoid muscle denervation and to stimulate the muscle
at acceptable levels. A thorough assessment of phrenic nerve function should be performed in all patients
contemplating phrenic nerve or diaphragm motor point pacing. Unfortunately, many patients with SCI have
sustained injury to the phrenic motor neurons in the spinal cord and/or phrenic rootlets. If phrenic nerve
function is absent or significantly reduced, phrenic nerve or diaphragm pacing should not be undertaken.
Phrenic nerve function should be assessed both by measurements of phrenic nerve conduction times
and/or by fluoroscopic evaluation of diaphragm movement during phrenic nerve stimulation (PNS) as has
been described.12
The present method of detecting an intact phrenic nerve is plagued by technical difficulties and
inherent false positive and false negative results. In a recent report, the “gold standard” phrenic nerve
study had 50% false negative or false positive test results when compared to direct surgical stimulation of
the diaphragm.13 The ultimate test is direct surgical stimulation of the diaphragm muscle which can easily
be done with the direct pacing (DP) laparoscopic technique. Most patients are willing to undergo an
outpatient diagnostic laparoscopy to see if they can be removed from the adverse effects of a ventilator. If
the diaphragm is stimulable during the diagnostic laparoscopy, then the phrenic or DP system can be
implanted.
Once the diagnosis of diaphragm paralysis is confirmed, treatment options can be supportive via
oxygen or augmented ventilation such as noninvasive ventilation or surgical. The remaining chapter will
focus on surgical therapies for the paralyzed diaphragm.
DIAPHRAGM PLICATION
Diaphragm plication surgery was first reported in the 1920s. The goal of plication is to decrease the size
and flatten the dome of the elongated atrophied diaphragm muscle and is only indicated for symptomatic
patients.14,15 Contraindications to the surgery include obesity and neuromuscular disease. Generally,
plication surgery is intended for those with unilateral diaphragm paralysis although there are recent
reports of bilateral plication in a patient with Charcot disease.16 Through the years, surgery has been
refined and there are now several approaches which include open thoracotomy, thoracoscopic and
laparoscopic.
Open transthoracic plication is the traditional approach. It is performed via a posterolateral
thoracotomy in the 6th, 7th, or 8th intercostal space using single-lung ventilation through a double-lumen
endotracheal tube. The diaphragm is plicated from medial to lateral with a series of sutures until it
becomes taut and flat. A variety of techniques include using hand-sewn U stitches, mattress sutures,
running sutures with or without pledgets, and stapling devices with or without mesh reinforcement. The
plication may require several overlapping layers for reinforcement. One to two chest tubes are placed for
pleural drainage. Pain control is achieved with a thoracic epidural catheter and patients are discharged
after their chest tube is removed.17
Video-assisted thoracoscopic surgery (VATS) is an alternative approach which can be performed using
two to four ports. Similar to the open thoracotomy, the plication can be done using sutures and/or
laparoscopic stapling devices. This approach is a minimally invasive alternative to open thoracotomy and
may be just as effective. Several plication techniques include use of continuous sutures, interrupted
sutures, and laparoscopic stapling devise. Its limitations include single-lung ventilation and less work
space caused by the rib cage and the elevated hemidiaphragm. It may be more difficult to obtain a
sufficiently tense diaphragm with this technique.
Laparoscopic diaphragm plication can be performed using a three- or four-port technique. Patients
undergo general anesthesia with a single-lumen endotracheal tube. After establishing pneumoperitoneum,
the affected diaphragm is taut and displaced cephalad. The use of an additional 5-mm port thorascopically
in the affected chest allows the diaphragm to be displaced downward with minimal controlled insufflation
in the chest cavity and allows easier laparoscopic plication of the diaphragm. This port is then used for a
pigtail catheter at the end of the procedure. The plication is carried in a medial to lateral direction starting
posteriorly. As in the thoracic approach, multiple imbricating layers can be done until the diaphragm is
taut (Fig. 51.1). Nonabsorbable sutures, with or without pledgets, are used to tie the diaphragm down in a
stable position. Advantages of this approach is good visualization of the elevated diaphragm and ample
work space unlike the thoracoscopic plication. It also avoids the intercostal pain associated with a
thoracotomy or thoracoscopy. Single-lung ventilation can also be avoided.18
FIGURE 51.1 Laparoscopic left diaphragm plication after two imbricating interrupted sutures rows have been completed.
Simultaneous thorascopic visualization would then be performed to allow the diaphragm to be forced caudad for the additional
suturing to be performed.
Complications for all approaches include pneumonia, pleural effusions, abdominal compartment
syndrome, conversion to open (for minimally invasive approaches), abdominal viscus injury, deep vein
thrombosis, stroke, upper gastrointestinal hemorrhage, pulmonary emboli, arrhythmia, and acute
myocardial infarction.
PHRENIC NERVE PACING
Electrical activation of the diaphragm muscle, by way of PNS or through direct diaphragm pacing (DP) at
the motor point, have been developed to provide stimulation of the diaphragm to improve ventilation in
several diseases. The concept of PNS to provide ventilatory support dates to the 18th century. In the
1940s, a group first demonstrated that ventilation could be maintained with percutaneous electrodes in
patients with poliomyelitis.19 In the 1960s, significant technological advances were made that led to the
development of traditional PNS systems (Avery Mark IV Breathing Pacemaker System, Avery Biomedical
Devices, Commack, NY). They developed an implantable electrode/receiver system which could be
activated by radiofrequency waves generated by a power source external to the body. These investigators
also accumulated significant clinical experience which defined patient evaluation methods, surgical
techniques, and safe parameters of stimulation which resulted in diaphragm conditioning via stimulation
of the phrenic nerve.20
Presently two additional PNS systems besides the Avery Mark IV Breathing System are available
worldwide with a number of features in common. Electrodes are implanted on the phrenic nerves and
attached to an internal stimulator that is powered by an external controller through the skin via a
radiofrequency link. Low levels of electrical current pass through these electrodes exciting the nerve
which leads to contraction of the diaphragm muscle.
The Astrostim (Atrotech, Tampere, Finland) system differs from the Avery system in the electrode
technology. The electrode is made of two identical strips of Teflon fabric with two platinum buttons
mounted onto each strip. This four-pole arrangement divides the nerve into four stimulation compartments,
each of which is designed to activate a quadrant of the phrenic nerve. During a single stimulation
sequence, which consists of four current combinations, one pole acts as a cathode and one pole, on the
opposite side, as an anode. Consequently, there are four excitation compartments around the nerve.
Theoretically this stimulation pattern is intended to more closely mimic natural activation of the nerve and
should enhance the transformation of muscle fibers into slow-twitch fatigue-resistant fibers thus
improving endurance characteristics of the diaphragm and shortening the conditioning process.
The “Vienna phrenic pacemaker” (Medimplant, Vienna, Austria) system is also unique in terms of
electrode design, involving multiple electrode contacts with the nerve. A microsurgical technique is
required to suture four electrode leads to the epineurium of each phrenic nerve. The nerve tissue between
each electrode lead provides different stimulation compartments. As many as sixteen different electrode
combinations can be adjusted individually for each nerve although only one electrode combination is
stimulated during any given inspiration. As with the Atrotech device, only a portion of the nerve is
stimulated at any given time allowing more time for recovery. This form of stimulation, referred to as
carousel stimulation, is also thought to reduce the incidence of fatigue when compared to the unipolar
design. Neither this system nor the Astrostim system is available in the United States.
Surgical implantation of the PNS can be done via a cervical or thoracic approach. Some centers prefer
to place the electrodes in two separate procedures with 1 to 2 weeks between each operation. For
cervical placement, a transverse skin incision is made lateral to the sternocleidomastoid muscle. The
scalene muscles are divided, and the phrenic nerve is identified just anterior to the scalenus medius. A
nerve stimulator can be used with fluoroscopic observation of the diaphragm to confirm correct
identification. The electrode is placed under the nerve and sutured into place. The connecting wire is then
tunneled subcutaneously to a position on the anterior chest. Cervical electrode placement, while less
invasive surgically, is controversial for several reasons. Cervical PNS may result in incomplete
diaphragm activation due to the occurrence of an accessory branch from a lower segment of the cervical
spinal cord which joins the main trunk of the phrenic nerve in the lower neck region or thorax. Moreover,
other nerves in close vicinity to the phrenic nerve may be activated resulting in pain or undesirable
movement. Finally, neck movement may place significant mechanical stress on the nerve/electrode system
increasing the risk of injury to the nerve and connection failure.
Intrathoracic implantation of the device is performed through a limited anterior thoracotomy in the
second or third intercostal space. The phrenic nerve is identified at the mediastinal surface, anterior to the
pulmonary hilum. An electrode location is chosen based on accessibility and the ability to position the
cuff of the electrode to lie flat. The mediastinal pleura is incised parallel to the nerve. The electrode is
slipped beneath the mobilized phrenic structures, such that the phrenic nerve rests inside the half-cuff
platinum contact of the electrode and sutured into place. With careful attention to the surgical technique,
injury to the phrenic nerve can be avoidable. The other end of the electrode is passed carefully through
the chest wall using a chest tube to avoid trauma during its passage. Redundant wire is left within the
thorax to avoid tension on the electrode with lung expansion. A subcutaneous pocket is created over a flat
portion of the lower anterolateral rib cage to house the receiver.
Thoracic placement is now more routinely done thoracoscopically which decreases the morbidity.21
The patient is positioned in a supine clamshell position; rotation of the bed allows surgery to be
performed on both sides without repositioning of the patient. The use of a double-lumen endotracheal tube
is necessary. Three ports are usually placed.21 This thoracoscopic procedure lends itself to computer-
aided robotic techniques, allowing increased visualization and instrument dexterity. Use of the Da Vinci
robotic system (Intuitive Surgical, Mountain View, CA) has been described in six patients. The patients
were placed in a supine position with the ports in the second, fourth, and sixth intercostal spaces. The
phrenic nerve was dissected free from the pericardium at the level of the left pulmonary artery on the left,
and at the confluence of the superior vena cava and right atrium on the right. Five of the six patients
underwent bilateral implantation with no operative complications and an average hospital stay of only 2
days.22,23
A potential complication of PNS placement is iatrogenic injury to the phrenic nerve and subsequent
pacemaker failure. It is critical that the phrenic nerves are carefully manipulated to avoid stretching or
tension on the nerve during surgery. To prevent ischemic injury, the network of blood vessels within the
perineurium must be preserved. The greatest technical challenge comes from thoracoscopically placing
the electrode nerve cuffs in position below the nerve and sutured into place while allowing some “slack”
to avoid traction tension on the nerve itself.
The electrode wires are connected to two implanted radiofrequency receivers which are usually
positioned superficially over the anterior chest wall. Two antennas are positioned over each radio
receiver and connected to an external radio transmitter. Threshold current values of each electrode should
be determined by gradually increasing stimulus amplitude until a diaphragm twitch is observed or
palpated. When values are increased above this level a smooth forceful diaphragm contraction should
occur. If threshold values are high, the electrode leads may need to be re-positioned. Pacing is usually not
started for at least 4 to 6 weeks after placement which allows for tissue reaction around the electrodes to
stabilize.
INTRAMUSCULAR DIAPHRAGM PACING

In the 1980s, the group at Case Western Reserve University in Cleveland showed the diaphragm could be
directly stimulated at the motor point to provide ventilation.24–26 In the late 1990s the device had been
refined for the initial human studies at University Hospitals Cleveland Medical Center and subsequent
standard laparoscopic implantation for SCI patients.27–30 Because muscle motor point electrodes can be
removed and used for short periods of time, Onders and colleagues began investigating its use in other
groups of patients including patients with ALS and for temporary use in the ICU. The present DP system
which has been used in over 1,800 patients (NeuRx RA/4 System, Synapse Biomedical, Oberlin, OH) is a
distinct method over phrenic nerve pacing and originally developed to provide negative pressure
ventilation and replace MV in high level tetraplegics.
The DP surgical procedure requires general anesthesia that is administered without neuromuscular
blocking agents. Short-acting agents such as propofol for amnesia, remifentanil for pain along with
inhalation agents are the preferred anesthetic management for patients undergoing DP.31 Standard four-
port laparoscopy begins with generous amounts of preemptive local anesthetic being placed into the
incisions to decrease pain and intraoperative spasms. The abdomen is insufflated and the falciform
ligament is divided allowing easier access of the implant instruments to the diaphragm bilaterally. 12-mm
epigastric port is placed for the implant instrument and to provide an unimpeded exit for the pacing
electrodes.
The next step of DP surgery is mapping of the diaphragm. This process identifies the motor point. The
tip of a laparoscopic dissector is touched against the diaphragm muscle (Fig. 51.2A,B). A twitch stimulus
is delivered from a clinical station to the instrument and both qualitative and quantitative data is obtained.
Quantitatively, changes in abdominal pressure are measured through tubing that is attached to one of the
surgical ports and connected to the clinical station. A greater change in pressure indicates closer
proximity to the motor point of the phrenic nerve and a larger diaphragm muscle contraction.
Qualitatively, visual observation of the diaphragm is made during stimulation.
FIGURE 51.2 A: The laparoscopic dissector is placed against the left diaphragm and an electrical burst from the clinical station
externally will allow contraction if the phrenic nerve is intact and subsequent mapping will show ideal location for implantation.
B: The diaphragm has an excellent strong contraction even though this is a spinal cord injured patient on a ventilator for 5 years.
Diaphragm conditioning will then convert to slow twitch muscle fiber for continuous diaphragm pacing to allow ventilation without
the ventilator.
The area of electrode placement is chosen based on the location of larger contraction with a strong
preference for the posterior diaphragm to facilitate posterior lung lobe ventilation that will decrease
atelectasis. Two electrodes are implanted into the right and left diaphragm muscle. Placement of two
electrodes in each diaphragm provides redundancy and synergy for maximal muscle recruitment. The
electrodes are implanted using an implant instrument (Fig. 51.3). The electrode is threaded through the
instrument to the tip of needle. The needle at the end of the instrument is skived into the muscle and the
polypropylene barb on the end of the electrode releases upon withdrawal of the needle. The four
electrodes and an anode are then tunneled subcutaneously to an appropriate exit site. A chest x-ray is
taken at the end of the case to assess for the presence of a capnothorax that may result from carbon
dioxide tracking from the abdominal cavity into the pleural space from the diaphragm. Small
capnothoraxes resolve spontaneously where a larger one may need to be aspirated.32
FIGURE 51.3 The implant instrument is placing a second electrode in the left diaphragm. The implant instrument houses the
diaphragm pacing electrode which is a double helix of 14 stainless steel wires that are Teflon coated. The needle of the implant
instrument enters the diaphragm muscle and a polypropylene barb allows the electrode to be fixated.
The implanted intramuscular electrodes are connected to a four-channel external pulse generator
(EPG) (Fig. 51.4). This stimulator provides capacitively coupled charge-balance biphasic stimulation to
each subcutaneous electrode. The EPG is programmed with patient-specific parameters of pulse
amplitude, pulse duration, inspiratory time, pulse rate, and respiratory rate by a clinician. The DP EPG
will be programmed to provide a tidal volume that provides 15% above the basal needs (5 to 7 cc/kg)
and that the patient can easily tolerate. The settings will always be below 25 in amplitude, below 20 in
frequency, and below 200 in pulse width. DP users simply connect and turn the device on and/or off. The
goal for patient settings is to use the highest settings within the safety parameters that do not cause any
patient discomfort while providing conditioning for the diaphragm or ventilation.
Once implanted, the device can be utilized immediately to begin diaphragm conditioning. Each patient
should have a customized conditioning program that entails initiation of DP use which gradually increases
over time. Patients often begin with 30 minutes of DP use several times daily and increase usage every 3
to 5 days. This DP conditioning regimen will convert the atrophied muscle fibers from fast-fatigueable
type 2B muscle fibers to slow twitch type 1.
The diaphragm electrodes can also be utilized to monitor and guide therapy through diaphragm
electromyography (dEMG). Because the electrodes are implanted, there is standardization of electrode
positioning providing consistency in the recordings regardless of when the recordings are obtained.
Additionally, dEMG can be evaluated during normal automatic breathing, with maximum inspirations,
during sleep, and with positive pressure ventilation regardless of mode (invasive and or noninvasive
MV). These recording have been instrumental in identifying the effects of DP on positive respiratory
neuroplasticity.
FIGURE 51.4 The four implanted electrodes along with a subcutaneously placed ground electrode are placed in a block that
connects to the external pulse generator that is programmed to provide diaphragm conditioning. This is providing ventilation while
the patient has his tracheostomy capped with a Passey-Muir valve. Gastrostomies or gastrostomy buttons as seen in this case
can be placed simultaneously without increasing the risk of infection with an external pulse.
RESULTS
Patients with unilateral diaphragm abnormalities need to be differentiated into those whose diaphragms
can be rehabilitated and with return of function with temporary diaphragm pacing and those whose
diaphragms are permanently denervated and need to undergo diaphragm plication. Patients, who do
undergo necessary plication can still experience alleviation of symptoms, improved pulmonary function
testing, and improved quality of life.14 Celik and Celik33 reviewed long-term data (5.4 years post
plication) on 12 patients who underwent diaphragm plication surgery. In his study, he reports eight
patients being able to return to work who previously left work due to dyspnea. There was an improved
percentage in Forced Vital Capacity percent of 30.6%. He also reports improved dyspnea scores and
radiologic findings.
A more recent report from Welvaart reviewed pulmonary testing and cardiopulmonary exercises pre
and post plication. He showed there was an improvement in tidal volume and total lung capacity and a
decrease in respiratory rate. However, there was not a difference in exercise capacity pre and post
plication. He attributes the alleviation of symptoms to the increase is tidal volume and decrease in
respiratory rate.34 Groth and colleagues reported on a series of 25 patients who underwent laparoscopic
plication. They found significant improvements in pulmonary testing, and chest x-ray both in short-term
(1-month) and at 1-year post plication. Additionally, they had profound improvements in the respiratory
quality of life scores.18
Temporary diaphragm pacing has more recently been utilized in patients with unilateral or bilateral
diaphragm dysfunction (DD). Onders and colleagues13 reported on the extended use of diaphragm pacing
in patients with DD leading to symptomatic hypoventilation. In this study 21 patients with a mean of 36
months of respiratory symptoms were implanted with DP. DD in this report was a result of phrenic nerve
injury from thoracic surgery (4), shoulder surgery or neck trauma (5), idiopathic (9), spinal muscle
atrophy (SMA) (1), Charcot–Marie–Tooth disease (1) and one diaphragm flutter (Belly Dancer
syndrome) (1). Thirteen patients (62%) had clinically relevant respiratory improvements, and four had
partial improvement. Four patients were able to be completely weaned from MV. In these patients, the DP
system was removed, again highlighting the possibility of a temporary DP system for weaning patients
from MV in the ICU.
Unilateral diaphragm paralysis is a relatively rare occurrence with half the population with unilateral
paralysis being asymptomatic. Patients who are symptomatic and have the ability to recover diaphragm
function and even in those patients who are asymptomatic presently, temporary diaphragm pacing surgery
should be considered. If diaphragm pacing is not an option, thorascopic and laparoscopic approaches to
diaphragm plication have shorter hospitalization, less pain, and complications and could improve a
patients’ quality of life therefore should be offered to patients. With the advent of the ability to obtain
recovery of diaphragm function with temporary diaphragm pacing, plication may be reserved for those
patients with complete denervation of the diaphragm where diaphragm pacing is not indicated. Plication
should also be delayed until the chance for re-innervation or recovery of the nerve is no longer viable
which may be 18 months to 2 years post injury. Diaphragm plication with the suturing of the diaphragm
can permanently injure the nerve with crushing and should be reserved until after nerve recovery has been
exhausted.
Phrenic nerve pacing has been successful in SCI since the 1970s but still is not widely used. DP was
first implanted in an SCI patient in 2000. The initial FDA multicenter clinical trial of DP in SCI
dependent on tracheostomy MV showed 100% of implanted patients were able to breathe for 4
consecutive hours with DP alone. Fifty percent were able to replace MV full time. The patients ranged in
age from 18 years to 74 years (36 years old average). There were 37 males with the majority of injuries
resulting from motor vehicle accidents followed by sports injuries. Patients were on prolonged
mechanical ventilation from 3 months to 27 years prior to DP implant with the average time of injury to
implant being 5.6 years. With an intact phrenic motor neuron, phrenic nerve, and diaphragm muscle there
is no time limit from injury to successful diaphragm stimulation for ventilation. The longer the time from
injury to surgery, the longer it will take to rehabilitate the diaphragm.
When comparing the monthly cost of maintaining a patient at home with a portable ventilator including
the cost of long-term equipment replacement/rental, medical, and nursing care, PNS and DP are cost
effective. Onders et al.29 describes the cost savings of $13,000 monthly for one SCI patient who was
successfully weaned off the ventilator to full-time pacing. Pacing allows natural negative pressure
ventilation preferentially aerating the posterior lobes of the lungs and increasing respiratory compliance
and therefore should decrease pneumonia rates in this patient population. Hirschfeld et al.35 analyzed 64
spinal cord patients with chronic respiratory insufficiency in whom 32 were able to receive either a
phrenic or diaphragm pacer and 32 who did not. Pacing the diaphragm and allowing negative pressure
ventilation decreased respiratory infections from 2 per 100 days to 0 with pacing (p <0.001). Another
report looked at the quality of life of patients with pacing compared to when they were on the ventilator
and all patients would recommend pacing to other patients.36 They found that PNS or DP improved
patients’ ability to go outside of the home, participate in leisure activities, and relationships with others.
This study also showed a significant improvement in olfaction and taste with the use of pacing.
A multicenter report done with DP in SCI but focused on DP in SCI patients with a permanent internal
cardiac pacemaker was completed in 2010. The study included 20 SCI patients who had both cardiac
pacemaker and DP. This study showed that all patients were able to achieve tidal volumes to meet their
basic metabolic needs with 71% able to replace MV with DP full time. The internal cardiac pacemakers
were interrogated at the time of DP implant with DP being set at maximal stimulations settings and the
cardiac pacemakers being set at their most sensitive. No device interactions were noted.37 More recently
there has been no interactions reported with cardiac defibrillators or left ventricular assist devices
(LVAD).38
DP has been implanted successfully in pediatric patients. A report of six pediatric SCI patients ranging
in age 3 to 17 years (average age 9 years old) with an average weight of 32.6 kg were successfully
implanted with no technical difficulties. Unique to the pediatric population is growth that may require DP
reprogramming and scoliosis, which may need to be addressed prior to implantation and/or may affect
ventilator weaning. Pediatric patients experienced the same success with being liberated from MV as
their adult counterparts.39
More recent and exciting data on DP in the SCI population was published in 2014. This study focused
on early implantation of DP in SCI.40 Their analysis included 29 patients, 22 of whom were implanted; 7
patients had denervated “dead diaphragms” at surgery. These diaphragms could not be stimulated because
of complete destruction of the lower motor neurons from the trauma insult. The average time frame of
injury to implant was 3 to 112 days with a median of 33 days. Seventeen percent of patients were weaned
completely off MV in an average of 13.1 days. A subset of patients implanted within 11 days of injury
weaned off MV in 5.7 days. Some patients (36%) implanted early after injury had recovery of respiration
and were able to wean off of DP. The ability to record dEMG in this SCI population highlighted the
potential of electrical stimulation from DP and neuroplasticity of the spinal cord allowing recovery of
phrenic nerve function. Also noteworthy was the fact that early identification of those patients with “dead
diaphragms” will save significant amounts of time, frustration, and money on futile ventilator weaning and
also allows early consideration of the growing use of nerve transfer techniques to allow recovery.
ALS is a progressive neurodegenerative disorder of both UMN and LMN that ultimately leads to
respiratory failure. Diaphragm pacing in this population can replace the lost signal of the nonfunctioning
UMN. If an ALS patient is primarily LMN then DP will not be successful which is why preoperative and
intraoperative neurophysiologic testing is important. Unlike in SCI, DP in ALS is not intended to replace
MV but to delay the onset of respiratory failure. Long-term results from the initial pilot study of 16
patients showed median survival was 19.7 months from DP implant, 39.5 months from diagnosis, and 51.1
months from initial onset of symptoms.41 This study showed that the post-DP implant diaphragm muscle
thickness, as evaluated by ultrasound, was consistently greater for all patients than at preimplant. This
showed the ability of DP to overcome disuse atrophy and improve diaphragm strength. Further, an
evaluation of 86 ALS patients with chronic hypoventilation and preserved bilateral phrenic nerve function
showed that DP used with or without concurrent NIV improved survival when compared to historical
controls.42 Evidence of probable benefit include 16-month improvement of survival from diagnosis and
an additional 9 months of improved survival from the start of NIV. There was a significant improvement
in sleep with the use of DP.43 In a group of ALS patients undergoing simultaneous DP and gastrostomy
(PEG), a significant improvement was seen in both 30-day mortality and 1-year survival compared with
PEG alone (76% survival at 1 year with DP and PEG vs. only 23% with PEG alone).42 This improvement
in survival can be explained by the ability of DP to maintain diaphragm function and overcome the
sedation effects on diaphragm ventilation compared with PEG alone. In addition, DP increases
respiratory compliance by decreasing posterior lobe atelectasis.
A study published in 2015 highlighted respiratory abnormalities found in ALS patients that can lead to
the success of DP.44 ALS patients can have a unilaterally elevated diaphragm from paradoxical
movements leading to shortness of breath, sleep abnormalities, and increased atelectasis leading to
increased pneumonia risks. It was found at surgery that some patients have intact LMN and diaphragm
motor units that exhibit great response to electrical stimuli. In these patients, dEMG analysis confirmed
the loss of neural control of respiration on a unilateral side. With the loss of the UMN signal, the
diaphragm muscle does not contract resulting in disuse atrophy and DP can reverse this in this subgroup of
patients.
FUTURE TRENDS IN MANAGING VENTILATOR INDUCED DIAPHRAGM

DYSFUNCTION
The previous section showed how DP can significantly improve ventilation in a diverse group of orphan
diseases. There is a much larger group of patients who require prolonged temporary use of MV. These
patients, often referred to as “failure to wean” (FTW), present a significant physiologic and economic
burden to the health care system. Up to 50% of ICU patients require MV, and 20% are on a ventilator for
over 7 days. Over 40% of this time is spent weaning a patient from MV after the initial event that caused
intubation for MV. There are multiple etiologies contributing to FTW resulting in long-term mechanical
ventilation (LTMV) which includes heart failure, primary pulmonary disease, and critical illness
neuropathy. In addition to medical etiologies, MV has its own deleterious effects. Positive pressure MV
leads to inactivity of the diaphragm muscle, causing atrophy and weakness.5 Because the diaphragm is the
primary inspiratory muscle, VIDD is widely recognized as a major contributing factor to FTW.
LTMV has a 20% to 50% 1-year mortality rate, poor functional outcomes, and a median cost of
$306,000.45 Additionally, FTW patients have longer hospital days (median 17 vs. 6 days), higher co-
morbidities, and increased costs. The number of LTMV patients is growing at 5.5% annually. It is
estimated there will be 605,000 patients requiring LTMV by 2020 at a cost of $64 billion, making
prevention and treatment of FTW a priority. DP has been successfully used in SCI and in other causes of
FTW to replace or decrease MV. In SCI patients, early implantation of DP has substantial benefits and as
of yet no known drawbacks. Recent studies in FTW patients are highlighting some new therapies in which
stimulation for inspiration may decrease MV days.
A newly designed temporary electrode was developed to address this problem and a human trial was
completed. This was a prospective FDA study (IDE #G150040), IRB-approved, and listed on
clinicaltrials.gov (NCT 02410798) that evaluated the feasibility of temporary diaphragm electrodes to
provide ventilation with stimulation. At the end of the subject’s primary surgical procedure, two
temporary diaphragm pacing electrodes were placed intramuscularly in each hemidiaphragm at the
expected motor point where, with stimulation, diffuse diaphragm contraction would occur because of
proximity to the phrenic nerve. This was done without mapping the diaphragm which is a component of
the permanent electrode previously utilized. The electrodes exited the abdominal or chest cavity on each
lateral side without tunneling to a central location, which is standard with the permanent system used in
SCI and ALS patients. The electrodes would be attached immediately at the bedside to an EPG with
connecting cables to begin diaphragm conditioning.
There were eight males and four females who underwent three different approaches: four median
sternotomy, four laparoscopy, and four laparotomy. Subjects had multiple comorbidities. In all patients,
electrode stimulation exceeded ideal tidal volumes by an average of 37% (0% to 95%). This confirms
that in this group of patients mapping the diaphragm would not be necessary to adequately provide
ventilation. A daily electromyogram was obtained to analyze respiratory function and confirming stability
of placement until removal.
This study confirmed that these electrodes could be utilized throughout a patient’s hospitalization to
maintain diaphragm strength and prevent atrophy. There were no complications with the placement of the
electrodes and all 48 study electrodes remained in place until removal prior to discharge. There was
complete intact removal of all 48 electrodes at the bedside. This trial demonstrates the ease of placement,
removal, functionality, and safety of temporary DP electrodes.46
Smith and colleagues have also reported on the use of diaphragm pacing as a rehabilitative tool for
patients with Pompe disease who are ventilator dependent. In this group of three patients with a
nonreversible underlying disease, they were still able to increase tidal volumes after utilization of
diaphragm pacing. Their conclusion is that diaphragm pacing has rehabilitative value in overcoming
disuse atrophy.47
At the American Thoracic Society Meeting in May 2016, the group from University Hospitals in
Cleveland reported the use of the DP system in a series of FTW patients. This was a retrospective review
of compassionate, off-label use of an FDA-approved device under IRB approval.38 Immediately after
implantation, the DP system was used to drive ventilation, with subsequent weaning from MV. Ten
patients were implanted laparoscopically with no complications. The primary diagnosis causing FTW
was the result of seven patients who had a median sternotomy with acute phrenic nerve injury (two heart
transplant, one left ventricular device, three CABG, one atrial myxoma), one aspiration pneumonia, one
liver transplant, and one idiopathic diaphragm paralysis. Mean duration of positive pressure MV prior to
intervention was 44 days (range 4 to 148 days). All 10 were successfully weaned. Mean time to
completely wean from invasive ventilation was 15 days (range 1 to 35). All tracheostomy patients were
decannulated. In the six patients implanted 12 months or longer, there is an average survival of 34.84
months (14.4 to 58 months). All live at home, perform activities of daily living independently, and are at
or near pre-respiratory failure function.
The conclusion is that DP can be used as a therapy to treat FTW. The long-term survival and
functionality of this group is significantly better than typical reports of prolonged MV patients. The last
patient in this report was identified with significant diaphragm dysfunction post-median sternotomy with
only four days of invasive ventilation. He was weaned with DP in one day, obviating the need for
tracheostomy. This suggests that DP could alter the paradigm of prolonged MV and should be studied
more extensively in select groups of patients. Expanding stimulation of the diaphragm in the ICU could
significantly decrease over 100,000 temporary tracheostomies performed a year in the United States for
FTW, and might decrease the burden of long-term MV.
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24. Nochomovitz ML, Hopkins LM, Broadkey J, et al. Conditioning of the diaphragm with phrenic nerve stimulation after prolonged disuse.
Am-Rev-Respir-Dis 1984;130(4):685–688.
25. Nochomovitz M, Peterson DK, Stellato TA, et al. Electrical activation of the diaphragm. Clin Chest Med 1988;9:349–358.
26. Peterson DK, Nochomovitz ML, Stellato TA, et al. Long-term intramuscular electrical activation of phrenic nerve: efficacy as a
ventilatory prosthesis. IEEE Trans Biomed Eng 1994;41:1127–1135.
27. Dimarco AF, Onders RP, Kowalski KE, et al. Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm electrodes. Am
J Respir Crit Care Med 2002;166:1604–1606.
28. Onders RP, Aiyar H, Mortimer JT. Characterization of the human diaphragm muscle with respect to the phrenic nerve motor points for
diaphragmatic pacing. Am Surg 2004;70:241–247.
29. Onders RP, Ignagni AI, Aiyer H, et al. Mapping the phrenic nerve motor point: the key to a successful laparoscopic diaphragm pacing
system in the first human series. Surgery 2004;136:819–826.
30. Onders RP, Ignagni AI, DiMarco AF, et al. The learning curve of investigational surgery: lessons learned from the first series of
laparoscopic diaphragm pacing for chronic ventilator dependence. Surg Endosc 2005;19:633–637.
31. Onders RP, Carlin AM, Elmo MJ, et al. Amyotrophic lateral sclerosis: the midwestern surgical experience with diaphragm pacing
stimulation system shows that general anesthesia can be safely performed. Am J Surg 2009;197:386–390.
32. Onders RP, Elmo M, Khansarinia S, et al. Complete Worldwide Experience in laparoscopic diaphragm pacing: results and differences in
spinal cord injured patients and amyotrophic lateral sclerosis patients. Surg Endosc 2009;23:1433–1440.
33. Celik S, Celik M. Long-term results of diaphragm plication in adults with unilateral diaphragm paralysis. J Cardiothorac Surg
2010;5(111):1–7.
34. Welvarrt WN, Jak P, van de Veerdonk MC, et al. Effects of diaphragm plication on pulmonary function and cardiopulmonary exercise
parameters. Eur J Cardiothorac Surg 2013;44:643–647.
35. Hirschfeld S, Exner G, Luukkaala T, et al. Mechanic ventilation or phrenic nerve stimulation for treatment of spinal cord-induced
respiratory insufficiency. Spinal Cord 2008;46:738–742.
36. Adler D, Gonzalez-Bermejo J, Duguet A, et al. Diaphragm pacing restores olfaction in tetraplegia. Eur Respir J 2009;34:365–370.
37. Onders RP, Khansarinia S, Weiser T, et al. Multi-Center Analysis of Diaphragm pacing in tetraplegic with cardiac pacemakers: positive
implications for ventilator weaning in intensive care units. Surgery 2010;148:893–897.
38. Onders R, Elmo M, Kaplan C, et al. Diaphragm pacing as successful salvage therapy in failure to wean Patients: should this novel
technology be used earlier. Am J Respir Crit Care Med 2016;193:A7653.
39. Onders RP, Ponsky TA, Elmo MJ, et al. First reported experience with intramuscular diaphragm pacing in replacing positive pressure
mechanical ventilators in children. J Pediatr Surg 2011;46:72–76.
40. Posluszny JA, Onders R, Kerwin AJ, et al. Multicenter Review of diaphragm pacing in spinal cord injury: successful not only in weaning
from ventilators but also in bridging to independent respiration. J Trauma Acute Care Surg 2014;76:303–310.
41. Onders, R., Elmo, M., Kaplan C, et al. Final analysis of the pilot trial of diaphragm pacing in amyotrophic lateral sclerosis with long term
follow-up: diaphragm pacing positively affects diaphragm respiration. Am J Surg 2014;207:393–397.
42. FDA: HDE H100006. (2011) U.S. Food and Drug Administration. NeuRx DPS™, Diaphragm Pacing System. Summary of Safety and
Probable Benefit (SSPB). http://www.accessdata.fda.gov/cdrh_docs/pdf10/H100006b.pdf. Accessed August 15, 2016.
43. Gonzalez-Bermejo J, Morelot-Panzini C, Salachas F, et al. Diaphragm pacing improves sleep in patients with amyotrophic lateral
sclerosis. Amyotroph Lateral Scler 2012;13:44–54.
44. Onders, R, Elmo, MJ, Kaplan C, et al. Identification of unexpected respiratory abnormalities in patients with amyotrophic lateral
sclerosis through electromyographic analysis using intramuscular electrodes implanted for therapeutic diaphragmatic pacing. Am J Surg
2015;209:451–456.
45. Damuth E, Mitchell J, Bartock B, et al. Long-term survival of critically ill patients treated with prolonged mechanical ventilation: a
systematic review and met-analysis. Lancet Resp Med 2015;3:544–553.
46. Onders R, Markowitz A, Hardacre J, et al. Completed FDA Feasibility Trial of Surgically Placed Temporary Diaphragm Pacing
Electrodes: a promising option to prevent and treat respiratory failure. Am J Respir Crit Care Med 2016;193:A7654.
47. Smith BK, Fuller DD, Martin AD, et al. Diaphragm pacing as a rehabilitative tool for patients with pompe disease who are ventilator-
dependent: case series. Phys Ther 2016;96(5):696–703.
52
Congenital Posterolateral Diaphragmatic
Hernias and Other Less Common Hernias
of the Diaphragm in Infants and Children
Priscilla Chiu ■ Jacob C. Langer
INTRODUCTION
Congenital diaphragmatic hernia (CDH) is a relatively rare developmental defect of the muscular
diaphragm. Until the 1990s, the defect was highly lethal with mortality rates widely reported at greater
than 50%. Over the past two decades, concerted efforts have been directed at improving resuscitation
protocols, ventilation strategies, and other interventions. These measures have improved mortality rates to
less than 20% at many specialized centers, but the challenge of improving outcomes for the sickest 10% to
20% of CDH cases remains. Moreover, CDH can be detected by prenatal ultrasound (US) and therefore
has garnered much clinical and research attention to develop prenatal risk stratification and interventions
that may improve the postnatal outcomes of the most severely affected cases. This chapter will highlight
the developmental defects of the diaphragm; the physiologic defects affecting the lung and foregut;
perinatal, surgical, and long-term outcomes for CDH patients; and the interventions that have been
proposed for the future treatment of CDH.
CLASSIFICATION OF DIAPHRAGMATIC HERNIAS

The most commonly used classification of CDH is based on the anatomic location of the diaphragmatic
defect. Posterolateral or Bochdalek (named after the 19th century Czech anatomist Vincent Bochdalek)
hernias most commonly occur on the left side, but can also be right sided or bilateral. Diaphragmatic
agenesis involves the complete absence of the muscular diaphragm. These anomalies represent a
fundamentally different pathophysiology and clinical spectrum of disease compared to the relatively more
“benign” conditions associated with the diaphragmatic hernias arising in the hiatus (hiatal hernias, HHs)
or the central retrosternal area (Morgagni hernias).
Diaphragmatic hernias may also be classified based on etiology as congenital or acquired, the latter
arising from iatrogenic, traumatic and other causes in pediatric and adult patients. Finally, diaphragmatic
hernias may also be classified based on whether there is a sac, which is usually composed of peritoneum,
or “slack” diaphragm which consists of an eventration resulting in a “high-riding” diaphragm encroaching
into the thoracic domain (Fig. 52.1). Eventration of the diaphragm does not have visceral herniation
directly into the pleural cavity, and the surgical management usually involves plication of the diaphragm
rather than a complete repair that would be used for true Bochdalek hernia. In this chapter, the main focus
will be on the clinical presentation and management of Bochdalek hernias and diaphragmatic agenesis.
BOCHDALEK HERNIA AND DIAPHRAGMATIC AGENESIS
EMBRYOLOGY
The diaphragm consists of a muscular perimeter with a central tendon resulting from the confluence of
multiple embryologic structures. The embryologic origins of the diaphragm were defined from animal
studies, especially those in rodents. The use of teratogenic and genetic models of CDH further helped to
clarify the origins of this defect that occurs early in gestation.1 Furthermore, significant insights from these
models have revealed a vital role of the retinoic acid signaling pathway in CDH pathogenesis.2 The
current theory of CDH development is summarized here but comprehensive reviews are available
elsewhere.3
Prior to week 4 of gestation the coelomic cavity comprises the entire span of the embryo without
separation into a thorax and abdomen. During the fourth week of embryologic development the
diaphragmatic precursors of the mesoderm become defined and mobilized—lateral extension of the
septum transversum toward the lateral margins of the pleuroperitoneal fold (PPF) bridge the coelomic gap
to form the membranous (central tendon) and the muscular diaphragm. The dorsal and crural margins are
derived from the esophageal mesentery (hence the classification of CDH as a foregut anomaly by some
researchers and clinicians) and join the PPF while the abdominal wall itself completes the ventral
diaphragmatic circumference in the developing and elongating embryo. The developing lung occupying
that space above the developing diaphragm is thought to provide the “sealant” for all of the above
contributors to the diaphragm. The process is complete by the end of the first trimester. In this model, it is
believed that Bochdalek hernias arise from failure of the PPF and mesenchyme to give rise to the central
tendon and the muscular diaphragm.
FIGURE 52.1 Chest x-ray images showing diaphragmatic eventration of the right hemi-diaphragm. A: Posterior–anterior chest
x-ray view of right eventration showing the elevated right hemi-diaphragm. B: Lateral chest x-ray view of the elevated right
hemi-diaphragm.
From animal studies using teratogenic models, it was shown that laterality of the CDH depended on the
timing of the exposure; earlier application of the teratogen in gestational age created more left-sided CDH
compared to mostly right-sided CDH when the teratogen was given later in gestation. There are
insufficient data in human cases to substantiate the correlation between timing of the embryologic changes
and any teratogenic exposure as there has yet to be identified any teratogenic basis for human CDH.
However, left-sided Bochdalek hernias and agenesis cases outnumber right-sided disease 10 to 1,
suggesting that the left diaphragm is at least more vulnerable to this defect during development.
PATHOPHYSIOLOGY
The most significant anatomic feature of Bochdalek CDH is the posterolateral diaphragmatic defect
allowing abdominal viscera to herniate into the pleural cavity. However, the most life-threatening feature
of Bochdalek and agenesis CDH is respiratory insufficiency and pulmonary hypertension from underlying
pulmonary hypoplasia. The recognition that the correction of the former does not improve the latter
features became the basis for many changes in the management philosophy of CDH in the last two
decades.
Pulmonary hypoplasia associated with CDH is the single leading factor of CDH mortality and
morbidity but it appears to be different from other congenital conditions associated with pulmonary
hypoplasia such as omphalocele4 or Potter syndrome. Pulmonary hypertension produces right heart strain
and decreases overall cardiac output. While the etiology is still unclear, the pathologic defects of the
CDH lung are many and are comprised of at least some of the following in the lungs: an absolute decrease
in total lung mass,5 decreased number of branching airways,6 decreased number of pulmonary arterial
vessels6 possibly due to the failure of angiogenesis in lung development,7 and the hypermuscularization of
those vessels.6
Pulmonary hypoplasia associated with CDH can affect both lungs and ranges from mild to a level of
severity that is incompatible with life. The decrease in total lung parenchyma and branching airways
results in oxygenation and ventilation deficits that are not reversible. Initial ventilation strategies,
therefore, should aim to optimize patient oxygenation and ventilation with the lowest airway pressures
possible as the hypoplastic lung is “nonrecruitable” lung volume. Pulmonary hypertension may gradually
lead to right ventricular failure unless right-to-left shunts off-load the right heart. However, this decreases
overall oxygen delivery and results in progressive hypercarbia and metabolic acidosis. Pulmonary
hypertension remains one of the leading causes of death in CDH neonates.
ASSOCIATED SYNDROMES AND CONDITIONS

Increasingly, population-based reports indicate that up to 40% of CDH cases have associated genetic,
syndromic, or structural anomalies,8,9 although reports that include both antenatal and postnatal data have
cited rates of potentially lethal anomalies at 50%.10 In approximately 10% of cases, CDH infants present
at birth with other anomalies including cardiac, urogenital, pulmonary,11 and brain or spinal cord defects.
CDH is seen with chromosomal aneuploidy such as Trisomy 13, 18, and 21. Known genetic syndromes
variably associated with CDH include Cornelia de Lange syndrome, Fryns syndrome, Matthew-Wood
syndrome, Denys–Drash syndrome, and Donnai–Barrow syndrome.10,12 Microarray analyses have further
revealed microdeletions and gene copy number variations not previously identified in CDH patients.13–16
Research efforts correlating copy number variations and genetic mutations with CDH phenotype, such as
mutations in the GATA4 gene, are currently under investigation.17
EPIDEMIOLOGY, PRENATAL DIAGNOSIS, AND CARE

CDH is not common and population studies are required to yield details on disease epidemiology. CDH
prevalence in Europe is approximately 2.3 cases per 100,000 live births and affects males more
frequently, with a male-to-female ratio of 1:0.69.8 The population incidence has not changed significantly
over time and the incidence did not appear to be affected by maternal age. Data from Washington State
suggest that maternal factors such as pregestational diabetes and alcohol use are linked with CDH
diagnoses.18
Routine prenatal US can detect left-sided CDH by the presence of bowel loops, liver, and/or stomach
in the left fetal thorax as early as 18 weeks of gestation. The detection of right-sided CDH may be more
challenging as isolated liver herniation without bowel herniation in the right fetal thorax may be more
difficult to detect. Other indirect signs suggestive of fetal CDH include mediastinal shift, hydrops, and
intrauterine growth delay.
The diagnosis of CDH on routine prenatal US has changed the landscape for CDH management and
risk stratification. Prior to prenatal diagnosis, the main focus in CDH management was on perinatal
resuscitation and stabilization through which clinicians identified biomarkers of mortality, such as the first
arterial blood gas or pH. Based on those postnatal assessments, efforts were largely directed at
improvements in resuscitation techniques and neonatal management. Prenatal diagnosis now allows for
much more comprehensive prenatal CDH care including multidisciplinary consultation and obstetrical
planning especially for the severe cases. With the advances in prenatal imaging by US and magnetic
resonance imaging (MRI), many prenatal markers have been identified to predict postnatal outcomes and
now drive the efforts to identify those with the most severe disease for fetal interventions.
PRENATAL MARKERS OF OUTCOMES: ANATOMY, LUNG-TO-HEAD RATIO,

O/E LUNG-TO-HEAD RATIO, O/E TOTAL FETAL LUNG VOLUME
Given the range of severity of CDH outcomes, the need to develop accurate prognostic tools early in
gestation became an important part of prenatal counseling and preparation. One of the limitations in the
prognostication of prenatally diagnosed CDH has been variability of the timing of prenatal US and the
detection of the CDH defect. Anatomic features widely used in CDH prognostication include liver
position, stomach position, and lung size. Simply, liver19 or stomach20 position in the thorax correlated
with worse postnatal outcomes. However, measurements of lung size for prognostication were more
complex. While the fetal lung-to-head ratio (LHR), defined as the measurement of the fetal head size
compared to the fetal lung contralateral to the CDH, has been used since the 1990s to prognosticate the
severity of pulmonary hypoplasia associated with CDH,21 it was difficult to standardize due to variability
of the ratio with gestational age and fetal position to assure the correct cross-sectional plane of
assessment. The “normalization” of the LHR across the gestational period finally allowed this
standardization through reporting of the observed LHR compared to the expected or predicted LHR (o/e
LHR) using a nomogram (reviewed22). Similarly, the calculation of the total fetal lung volume (TFLV) by
MRI provided volumetric calculation of the fetal lung size to compare the lung ipsilateral to the CDH
compared to normal gestational age-matched controls, reporting the percentage as “observed over
expected total fetal lung volume” or o/e TFLV. The clear advantage of MRI was the multiplanar
assessment of the fetal thorax independent of the fetal position or accessibility of sonographic windows.
Some centers have also utilized TFLV tracked over time to produce growth curves that forecast
survival.23 Using these approaches, it has become feasible to standardize prenatal CDH assessments to
determine and compare fetal prognostic markers within centers, between centers, and across gestational
ages. This is particularly useful in guiding individual centers regarding prenatal care, postnatal
management, and, where available, the opportunity to enroll in clinical trials for fetal intervention.24
PRENATAL INTERVENTIONS
While efforts were focused on neonatal resuscitation, reports on the “hidden mortality” of CDH revealed
that infants with the most severe pulmonary hypoplasia never survived long enough to be transported to
tertiary care ICU settings.25 As CDH pulmonary hypoplasia is largely irreversible after birth, attention
was directed at correcting the pulmonary hypoplasia during fetal development. The pioneers of fetal
surgery, Michael Harrison and his team at the University of California at San Francisco, devised
protocols, techniques, and tools to address the surgical and obstetrical challenges of open fetal surgery,
including intraoperative management of the amniotic fluid, minimization of uterine bleeding following
hysterotomy, monitoring of the fetus, and tocolytic management during and following fetal surgery. Initial
attempts were focused on severe CDH cases with prenatal diagnosis prior to 24 weeks of gestation for
open fetal surgical repair of the CDH near the end of the second trimester. However, open fetal surgery
for CDH was associated with very high intraoperative and postoperative mortality due to fetal stress,
preterm labor, and difficulty reducing the intrathoracic liver in fetuses with a very large defect or
diaphragm agenesis.26,27
The subsequent phase in CDH fetal therapy was spawned by the intriguing findings of a rare congenital
defect known as congenital high airway obstruction syndrome (CHAOS).28 This defect resulted in
massively enlarged lungs due to fetal tracheal obstruction just distal to the larynx which trapped amniotic
fluid in the lungs and airways that would normally flow freely in and out of the tracheobronchial tree. It
was then shown in animal models that fetal tracheal occlusion (FETO) can significantly increase lung size
in experimental CDH.29 The next challenge was to develop techniques for accessing the fetus, occluding
the airway in utero, and reversing the tracheal occlusion prior to delivery. In a stroke of good timing, the
introduction and popularization of minimal access surgical techniques coincided with these discoveries.
Thus, “FETENDO” became the preferred approach for accessing the fetal airway in CDH cases in lieu of
open fetal surgery.30 This technique was developed by Harrison’s team in fetal lambs and then
subsequently through several iterations in human fetuses with CDH, culminating in the first randomized
controlled trial of fetal surgical therapy. Unfortunately, this study failed to show a survival benefit of
FETO for severe CDH cases compared to control patients.31 Upon further analysis, there are at least three
potential explanations for this failure to demonstrate benefit. First, it was clear from this trial that there
was a higher than expected survival rate of 77% for the “standard care” patients compared to 50% or
lower of historical cohorts, indicating the benefits of the protocolized postnatal care for CDH patients in
general. Second, the inclusion criteria for FETO at the LHR threshold of 1.4 may have included those for
whom survival was not in question (e.g., those with LHR between 1.07 and 1.39 where there was 100%
survival in both the standard care and FETO groups), possibly masking the beneficial effect of FETO in
the highest-risk patients. Lastly, there was a significantly higher incidence of preterm delivery for the
FETO cases resulting in premature births at 30.8 weeks on average compared to term births at 37 weeks
for the controls that may have negated the survival benefit attributed to FETO-induced lung growth. In
addition, it is possible that there may have been less morbidity in the FETO group despite no difference in
mortality.
Despite this result, the enthusiasm for fetal intervention for CDH has not abated in many centers,
particularly in Europe, where Jan Deprest and his team in Leuven, Belgium have continued to develop
less invasive techniques to accomplish tracheal occlusion.32 Two multicenter trials are currently enrolling
patients in Europe evaluating the role of FETO in moderate (for o/e LHR between 26% and 49%) and
severe (o/e LHR <25%) cases of CDH (www.totaltrial.eu). However, the protocol for the trials has
received some criticism. The maternal care post FETO is given back to the primary referral center and
the postnatal care, while guided by a research protocol, may not be uniformly followed. Lastly, the
reporting of long-term outcomes aside from mortality and early morbidity are not included. Other centers
have also conducted smaller randomized trials reporting some benefit of FETO,33 especially in the most
severe cases.34 It is clear that the role of FETO for CDH will continue to generate interest and debate in
the years to come.
PERINATAL RESUSCITATION
Prenatal diagnosis of CDH has allowed perinatal teams to plan for the delivery and resuscitation of the
newborn CDH infant. In such cases, deliveries at high-volume perinatal centers with neonatal intensive
care units have been associated with the best survival,35 suggesting that high-volume centers may be
preferable for optimal CDH perinatal management.
RESPIRATORY MANAGEMENT
In the era of prenatally diagnosed CDH patients, immediate postnatal care can be carefully planned and
anticipated. For those CDH cases not prenatally diagnosed, the rapid and systematic management of
respiratory compromise of the CDH newborn is critical. Chest x-ray for the possibility of CDH diagnosis
should be considered for any newborn presenting with unexplained respiratory distress. The immediate
management of a CDH neonate consists of respiratory monitoring, insertion of a nasogastric tube for
bowel decompression, intravenous access and application of oxygen by noninvasive means, or invasive
endotracheal intubation if respiratory compromise is apparent. Use of noninvasive positive-pressure
respiratory support (i.e., nasal or bag-mask CPAP) must be avoided, as it leads to further gaseous
distension of the herniated viscera that may further exacerbate cardiorespiratory compromise. In those
CDH patients who display minimal signs of respiratory distress, endotracheal intubation should be
avoided unless prolonged transport is planned and routine imaging and laboratory investigations before
elective CDH repair are the only investigations required. More commonly, CDH patients present with
gross respiratory failure requiring immediate endotracheal intubation, fluid resuscitation, and
hemodynamic support. The most common tools used to support the most severely affected CDH neonates
are “gentle ventilation” techniques, extracorporeal membrane oxygenation (ECMO), and/or pulmonary
vasodilators.
VENTILATOR MANAGEMENT
Up until the mid-1990s, mechanical ventilation was used not only to support the pulmonary insufficiency
of the CDH infant but also to minimize right-to-left shunting through the patent ductus arteriosus (PDA)
which was thought to exacerbate the hypoxia and ventilatory mismatch. Therefore, hyperventilation to
induce respiratory alkalosis was aggressively attained through high-pressure mechanical ventilation to
decrease shunting through the PDA. It is now generally recognized that this approach was responsible for
significant ventilator-induced lung injury including the development of pneumothoraces, respiratory
failure, and even death during the early resuscitation period and bronchopulmonary dysplasia in CDH
survivors.36,37 It was the work of Wung and colleagues38 who first identified this iatrogenic problem and
proposed the acceptance of higher arterial partial pressure of carbon dioxide (PaCO2) levels.
To preserve and protect lung function in the context of CDH-related pulmonary hypoplasia, the “gentle
ventilation” approach uses a minimal ventilatory strategy of permissive hypercapnia while maintaining an
acceptable level of oxygenation and ventilation through conventional or high-frequency oscillation
ventilation (HFOV) techniques.39 Acceptable levels of oxygenation, especially among CDH infants with
right-to-left shunting due to pulmonary hypertension, means accepting lower postductal oxygen saturations
(>85%) with considerations for optimizing hemoglobin levels to compensate for and to maximize oxygen-
carrying capacity. Positive end expiratory pressure (PEEP) is restricted to 5 mm Hg to minimize
barotrauma to the normal lung while recognizing that the nonrecruitable hypoplastic lung cannot be further
expanded by increasing airway pressures. The frequency of pneumothorax has decreased with the use of
pressure-limited ventilation techniques from 25%37 to less than 5%.40 The experience has increased with
this technology such that HFOV is now routinely used early to “gently ventilate” the CDH patient when
ventilatory pressures increase as the oxygenation levels decrease. When permissive hypercapnia
approaches the threshold for conventional ventilation (pH <7.25), HFOV is also the ideal ventilation
mode for managing hypercarbia and pH when oxygenation is manageable. Once ventilation stabilizes, the
patient is weaned back to conventional ventilation. Operative repair can be performed either when the
patient is transitioned back to conventional ventilation or while on HFOV.
The optimal ventilatory strategy for the CDH newborn continues to garner a great deal of debate. Mode
of ventilation is one area of contention. Thus, the European CDH Consortium conducted an international,
multicenter randomized controlled trial (the VICI Trial;
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1310) to compare the ventilatory effects of
conventional mechanical ventilation versus HFOV.41 This is the first study to include, as its outcomes, not
only patient survival but also the long-term incidence and severity of pulmonary outcomes including
bronchopulmonary dysplasia for CDH infants. The results from this trial will likely impact all perinatal
centers in the ventilatory management for CDH patients.
EXTRACORPOREAL MEMBRANE OXYGENATION

Since ECMO was first shown to be of benefit in the CDH population, multiple series have reported
improved survival using ECMO support for lung preservation when standard therapies have failed.42,43
The indications for ECMO support of the CDH infant continue to evolve. The primary role of ECMO is to
provide respiratory support during the early postnatal period of pulmonary vascular reactivity. As
pulmonary hypoplasia remains the leading cause of death for CDH patients on ECMO, it is clear that
ECMO does not correct the underlying pulmonary defect of CDH and that its use may be futile in patients
with irreversible and lethal pulmonary hypoplasia (i.e., those who have never demonstrated normal PaO2
levels).44 For many centers, ventilatory criteria for ECMO cannulation include the inability to maintain
preductal oxygen saturations >85%; peak inspiratory pressure >28 cm H2O, mean airway pressure >15;
pressure-resistant hypotension; inadequate oxygen delivery based on persistent metabolic acidosis or
rising serum lactate level; and inability to wean from FiO2 100% in the first 48 hours of life. When the
patient requires more than the set level of ventilatory support, ECMO is utilized rather than escalating the
settings on positive-pressure ventilation. Inclusion criteria also include birth weight >2 kg, gestational
age >34 weeks, absence of intracranial hemorrhage >grade I, and absence of other congenital or
chromosomal anomalies.42 Some centers offer ex utero intrapartum therapy (EXIT) to ECMO support in
those CDH cases where prenatal prognostic markers indicate high risk, such as those with co-morbid
congenital heart defects.45 However, this approach should be reserved for highly selected cases.
OTHER VENTILATION ADJUNCTS (LIQUID VENTILATION AND

SURFACTANT REPLACEMENT)
The role of other adjuncts to optimize ventilation has been studied but the outcomes have been generally
negative. Liquid ventilation (LV) using perfluorocarbons (or PFC, inert liquids with high gas solubility)
as a ventilation strategy in the pediatric population was initially conceived for use for the extreme
premature infants with severe pulmonary hypoplasia of prematurity.46 The advantages of LV, whereby gas
exchange occurs through the liquid medium rather than air, included minimization of lung damage by
replacing the gas–fluid exchange interface to a fluid–fluid interface, thus minimizing the surface tension
required for gas exchange, decreasing alveolar pressure and improving pulmonary blood flow. Tidal LV
involves the complete replacement of gas exchange from the gas–liquid interface to a liquid–liquid
interface. In contrast, partial LV would only fill the functional residual capacity (FRC) of the lung with
PFC while gas exchange would still occur in the mechanically ventilated parts of the lung. The theoretical
advantages of partial LV are the protection of the surfactant-deficient lung from the mechanical ventilation
pressures required for gas exchange, and the distension of the hypoplastic lung with PFC that may
stimulate growth over time. Partial LV was investigated as a possible treatment for CDH in a pilot trial to
evaluate its safety.47 However, corporate support for LV was withdrawn completely from clinical trials
and the use of LV for CDH and other diagnoses was prematurely terminated.46
Reports of surfactant insufficiency limiting alveolar expansion or nitric oxide response in CDH48,49
resulted in trials assessing surfactant replacement during perinatal resuscitation. However, surfactant
therapy has not been shown to significantly improve survival in term,50 preterm,51 or ECMO-treated52
CDH patients. More importantly, there is evidence that this treatment may cause harm rather than help the
CDH infant.50
PULMONARY HYPERTENSION MANAGEMENT

The management of pulmonary hypertension in CDH infants remains a challenge. This is due to the
complex combination of abnormal angiogenesis, smaller caliber pulmonary arteries, hypertrophied and
hypermuscularized adventitial and medial layers, and failure of postnatal remodeling affecting both lungs
of the CDH patient (reviewed53). The mechanisms underlying these defects are still not understood,
further increasing the difficulty of correcting them. Animal models of CDH have helped to inform some of
the critical features and pathways leading to these defects including aberrant levels of pulmonary
vasoconstrictor proteins or function of pulmonary artery endothelial progenitor cells.54 Interestingly,
higher plasma levels of endothelin-1, a potent regulator of pulmonary vasoconstriction and smooth muscle
cell mitogen, were found in those CDH infants with severe pulmonary hypertension.55 Further
translational research into the pulmonary vasculature defects will be needed to rescue CDH infants
postnatally from recalcitrant pulmonary hypertension.
At the bedside, severe pulmonary hypertension can present with hypotension and right heart failure
causing death. Pulse oximetry monitoring may reveal preductal and postductal arterial oxygen saturation
gradients, indicating the persistence of right-to-left shunting through a PDA or septal defect. The use of
prostaglandin E1 (PGE1) to maintain the PDA can be sufficient to reverse the hemodynamic instability but
may not improve overall survival.56 In cases of severe, suprasystemic pulmonary hypertension, the PDA
will serve as a “pressure release” valve to off-load the right heart, preserving cardiac output and right
heart function.39 Two-dimensional echocardiography remains the most accurate modality for the real-time
assessment and monitoring of pulmonary arterial pressure and right heart function at the bedside.57
Interventional cardiology and pulmonary angiography are rarely used aside from the deployment of
intravascular stents to maintain the PDA or for septostomy creation in severe cases where the PDA is
irreversibly closed.
In the presence of high right ventricular pressures or decreased right ventricular function, adjunctive
treatments are required to control pulmonary hypertension. The utility of pharmacologic pulmonary
vasodilators, such as inhaled nitric oxide (iNO), sildenafil (a type 5 phosphodiesterase inhibitor),
prostacyclins, and bosentan (an endothelin-1 receptor antagonist), remains speculative for CDH patients
as no studies to date have shown clearly beneficial effects for CDH-associated pulmonary hypertension.
The largest randomized controlled trial of early iNO therapy in patients with CDH showed no difference
in the combined endpoint of death/ECMO utilization between iNO-treated and controls.58 Despite the lack
of clear evidence, however, iNO is widely used in this group of patients and patients must be monitored
for methemoglobin levels with its use.
Mechanical supports of right heart function in severe cases of pulmonary hypertension are few and
experimental in some cases. The use of ECMO in support of intractable pulmonary hypertension with or
without concomitant ventilatory compromise remains an option59 but the fixed component of pulmonary
hypertension may be insurmountable if pulmonary hypoplasia is severe. Weaning a patient from ECMO
support in this scenario is often difficult in conjunction with associated respiratory failure, and the
predicted mortality for this patient population is high.19
POSTNATAL PREDICTORS OF MORTALITY

There are a large number of reported biomarkers and scores of disease severity that have proved to be
highly accurate and clinically useful for CDH prognostication. It is beyond the scope of this chapter to
include all of them but several warrant mention for their simplicity and accuracy that facilitate their wide
application at all centers.
OXYGENATION INDEX
The oxygenation index (OI) is a marker of oxygenation deficit easily calculated as the ratio of the fraction
of inspired oxygen (FiO2) and mean airway pressure (MAP) against partial pressure of oxygen in the
arterial blood (PaO2):
The OI is widely used in both the pediatric and adult critical care contexts and is routinely calculated
to guide ventilatory management especially with regard to transitioning to alternative ventilatory
strategies such as ECMO. The best OI on day of life 1 was shown to have the highest sensitivity and
specificity for predicting 28-day survival compared to liver position, primary repair (see below) and
LHR60 and appears to be a good predictor of outcome across centers.61,62 The OI may also be used as a
serial marker over time to prognosticate CDH outcome.63
PATCH REPAIR OR DEFECT SIZE

The size of the diaphragmatic defect strongly correlates with CDH survival and subsequent morbidity
likely due to the fact that diaphragm defect size correlates with the degree of pulmonary hypoplasia as
reflected by the size of the ipsilateral lung. The correlation between diaphragm defect size, or conversely
the need for patch repair in order to close the diaphragmatic defect, and mortality was consistently found
using two large CDH population databases generated from multiple centers by the Canadian Pediatric
Surgery Network (CAPSNet)64 and from the International CDH Study Group.65 Brindle et al. reported that
while patch repair and day 1 SNAP-II (score for neonatal acute physiology-II) were significant predictors
of mortality in univariate analysis, multivariate analysis showed that only patch repair was predictive of
outcome with an adjusted odds ratio (OR) of 17.1. The CDH Study Group reported survival differences
between those who underwent primary closure of the diaphragm (survival rate of 97%) compared to 57%
survival for those with diaphragmatic agenesis requiring patch repair (OR for mortality 14.07). Those
patients without agenesis but still requiring patch repair were also at a higher risk of death (OR 5.04).
The requirement for patch repair also correlated with longer days on mechanical ventilation and length of
hospital stay.
LATE PRESENTATION
All clinicians involved in the care of CDH infants recognized that those Bochdalek CDH infants who
present after the neonatal period are significantly different physiologically from those who present
prenatally or in the immediate neonatal period.66 The CDH Study Group reported that infants who present
with CDH after age 30 days were likely to present with respiratory or gastrointestinal symptoms, unlikely
to require patch repair and have excellent (100%) survival to discharge.67
OPERATIVE MANAGEMENT
The goal of surgical treatment of CDH is the reduction of the herniated contents and closure of the
diaphragmatic defect—either primarily or with a patch, using nonabsorbable sutures (Figs. 52.2 and
52.3). Today, optimal management includes delay in operative repair, which is no longer urgently
anticipated after the infant arrives in the intensive care unit, as was practiced up to the early 1990s. It was
previously thought that emergency CDH repair was essential to improve ventilation by reducing
intrathoracic pressures by the reduction of herniated contents and improvement of respiratory mechanics
with the presence of two intact diaphragms.38,39,68,69 Instead, surgical repair for the unstable patient is
now deferred until cardiorespiratory stabilization is achieved even if operative repair is deferred for
weeks38,68–71 with no increase in mortality risk when adjusted for disease severity.72 Delayed repair has
the potential advantage of improving outcome as it has been shown that surgical repair of the fragile CDH
patient can contribute to respiratory deterioration and instability secondary to a decrease in pulmonary
compliance.37
OPEN VERSUS MINIMAL ACCESS SURGERY REPAIR

With the increasing popularity and technical advancement of minimal access surgery (MAS) in neonatal
surgery, multiple centers have adopted and applied successfully the laparoscopic73,74 and
thoracoscopic75,76 (Fig. 52.4) approaches to CDH repair in neonates. These approaches provide the
obvious advantages of minimal incisions with better cosmetic results, minimal postoperative pain, and
possibly fewer long-term sequelae associated with the conventional abdominal incision, such as chest
wall deformities, incisional hernia development, and bowel obstruction. Reports over the past decade
indicated that this approach is technically feasible and cosmetically superior, but the long-term outcomes
are concerning. Many centers have reported exceptionally high recurrence rates after thoracoscopic repair
in neonates.76–78 These results suggest that a significant “learning curve” and technical challenges may be
associated with the long-term success of this surgical approach and that quality assurance processes
coupled with long-term follow-up are needed to verify its efficacy against the traditional operative
management.77 In addition, insufflation of carbon dioxide even to low pressures for thoracoscopic CDH
repair in the context of underlying pulmonary hypoplasia may predispose CDH infants to high blood
carbon dioxide levels and low arterial pH intraoperatively compared to thoracoscopic repairs of other
neonatal anomalies,79 suggesting that physiologic compromise may be significant using the MAS
approach. Although these controversial findings raised concerns about the safety of the thoracoscopic
approach to CDH repair, further studies will be required to evaluate both short- and long-term sequelae
of the thoracoscopic approach on CDH infants.
PATCH VERSUS PRIMARY REPAIR

The options for closure of large CDH defects have increased over the past decade with the availability of
engineered biosynthetic porcine submucosal matrix (Surgisis), acellular dermal matrix (Alloderm),
Marlex, polytetrafluoroethylene (PTFE) or Gore-tex, and abdominal wall muscle flap (Fig. 52.5).80–87
Outcomes associated with patch repairs reported from multiple centers have consistently shown increased
morbidity and mortality in this patient subset compared to those repaired without a patch (see Early
Outcomes section). More importantly, published reports have revealed long-term morbidity associated
with prosthetic patch repairs, including an increased incidence of patch infection, bowel obstruction,
diaphragmatic hernia recurrence, and development of chest and abdominal wall deformities.88–90
Unfortunately, the use of newer biosynthetic patches have not significantly improved these outcomes, as
recent reports have indicated no difference or higher diaphragmatic hernia recurrence rates and incidence
of postrepair bowel obstruction when biosynthetic and Gore-tex patch repairs are compared.91
CDH REPAIR ON ECMO

With the trend toward delayed CDH repair and the increased use of ECMO, CDH repair on ECMO has
also become increasingly common,92 particularly among infants with the most severe disease.93 Until
recently, a large proportion of CDH patients placed on ECMO preoperatively undergo repair while on
ECMO,94,95 with up to 85% of infants requiring ECMO support having this initiated prior to repair.93 Of
the patients placed on ECMO prerepair, 54% were repaired while on ECMO and 30% underwent repair
after decannulation, leaving 16% that never survived to repair.
FIGURE 52.2 The chest x-ray images of a left congenital diaphragmatic hernia. A: Prerepair chest x-ray showing bowel loops
and stomach (NG tube in situ) in the left chest associated with mediastinal shift to the right chest. B: Immediately post primary
repair with the hypoplastic left lung hanging from the left hilum. C: Two weeks following repair with pleural fluid filling the left
pleural cavity. The fluid turned out to be positive for chylomicrons indicating a left chylothorax. D: The patient at 9 months post
repair with good expansion of the hypoplastic left lung filling the left pleural cavity and normalization of the previous mediastinal
shift.
Infants that underwent repair on ECMO encountered more complications and had a higher mortality
than those who underwent repair prior to or after coming off ECMO support. Mortality rate in excess of
50% was associated with a significantly higher rate of bleeding, sepsis, and other complications,96,97
leading many to advocate delaying repair until ECMO support has been weaned off.97–99 The most
significant complication of CDH repair on ECMO is life-threatening hemorrhage.92,100,101 The use of
hemostatic agents, patch repair with running monofilament suture, as well as decreasing the
anticoagulation during repair have decreased bleeding risks.92,102–105
Another factor affecting the timing of surgery in the ECMO patient is the patient’s fluid status.
Occasionally, CDH patients require volume resuscitation to allow for weaning of inotropic support.
While volume loading may be beneficial and necessary, operative repair with edematous tissues can be
treacherous with higher risk of CDH recurrence and inability to close the abdomen following repair.106
Therefore, repair should ideally be performed when significant diuresis has occurred after hemodynamic
stability and oxygenation improvement have been achieved.
FIGURE 52.3 Chest x-ray images showing right congenital diaphragmatic hernia. A: Prerepair with herniated bowel loops in
the right chest and mediastinal shift to the left. B: Immediately post primary repair. C: Two months post repair with correction of
the mediastinal shift.
COMPLICATIONS
The CDH infant may encounter many complications during initial hospitalization and operative repair.
Critically ill CDH infants with prolonged hospital stays and invasive monitoring are at risk for infectious,
thrombotic, and other complications. Aside from the complications of their critical illness, surgical
complications include postoperative hemorrhage from mobilization of the diaphragmatic muscle or from
solid organs such as the liver or spleen. For those patients on ECMO support, hemorrhage and thrombo-
embolic complications may not only affect the surgical site101 but there is also a significant incidence of
intracranial events, which is the most devastating acute and long-term complication.95
Chylothorax can result from surgical mobilization of the diaphragm or other structures during repair
resulting from the disruption of lymphatic channels (Fig. 52.2C).107–109 Teratogenic models of CDH
showed that the CDH defect itself may be associated with abnormal pulmonary lymphatics, suggesting that
traumatic disruption during surgical repair alone may not be responsible for lymphatic leak in the
ipsilateral thorax.110 Patients repaired with patch, on ECMO or HFOV support and requiring blood
transfusion before repair are at highest risk for developing chylothorax.108,109 The overall incidence of
this complication is low, survival is unaffected, and the lymphatic leak is successfully managed
nonoperatively in the majority of cases with parenteral nutritional support and other adjuncts.111 However,
patients who developed chylothorax have longer length of hospital stay, more central line days, and
increased oxygen use compared to those patients who do not.
FIGURE 52.4 Thoracoscopic repair of left congenital diaphragmatic hernia in a neonate. A: Thoracoscopic view of the left
lateral chest wall with stomach (S) reduced into the abdomen and diaphragm edges (arrows) indicating the size of the
diaphragmatic defect. B: Placement of a 3-0 Ethibond suture to the most lateral part of the diaphragmatic defect. This most
lateral stitch is anchored to the ribs to ensure complete closure of the lateral defect. C: Thoracoscopic view of the left lateral
chest wall after the interrupted 3-0 Ethibond suture (arrow) was placed to close the most lateral margin of the diaphragm.
CDH recurrence can occur early or late (see long-term morbidity section below) in the patient’s
course. Early recurrences are more likely to occur with patch repair and MAS repair78 and can only be
ruled out with chest imaging. Recurrences can result in devastating outcomes and should be addressed
surgically as soon as possible.
FIGURE 52.5 Patch repair of left congenital diaphragmatic hernia in a neonate. Thoracoscopic view of the patched closure of
the left diaphragm using 3-0 Ethibond sutures and Surgisis patch.
PATIENT OUTCOMES
Early Outcomes
The majority of CDH patients undergo repair and are discharged home with minimal support. However,
some CDH infants experience sufficient cardiorespiratory compromise that they require home O2 therapy
(for hypoxia and pulmonary hypertension management), nutritional support for failure to thrive (tube feed
supplementation), and occupational and physiotherapy (for feeding and neuromotor function) in order to
transition from the acute care setting to discharge (see the following section on Long-Term Outcomes).
Gastroesophageal reflux (GER) is common among CDH infants and can be severe, causing failure to
thrive or acute life-threatening episodes. The pathophysiology underlying GER in CDH patients is
complex but at least in some part is due to tachypnea and aerophagia associated with respiratory
insufficiency,112 impaired diaphragmatic excursion of the repaired diaphragm,113 as well as anatomic
changes of the lower esophageal sphincter for children with left-sided CDH. Surgical intervention,
including fundoplication prior to discharge may be required for those with severe GER who fail medical
therapy. The need for ongoing postdischarge care is critical for this patient cohort and is facilitated by the
presence of a multidisciplinary CDH clinic which has now been established in multiple centers.114–116
MORTALITY RATES/MORTALITY RISKS

Institutional survival rates for CDH reported since 2000 have been in the 70% to 90% range, which is a
significant improvement compared to the 50% or less survival rates reported prior to that time.36,117
However, population-based studies continue to report higher mortality rates as they include mortality of
cases managed outside pediatric surgical centers.118 Even with all of the advances made in the past two
decades, 10% to 30% of CDH infants still succumb to this disease due to respiratory insufficiency,
pulmonary hypertension, or from the complications of those treatments. Furthermore, prognostication for
some CDH patient subgroups remains ill-defined. For example, it is still unclear whether infants with
right-sided CDH have a higher mortality risk than left-sided CDH patients.119–121 Patients with
diaphragmatic agenesis have the highest mortality rate at 50%.122 Those CDH patients with co-morbid
genetic or congenital anomalies also have higher mortality rates than those with isolated CDH.115 As more
centers report improved mortality outcomes, the ongoing challenge for clinicians treating CDH will be to
improve mortality in the most severe cases.
HIGH-VOLUME VERSUS LOW-VOLUME CENTERS

CDH is a rare disease. As such, there is controversy whether CDH outcomes are related to patient
volume. While there are no clear definitions regarding what constitutes high-volume versus low-volume
centers, and the spectrum of CDH disease is wide and variable, it is clear that some quaternary pediatric
centers may admit over 15 CDH newborns each year and some institutions rarely see more than one or
two cases each year. Because high-volume centers gain more expertise and may have more resources to
support this complex patient population, it has been speculated that survival rates might be lower in low-
volume centers. However, reported outcomes do not support this hypothesis for academic centers in the
United States.123 In Canada, unadjusted mortality rates for CDH infants at high-volume centers (those
centers with greater than 5 CDH cases per year) was 21% compared to 32% at low-volume centers
(those centers with fewer than 2 cases per year).124 However, a subsequent analysis several years later
failed to demonstrate a difference between high- and low-volume centers, perhaps because of quality
improvement measures having been instituted at the lower-volume centers as a result of the initial
analysis.125 Volume-based outcomes analyses such as these reports provide important and valuable
information that identify best practices to improve CDH outcomes for all centers.
LONG-TERM OUTCOMES: MULTISYSTEM MORBIDITY AND

MULTIDISCIPLINARY FOLLOW-UP
Long-term outcomes are now frequently reported for CDH patients. The universal theme has been the
presence of multisystem morbidity for many survivors, the persistence of morbidity and/or symptoms into
adulthood, and the need for an organized approach to address these issues including transitional care.
CDH survivors continue to experience respiratory, nutritional, musculoskeletal, and neurologic
morbidities,95,114,115,126,127 many of which will improve with patient growth and development. To
coordinate this care, some centers have adopted a structured approach to monitor anatomic and functional
outcomes.128–131 These programs should focus on the early detection and treatment of complications and
problems in order to prevent further deterioration. In addition, standardized multidisciplinary follow-up
programs must be part of CDH clinical trial protocols to evaluate and inform of the possible benefits or
complications of new treatment modalities. Structured data collection from such programs may provide us
with valuable information on long-term morbidity and can be used for the education of parents and
caregivers such as in prenatal counseling.
NEUROLOGIC MORBIDITY
One of the most devastating and complicated issues for CDH survivors is neurologic morbidity. The
reported incidence of neurologic and neuromuscular impairment among CDH survivors not only
accounted for the severity of critical illness of the most severely affected patients but was also associated
with the use of ECMO, muscle relaxants, and ototoxic drugs during the acute resuscitation or for the
premature CDH newborn.95,132–135 Many centers now provide standardized care and functional evaluation
including neuromotor, neurocognitive, neuroimaging, and other evaluations to identify and address these
deficits.134 Persistent findings of delayed speech and language development, motor deficits, and
neurocognitive impairment have been reported in early and late childhood regardless of ECMO
exposure.134,136,137 Evaluation of older CDH survivors has also revealed learning deficits and
psychologic impairment.137,138 The input of the multidisciplinary team and educational experts, along with
parental involvement, is needed to address and correct these challenges for the CDH survivor.
CARDIORESPIRATORY MORBIDITY
Due to the fact that pulmonary hypertension is a significant contributor to early mortality for CDH
patients, few CDH survivors have persistent pulmonary hypertension.139 Routine cardiology follow-up of
CDH survivors is advised and should include electrocardiogram and echocardiogram evaluations to
document right ventricular pressures and function. Those patients on pulmonary vasodilator therapy
warrant vigilant monitoring to guide weaning of therapy and to address problems of right ventricular
failure. Ventilation–perfusion scans may be informative but minor mismatches are generally clinically and
functionally insignificant.140,141
CDH survivors should undergo pulmonary function tests (PFT) to inform long-term care. Infant PFT’s
have demonstrated hyperinflation in CDH lungs with larger FRC and decreased expiratory flows at 1 year
of life, especially among those treated with ECMO.142 However, some PFT changes eventually
normalized by age 24 months even among those who received patch repair.143 CDH survivors
experienced persistent respiratory morbidity with 55% of CDH patients developing recurrent infections
regardless of whether they had chronic lung disease at 5 years of age.144 ECMO-treated CDH patients had
more severe air flow obstruction than children who underwent neonatal ECMO for other diagnoses and
respiratory problems seemed to deteriorate over time.142
NUTRITIONAL AND GASTROINTESTINAL MORBIDITY

Nutritional morbidity remains one of the ongoing challenges for CDH survivors, as nutritional
complications often persist beyond infancy into adolescence.127,145 Moderate to severe GER should be
investigated with imaging, functional, and endoscopic procedures. Symptoms should be managed with
medical and surgical antireflux therapy, as long-term complications of esophagitis and even esophageal
cancer have been documented in CDH survivors.146,147 Large diaphragmatic defects and significant
antenatal prognostic risk (liver up by antenatal US) have been shown to be predictors of reflux symptoms
and the need for antireflux surgery.148,149 Oral aversion was also prevalent among CDH survivors and
tube feed supplementation may persist into adolescence to meet nutritional demands.145 Nutritional
support sufficient to achieve growth milestones is the key determinant for the implementation and
maintenance of feeding supplements.
Bowel obstruction in CDH patients has been repeatedly reported. Adhesive bowel obstruction can
occur without CDH recurrence, with patch-repaired patients more affected than those repaired
primarily.150 Surgical management for such cases should proceed as for standard cases of bowel
obstruction, with conservative management attempted unless the obstruction is complicated by intestinal
ischemia, failure to respond to bowel decompression, or if CDH recurrence is the cause. At laparotomy,
it should be determined that CDH recurrence is not a contributor to the obstruction to avoid future
reoperation for persistent bowel obstruction.
MUSCULOSKELETAL MORBIDITY
Infant laparotomy, synthetic patch repair,131,151,152 and persistent respiratory distress are the main
contributors to scoliosis and chest wall deformities in the CDH population. Although early signs of chest
wall deformities following CDH repair may be evident in childhood, more long-term follow-up data are
required to reveal the true incidence of musculoskeletal effects of CDH repair, especially as these
changes become more apparent during adolescence.115,147 A previous history of CDH repair should not
preclude these children from the option of pectus excavatum correction by Nuss procedure.153 Scoliosis
management should include early orthopedic consultation, although surgical management is often deferred
until adolescence.150
CDH RECURRENCE
CDH recurrence can be symptomatic or asymptomatic. Routine follow-up should include chest x-rays for
surveillance (Fig. 52.6). Symptomatic recurrences result largely from incarcerated abdominal organs and
may present with respiratory distress, chest pain, and vomiting due to intestinal obstruction. In long-term
follow up, CDH patients repaired without patch by open surgery had a 10-year recurrence rate of less
than 5% with recurrences occurring in mid- to late-childhood.151 By contrast, patients with patch repairs
or those repaired by MAS approach (see previous section on MAS repair) experienced higher rates of
recurrence, nearing 30%. All of the patches used for CDH repair had their failings as synthetic
nonabsorbable single-layer patches were associated with higher recurrence rates, adhesive bowel
obstruction, and mesh erosion/migration154 while absorbable patches were associated with earlier and
even higher recurrence rates.91,155 Composite patches are very expensive, and although early results are
promising, long-term outcomes are lacking. Abdominal wall muscle flaps fared no better, with similar
recurrence rates as synthetic patches155 and may develop an eventration appearance on CXR in some
patients over time. Finally, there is a good argument to be made that it is the technique rather than the type
of repair that is the cause of CDH recurrence and/or musculoskeletal changes, as taut patches placed
under tension are more likely to pull away from the chest wall during growth to cause a recurrence, or
conversely to pull the chest wall inward causing chest contour changes.156 The use of tension-free, dome-
shaped patch repairs will have to be tracked prospectively to determine whether the technique is truly
better in preventing CDH recurrence and musculoskeletal changes for patch repaired CDH patients.
TRANSITIONAL CARE
The presence and persistence of multisystem morbidity and the potential for CDH recurrence in adulthood
mandates a formal and smooth transition of the CDH adolescent to adult care. However, this is rarely the
case. While most CDH survivors exhibit limited physiologic compromise, complications such as silent
GER157 persists to adulthood and surveillance upper endoscopy is generally recommended to diagnose
and treat the long-term complications. Surveillance for CDH recurrence and pulmonary function is also
necessary and ideally conducted in a respiratory medicine or thoracic surgical unit. Nutritional
assessments of adult CDH patients may require specialized teams knowledgeable in dietary management
of foregut dysmotility and GER disease as dysphagia symptoms persist. Those patients with persistent
pulmonary hypertension or respiratory compromise should be assessed for possible transplantation as
adults. In summary, the coordinated care of the CDH survivor as an adult should be addressed in a
planned and expectant fashion.
FUTURE DIRECTIONS
Outcomes Research
The clinical progress of CDH care has been driven in part by the data accumulated by CDH registries, the
largest of which is the international CDH Study Group (CDHSG) founded by Kevin Lally
(https://med.uth.edu/pediatricsurgery/research/research-centers-and-programs/cdhsg/). The most recent
update of this voluntary database included 112 centers and over 8,000 patients since its inception,
resulting in 35 publications. Data accrual from a large number of centers may be challenging but it
supports a unique ability to address many of the bedside issues with the care of infants with CDH.158
Other national and regional registries have also been established to document disease outcomes and
coordinate research objectives. Specialized, disease-specific research groups such as DhREAMS
(Diaphragmatic Hernia Research and Exploration, Advancing Molecular Science) have also been formed
to coordinate basic, translational, and clinical research for CDH (www.cdhgenetics.com).
NOVEL FETAL THERAPIES AND REGENERATIVE MEDICINE

In addition to fetal surgical interventions, other novel therapies have been investigated to treat prenatally
diagnosed CDH cases associated with a poor prognosis. Prenatal steroids to promote lung maturation
have been evaluated but no study has shown benefit in human trials.159 Other agents administered
prenatally to promote lung and pulmonary vascular growth, such as vitamin A, sildenafil, and endothelin-
1 antagonists are undergoing further investigations in animal models of CDH.160
Regenerative medicine and tissue engineering have also been investigated in preclinical models. The
role of stem cell–based treatments to rescue pulmonary growth defects in animal models of CDH is
currently being investigated (reviewed161). The application of mesenchymal stem cells for the promotion
of lung maturation showed promise in improving alveolar development, surfactant levels, and pulmonary
architecture while the availability and feasibility of harvesting amniotic fluid to source mesenchymal stem
cells for CDH have also been investigated.162,163 Tissue engineering has also been evaluated to generate
replacement diaphragm in lieu of synthetic patches. The use of fetal myoblasts to generate functional and
structurally sound diaphragm tissue in the fetal lamb model appeared to show better efficiency and quality
compared to mature myocyte or acellular scaffold replacements.164,165 Future directions from this
research include the use of inducible pluripotent stem cells derived from patients to generate diaphragm
patches.
FIGURE 52.6 Congenital diaphragmatic hernia recurrence. A: CDH primary repair and recurrence. 1: This image is the
sagittal view of a chest computed tomography (CT) scan of a 15-year-old CDH patient. She had no symptoms and the
recurrence was found incidentally on chest CT for cardiac investigations. The arrow points to the herniated fat above the left
hemi-diaphragm. 2: This recurrent CDH was not seen on her chest x-ray’s PA (left panel) or lateral (right panel) views. B:
CDH patch repair and recurrence shown in the coronal images of a chest/abdominal CT scan of an asymptomatic 7-year-old
patient. The arrow indicates the radio-opaque Gore-tex patch and the bowel loops situated above the patch. C: Chest x-ray
showing left CDH recurrence 11 months following thoracoscopic repair. This patient presented to the emergency department
with respiratory distress and vomiting.
MORGAGNI HERNIA
Morgagni hernia, named after the 18th century anatomist Giovanni Morgagni, arises from the congenital
defect of the midline diaphragm resulting in herniation of abdominal viscera such as colon, small bowel,
and omentum into the anterior mediastinum (Fig. 52.7). It is even rarer than Bochdalek hernias, accounting
for less than 5% of diaphragmatic hernias, and is discussed in more detail in Chapter 49. The
embryologic defect resulting in Morgagni hernia is not well understood, but Morgagni hernias may
present with other midline chest and abdominal wall defects such as omphalocele, sternal, and
pericardial defects, and congenital cardiac anomalies forming the pentalogy of Cantrell spectrum.166
Morgagni hernias have a higher incidence of associated anomalies (up to 70% in some series) and are
highly associated with genetic syndromes such as Turner syndrome, Noonan syndrome, Prader–Willi
syndrome, and Trisomy 21,167 suggesting a genetic or common pathway basis for these co-existing
conditions. Despite this complexity, outcomes for patients with a Morgagni hernia are excellent due to
absence of the pulmonary defects seen with Bochdalek hernias. Morgagni hernias often present beyond the
neonatal period and are commonly diagnosed incidentally following routine chest x-ray for other
conditions. Definitive diagnosis is made with cross-sectional imaging such as computed tomography (CT)
or MRI although chest x-ray findings are often unmistakable (Fig. 52.7).168 Preoperative
echocardiography to rule out potential cardiac defects rounds out the routine investigations for a
Morgagni hernia.
Surgical repair of Morgagni hernia is generally approached via laparotomy or more recently using a
laparoscopic technique (Fig. 52.8). The diaphragmatic defect is situated between the upper abdominal
wall and the pericardium. Primary repair with nonabsorbable sutures is the most common procedure with
patch repairs reserved for large defects extending beyond the midline, laparoscopic repair,81 or
recurrences.169 Laparoscopic approach usually requires a small counter incision at the anterior abdominal
wall to exteriorize the sutures and tie the knots on the outside of the abdomen. The hernia sac associated
with Morgagni hernias may be large, can be intramediastinal or intrapleural in location, and may be
adherent to intrathoracic or mediastinal structures. As a result, excision of the sac may be difficult from a
laparoscopic approach and may be unnecessary in order to repair the diaphragmatic defect.170
Long-term outcomes for isolated Morgagni hernias are excellent.171 Repairs in patients with associated
syndromes also have favorable outcomes that are largely dependent on their preexistent co-morbidities.
The recurrence rates are similar to patch-repaired Bochdalek hernias in some series,169 indicating that
medical follow-up for Morgagni hernias should include surveillance by chest x-ray to detect recurrences
that are commonly asymptomatic.
HIATAL HERNIA
HHs result from defects at the crural portion of the muscular diaphragm with gastric herniation being the
most common consequence. It is an uncommon hernia in infants but its true incidence is unknown. Similar
to adult HH, pediatric HHs are classified based on the extent of herniation and mechanism, ranging from
minimal sliding (type 1) to massive multiorgan hernia (type 4). In children, the clinical presentation of
HH ranges from completely asymptomatic identified incidentally on imaging to severe GER, cough,
vomiting, or anemia.172 Among infants and children with known GER, the incidence of HH is
approximately 20%.173 Congenital HHs tend to be large and present in early infancy, whereas HHs
associated with other conditions such as increased intra-abdominal pressure can present later in
childhood. Congenital HHs may be associated with genetic syndromes such as Marfan syndrome.174 Other
conditions that have been associated with HHs include Bochdalek hernias, gastroschisis, achalasia,175
and ventriculoperitoneal shunts.
Routine chest x-ray may reveal the presence of HH if a gas-filled fundus is situated in the mediastinum
(Fig. 52.9). Incarcerated or strangulated HH may present with the patient in extremis along with a fluid-
filled mass on chest x-ray.176 Investigations for GER, dysphagia, or esophageal and gastric obstruction
will also identify the presence of HH. Dysphagia in the preschool age child should warrant further
investigations such as upper GI contrast study, which may be diagnostic for HH but will also rule out
ingested foreign body among other differential diagnoses. Upper endoscopy, impedance studies, and pH
manometry are all adjuncts for the diagnosis of GER that may reveal the presence of HH.
FIGURE 52.7 Morgagni hernia in the neonate and toddler. A: This newborn presented with respiratory distress and difficulty
with insertion of a nasogastric tube. The chest x-ray to check placement of the NG tube revealed a large diaphragmatic defect
spanning the midline to the left and right sides. B: CT scan of the neonate’s chest and upper abdomen revealed herniation of the
left lobe of the liver into the right chest and midline. C: This asymptomatic patient with Trisomy 21 presented with incidental
finding of Morgagni hernia associated with transverse colon herniating into the retrosternal area as seen on this CT chest
transverse image. D: The same patient with the Morgagni hernia shown on the CT chest sagittal image.
FIGURE 52.8 Repair of Morgagni hernia by laparotomy (A) or laparoscopy (B). A: A subxiphoid incision is made and extended
to the left subcostal margin to expose the retrosternal defect of the midline. The defect is small and is approximated with
interrupted nonabsorbable sutures. B: The laparoscopic view of the midline hernia defect filled with omentum. The omentum
was reduced and the defect was closed with multiple, interrupted, nonabsorbable sutures exteriorized through a midline counter-
incision.
Diastasis of the hiatus may be sufficiently large that reduction of herniated contents, especially if
incarcerated, may require combined thoracic and abdominal approaches. Repair of the hernia can be
approached through open or MAS techniques with the use of prosthetic patches rarely used in children.
As in adults, fundoplication with closure of the hiatus is generally, although not universally, performed.
Similar to adult HH, large defects requiring patch repair can be approached with a biosynthetic patch.
Recurrences have been described, but are poorly documented in the literature as life-long follow-up for
childhood HHs is lacking. Outcomes for children with HHs are good unless there is incarceration or
strangulation of the hernia.172
FIGURE 52.9 Hiatal hernia as seen on plain chest or abdominal x-ray and confirmed by contrast study of the upper
gastrointestinal tract. A: The chest x-ray showed a large “bubble” above the right hemi-diaphragm in a 2-month-old infant with
recurrent vomiting. B: The contrast study showed most of the stomach situated above the diaphragm with the pylorus situated at
the level of the hiatus. C: Post repair, the gastric bubble is clearly seen in the left upper quadrant of the abdomen under the left
diaphragm on chest x-ray.
EVENTRATION AND PHRENIC NERVE PALSY
Eventration of the diaphragm is the term for a “slack” diaphragm which is abnormally elevated and
poorly functioning. Congenital eventration and CDH with a sac are often considered part of the Bochdalek
CDH spectrum and may be associated with a variable degree of pulmonary hypoplasia or may present
without any symptoms.177 Eventration may affect only one diaphragm (Fig. 52.1) or, in rare cases, both
diaphragms with clinical signs of respiratory distress (Fig. 52.10). Eventration must also be differentiated
from paralysis of the hemi-diaphragm that occurs following phrenic nerve injury, usually from birth
trauma or after cardiac or other types of thoracic surgery. Phrenic nerve palsy is not associated with
pulmonary developmental defects, and is often reversible if the phrenic nerve has undergone neurapraxia
rather than complete division. Respiratory compromise may result due to poor respiratory excursion, and
endotracheal intubation and ventilatory support may be required. If the diaphragm has not recovered after
a period of observation, surgical repair may be indicated in order to successfully wean the patient off
mechanical ventilatory support.178
Diagnosis of eventration or phrenic nerve palsy is usually made on imaging. Routine chest x-ray may
reveal a high-riding diaphragm without evidence of abdominal viscera in the lung field (Figs. 52.1 and
52.10). US is now routinely used to document diaphragmatic excursion and to evaluate diaphragm
function.168 Eventration appears as a “floppy” diaphragm with paradoxical motion compared to the
contralateral diaphragm during spontaneous respiration. Fluoroscopy can also be used to demonstrate
these changes. Occasionally, CT imaging is required to distinguish right-sided eventration from right-
sided CDH as herniation of solid organs such as the liver can be missed on plain radiographs or US.
Diaphragmatic eventration in the asymptomatic patient with uncompromised pulmonary function can be
observed and followed. However, functional compromise and diminishing lung volumes require surgical
intervention by diaphragm plication (Fig. 52.11). The objective of surgical plication of eventration or
phrenic nerve palsy is to “tighten” the slack diaphragm in order to eliminate the paradoxical motion and
respiratory compromise. The approach to diaphragmatic plication can be through the chest or abdomen
and MAS approaches are especially useful in older infants and children. Unilateral plication usually
results in prompt relief of respiratory symptoms and is not associated with any long-term sequelae. Cases
of eventration where the diaphragm has little muscular rim should be managed like a Bochdalek CDH
with a sac; the redundant sac should be resected and the resulting defect repaired either primarily or with
patch repair.
FIGURE 52.10 Bilateral diaphragmatic eventration of the newborn. A: Chest x-ray showing the initial presentation of a
symptomatic newborn with bilateral eventration. Note the small lung fields and diaphragms situated at the level of the 5th rib
space. B: Five years post repair of the bilateral eventration by plication with chest x-ray showing flattened diaphragms and large
lung fields bilaterally.
FIGURE 52.11 Thoracoscopic plication of the right diaphragm for eventration. A: Interrupted sutures of nonabsorbable braided
material are placed to plicate the eventration while an instrument is used to keep the slack diaphragm depressed to allow the
sutures to be placed in the diaphragm muscle. B: The thoracoscopic appearance of the finished plication.
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129. Safavi A, Synnes AR, O’Brien K, et al. Multi-institutional follow up of congenital diaphragmatic hernia (CDH) patients reveals severe
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131. Valfre L, Braguglia A, Conforti A, et al. Long term follow-up in high-risk congenital diaphragmatic hernia survivors: patching the
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132. Ahmad A, Gangitano E, Odell RM, et al. Survival, intracranial lesions, and neurodevelopmental outcome in infants with congenital
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133. Bernbaum J, Schwartz IP, Gerdes M, et al. Survivors of extracorporeal membrane oxygenation at 1 year of age: the relationship of
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134. Chen, C., Friedman S, Butler S, et al. Approaches to neurodevelopmental assessment in congenital diaphragmatic hernia survivors. J
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135. Jaillard S, Pierrat V, Dubois A, et al. Outcome at 2 years of infants with congenital diaphragmatic hernia: a population-based study. Ann
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136. Danzer E, Gerdes M, Bernbaum J, et al. Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively
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137. Frisk V, Jakobson LS, Unger S, et al. Long-term neurodevelopmental outcomes of congenital diaphragmatic hernia survivors not treated
with extracorporeal membrane oxygenation. J Pediatr Surg 2011;46:1309–1318.
138. Peetsold M, Huisman J, Hofman VE, et al. Psychological outcome and quality of life in children born with congenital diaphragmatic
hernia. Arch Dis Child 2009;94:834–840.
139. Chiu P, Ijsselstijn H. Morbidity and long-term follow-up in CDH patients. Eur J Pediatr Surg 2012;22:384–392.
140. Arena F, Baldari S, Centorrino A, et al. Mid- and long-term effects on pulmonary perfusion, anatomy and diaphragmatic motility in
survivors of congenital diaphragmatic hernia. Pedatr Surg Int 2005;21:954–959.
141. Stefanutti G, Filippone M, Tommasoni N, et al. Cardiopulmonary anatomy and function in long-term survivors of mild to moderate
congenital diaphragmatic hernia. J Pediatr Surg 2004;39:526–531.
142. Spoel M, Laas R, Gischler SJ, et al. Diagnosis-related deterioration of lung function after extracorporeal membrane oxygenation. Eur
Respir J 2012;40(6):1531–1537.
143. Koumbourlis AC, Wung JT, Stolar CJ, et al. Lung function in infants after repair of congenital diaphragmatic hernia. J Pediatr Surg
2006;41(10):1716–1721.
144. Gischler S, van der Cammen-van MH, Mazer P, et al. A prospective comparative evaluation of persistent respiratory morbidity in
esophageal atresia and congenital diaphragmatic hernia survivors. J Pediatr Surg 2009;44:1683–1690.
145. Haliburton B, Mouzaki M, Chiang M, et al. Long-term nutritional morbidity of congenital diaphragmatic hernia survivors: failure to thrive
extends well into childhood and adolescence. J Pediatr Surg 2015;50(5):734–738.
146. Steven M, Fyfe AH, Raine PA, et al. Esophageal adenocarcinoma: a long-term complication of congenital diaphragmatic hernia? J
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147. Vanamo K, Peltonen J, Rintala R, et al. Chest wall and spinal deformities in adults with congenital diaphragmatic defects. J Pediatr
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148. Diamond I, Mah K, Kim PC, et al. Predicting the need for fundoplication at the time of congenital diaphragmatic hernia repair. J
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149. Su W, Berry M, Puligandla PS, et al. Predictors of gastroesophageal reflux in neonates with congenital diaphragmatic hernia. J Pediatr
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150. Jancelewicz T, Chiang M, Oliveira C, et al. Late surgical outcomes among congenital diaphragmatic hernia (CDH) patients: why long-
term follow-up with surgeons is recommended. J Pediatr Surg 2013;48:935–941.
151. Jancelewicz T, Vu LT, Keller RL, et al. Long-term surgical outcomes in congenital diaphragmatic hernia: observations from a single
institution. J Pediatr Surg 2010;45:155–160.
152. Kuklová P, Zemková D, Kyncl M, et al. Large diaphragmatic defect: are skeletal deformities preventable? Pediatr Surg Int
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153. Metzelder M, Ure BM, Leonhardt J, et al. Impact of concomitant thoracic interventions on feasibility of Nuss procedure. J Pediatr
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154. Gasior A, St. Peter S. A review of patch options in the repair of congenital diaphragm defects. Pediatr Surg Int 2012;28:327–333.
155. Nasr A, Struijs MC, Ein SH, et al. Outcomes after muscle flap vs prosthetic patch repair for large congenital diaphragmatic hernias. J
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156. Tsai J, Sulkowski J, Adzick NS, et al. Patch repair for congenital diaphragmatic hernia: is it really a problem? J Pediatr Surg
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157. Vanamo K, Rintala RJ, Lindahl H, et al. Long-term gastrointestinal morbidity in patients with congenital diaphragmatic defects. J
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158. Harting M, Lally K. The Congenital Diaphragmatic Hernia Study Group registry update. Semin Fetal Neonatal Med 2014;19(6):370–
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159. Lally K, Bagolan P, Hosie S, et al. Corticosteroids for fetuses with congenital diaphragmatic hernia: can we show benefit? J Pediatr
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160. Thebaud B, de Lagausie P, Forgues D, et al. ET(A)-receptor blockade and ET(B)-receptor stimulation in experiment congenital
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161. Jeanty C, Kunisaki SM, MacKenzie TC, et al. Novel non-surgical prenatal approaches to treating congenital diaphragmatic hernia.
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162. DeKoninck P, Toelen J, Zia S, et al. Routine isolation and expansion late mid trimester amniotic fluid derived mesenchymal stem cells in
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163. Yuniartha R, Alatas FS, Nagata K, et al. Therapeutic potential of mesenchymal stem cell transplantation in a nitrofen-induced congenital
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164. Fauza D, Marler JJ, Koka R, et al. Fetal tissue engineering: diaphragmatic replacement. J Pediatr Surg 2001;36(1):146–151.
165. Kunisaki S, Fuchs JR, Kaviani A, et al. Diaphragmatic repair through fetal tissue engineering: a comparison between mesenchymal
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1988;23:749–751.
53
Foramen of Morgagni Hernia
Federico Venuta ■ Marco Anile ■ Erino A. Rendina
DEFINITION
Morgagni hernia is an uncommon type of diaphragmatic hernia related to the herniation of abdominal
contents into the thorax through the foramen of Morgagni or parasternal hiatus. It is related to a defect in
the development of the septum transversum during the embryonic life with consequent lack of fusion of the
sternal and costal fibrotendineous elements of the diaphragm.1,2
In 1769, Giovanni Battista Morgagni, an anatomist and pathologist from the University of Padua, first
reported3 the observation of this rare anterior diaphragmatic defect through the space of Larrey, named in
honor of Napoleon’s surgeon, who previously described a retrosternal approach to the pericardium.
Morgagni reported this autopsy finding in a patient who died of a gangrenous colon herniated through this
opening.
Morgagni hernias accounted for 1.5% of the congenital diaphragmatic hernias in the first report by
Herrington in 1948 (7 out of 430 patients).4 Subsequent series report an incidence up to 7%5; it is the
rarest diaphragmatic hernia. This condition may be associated with Down syndrome,6 pentalogy of
Cantrell, Noonan syndrome, Prader–Willi syndrome, and Turner’s syndrome.7 The Morgagni hernia is
uncommon at any age but despite their congenital etiology it is detected less frequently in children than in
adults.7 They are more frequent in women and in obese patients.
ANATOMICAL DETAILS
The diaphragm originates embryologically from four structures: an unpaired ventral portion (the septum
transversum), two paired dorsolateral portions (the pleuroperitoneal membranes or folds), and an
irregular medial dorsal portion (the dorsal mesentery). The body wall muscles contribute to the
development of the diaphragm. At approximately the eighth week of gestation, the right and left
pleuroperitoneal membranes close and definitively separate the thoracic and abdominal sides from one
another; the right pleuroperitoneal canal closes earlier than the left.8 Failure of formation or fusion of one
or more of these structures can cause a variety of diaphragmatic anomalies. Particularly, the lack of fusion
or muscularization of the pleuroperitoneal membrane anteriorly leads to a defect in the costosternal
trigones known as the foramen of Morgagni; the internal mammary artery crosses this space to enter the
rectus abdominis sheath and become the superior epigastric artery. This triangular space is located
posteriorly and laterally to the sternum on either side of the xiphoid, at the level of the 7th costosternal
junction. The Morgagni hernia is also called retrosternal, parasternal, substernal, or subcostosternal
hernia. Conventionally, a right-side hernia is called Morgagni hernia while a left-side hernia is called
Larrey hernia. The “ligamentum teres” defines the medial border of the hernia on both sides.
In contrast to the Bochdalek hernia, a peritoneal sac (true hernia sac) always surrounds the contents of
a Morgagni hernia. They are more often observed on the right side probably because the pericardial sac
and the heart cover the contralateral defects. Morgagni hernias are often associated with obesity. In most
of the cases the hernia contains only the omentum but the stomach (Fig. 53.1), transverse colon (Fig.
53.2), small bowel, or liver may also be involved. Bilateral hernias have also been described.9–11
CLINICAL FEATURES AND DIAGNOSIS

Patients are usually asymptomatic; however, retrosternal pain and respiratory or gastrointestinal
symptoms may occur.12 Symptoms are equally distributed in the adult and pediatric population although
children are more often asymptomatic. Patients frequently describe pain or constipation from intermittent
partial colonic obstruction, epigastric or substernal fullness, or a right subcostal discomfort. Missing the
diagnosis may lead to severe life-threatening complications. Particularly, incarceration or strangulation
with necrosis of a viscus blocked in the hernia, although rare, is associated with an acute or subacute
presentation.11 Cardiorespiratory symptoms with dyspnea and palpitations are less common.13 Right
middle lobe torsion has also been described.14 Any condition producing an increased intra-abdominal
pressure may cause the onset or exacerbation of symptoms. Also exercise and athletic activity as well as
trauma and pregnancy15 may be precipitating events.16 The noncontinuous presence of symptoms may be
related to the sliding of the hernia content in and out of the defect.
FIGURE 53.1 Morgagni hernia with the stomach incarcerated in the retrosternal space.
FIGURE 53.2 Morgagni hernia with the transverse colon and the omentum in the retrosternal space.
The imaging appearance depends on the herniated content. Chest radiography usually demonstrates a
right paracardiac, well-defined, homogeneous shadow; in the lateral film it is localized in the anterior
retrosternal space. The “sign of the cane” has been described for small hernias: a curvilinear
accumulation of fat in continuity with the fat line of the anterior abdominal wall.17 The presence of the
omentum only in the hernia is related to the full opacification of the mass. Inhomogeneity may be the result
of predominant fat content or air in the herniated bowel.18 Contrast studies of the gastrointestinal tract may
confirm the diagnosis when visceral herniation is present. Confident diagnosis can be made on computed
tomography (CT) and magnetic resonance imaging (MRI) (although usually not required) by
demonstration of continuity of the herniated fat with the abdominal omentum through the defect.1,12
SURGICAL REPAIR
Surgical treatment is recommended in patients with and without symptoms, to prevent the onset of
dreadful complications. Both the abdominal and thoracic approaches have been described.19
The transthoracic approach through a lateral thoracotomy provides a wide exposure and easy repair of
the diaphragmatic defect; however, bilateral hernias may be missed. On the other side of the diaphragm,
an open transabdominal approach can be considered through an upper midline, subcostal, or paramedian
incision. This route should be preferred in patients with complications. Laparoscopic repair has been
increasingly described20–22; this approach allows to significantly reduce the length of postoperative
hospitalization.23 Whatever approach is chosen, the margins of the hernia should be clearly identified and
the sac resected. Resection of the sac shows the following advantages: reduction of tissue trauma since
only the sac is manipulated; decreased chance for symptomatic fluid collection, since the serous lining
membrane is removed; obviation of the risk that the sac itself may recur as a lead point for recurrence.7 A
tension-free closure is required to prevent recurrence. For defects smaller than 3 cm in diameter, repair is
accomplished with nonabsorbable mattress sutures. The diaphragm is usually secured to the posterior part
of the sternum and to the posterior rectus sheath.
For larger defects when tissues on the border of the hernia are particularly weak, repair with
prosthetic material should be considered; this includes polypropylene mesh and a variety of composite
prosthesis such as expanded polytetrafluoroethylene (ePTFE) and hydrophilic reabsorbable film. Dual-
sided ePTFE is usually preferred to minimize the risks of adhesions to the prosthetic surface.7
The results of surgical repair are excellent. Operative morbidity and mortality are low and are usually
observed in patients with strangulated bowel.7 Recurrence is rare.24
REFERENCES
1. Tarver RD, Conces DJ, Jr, Cory DA, et al. Imaging of the diaphragm and its disorders. J Thorac Imaging 1989;4:1–18.
2. Panicek DM, Benson CB, Gottlieb RH, et al. The diaphragm: anatomic, pathologic and radiologic considerations. RadioGraphics
1988;8:385–425.
3. Morgagni GB. The Seats and Causes of Disease Investigated by Anatomy. London: Millar and Cadell; 1769:205.
4. Harrington SW. Various types of diaphragmatic hernias treated surgically: report of 430 cases. Surg Gynecol Obstet 1948;86:735–755.
5. Comer TP, Clagett OT. Surgical treatment of hernia of the foramen of Morgagni. J Thorac Cardiovasc Surg 1966;52:461–468.
6. Taskin GA, Tuncer O, Demir N, et al. Association of Down syndrome and Morgagni hernia. Genetic Couns 2014;25:345–347.
7. De Hoyos A. Foramen of Morgagni hernia. In: Shields TW, Locicero J, III, Reed C, et al., eds. General Thoracic Surgery.
8. Venuta F, Rendina EA. Diaphragm: anatomy, embryology, pathophysiology. In: Patterson GA, Cooper JD, Deslauriers J, et al., eds.
Pearson’s Thoracic and Esophageal Surgery. 3rd ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2008:1367–1379.
9. Lammy S, Stewart M, Carnachan FM, et al. Bilateral Morgagni hernia: operative discovery of appendix lying on superior pulmonary
vein. Scott Med J 2013;58:1–3.
10. Al-Salem AH, Zamakhshary M, Al Mohaidly M, et al. Congenital Morgagni’s hernia: a national multicenter study. J Pediatr Surg
2014;49:503–507.
11. Loong TP, Kocher HM. Clinical presentation and operative repair of hernia of Morgagni. Surgical Records 2005;29:41–44.
12. Boiselle PM, Rosado de Christenson ML. Fat attenuation lesions of the mediastinum. J Comput Assist Tomogr 2001;25:881–889.
13. Tone K, Kiru I, Yoshida M, et al. Morgagni hernia with respiratory failure aggravated by noninvasive positive pressure ventilation: a
case report and overview of the literature. Respir Invest 2014;52:203–208.
14. D’Souza DM, Presser N, Graham R, et al. Right middle lobe torsion from Morgagni hernia. Am Surg 2014;80:E108–E110.
15. Thomas VP. A rare case of Morgagni diaphragmatic hernia presenting in pregnancy. Indian J Surg 2012;74:348–350.
16. Ellyson JH, Parks SN. Hernia of Morgagni in trauma patients. J Trauma 1986;26:569–570.
17. Lanuza A. The sign of the cane. A new radiologic sign for the diagnosis of small Morgagni hernias. Radiology 1971;101:293–296.
18. Raymond GS, Miller RM, Muller NL, et al. Congenital thoracic lesions that mimic neoplastic disease on chest radiographs of adults. Am
J Roetgenol 1997;168:763–769.
19. Aydin A, Altuntas B, Ulas AB, et al. Morgagni hernia: transabdominal or transthoracic approach? Acta Chir Belg 2014;114:131–135.
20. Kuster G, Kline LE, Garzo G. Diaphragmatic hernia through the foramen of Morgagni: laparoscopic repair. J Laparosc Surg
1992;2:93–100.
21. de Vogelaare K, de Backer A, Delvaux G. Laparoscopic repair of a diaphragmatic Morgagni hernia. J Laparoendosc Adv Surg Tech
2002;12:457–460.
22. Park A, Doyle C. Laparoscopic Morgagni hernia repair: how to do it. J Gastrointest Surg 2014;18:1858–1862.
23. Yamaguchi S, Marshall MB. Outpatient laparoscopic repair of a Morgagni hernia. Surg Innov 2013;20:NP38–NP39.
24. Garriboli M, Bishay M, Kiely EM, et al. Recurrence rate of Morgagni diaphragmatic hernia following laparoscopic repair. Pediatr Surg
Int 2013;29:185–189.
54
Primary Tumors of the Diaphragm
Thoracic Surgery
Min P. Kim ■ Wayne Hofstetter
Diagnostic Imaging
Daniel Ocazionez ■ Carlos S. Restrepo
Primary tumors of the diaphragm are very rare. The most common benign lesion is a cyst and most
common benign solid tumor is lipoma. Benign tumors of the diaphragm are usually resected in situations
where the lesion is symptomatic or if there is concern for malignancy that cannot be addressed by other
noninvasive methods. The most common primary malignant tumor of the diaphragm is rhabdomyosarcoma.
Primary malignant tumors should be treated based on the size and extent of the tumor with en bloc surgical
resection with negative margins. The approach and reconstruction of the diaphragm should be guided by
the size of the tumor and the size of the defect requiring reconstruction.
HISTORY
The adult diaphragm is anatomically composed of skeletal (striated) muscle in the periphery, a large
central fibrous tendon (an aponeurosis), arcuate ligaments, and the posterior muscular crux. It also
contains vessels (phrenic arteries and veins), nerves (phrenic nerve and branches) and a rich internal
lymphatic network, all of which can give rise to tumors. There are three hiatuses in the diaphragm at the
thoracic outlet; the caval, aortic, and esophageal. The diaphragm is covered on its thoracic side by the
firmly attached parietal pleura, and on the abdominal surface by the peritoneum and the bare area that is
occupied by the liver. The intimate relation of the diaphragm with the thoracic and abdominal viscera
facilitates secondary tumoral involvement from the respective body cavities, but this chapter will focus
on primary lesions only.
The diaphragm is composed mainly of mesenchymal elements, so it is not surprising that the majority
of primary diaphragmatic tumors are mesenchymal in origin. A primary tumor of the diaphragm is a very
rare lesion that was first described in modern literature by Grancher in 1868. In his report he describes
finding a fibroma of the diaphragm during autopsy.1 To date, there have only been a total of about 200
cases of primary tumors of the diaphragm reported in the literature.2–32 Primary tumors of the diaphragm
are classified as benign or malignant. The most common benign lesions of the diaphragm are
diaphragmatic cysts, while the most common benign solid lesion of the diaphragm is lipoma. The most
common malignant primary lesion of the diaphragm is rhabdomyosarcoma.
Our analysis of the reported literature on diaphragm tumors shows that these lesions affect both sexes
equally. The average age of presentation was 40 years old with presentation as early as fetal hydrops at
32 weeks’ gestation33 and as late as 80 years of age.34 Most of the tumors that were reported in the
literature were benign tumors of the diaphragm without any predilection for side (right vs. left) of the
diaphragm. The size of the lesion typically affects the presence or absence of symptoms. Patients with
small lesions have a tendency toward incidental discovery of a diaphragm lesion on an imaging
performed for another reason, while bigger tumors lead to chest pain, shortness of breath, abdominal pain,
or an abdominal mass.
IMAGING
Typical imaging modalities performed in patients with suspected diaphragmatic tumors are computed
tomography (CT) and magnetic resonance imaging (MRI). Ultrasound is also used in the diagnostic
evaluation, especially in the pediatric population.35 CT demonstrates the location of the tumor,
relationship with neighboring structures, and any invasion of vital structures. CT is also helpful in
narrowing the differential diagnosis as many of these lesions can be characterized based on their
attenuation parameters and enhancement characteristics and allows the differentiation between solid and
cystic tumors. CT is also helpful in the evaluation of metastatic disease in cases of malignant neoplasms.
MRI provides higher contrast resolution as compared to CT, therefore it can help in the more accurate
evaluation of the internal characteristics of the tumor.36 Several solid tumors of the diaphragm can be
initially described as a primary intra-abdominal mass or pleural mass on imaging with ultimate diagnosis
of the tumor made at the time of resection.37
TABLE 54.1 Common Benign Diaphragm Tumors

Tumor Frequency
Lipoma 38.5%
Cysts 24%
Neurogenic tumors 18%
Fibroma 7.3%
Angiofibroma 4%
Leiomyoma 3%
Benign Primary Tumor (Table 54.1)
MESOTHELIAL CYSTS
The most common benign lesion of the diaphragm is a cyst, most often characterized as either a
mesothelial or bronchogenic cyst. Mesothelial cysts are congenital lesions arising from coelomic
remnants that can be found in the adrenal gland, ovary, falciform ligament, spleen, vaginal process of the
testicle, mesentery, and rarely the diaphragm.38 The cyst is seen in children20,38 and rarely in adults.28,39–41
Ultrasound is often the initial diagnostic study for children and typically showed a thin-walled cystic
structure.20,38 The CT scan shows homogeneous, nonenhancing, well-defined structure of water
density20,38 and MRI shows a thin-walled cystic structure attached to the diaphragm.20,38 The diagnosis of
mesothelial cyst of the diaphragm is typically made based on the imaging.
In children, a mesothelial cyst may regress or resolve and it may not be necessary to perform surgical
resection of the lesion. Akinci et al. reported on 11 patients who were followed with serial ultrasound
showing regression or complete resolution in six patients and no change in size for five patients (follow-
up 5 months to 6 years).20,38 If these patients are symptomatic, ethanol sclerotherapy has been described
as a potential method of treatment leading to resolution of the cyst. Five patients underwent injection of
cyst volume with 95% ethanol which lead to resolution of the cyst in all patients.38 In adults, symptomatic
patients may complain of chest pain, upper abdominal discomfort, and/or dyspnea that may be an
indication for surgical resection of the cyst.
BRONCHOGENIC CYST
Bronchogenic cysts are foregut-derived developmental anomalies that are usually located in the
mediastinum or lung parenchyma. It is an aberrant bud from the tracheobronchial tree that rests in an odd
location.42 It is rare but there are some isolated case reports of bronchogenic cysts of the
diaphragm.13,28,43 Histological findings reveal that the cyst wall is lined with ciliated pseudostratified
columnar epithelium, the sine qua non of bronchogenic cysts. The histology is similar to bronchial wall
and the uncomplicated cyst is filled with viscous mucoid material.43 While some patients had no
symptoms,13,42 most of the patients reported cough, discomfort, pain, or hiccups.28,43 The symptomatic
patients typically had very large cysts causing compression of surrounding structures. The lesion may be
detected on chest x-ray as a bulging mass over the diaphragm.42 CT of a bronchogenic cyst would reveal
linear and nodular calcifications along the cyst wall with soft tissue density within the lesion (Fig.
54.1).42,44 Ultrasound shows a hypoechoic lesion42,44 and an MRI would show a fluid-containing lesion.44
It is difficult to confirm the exact diagnosis from preoperative imaging.13,43,44 In most cases the cystic
lesions were removed to establish a diagnosis, to alleviate symptoms or to rule out intracystic
carcinoma.42 However, there are no reports of intracystic carcinoma of the diaphragm in the literature.
Overall, benign cysts can be observed, but if symptomatic or if there is a question about the definitive
diagnosis, the cyst should be removed.
HYDATID CYST
Hydatid cyst is the result of Echinococcus which is prevalent in Mediterranean countries.11 The eggs of
the tapeworm Echinococcus granulosus excreted by carnivores may infect various species as
intermediate hosts such as sheep, cattle, deer, and humans.4 It is mostly found in the liver since the embryo
hexacanth enters through the intestine into the portal system and forms cysts in the liver.11 It is rarely found
in the diaphragm (incidence is about 1%). It travels to the diaphragm through the vascular system or direct
extension from the liver or the lung.11 All reports of confirmed hydatid cysts of the diaphragm are from
Greece, Tunisia, and Turkey4,8,19,45–47; however, for patients with a cystic lesion of the diaphragm who
have a travel history to endemic areas, this disease should be included in the differential diagnosis. Most
patients present with pain10,19; there is even a reported case of ruptured diaphragmatic hydatid cyst.4 The
diagnosis can be made by indirect hemagglutination test that is usually positive and an ultrasound shows a
cyst with multiple vesicles. A CT scan would show a mass lesion with solid and cystic components.4
MRI shows a cystic structure with multiple vesicles inside of it.19 The treatment is careful, complete
surgical resection, usually cystotomy and removal of daughter cyst and the germinative membrane,
followed by excision of most of the pericyst followed by diaphragmatic repair.19 After resection of
hydatid cysts, patients should be given albendazole for a period of time.19
FIGURE 54.1 Diaphragmatic and intra-abdominal bronchogenic cyst in a 32-year-old male with left upper quadrant abdominal
pain. CT shows a well-defined cystic lesion attached to the left hemidiaphragm (white arrows). The lesion was removed and
histopathology examination revealed a respiratory epithelium-lined cyst arising from the left hemidiaphragm (black arrow)
consistent with a bronchogenic cyst.
LIPOMAS
Lipomas of the diaphragm are the most common benign solid tumors of the diaphragm. Lipomas are soft
encapsulated fatty tumors. There are two forms of diaphragmatic lipomas: sessile lipomas which develop
from subpleural mature fatty tissue, and hourglass-shaped lipomas which develop from embryologically
undifferentiated tissue.48,49 Most of the patients with lipoma are asymptomatic; however, patients with a
large lipoma might present with cough, pain, or dyspnea. The best imaging modality is CT as these lesions
demonstrate homogenous low attenuation of less than 0 Hounsfield Units without any enhancing
components (Fig. 54.2).48,50 On MRI, lipomas appear as nonenhancing lesions that are hyperintense on
T1-weighted images and demonstrate signal dropout on the fat-saturated sequences confirming the fatty
nature of the tumor.51 Sometimes, a primary lipoma of the diaphragm is mistaken for a Bochdalek hernia.
A potentially distinguishing CT finding is that the integrity of the diaphragm is complete with a lipoma
while Bochdalek hernias present with a V-shaped discontinuation of the diaphragm.21,50 There are reports
of primary liposarcoma of the diaphragm in the literature.52,34 The CT and MRI finding for liposarcoma of
the diaphragm was a heterogeneous enhancing solid lesion with fat and septae of connective tissue.52 The
lesion was removed confirming the diagnosis of liposarcoma.52 There is suggestion that patients with
small incidentally recognized lipomas can be observed48; however, in symptomatic patients or
asymptomatic patients with concern for liposarcoma, the lesion should be resected.50,52 Noteworthy is that
there may be no defining features of one over the other and differentiating lipoma from liposarcoma may
require histologic examination of the lesion.
SOLITARY FIBROUS TUMOR

Solitary fibrous tumor is a spindle cell tumor that arises from pleura with about 80% of the tumors arising
from the visceral pleura.53 Most of these lesions are benign, however, about 20% are found to have
malignant features.54 There are several case reports of solitary fibrous tumor of the diaphragm.35,37,55–57
Based on the size of the tumor, patients presented with an abnormal chest x-ray or an abdominal mass. CT
showed a large mass and MRI showed a lobulated, heterogeneous soft tissue with short T1-weighted
imaging and a flake long T2-weighted imaging signal with heterogeneous enhancement with contrast.37
Patients underwent en bloc resection and only one out of the five patients had solitary fibrous tumor with
malignant potential on pathology.
OTHER BENIGN PRIMARY TUMORS

Other solitary primary benign tumor of the diaphragm include neurofibroma,14,28 angiofibroma,28
fibroma,28 hemangioma,9,24,58 schwannoma,2,28 chondroma,28,59 hemangioendothelioma,28,29
angioleiomyoma,23 endothelioma,28 fibrolymphangioma,28 fibroangioendothelioma,28 fibromyoma,28
leiomyoma,28 hamartoma,28 lymphangioma,28 myofibroma14 and rhabdomyofibroma.28 In case reports and
descriptive series, most of the patients presented with symptoms of pain or dyspnea. Other cases were
found incidentally during autopsy. In patients who presented with symptoms, a CT scan was obtained that
showed a diaphragmatic lesion although it was often hard to distinguish from an intra-abdominal or
pleural lesion. In most cases, the lesion was resected and the final pathology confirmed a benign tumor of
the diaphragm.
FIGURE 54.2 Intradiaphragmatic lipomas (arrows) with characteristic low density in two different patients. Common location
of diaphragmatic lipomas is in the posterior and medial aspect of the diaphragm.
Malignant Primary Tumors of the Diaphragm (Table 54.2)
RHABDOMYOSARCOMA
Rhabdomyosarcoma is a malignant tumor arising from embryonal mesenchymal cells with potential to
differentiate into skeletal muscle cells. There are four histologic classes of rhabdomyosarcoma:
pleomorphic, alveolar, botryoid, and embryonal.5 Embryonal is the most common type.60 It can occur at
any site but is usually found in the head and neck region (42%), urogenital tract (34%), or extremities
(11%). It is very rarely found in the diaphragm. Much of what is known about rhabdomyosarcoma is
derived from data related to disease found other than at the diaphragm. Of the few cases involving the
diaphragm, most patients were asymptomatic but some presented with chest pain, cough, dyspnea,
dysphagia, or abdominal mass.25,32 On a diagnostic CT scan, a rhabdomyosarcoma of the diaphragm
appears as a heterogeneous, enhancing diaphragmatic mass (Fig. 54.3). Histologic diagnosis is generally
made by image-guided biopsy. Recommendation for treatment is typically resection with adjuvant
chemoradiation if the tumor and patient are amenable. For larger tumors, induction chemotherapy
followed by surgical resection and adjuvant radiation has been described.61,62
TABLE 54.2 Common Malignant Diaphragm Tumors

Tumor Frequency
Rhabdomyosarcoma 22%
Fibrosarcoma 15%
Leiomyosarcoma 9%
Ewing sarcoma 7%
Synovial sarcoma 5%
Germ cell tumor 5%
Hemangiopericytoma 4%
Undifferentiated, mixed cellularity 17%
LEIOMYOSARCOMA
Leiomyosarcoma is most frequently found in the uterus and gastrointestinal tract.63,64 It is rarely found in
the diaphragm. Most of the patients with diaphragm involvement described in the literature presented
without any symptoms but when they did have symptoms, it was typically abdominal pain. On CT scan a
leiomyosarcoma appears as a heterogeneous mass with low density and MRI shows a mass with low
signal intensity at T1 and iso-intensity at T2 (Fig. 54.4). Surgical resection is considered the best
treatment. There are no known therapeutic benefits from chemotherapy or radiotherapy in resectable
lesions.63
FIGURE 54.3 Rhabdomyosarcoma of the diaphragmatic crura in a 14-year-old male. Contrast enhanced CT (A) and
noncontrast MR images (B,C) demonstrate a large soft tissue mass infiltrating the retrocrural space (arrows). Lumbar spine
involvement is also appreciated (small arrow).
FIGURE 54.4 Leiomyosarcoma of the left hemidiaphragm in a 70-year-old male with difficulty breathing. CT (A,B)
demonstrates a large left-sided mass (black arrows) with central necrosis (white arrows). Sagittal T2-weighted MRI (C) shows
the high signal intensity within the central necrotic region as well as a loculated left pleural effusion. Pathology (D) was
consistent with a leiomyosarcoma. (Courtesy Sarita Magu M.D., Rohtak, India.)
OTHER MALIGNANT PRIMARY TUMORS OF THE DIAPHRAGM

Other primary malignant lesions of the diaphragm are fibrosarcoma (Fig. 54.5),17,28,29 neurofibrosarcomas
and malignant schwannomas (also classified as malignant peripheral nerve sheath tumor [MPNST]) (Fig.
54.6),17,28,29 Yolk sac tumor,14,29 Ewing sarcoma,18,65 fibromyosarcoma,28 angiosarcoma,7
chondrosarcoma,29 desmoid tumor,66 germ cell tumor,16 hemangiopericytomas (Figs. 54.7 and 54.8),28,29
liposarcoma,34,52 pheochromocytoma,22 pleomorphic myxoid sarcoma (Fig. 54.9), malignant fibrous
histiocytoma,67mesothelioma,28 mixed cell sarcoma,28 myoblastic sarcoma,28 myosarcoma,28 synovial
sarcoma (Figs. 54.10 to 54.12), vascular sarcoma, and undifferentiated sarcoma (Fig. 54.13).28 Most of
the other malignant primary tumors of the diaphragm should be treated based on tumor type found on
biopsy and resectability on imaging. When formulating a treatment plan for these extremely rare lesions,
one should use the knowledge of a tumor’s historical response to chemotherapy, radiotherapy, and surgery
extrapolated from similar histology at other primary sites.14
FIGURE 54.5 Fibrosarcoma in a 30-year-old male. CT shows a large solid enhancing mass. Attachment to the central tendon
of the diaphragm was found during surgical exploration.
FIGURE 54.6 Malignant peripheral nerve sheath tumor of the diaphragm in a 25-year-old male with neurofibromatosis type 1.
This tumor, previously known as malignant schwannoma or neurofibrosarcoma, results from malignant transformation of
neurogenic tumors in NF1 patients. CT demonstrates a large heterogenous soft tissue mass (*) diffusely involving the left
hemidiaphragm (arrows).
FIGURE 54.7 Hemangiopericytoma. Noncontrast MRI. A heterogenous signal intensity in a large mass (*) involving the right
hemidiaphragm, pleural cavity, and mediastinum.
FIGURE 54.8 Malignant hemangiopericytoma of the diaphragm in a 77-year-old female patient. A tumoral mass of the left
hemidiaphragm is shown (black arrows). Metastatic disease is also noted in the AP window (white arrow).
FIGURE 54.9 Pleomorphic myxoid sarcoma of the diaphragm. Contrast enhanced CT demonstrates an ovoid mass with
extrinsic compression of the liver and chest wall involvement.
FIGURE 54.10 Synovial sarcoma of the diaphragm in a 49-year-old female patient. A soft tissue mass involving the posterior
and medial left hemidiaphragm is shown.
FIGURE 54.11 Recurrent synovial sarcoma of the diaphragm. Postoperative follow-up CT reveals tumoral recurrence with soft
tissue mass on the medial and posterior left hemidiaphragm (arrows).
FIGURE 54.12 Synovial sarcoma of the diaphragm. A large tumoral mass is appreciated in the right hemithorax. During
surgical exploration extensive attachment to the right diaphragm was found.
FIGURE 54.13 Undifferentiated sarcoma of the diaphragm in an 80-year-old male. CT (A) and MRI (B,C) demonstrate a
lobulated mass in the right costophrenic angle with extrinsic compression of the right atrium and liver.
SURGICAL TREATMENT
Surgical treatment of primary diaphragmatic tumors is indicated for patients with symptomatic benign
lesions, for resectable malignant lesions, or when there is a doubt about the malignant potential of the
lesion. The diaphragm is a unique structure that may be approached through the abdomen or chest, and
ultimately the decision for which approach to undertake should be based on the location of the lesion. The
use of minimally invasive laparoscopic or thoracoscopic approaches has been described and seems to be
related to the size of the lesion and the expertise of the surgeon.
Regardless of the approach, patients should have en bloc resection of the diaphragmatic lesion with
negative surgical margins. The size of the lesion and resultant diaphragmatic defect that is left after
resection provide important consideration about the reconstruction. For patients with small defects, we
prefer primary repair with interrupted nonabsorbable suture. Alternatively, large defects should be
reconstructed with some sort of mesh. Options for reconstructive mesh include various prosthetic
materials suitable for diaphragm reconstruction.68 Lack of appropriate repair can lead to life-threatening
complications. A poorly reconstructed diaphragm with too large of a mesh can result in symptomatic
atelectasis and/or recurrent pneumonia from intrathoracic volume loss. On the other hand, too much
tension can ultimately lead to failure of the repair and a diaphragmatic hernia with potential for serious
complications. This can occur with rapid or insidious onset and it long-term periodic radiographic
surveillance is recommended for any patient that has had a diaphragm resection.
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Section
XII
THE PLEURA
55
Anatomy of the Pleura
Isabelle Opitz
EMBRYOLOGY
Mesothelial cells are derived from the coelomic cavity lining cells which originate from mesodermal
mesenchyme via mesenchymal–epithelial transition (MET).
The mesoderm differentiates to create the lateral mesoderm, which is one of the early precursors of the
pleural sac during the third week of gestation. The pleural cavity derives from the primitive coelom by
splitting of the lateral mesoderm into splanchnic (future visceral serous membrane) and somatic (future
parietal serous membrane) layers.
The paired cavities are separated by three partitions into three subdivisions: (1) pericardial, (2)
pleural, (3) peritoneal cavity. The three partitions are:
1. Unpaired septum transversum: a thick plate of the mesodermal tissue which serves as an early, partial
diaphragm, which incompletely separates the thoracic and peritoneal cavities ventrally
2. Paired pleuropericardial folds, which divide the pericardial and pleural cavities and contain the
cardinal veins approaching the heart
3. Paired pleuroperitoneal folds, which unite with the septum transversum to complete the partition
between each pleural cavity and the peritoneal cavity.
In the beginning the division remains incomplete, as the precursor of the pleural and peritoneal cavities
are connected by the paired pericardioperitoneal canals. At the fourth week, the laryngotracheal
outgrowth from the floor of the pharynx starts, and in the fifth week, the two lung buds begin to enlarge
into the respective pleural canals. As the growing primordial lung buds bulge into the right and left
pleural cavities, they carry with them a covering of the lining mesothelium, which becomes the visceral
pleura. As the separate lobes evolve, they retain their mesothelial covering. This covering becomes the
visceral pleura in the fissures. The lining mesothelium of the pleural cavity becomes the parietal pleura.1,2
The lung buds will grow into the pericardioperitoneal canals from the mediodorsal side and will then
expand rapidly caudally. The growth of the pleuroperitoneal folds from dorsal to ventral leads to a
desobliteration of the pericardioperitoneal canals. At the same time the paired pleuropericardial folds,
containing the cardinal veins and the phrenic nerves, will grow from the lateral sides.
With formation of the lung buds covered by the visceral pleura, the pleural cavity is complete within
the third month (Fig. 55.1).
HISTOLOGY
The pleura is generally divided into five layers: The pleural cavity is lined by (1) mesothelial cells, (2)
overlying vascularized connective tissue, separated by each other by a thin basal lamina, (3) a thin
superficial elastic layer, (4) a loose connective tissue layer, and (5) deep fibroelastic layer.3 The
connective tissue layer consists of variable amounts of collagen, elastic fibers, capillaries, and
lymphatics.4 The connective tissue layer in the visceral pleura has two important functions: (a) it
contributes to the elastic recoil of the lung, which is important in expelling air from the lung, and (b) it
restricts the volume to which the lung can be inflated, thereby protecting it.2,5 Small blood vessels and
lymphatics are found in the connective tissue.
The two pleural layers have similar histologic features with the exception of the presence of stomata in
the parietal pleura that are absent in the visceral pleura. Also the thickness is approximately the same,
averaging 30 to 40 μm,6 but the visceral pleura being usually less thick. The serous membranes are lined
by a single layer of mesothelial cells resting on a basement membrane and a submesothelial layer (Fig.
55.2). The mesothelial cells of the parietal pleura are separated by gaps communicating with the
underlying lymphatic vessels.
FIGURE 55.1 Embryonal development of the pericardial and pleural cavities. A: View from front left of a 5-week-old embryo.
The cranial part and the ventral body wall are removed. Arrows in the coelom canals. B–D: Transversal cut through a 5-week
(B), 6-week (C), and 7- to 8-week (D) old embryo through the pericardial cavity. The arrows in (B) and (C) show the main
growth direction of the lung. (Adapted with permission from Joachim K, Albrecht MC, Dietrich L, et al. Taschenlehrbuch
Anatomie. Stuttgart: Georg Thieme Verlag KG; 2011. Copyright © Georg Thieme Verlag KG.)
Ultrastructurally, mesothelial cells have a fairly dense cytoplasm that contains ribosomes, rough
endoplasmic reticulum, perinuclear tonofilaments, and moderate numbers of mitochondria.
Immunohistochemically, mesothelial cells express both low- and high-molecular-weight cytokeratin.7,8
The most characteristic feature is the presence of long surface microvilli of up to 3.0 μm length (Fig.
55.2A), which are most abundant in the caudal portions of the pleura.9 The exact function of these
numerous microvilli is thought to enmesh glycoproteins that are rich in hyaluronic acid, especially in the
lower thorax, to lessen the friction between the lung and the chest wall.10
The boundary of the pleura against the lung consists of segments of elastic fibers continuously
connected with the elastic fibers of the interalveolar septula, and thus helps to distribute mechanical
stress evenly throughout the structure.11 In this layer, lymphatic vessels can be seen occasionally.
The parietal pleura contains a particular feature not present in the visceral pleura. A rich network of
lymphatic vessels is concentrated in the posteroinferior portion of the chest, communicating directly with
the pleural space through openings, or “stomata.”11 These stomata ranging in diameter between 2 and 6
μm permit the cleavage of material into the lymphatic system.
Kampmeier foci, or milky spots, were described in the lower portion of the mediastinal pleura and
consist of an aggregate of macrophages, lymphocytes, histiocytes, plasma cells, mast cells, and
undifferentiated mesenchymal cells encircling thick blood capillaries and lymphatic channels.3
Kanazawa12 demonstrated that Kampmeier foci participate in the defense of the pleural space in different
ways. They exhibit phagocytic activity, trap macrophages and particles, appear to exert some focal
suction, and have the capacity to produce leukocytes under the stimulus of inflammation, not unlike the
lymphoid tissue in the tonsils.11
When the normal layer of mesothelial cell lining of the pleura is disrupted, the defect is repaired
through mitosis and migration of the mesothelial cells.13,14 When irritated, they retract but retain continuity
with adjacent cells by projections called cellular bridges. Mesothelial cells are frequently dislodged
from the pleural surfaces and thereby free in the pleural fluid. When free in the pleural space, the cells
become round and oval.14 Their cytoplasm is rich in organelles. From this state, they may be transformed
into macrophages capable of phagocytosis and erythrophagocytosis.14 Such transformed cells frequently
have vacuoles in their cytoplasm. Not all the macrophages in the pleural fluid evolve from mesothelial
cells; some definitely evolve from peripheral blood mononuclear cells, and some may evolve from
alveolar macrophages.15 An immunologic role has been suggested for the macrophages derived from the
mesothelial cells.2,15
Beneath the parietal pleura, fat cells are normally seen belonging to the chest wall. The endothoracic
fascia separates these fat cells from the inner periosteum of the ribs. In so-called pleurectomies, the
endothoracic fascia is the plane of surgical dissection.
FIGURE 55.2 Surface of mesothelial cells. A: The pleural surface is covered unevenly by bushy microvilli. The boundaries of
mesothelial cells are obscured by the microvilli. (Scanning electron micrograph, parietal pleura, rabbit, original magnification ×
1,300.) (From Wang NS. Anatomy of the pleura. Clin Chest Med 1998;19:229–240. Copyright © 1998 Elsevier. With
permission.) Normal visceral pleura (HE (B), Pancytokeratin (C)). Parietal pleura (HE (D), Pancytokeratin (E)). (From B.
Vrugt, Institute of Pathology, University Hospital Zurich.)
FIGURE 55.3 The parietal pleura covers the inner surface of chest wall (costal pleura), mediastinum (mediastinal pleura), and
diaphragm (diaphragmatic pleura). (Modificated after Paulsen F, Waschke J, Sobotta J. Sobotta Atlas der Anatomie. 24th ed.
Munich:Urban & Fischer; 2017. Copyright ©Elsevier GmbH. With permission.)
GROSS ANATOMIC FEATURES

The lung, excluding the hilum, is completely covered by the visceral pleura, which is separated from the
parietal pleura by the pleural cavity (Fig. 55.3). In the pleural cavity, a serous fluid film of about 1 to 4
mL forming a layer of about 10 μm thickness and containing 1 to 2 g of protein per 100 mL and 1,400 to
4,500 cells in 1 μL fulfills several functions3: it lubricates the two pleural surfaces and allows the two
layers of pleura to slide smoothly over each over during respiration. The surface tension allows the lung
surface to stay connected to the chest wall, and it creates a seal between the two pleural surfaces. The
parietal pleura covers the inner surface of chest wall (costal pleura), mediastinum (mediastinal pleura),
and diaphragm (diaphragmatic pleura) (Fig. 55.3). The diaphragmatic and the mediastinal pleura are
tightly adherent to the underlying diaphragm and pericardium, and a cleavage plane is difficult to obtain in
contrast to the remaining mediastinal pleura, the pleura of the dome, and the costal pleura which can be
dissected from the underlying tissue.
The visceral pleura is completely adherent to the surface of the lung parenchyma, so that after
decortication of the visceral pleura, a raw surface with air leaks and small bleeding vessels is left
behind.
The two layers combine around the root of the lung—so the root of lung has no pleural coverage, the
layers combine to form the pulmonary ligament, which runs inferiorly and attaches the root of the lung to
the diaphragm and may contain large lymphatic vessels.
The right and the left pleural cavities are completely separated from each other by the mediastinum and
the pericardial cavity. The dome (or cupola) of the pleural cavity extends above the first rib for 2 to 3 cm
and reaches under the subclavian vein and artery.
The reflections of the pleural limits to the chest wall are summarized in Table 55.1 and Figure 55.4.16
The pleural cavities run out ventrally between mediastinum and chest wall and caudally between
diaphragm and chest wall into so-called recesses into which parts of the lung enter during deep
inspiration. The costodiaphragmatic recess is the deepest reserve space and reaches laterally into the
middle axillar line 5 cm between diaphragm and chest wall (Fig. 55.4). It reaches on the right side behind
the right lobe of the liver, on the left side caudal behind the stomach and the spleen, and can even reach
the upper pole of the kidneys. The costomediastinal recess lies ventrally between mediastinum and chest
wall (Fig. 55.4). The costomediastinal lies dorsal of the mediastinum next to the spine, and the
phrenicomediastinal recess in anterior–posterior direction, between the mediastinal and diaphragmatic
pleura.
TABLE 55.1 Borders of the Pleura and the Lung in Comparison

Sternal Line Medioclavicular Line Middle Axillar Line Paravertebral Line
Border of the pleura 6th rib 7th rib 9th rib 12th rib
Border of the lung 6th rib 6th rib 8th rib 11th rib
Adapted from Benninghoff, Drenckhahn D. Atemsystem. In: Drenckhahn D, Waschke J, eds. Taschenbuch Anatomie. 2nd ed. Münschen:
Urban & Fischer; 2014.
FIGURE 55.4 Reflection of the recesses of the pleural cavity to the chest wall from anterior (A), posterior (B), and lateral (C)
view.
BLOOD SUPPLY
The arterial vascularization of the parietal pleura comes from the systemic circulation through the internal
mammary and intercostal arteries. The costal pleura is supplied by intercostal arteries and branches from
the internal mammary arteries; the mediastinal pleura is vascularized by bronchial, upper diaphragmatic,
and internal mammary arteries. The blood supply to the cervical pleura (pleural dome) comes from
subclavian arteries. For most parts of the parietal pleura, venous blood drains into peribronchial veins or
directly into the venae cavae11 via intercostal veins. The 2nd to 11th anterior intercostal veins drain into
the internal thoracic veins, the supreme intercostal vein drains into the brachiocephalic vein, and the
posterior intercostal veins drain into the azygos venous system.17
Disagreement exists about the arterial blood supply of the visceral pleura. The visceral pleura seems
to be vascularized by both the systemic (through the bronchial arteries) and the pulmonary circulation.
Newer studies confirm that bronchial arteries are the main supply.18 Venous blood is drained into the
pulmonary venous system.
LYMPHATIC DRAINAGE
The pleural space is on the boundary of two lymphatic systems, both of which play a major role in the
removal of fluid, cells, and foreign particles from the pleural space.
In the subpleural space of the visceral pleura, large lymphatic capillaries—especially in the lower
lobe—form a meshed network running through the basement membrane. This lymphatic network drain
fluid accumulated within the interstitium of the pulmonary parenchyma into intralobar and hilar lymph
nodes (Fig. 55.5).
The lymphatic drainage of the parietal pleura is more elaborate, with direct communication between
the pleural space and the parietal pleural lymphatic channels. These communications, called stomata (see
histology), have endoluminal valves and drain into a network of submesothelial lymphatic channels.
Depending on their location, these channels drain into diaphragmatic, retrosternal, internal mammary,
paraesophageal, or even celiac lymph nodes.19 The subpleural lymphatics play an important role in the
reabsorption of fluid and the removal of proteins, particles, and cells from the pleural space.
NERVE SUPPLY
The visceral pleura is devoid of somatic innervation; in contrast, the parietal pleura is innervated through
a rich network of somatic, sympathetic, and parasympathetic fibers. At the costal pleura level, these fibers
travel through the intercostal nerves. The diaphragmatic pleura is supplied by the phrenic nerves. The
parietal pleura senses pain which is projected to different surface projection.
FIGURE 55.5 Schematic illustration of the relationship between airways, pulmonary arteries, pulmonary veins, and lymphatics.
ACKNOWLEDGMENTS
I thank Prof. Dr. Lukas Sommer, Dr. Bart Vrugt, and Dr. Chloé Spichiger for revision of the chapter and
Dr. Bart Vrugt for providing the histologic images.
REFERENCES
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4th ed. Philadelphia, PA: Elsevier Saunders; 2005:1913–1960.
2. Light RW. Pleural Diseases. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins, a Wolters Kluwer health; 2007.
3. Wang NS. Anatomy of the pleura. Clin Chest Med 1998;19:229–240.
4. Churg A, Cagle PT, Roggli VL. Anatomy, development, and normal function of the serosal membranes. In: Silverberg SG, Sobin LH,
eds. AFIP Atlas of Tumor Pathology Tumors of the Serosal Membranes. 4th ed. Silver Spring, Maryland: ARP Press; 2006:1–7.
5. Del Fabbro M. An improved technique for studying pleural fluid pressure and composition in rabbits. Exp Physiol 1998;83:435–448.
6. Staub N, Wiener-Kronish J, Albertine K. Transport through the pleura: physiology of normal liquid and solute exchange in the pleural
space. In: Chretien J, Bignon J, Hirsch A, eds. The Pleura in Health and Disease. New York: Marcel Dekker; 1985:169–193.
7. Dervan PA, Tobin B, O’Connor M. Solitary (localized) fibrous mesothelioma: evidence against mesothelial cell origin. Histopathology
1986;10:867–875.
8. Bolen JW, Hammar SP, McNutt MA. Reactive and neoplastic serosal tissue. A light-microscopic, ultrastructural, and
immunocytochemical study. Am J Surg Pathol 1986;10:34–47.
9. Carter D, True L, Otis C. Serous membranes. In: Sternberg S, ed. Histology for Pathologists. New York: Raven Press; 1992:499–
514.
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11. Mehran RJ, Deslauriers J. Anatomy and physiology of the pleural space. In: Pearson F, Cooper J, Deslauriers J, Ginsberg R, Hiebert C,
Patterson G, et al., eds. Thoracic Surgery. 2nd ed. Philadelphia, PA: Churchill Livingstone; 2002:1133–1139.
12. Kanazawa K. Exchanges through the pleura. In: Chrétien J, Bignon J, Hirsch A, eds. Pleura in Health and Disease. New York:
Marcel Dekker; 1985.
13. Miserocchi G, Agostoni E. Contents of the pleural space. J Appl Physiol 1971;30:208–213.
14. Albertine KH, Wiener-Kronish JP, Staub NC. The structure of the parietal pleura and its relationship to pleural liquid dynamics in sheep.
Anat Rec 1984;208:401–409. 10.1002/ar.1092080310
15. Wang PM, Lai-Fook SJ. Regional pleural filtration and absorption measured by fluorescent tracers in rabbits. Lung 1999;177:289–309.
16. Benninghoff, Drenckhahn D. Atemsystem. In: Drenckhahn D, Waschke J, eds. Taschenbuch Anatomie. 2nd ed. Münschen: Urban &
Fischer; 2014.
17. Yalcin NG, Choong CK, Eizenberg N. Anatomy and pathophysiology of the pleura and pleural space. Thoracic Surg Clin 2013;23:1–
10, v. 10.1016/j.thorsurg.2012.10.008
18. Gilbert E, Hakim TS. Relative contribution of bronchial flow to subpleural region in dog lung. J App Physiol 1992;73:855–861.
19. Finley DJ, Rusch VW. Anatomy of the pleura. Thoracic Surg Clin 2011;21:157–63, vii. 10.1016/j.thorsurg.2010.12.001
56
Absorption of Gases Within the Pleural
Space
Vasileios Kouritas ■ Kostas Papagiannopoulos
MAIN CONSIDERATIONS
PLEURAL PHYSIOLOGY
The pleural cavity is a closed space formed between the visceral pleura, covering the lung and its hilar
reflection and the parietal pleura, which provides an inner lining for the chest wall.
It contains only a small amount of pleural fluid, which remains under a constant dynamic equilibrium
of production and reabsorption. It allows the movement of the visceral pleura against the parietal pleura
reducing friction throughout the breathing cycle. As pleural fluid is constantly recycled it generates a
transmission of forces between the chest wall and the lung, enabling mechanical coupling between them;
the outward trend of the chest wall to expand counteracts the inward trend of the lung to recoil, thus
producing a negative pressure (lower than the atmospheric) within the pleural space. The pleural fluid
mediates this pressure.
Hence, the pleural cavity consists of a closed pressure chamber with a variable pressure during the
breathing cycle filled by an appropriate amount of fluid; enough to ensure lubrication but also coupling of
the lung to the chest wall.
The pleural pressure is conventionally perceived homogenous throughout the cavity measured at −5 cm
H2O at functional residual capacity (FRC). In reality though, there is a pressure gradient of 0.3 cm
H2O/cm from apex to base in upright position with an average pressure difference of 8 cm H2O between
the lung apex and base. This is also variable during breathing, with the pleural pressure starting from −2.5
cm H2O at the beginning of inspiration becoming progressively more negative as the chest cavity expands
(due to contraction of diaphragm and intercostal muscles) increasing the elastic recoil force of the lung.
It is obvious that in normal circumstances the pleural cavity is airtight. No gases are normally present
in the pleural space.
Physics and Laws Describing Gas Principles

In order to discuss gas absorption in the pleural space it is essential to the reader to delve in the laws
describing gas principles.
The pressure (P) of a gas is inversely correlated to the volume (V) it occupies, at a constant
temperature: PV = k (constant) (Fig. 56.1). This equation is also known as Boyle law. If the mass of a gas
is variable, as it is in living organisms, then the pressure/volume relationship is described by the ideal
gas equation: PV = nRT (n is the amount of substance of gas in moles of gas, R is the universal gas
constant 8.31 J K−1 mol−1, T is the absolute temperature in Kelvin, V is the volume in m3, and P is the
pressure in Pa).
The particles in a gas mixture demonstrate high kinetic energy and collide with each other in a random
manner from every direction, a pattern also known as the Brown movement. This random movement and
the subsequent collision with other gas particles or surfaces are responsible for building up the pressure
of the gas. With higher amount of present particles, more collisions occur and therefore a higher gas
pressure is observed. The collision between particles provides the particles with the energy needed for
their movement. This movement is constant and free toward all directions and provides the principle of
the diffusion of gases.
Dalton law describes the pressure of a gas in a mixture of gases. According to it, in a mixture of
gasses, the total pressure exerted is equal to the sum of the partial pressures of the individual gasses.
Two gasses mainly constitute the room air that humans normally breath: oxygen (O2) and nitrogen (N2)
with 21% and 79%, respectively (CO2 is also present but in negligible quantities). Applying Dalton law,
the atmospheric pressure is 760 mm Hg (or 1037 cm H2O or 101,325 KPa; 1 Pa = 0.01 cm H2O or 0.0075
mm Hg at sea level), constituted by the sum of the partial pressure of O2 at 152 mm Hg and N2 at 608 mm
Hg (PN2 + PO2 = Patm 608 + 152 = 760 mm Hg).
FIGURE 56.1 Boyle law.
TABLE 56.1 Coefficients of Major Gases Implicated in Breathing

Diffusion Coefficient Solubility Coefficient
(Henry Law) (Graham Law)
Oxygen 0.024 1.0
Carbon dioxide 0.57 20.3
Carbon monoxide 0.018 0.81
Nitrogen 0.012 0.53
Helium 0.008 0.95
Similarly, gasses possess a partial pressure when found in fluids. This is proportional to their
concentration in the liquid and inversely proportional to the solubility coefficient of the gas; a coefficient
that describes the affinity of the gas to the fluid molecules; if a gas is attracted by water then it will be
easily diluted in a solution of liquids and therefore its partial pressure will be low. Henry law describes
this principle, with solubility coefficients being different for different gases (Table 56.1).
In closed chambers, gas particles tend to move from compartments with higher concentrations to those
with lower concentrations. This course of particle movement is regarded as the pressure gradient for
diffusion (Fig. 56.2), which practically refers to movement from higher to lower partial pressure states
according to the ideal gas equation described earlier.
This gradient between two points/sites of diffusion is different between different gases and is
described by the diffusion rate (D):
D ∆P × A × S
d × √MW,
where ΔP is the pressure difference, A is the area of diffusion, S is the gas solubility, d is the distance of
diffusion and MW is the molecular weight of the gas. S/√MW is also known as the gas diffusional
coefficient and describes the rate of gas diffusion with constant pressure differences (Graham law). Each
gas has its own coefficient (Table 56.1). O2 is resorbed 62 times more than N2 does whereas CO2 is 23
times more soluble than O2.
A different expression of this law is known as Fick law, which generally describes the diffusion of
substances across a membrane and is valid not only for gases. Fick law states that the net diffusion rate of
a gas across a membrane is proportional to the difference in partial pressure, the area of the membrane,
the diffusion properties of the gas and inversely proportional to the thickness of the membrane. In general,
gases diffuse across lipid bilayers easily and consequently across the cell membranes. Diffusion through
water compartments varies according to the previously mentioned principles and therefore diffusion is
proportional to diffusion in water.
FIGURE 56.2 Pressure gradient for diffusion of gases.
Physiology of Gas Transportation

The pressure outside the chest wall and in the alveoli is atmospheric (760 mm Hg) and more positive
compared to the pleural space pressure (by 5 cm H2O at FRC). As a convention, the atmospheric pressure
is set to 0 cm H2O.
Applying now basic science to practice and according to Boyle law, air enters the respiratory system
following the increase in volume of the thoracic cage, after diaphragm and chest wall muscle contraction,
which in turn causes a drop in the pressure of the respiratory system. This decrease in pressure produces
a pressure gradient between the airway and the atmosphere and thus, air moves down the airways.
The air in the alveoli is of different constitution in comparison to the environmental air, although the
pressure of both is considered to be equal. This difference in alveoli gas composition is attributed to the
humidification of the environmental air as it enters and flows within the airways, as well as the mixture of
the remaining and incoming air in the alveoli, which creates an increase in CO2 concentration and a
decrease in O2 due to the capillary exchange.
It must be noted that N2 pressure remains fairly constant as it is not metabolized. Consequently and
according to all the aforementioned, the mixture that reaches the alveoli is composed of N2 (571 mm Hg),
O2 (102 mm Hg), H2O (47 mm Hg), and CO2 (40 mm Hg) with the total gas pressure being 760 mm Hg
(atmospheric pressure) as dictated by Dalton law.
The alveoli are in close interaction with pulmonary arterioles and venules, where gas exchange
occurs. The gas composition in the arterioles, as measured from the arterial blood, is O2 (97 mm Hg),
CO2 (40 mm Hg), H2O (47 mm Hg always constant), and N2 (569 mm Hg) with a total of 753 mm Hg.
Therefore a 7 mm Hg pressure gradient between alveoli and arterioles is measured. As blood flows in
tissues, O2 is absorbed and CO2 is released, in a ratio equal to the respiratory quotient of 0.8. However,
due to the difference in solubility between O2 and CO2, the O2 concentration change is greater than that of
CO2. N2 and H2O concentration remain unchanged, since they do not metabolize in the body. The
measured pulmonary venule gas pressure and composition is 702 mm Hg [N2 (569 mm Hg), H2O (47 mm
Hg), O2 (40 mm Hg), and CO2 (46 mm Hg)] providing a pressure gradient of 58 mm Hg, compared to the
atmospheric pressure in the alveoli.
Knowing that gasses tend to move following a pressure gradient from higher to lower pressures in
communicating compartments, theoretically, if a gas in a chamber of the body has a pressure near the
atmospheric pressure, it will transfer easier in the venous system rather than the arterial.
When no open communication exists, gasses will diffuse across tissues and/or membranes, a process
that is described by Fick law as explained before. This applies for example under normal conditions as
O2, CO2 and N2 diffuse across the alveolar-blood barrier.
Putting now all previous statements together, one would expect that the pressure gradient of 5 cm H2O
between the alveolar pressure and the pleural cavity would drive gases to diffuse into it. However, the
measured 58 mm Hg (78 cm H2O) subatmospheric (negative) pressure gradient between the venules and
the alveoli, provides a 73 cm H2O net pressure gradient between the pleural cavity and the venous
system. Any gas within the pleural space undergoes continuous resorption, mainly by the venous system
(Fig. 56.3), a statement that explains why the pleural cavity is gas free under normal conditions.
FIGURE 56.3 Process of pressure equilibration of gases in the pleural cavity and lung capillaries, explaining progressive
absorption of gases and lung re-expansion.
Another explanation for this is based on the anatomical layers surrounding the alveoli which do not
allow air to enter the pleural cavity. The visceral pleura seems to play an important barrier to alveolar
gasses, a statement supported by the fact that sometimes air leaking from the alveoli to the surrounding
lung tissue will move toward the hilum presenting with a condition known as pneumomediastinum. In
situations where high pressures are experienced, that is, during Valsalva maneuver or with extensive and
vigorous coughing, air may then even pass through the visceral pleura and into the pleural cavity.
The restriction of gas leak through the pleura seems to many investigators contradictory, since the
mesothelial barrier was long perceived as an extremely “leaky” membrane, which offered unrestrictive
passage to particles and gases. It has however now been shown that the mesothelium possesses resistance
to flow and has conductivity and permeability characteristics.
If for any reason, air enters the pleural cavity, the subsequent rate of gas absorption will follow Fick
law and will depend on the extend and the state of the pleural membrane and the diffusion properties of
each gas component in the mixture.
PRACTICAL CONSIDERATIONS
PNEUMOTHORAX
Formation of Pneumothorax
This is the most important pleural pathology in everyday clinical practice. Pneumothorax is the result of a
communication between the pleural cavity with either the surrounding environment or the airway at the
level of alveoli. When the pleural cavity is breached, the pressure gradient activates the movement of air
into it.
In open pneumothoraces, the breach occurs from the chest wall and therefore the pleural space is
exposed to an open environment with a pressure of 760 mm Hg, with O2 and N2 being the only gases
entering the pleural cavity, as described earlier.
In closed pneumothoraces, the breach is present at the visceral pleura and the underlying interstitium.
The pleural cavity is now exposed to the alveolar environment with a pressure of 760 mm Hg and a
different gas mixture of O2, N2, CO2, and H2O. If a patient develops a closed pneumothorax while on
supplemental O2, it is logical that the partial pressure of the gases will be different with the O2 pressure
being higher and the N2 pressure being lower than room air, since O2 antagonizes N2 in the alveoli.
Initially, the pneumothorax progresses until the breach is sealed off or until a specific equilibrium of
gas pressures and mixture is reached. Until that point, gas is moved in and out of the pneumothorax
pocket, mainly according to the venous gas state, as described earlier, a result of the greater pressure
gradient for diffusion between the pleural space with the evolving pneumothorax and the veins.
Subsequently, there is a reciprocal gas movement from the pleural space toward the alveoli and the veins
until a steady state is reached (Fig. 56.3).
At this stage, the lung loses its mechanical coupling with the chest wall as the pleural pressure
increases resulting in lung collapse. If air continues to enter the pleural cavity, the increasing pressure
pushes the lung to a further collapsed state and the chest wall to expand. The volume of the affected
pleural space is now increased.
Although the pressure in the pleural cavity tends to reach atmospheric values, it is usually somewhat
less, measuring between 755 mm Hg and 758 mm Hg, unless a totally open pneumothorax is left untreated
or a tension pneumothorax is developing (where the pressure continues to rise). Such pressure is
established because the communication usually seals off before a total equilibration is achieved. At this
point, the pleural gas mixture is equalized with the venous system gas mixture (Fig. 56.3).
However, the size of pneumothorax is also dependent on the origin of the air within the pleural cavity.
O2 and N2 exhibit different solubility and are of great importance. In a closed pneumothorax, the amount
of O2 in the gas mixture is decreased when compared to open pneumothorax, as O2 is exchanged during
breathing. The N2 amount is similarly lower. As O2 is more soluble than N2, it will be resorbed at a faster
rate until it reaches venous pressure, whereas N2 at a slower rate. Additionally CO2 and H2O will be
released in the closed pneumothorax.
In this case, the overall amount of gases entering the pleural space will be less than the amount of
gases resorbed when the pneumothorax is established. This is more pronounced if the patient receives O2
therapy, which antagonizes N2 in the alveoli. The closed pneumothorax will be constituted mainly by O2,
CO2, and H2O without N2. However, because N2 amounts in greater concentration in blood, it will tend to
enter the pneumothorax while the large amount of O2 will tend to leave the pneumothorax. Additionally,
since no N2 will be present in the alveoli, the N2 returning in the lungs through the venous system will be
expelled in the alveoli and consequently the overall venous N2 concentration will be diminished. The net
effect is a faster absorption of gasses from the pleural space at the initial phase.
Long-Term Resorption of Pneumothorax

Air is mainly absorbed through the pleural capillaries in a spontaneous manner and to the largest extent
from the pleural veins. Partial gas pressures in the pleural venules [N2 (569 mm Hg) + O2 (40 mm Hg) +
CO2 (46 mm Hg) + H2O (47 mm Hg) = 507 mm Hg] provide a pressure gradient of 58 mm Hg. O2 exhibits
the greatest gradient and is resorbed quicker when compared with N2. The overall spontaneous
absorption of a pneumothorax is calculated to be 1% to 5%/24 hours.
As the pneumothorax is slowly absorbed, the lung expands occupying gradually more space in the
pleural cavity. According to Boyle’s law, this increases the pressure gradient, enhancing further
resorption of pneumothorax. This cycle continues until the lung couples to the chest wall with complete
resolution of pneumothorax (Fig. 56.3).
However, in clinical practice, most surgeons have witnessed sometimes incomplete re-expansion of
lung, that is, following lung resections. In these cases, the absorption of gasses is hindered due to a
thickened visceral pleura or trapped lung. Here, despite the pressure gradient, air must overcome the
thickened and fibrotic outer membrane/cortex, which results in greater flow resistance and markedly
decreased resorption from the pleural capillaries. As time progresses the pleural pressure drops at
venous pressure levels, the pressure gradient is abolished, and, air cannot be resorbed any more. As the
pressure within the pleural cavity is now higher than normal (equals the vein pressure), fluid might
“sweat” from the pleural arterioles. A deranged parietal pleura with impaired lymphatic drainage might
further exacerbate this phenomenon and the patient develops an hydropneumothorax within a permanent
“pocket” in the pleural cavity.
Patients with bronchopleural fistulas behave in a similar manner. Breathed air constantly enters the
pleural cavity and replenishes the gas mixture in the pleural space. This in turn increases the overall
pressure and prohibits lung re-expansion and coupling to the chest wall.
Rationale of O2 Treatment in Pneumothorax

The administration of supplementary O2 following an episode of pneumothorax drives N2 out of the
alveoli. N2 from blood is now expelled to the alveoli due to the alveolar-capillary pressure gradient for
N2 until its partial pressure is practically zero. Additionally, O2 levels in the arterioles and venules
increase subsequently to a level of 100 mm Hg. As CO2 and H2O pressure remain constant, the overall
pressure now in the venules amounts to PN2 + PO2 + PH2O + PCO2 = 0 + 100 + 47 + 46 = 193 mm Hg,
producing a pressure gradient which is nearly 10 times greater than without O2 therapy (Fig. 56.3).
If a patient develops a closed pneumothorax while on supplementary O2, the main gas within the
pleural cavity will be O2. This is an important fact as O2, being an extremely soluble gas, will get
absorbed rapidly from the pleural capillaries. It is therefore logical and advisable that patients at risk of
developing a pneumothorax during maneuvers, that is, imaging-guided biopsies, should receive 100%
supplementary O2, during the procedure.
SPECIAL CONDITIONS
The reader should note that all calculations mentioned earlier are performed with the convention that
atmospheric air has been calculated at sea level and normal conditions.
We need to be reminded that the atmospheric pressure decreases with altitude, reaching 565 mm Hg at
8,000 ft and 500 mm Hg at 11,000 ft. Additionally, gases expand with increasing altitude by 25% to 33%
at 8,000 ft in order for Boyle law to be fulfilled. Although, gas fractions remain the same, the O2 pressure
is decreased, with the dissociation curve shifting to the right and saturations dropping to 90%. These are
conditions present during a flight and should be taken under consideration when a patient with
pneumothorax or air pockets in his pleural cavity intends to travel.
In a similar scenario, deep sea divers that develop a pneumothorax while diving will be at risk of
tension pneumothorax during ascend as pressure decreases with subsequent expansion of the
pneumothorax.
SUGGESTED READINGS
Guyton AC, ed. Textbook of Medical Physiology. 8th ed. Philadelphia, PA: WB Saunders Co; 1991.
Irwin RS, & Rippe JM, eds. Intensive Care Medicine. 6th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2008.
Jindal SK, Shankar PS, Raoof S, et al., eds. Textbook of Pulmonary and Critical Care Medicine. 1st ed. New Delhi, India: Jaypee
Brothers Medical Publishers (P) Ltd; 2011.
Light RW, ed. Pleural Diseases. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
Metz C, ed. Shaum’s Outline of Physical Chemistry. 2nd ed. McGraw-Hill Companies Inc.; 1989.
Michael J based on Sircar S’s work. Fundamentals of Medical Physiology. 1st ed. New York: Thieme Medical Publishers; 2008.
Parikh DH, Crabbe DGG, Auldist AW, et al., eds. Pediatric Thoracic Surgery. 1st ed. London: Springer-Verlag; 2009.
Sherwood L, ed. Fundamentals of Human Physiology. 4th ed. Belmont, CA: Brooks/Cole; 2012.
Weinberger SE, Cockrill BA, Mandel J, eds. Principles of Pulmonary Medicine. 5th ed. Philadelphia, PA: Saunders Elsevier; 2008.
Wilmott RW, Boat TF, Bush A, et al., eds. Kendig and Chernick’s Disorders of the Respiratory Tract in Children. 8th ed. Philadelphia,
PA: Saunders Elsevier; 2012.
57
Pneumothorax
Federico Venuta ■ Daniele Diso ■ Erino A. Rendina
DEFINITION
Pneumothorax is defined as the collection of air in the pleural space, between the lung and the chest wall.
This space is normally virtual, with the apposition of the visceral pleura sliding over the parietal pleura
during respiration. The introduction of air causes partial or complete collapse of the lung with consequent
modifications in respiratory mechanics potentially affecting, even dramatically, ventilation and gas
exchange.
CLASSIFICATIONS
There are several classifications of pneumothorax. The etiologic classification defines this disease as
spontaneous (primary and secondary) or traumatic. The pathophysiologic classification includes three
categories: open, closed, and tension pneumothorax. Pneumothorax can be also quantified from the
radiologic point of view (radiologic classification).
HISTORICAL NOTES
The term pneumothorax was introduced by Itard in 18021; however, almost a century before, in 1724,
Boerhave was the first to report the abnormal presence of air in the pleural space and Meckel, in 1759,
described at postmortem examination tension pneumothorax.2 In 1819 Laennec3 reported the signs and
symptoms of spontaneous pneumothorax.
In 1932, Kjaergaard4 suggested that the rupture of blebs at the apex of the lung was the most frequent
cause of spontaneous pneumothorax in young and otherwise healthy adults. Until that time tuberculosis5
was considered the principal cause of this condition. The risk factors for the development of
pneumothorax further evolved until nowadays, when COPD is the leading cause of secondary
pneumothorax (SSP) along with interstitial lung disease. More recently, pneumocystis and
cytomegalovirus pneumonia, along with atypical mycobacterial infections associated with AIDS, became
common causes of pneumothorax.6–9
Bed rest has been considered the treatment of choice for a long period of time until tube thoracostomy
became the gold standard. Resection of apical blebs was first proposed by Bigger in 19372; in the same
year Sattler10 performed a thoracoscopic resection of a bulla in a patient with pneumothorax. However, at
that time thoracotomy was the gold standard and Tyson and Crandall11 first reported the results with this
approach in 1941. The aggressiveness of the surgical approach was subsequently progressively reduced:
Deslauriers et al.12 in 1980 reported axillary thoracotomy for the resection of apical blebs and apical
pleurectomy. With the development of minimally invasive surgery, video-assisted thoracic surgery
(VATS) gradually replaced the transaxillary approach; VATS became the gold standard since Levi et al.13
reported it in 1990 for bleb resection, pleural abrasion, or pleurectomy.
Since the mid 90s it became evident that pleurodesis should always be associated to optimize surgical
treatment and favor pleural adhesions in order to reduce the recurrence rate. Churchill in 1941 first
performed gauze pleural abrasion.2,14 Parietal pleurectomy was proposed by Gaensler15 in 1956 and by
Thomas and Gebauer16 in 1958. More recently the use of laser17,18 and talc poudrage19 have been
reported.
INCIDENCE
This disease may affect patients at any age; however, there are two peaks of incidence: one between the
ages of 20 and 30 years and the other between 60 and 70 years. The first group usually includes patients
with primary spontaneous pneumothorax (PSP) while the latter includes those with SSP, mainly related to
COPD, thus paralleling the incidence of chronic lung disease.
The incidence of PSP and SSP in the United States is three or four times higher in the male population:
18 to 28 per 100,000 men and 1.2 to 6 per 100,000 women.2,20–22 Cigarette smoking increases twenty
times the risk in men in a dose-dependent fashion.23,24
PRIMARY SPONTANEOUS PNEUMOTHORAX

A spontaneous pneumothorax occurring in a patient without an immediately obvious underlying lung
disease is defined as PSP. The most common cause of PSP is the rupture of small subpleural blebs; they
are small (<2 cm) collections of air contained within the visceral pleura. Blebs are usually found at the
apex of the upper lobes or in the apical segment of the lower lobes; they result from ruptured alveoli, and
are well-demarcated from the adjacent normal lung, being located between the elastic interna and externa
of the visceral pleura. This condition is usually considered as a variety of paraseptal emphysema and it
may be associated with apical fibrosis. A plausible explanation for bleb formation is the degradation of
elastic fibers of the lung due to imbalances between proteases and antiproteases and between oxidants
and antioxidants.25 This might be smoking related, although blebs can occur also in nonsmokers. It has
been postulated that the difference in alveolar pressure in humans between the apex and the base of the
lung may also play an important role. This is confirmed by the frequent ectomorphic physique of patients
with PSP, often associated by the rapid height increase during childhood and adolescence.26 Genetic
mutations have been observed in patients with pneumothorax.27
However, notwithstanding the evidence that the rupture of blebs causes PSP, this may not be the only
cause, since this condition can occur also in their absence.25,28,29 This concept has led to the “pleural
porosity theory,” as demonstrated by fluorescein-enhanced autofluorescence thoracoscopy.30,31
SECONDARY SPONTANEOUS PNEUMOTHORAX

This is a completely different situation caused by several pulmonary and nonpulmonary disorders (Table
57.1).
Chronic obstructive pulmonary disease (COPD) (Fig. 57.1) and bullous disease (Fig. 57.2) are
certainly the most frequent causes of SSP. When associated with this condition, pneumothorax is a marker
of disease severity and predicts survival; in fact, each episode of pneumothorax contributes to increase
the chance of dying by almost fourfold.32
SSP may be associated with cystic fibrosis at an advanced stage (Fig. 57.3).33 In these patients
treatment planning is crucial in the perspective of lung transplantation.34 Also acquired infections,
bacterial, viral, mycotic, parasitic, and tubercular may be associated with pneumothorax, as well as
empyema and subphrenic abscesses. In these patients surgery should not be attempted until adequate
medical treatment is administered.
Several reports have shown the association between pneumothorax and AIDS. This is probably related
to cystic lesions with subpleural air spaces filled with eosinophilic exudates, Pneumocystis carinii, and
macrophages with consequent tissue destruction and fibrosis.6
TABLE 57.1 Common Causes of Secondary Spontaneous Pneumothorax

Chronic Obstructive Pulmonary Disease
Asthma
Cystic fibrosis
Pulmonary fibrosis
Tuberculosis and other mycobacterial infections
Bacterial infections
Pneumocystis carinii infection
Parasitic infections
Mycotic infections
Acquired immunodeficiency syndrome (AIDS)
Bronchogenic carcinoma
Metastatic lung disease
Radiotherapy
Marfan syndrome
Ehlers–Danlos syndrome
Histiocytosis X
Sarcoidosis
Scleroderma
Lymphangiomyomatosis
FIGURE 57.1 Secondary pneumothorax in a patient with advanced emphysema. Computed tomography.
SSP has been described in association with primary35 and secondary tumors of the lung, particularly
metastatic sarcoma treated with pezopanib.36,37 It might also be associated with the administration of
chemotherapy and radiotherapy.38,39
Catamenial pneumothorax is defined as a recurring SSP occurring within 48 to 72 hours after the onset
of menstruation. This entity is part of the thoracic endometriosis syndrome (TES) that includes
hemothorax, hemoptysis, and lung nodules. It is a rare condition associated with the growth of
endometrial glands and stroma in the lungs, pleura, diaphragm, and tracheobronchial tree. There are
several theories trying to explain the onset of this syndrome,40 but none has been thoroughly validated.
Pneumothorax is certainly the most common presentation of TES41–45 and it is mostly unilateral and right
sided46 as pleural and diaphragmatic lesions. On the other hand, pulmonary endometriosis is usually
bilateral. Diaphragmatic fenestrations on the tendinous portion and implants are common and are
important to explain pathogenesis. Air may reach the pleural space from the cervix and abdomen through
congenital diaphragmatic defects; as an alternative, there might be focal thoracic endometrial implants on
the visceral pleura or in the lung with consequent air leakage occurring during menstruation.
FIGURE 57.2 Secondary pneumothorax in a patient with a lung bulla.
FIGURE 57.3 Secondary small left pneumothorax in a patient with cystic fibrosis.
Pneumothorax has been described during pregnancy,47 usually around the 26th week, in 1 out of 10,000
deliveries. It has also been described during dramatic changes in atmospheric pressure, during
thunderstorms and temperature fluctuations, particularly warm, dry weather and the passing of a cold
front.41,48
Pneumothorax may also occur following radiofrequency ablation of lung tumors, acupuncture, illicit
drug use, gastrointestinal endoscopy and during elective or emergency intubation.49–54 Pneumothorax has
also been described in the native contralateral lung after single lung transplantation.55,56
TRAUMATIC PNEUMOTHORAX
Blunt trauma or penetrating injuries to the chest wall may cause pneumothorax.57 The sharp stumps of the
fractured ribs may be directed inward damaging the surface of the lung; this may cause not only
pneumothorax but also hemothorax. Traumatic pneumothorax can also be observed in those exposed to
blasts, even without an evident injury to the chest.58
Medical procedures, such as the insertion of a central venous line or CT-guided lung biopsy and even
thoracentesis may lead to pneumothorax as a complication (iatrogenic pneumothorax). Pneumothorax has
also been described as a complication after deployment of unidirectional endobronchial valves for
bronchoscopic lung volume reduction in patients with emphysema.59,60
Divers are at increased risk for the onset of a pneumothorax. They breathe compressed air and may
suffer pneumothorax as a result from barotrauma from ascending just 1 m while breath-holding with their
lungs fully inflated.61 An additional problem in these cases is that those with other features of
decompression sickness are usually treated in a diving chamber with hyperbaric therapy; this can lead to
a small pneumothorax rapidly enlarging and causing features of tension.61
PATHOPHYSIOLOGY
From the pathophysiologic point of view a closed, open, or tension pneumothorax has been described.
Closed pneumothorax describes a situation with no communication between the pleural space and the
outside of the thorax. The amount of air is usually small and it is usually spontaneously reabsorbed in a
short period of time. Bed rest and monitoring are crucial to avoid and detect the rare development of
tension pneumothorax.
Open pneumothorax is referred to the presence of an open communication between the pleural cavity
and the outside of the chest. Air enters during inspiration and exits during expiration. The hole thorough
which air enters is usually located in the chest wall; however, more rarely, also rupture of the airway or
parenchymal lesions may cause the onset of this condition, if the opening is big enough. Although this
entity might be considered less dangerous than tension pneumothorax, prompt treatment is required; in
fact, the repeated shifts of the mediastinum during the respiratory cycle (mediastinal fibrillation) may
cause refractory bradycardia or even cardiac arrest.21
The onset of tension pneumothorax (Fig. 57.4) is usually an emergency situation. In this setting air
freely enters the chest cavity but it does not exit; the lesion through which air enters acts as a
unidirectional valve. The progressive accumulation of air within the pleural space causes increasing
pressure with complete lung collapse, contralateral shifting of the mediastinum, and compression of the
opposite healthy lung. Tension pneumothorax also induces a shunt with reduced oxygenation and cardiac
output. Eventually, both venae cavae are compressed and kinked with a marked reduction of cardiac
preload. However, the accumulation of air under tension is not the only explanation of the cardiovascular
modifications observed; the insufficient tissue oxygenation of the heart results in the inability to increase
cardiac output. The clinical status rapidly deteriorates with severe dyspnea and “empty heart syndrome.”
Immediate evacuation of air is mandatory.
FIGURE 57.4 Right tension pneumothorax: chest x-ray.
DIAGNOSIS
The most frequent symptoms are chest pain, dry cough, and dyspnea. Almost all patients refer sharp chest
pain at the onset of pneumothorax that subsequently becomes steady. Pain is the predominant symptom in
the young population while dyspnea is more frequent in elderly COPD patients.
Physical examination is positive only if lung collapse is significant; the patient shows a decrease in
chest wall movements, with tympanic resonance and attenuation or absence of the respiratory murmur in
the affected hemithorax. Tachycardia is almost always present. Patients with tension pneumothorax show
signs of respiratory distress, anxiety, cyanosis, hypotension, with a fixed hyperexpanded hemithorax.
The diagnosis of pneumothorax should always be confirmed radiologically with erect posteroanterior
and lateral chest radiographs showing the abnormal presence of air in the pleural space. Expiration films
can help to diagnose a small pneumothorax. The differentiation between pneumothorax and a large bulla
might be difficult and computed tomography (CT) is certainly helpful. In case of tension pneumothorax the
diagnosis is suggested by complete collapse of the affected lung, contralateral shifting of the mediastinum
and heart and depression or inversion of the hemidiaphragm, increased thoracic volume with rib
separation, contralateral lung compression, tracheal deviation, and deep sulcus sign.62
SIZE OF THE PNEUMOTHORAX

The amount of air contained in the chest cavity (size of the pneumothorax) is one of the crucial factors to
determine treatment.25,63–65 Chest x-ray is the most common way to estimate it; however, with this two-
dimensional imaging technique the amount of air is usually underestimated.66–68 For this reason several
indices and formulas have been proposed both at chest x-ray and CT: the Rhea method,66,69 the Light
index,70 the Collins formula.67 Even an automated formula is available on the Web at http://www.chestx-
ray.com/calculator/PTX.html.22 However, all these models are extremely uneasy to be employed in our
daily activities. The most practical sizing method is the one proposed by the ACCP; it defines small
pneumothoraces as those with the surface of the lung at less than 3 cm from the chest wall (Fig. 57.5) and
large pneumothoraces as those with a distance greater than 3 cm (Fig. 57.6).63 An even more simplified
method classifies a large pneumothorax as a complete separation of the visceral and parietal pleura and a
small pneumothorax as a partial separation.22
COMPLICATIONS OF PNEUMOTHORAX
Tension pneumothorax should be considered a complication and requires immediate drainage.
FIGURE 57.5 Small left primary spontaneous pneumothorax: chest x-ray.
Pneumomediastinum, pneumoperitoneum, and subcutaneous emphysema are rare; they occur more
often after major trauma. They are of no clinical significance in most of the cases. However, their
presence requires to rule out airway injury, perforation of the esophagus, and perforation of an abdominal
hollow viscus. Rarely, subcutaneous emphysema requires skin incision or subcutaneous needle placement
for decompression.
FIGURE 57.6 Large left pneumothorax with complete lung collapse: chest x-ray.
FIGURE 57.7 Right hemopneumothorax: collapse of the lower lobe associated with a level due to accumulation of blood: chest
x-ray.
Hemopneumothorax (Fig. 57.7) is a relatively rare complication usually related to rupture of a
vascularized pleural adhesion or a vascularized bleb or bulla. In trauma patients major vascular injury
must be ruled out as well as lesions of the intercostal arteries, particularly when rib fractures are
associated. It might be life-threatening and drainage, VATS surgery, and open thoracotomy should not be
postponed if the clinical status of the patient requires it.
Simultaneous bilateral pneumothorax (Fig. 57.8) accounts for 1% to 15% of the cases.2 It is
symptomatic in most of the patients, particularly when associated with an underlying lung disease like
tuberculosis, interstitial lung disease, COPD, and cystic fibrosis.
Recurrence (ipsilateral or contralateral) is certainly the most frequent complication of pneumothorax
and it is observed in up to 75% of the patients at 5 years after the first episode not surgically treated.71–73
After the first recurrence, if surgical treatment is not attempted, the risk of further episodes of
pneumothorax increases exponentially.25,65,74,75
FIGURE 57.8 Bilateral pneumothorax: chest x-ray.
TREATMENT
There are several management options for pneumothorax: oxygen administration with observation and bed
rest, simple aspiration, small-bore catheter insertion, tube thoracostomy, VATS, and open thoracotomy.
They are all intended to evacuate air from the pleural space, remove the cause of pneumothorax when
possible, and prevent recurrence. The decision making depends on the size of pneumothorax; the clinical
status of the patient; the presence of an open or closed communication; and whether the pneumothorax is
primary, secondary, or recurrent.
There is a tendency to a more conservative treatment in simple, small, uncomplicated, clinically
stable, asymptomatic pneumothoraces. In these cases, the BTS guidelines64 suggest bed rest and
observation. Oxygen administration favors healing by increasing the gradient for nitrogen absorption from
the pleural space64,76–79; it also ameliorates hypoxemia due to ventilation/perfusion imbalance. COPD
patients should be carefully monitored during oxygen administration to prevent hypercapnia.
Hospitalization is recommended for at least 24 hours.
Needle aspiration is recommended by the BTS guidelines for stable patients requiring intervention,
even if it shows a relatively high recurrence rate. Complications are extremely rare; damage of the
intercostal artery with consequent bleeding is enclosed.
Tube thoracostomy with underwater seal drainage remains the most common and effective treatment
for patients with moderate to large pneumothoraces. It allows easy removal of air from the pleural space
with consequent lung re-expansion. It is mandatory in symptomatic patients. The size of the tube should be
tailored on the base of the prediction, if it is possible, of a substantial air leak. The chest tube should be
directed toward the apex of the chest. The rate of complications associated with chest tube placement is
between 3% and 18%.80 Management of chest drains changes from center to center. Although underwater
seal drainage might be sufficient in most of the cases, at many institutions negative pressure from −10 to
−20 cm H2O is preferred at least during the first 24 hours or until the lung fully re-expands. However, the
application of suction immediately after chest tube placement has been associated with re-expansion
pulmonary edema.81–84 The chest tube is preferably removed when the air leak has stopped for at least 48
to 72 hours. Chest x-ray is recommended before discharge.
An air leak is defined as persistent when it continues after 48 hours of chest placement.22 Only 3% to
7% of patients with spontaneous pneumothorax show a persistent air leak for more than 7 days; however,
up to 40% of the patients with SSP show this complication.64 The ACCP guidelines suggest surgical
intervention after 4 and 5 days for PSP and SSP, respectively,63 since a longer waiting time does not
substantially modify outcome.
The indications for surgery in patients with PSP are reported in Table 57.2. The role of surgery is
clear in case of recurrence85 but it is much more debated during the first episode. In this situation,
persistent air leak, failed lung re-expansion, hemothorax, bilaterality, and occupational lifestyle issues are
in favor of surgery. The two major goals are the removal of the cause of pneumothorax and obliteration of
the pleural space.
The surgical strategy should be tailored on the base of intraoperative findings. Vanderschueren86
proposed this classification:
• Type I: Normal findings; no abnormalities

• Type II: Presence of pleural adhesions
• Type III: blebs/bullae <2 cm in diameter
• Type IV: blebs/bullae >2 cm in diameter
TABLE 57.2 Indications for Surgery in Primary Spontaneous Pneumothorax
First episode
Prolonged air leak
Non–re-expansion of the lung
Bilateral pneumothorax
Hemothorax
Tension pneumothorax
Complete pneumothorax
Occupational hazard
Absence of medical facilities in isolated areas
Associated single large bulla
Psychological
Second episode
Ipsilateral recurrence
Contralateral recurrence
In case of blebs or bullae a wedge resection (single or multiple) is necessary; major lung resections
are rarely required. Often (30% to 40% of the cases) no abnormal finding is observed on the surface of
the lung, especially when a single bleb ruptures and it cannot be visualized any longer (Vanderschueren
type I).2 A type II pattern (12% to 15%) suggests previous pneumothoraces or pleuropulmonary
infections. Type III is observed in 30% to 40% of the patients and type IV in 5% to 10% of the cases.2
The preferred surgical approach (VATS or limited thoracotomy) is still debated. The ACCP guidelines
recommend a thoracoscopic approach both for PSP and SSP.64 However, a meta-analysis showed an
overall percentage of recurrence rate of 5.4% for VATS and 1.1% for open surgery.87 Probably for this
reason, the BTS62 and the Belgian Society of Pulmonology88 report that thoracotomy and pleurectomy is
still the procedure of choice. Uniportal and awake VATS has recently been proposed as an alternative to
further reduce surgical trauma.89,90 Particular judgment is required in case of bilateral pneumothorax. In
this situation bilateral VATS is certainly a good option,91 although single-stage bilateral transaxillary
thoracotomies have been also proposed92 and even median sternotomy has been performed when the
bilateral disease is diagnosed before surgery.93 VATS has also been proposed in case of surgical
treatment after failure of a previous thoracoscopic approach.94,95 However, we should not hesitate to
convert to open surgery in case of difficulties or intraoperative complications.
The second key point for effective surgical treatment is obliteration of the pleural space. Several
techniques are available and almost equally effective: pleurectomy, pleural abrasion, or chemical
irritation.17,96–100 Apical parietal pleurectomy creates sufficient fixation of the lung to the endothoracic
fascia; results are excellent with a low recurrence rate and no respiratory functional restriction.15,101
However, some authors have reported significant complications after extensive pleurectomy.102 Pleural
abrasion allows a safe and effective obliteration of the pleural space; in addition, this technique shows
the advantage of preserving the extrapleural plane of dissection. This offers significant advantages for
patients subsequently requiring further surgical treatment, namely those undergoing lung transplantation
(cystic fibrosis, COPD, pulmonary fibrosis, etc.).33,34 In a review paper,103 the recurrence rate of
pneumothorax after pleural abrasion alone was 2.3%.
Chemical pleurodesis and Nd:YAG laser abrasion17 have been reported to achieve obliteration of the
pleural space. Several agents have been used: quinacrine, bleomycin, doxycycline, autologous blood,
tetracycline, and talc.104–108 The latter is the one used more frequently.109 Talc is a powder of hydrous
magnesium silicate containing several contaminants; it is commonly used to prevent recurrence of
malignant pleural effusions.110 Commercially available purified talc is free of asbestos and it is
considered safe for therapeutic use in patients with benign pleural diseases such as pneumothorax. It
induces the development of pleural adhesions, fever and pain has been reported after use of this agent,
and respiratory failure has been described if more than 10 g is used111–114—the latter complication is of
major concern particularly in young patients. For this reason a maximum dose of 5 g has been
recommended for intrapleural use.115 Talc can be insufflated during VATS throughout the thoracic cavity
by means of an atomizer or a disposable single use spray canister. In case patients are unfit for surgery, it
can be introduced as a slurry trough the chest tube.116,117 Overall, in a comparison study118 talc and
mechanical methods were superior to either Nd:YAG laser or autologous blood patch.
Catamenial pneumothorax requires special considerations: all the visible lesions on the lung surface
should be excised and visible diaphragmatic defects should be sutured. Mechanical abrasion or
pleurectomy should also be performed.119 Hormonal treatment with gonadotropin-releasing hormone
agonists may achieve a cure but they should be administered after surgical options have been exhausted
due to their systemic effects on hormone production.120
In patients with pneumothorax unfit for surgery or in other selected cases unidirectional endobronchial
valves and other stents have been deployed to isolate the lung parenchyma involved in the air leak.121–123
GUIDELINES
There are no completed randomized controlled trials comparing conservative and interventional
management of pneumothorax in adults. Thus, there is a lack of high-quality evidence for current
guidelines in management.124 For this reason, tailored management strategies still play a major role. The
British Thoracic Society (BTS) have recently published a list of guidelines.125 In most of the instances
these guidelines are based on the definition of the size of pneumothorax (large pneumothorax: presence of
a visible rim of >2 cm between the lung margin and the chest wall, according to the BTS classification).
When analyzing this list and comparing them with previous ACCP suggestions63 we have to take into
account that there are differences in the quantification of pneumothorax (large pneumothorax for ACCP is
>3 cm). When these measurements were compared directly to one another they showed poor
correlation.126 In a multicenter prospective audit of patients treated according to BTS guidelines, BTS
guidance was associated with the insertion of fewer chest drains in patients who would otherwise not
have suffered an enlarging pneumothorax or clinical compromise, whereas chest guidance would
encourage the insertion of chest drains in more patients who would otherwise not have suffered an
enlarging pneumothorax or clinical compromise.127
ACCORDING TO THE BTS GUIDELINES:
• SSP is associated with higher morbidity and mortality than PSP. (D)
• Pneumothorax is not usually associated with physical exertion. (D)
Clinical Evaluation
• Symptoms in PSP may be minimal or absent. In contrast, symptoms are greater in SSP, even if the
pneumothorax is relatively small in size. (D)
• The presence of breathlessness influences management. (D)
• Severe symptoms and signs of respiratory distress suggest the presence of tension pneumothorax. (D)
Imaging
• Standard erect chest x-rays in inspiration are recommended for the initial diagnosis rather than
expiratory films. (A)
• The adoption of digital imaging requires caution since the presence of a small pneumothorax may not
be easily visible. (D)
• CT scan is recommended for uncertain or complex cases. (D)
Size of Pneumothorax
• In defining the management strategy the size of a pneumothorax is less important than the degree of
clinical compromise. (D)
• Accurate pneumothorax size calculations are best achieved by CT scanning. (C)
Treatment Options for Pneumothorax
• Patients with pre-existing lung disease tolerate a pneumothorax less well, and the distinction between
PSP and SSP should be made at the same time of diagnosis to guide appropriate management. (D)
• Breathlessness indicates the need for active intervention as well as supportive treatment, including
oxygen. (D)
• The size of the pneumothorax determines the rate of resolution and is a relative indication for active
intervention. (D)
Management of Primary Spontaneous Pneumothorax
• Patients with PSP or SSP and significant breathlessness associated with any size of pneumothorax
should undergo active intervention. (A)
• Chest drains are usually required for patients with tension or bilateral pneumothorax who should be
admitted to hospital. (D)
• Observation is the treatment of choice for small PSP without significant breathlessness. (B)
• Selected asymptomatic patients with large PSP may be managed by observation alone. (A)
• Patients with a small PSP without breathlessness should be considered for discharge with early
outpatient review. However, these patients should also receive clear written advice to return in the
event of worsening breathlessness. (D)
• Needle aspiration is as effective as large-bore chest drains and may be associated with reduced
hospitalization and length of stay. (A)
• Needle aspiration should not be repeated unless there were technical difficulties. (B)
• Following failed needle aspiration, small-bore chest drain insertion is recommended. (A)
• Large-bore chest drains are not needed for pneumothorax. (D)
• Suction should not be routinely employed. (B)
• Caution with suction is required because of the risk or re-expansion of pulmonary edema. (B)
• High-volume low-pressure suction systems are recommended. (C)
• Referral to a respiratory physician should be made within 24 hours of admission. (C)
• Complex drain management is best effected in areas where specialist medical and nursing expertise is
available. (D)
Management of Secondary Spontaneous Pneumothorax
• All patients with SSP should be admitted to hospital for at least 24 hours and receive supplemental
oxygen in compliance with the BTS guidelines on the use of oxygen. (D)
• Most patients will require the insertion of a small-bore chest drain. (B)
• All patients will require early referral to a chest physician. (D)
• Those with persistent air leak should be discussed with a thoracic surgeon at 48 hours. (B)
• Medical pleurodesis may be appropriate for inoperable patients. (D)
• Patients with SSP can be considered for ambulatory management with Heimlich valve. (D)
Discharge and Follow-up
• Patients should be advised to return to hospital if increasing breathlessness develops. (D)

• All patients should be followed up by respiratory physicians until full resolution. (D)
• Air travel should be avoided until full resolution. (C)
• Diving should be permanently avoided unless the patient has undergone bilateral surgical pleurectomy
and has normal lung function and chest CT scan postoperatively. (C)
Medical Chemical Pleurodesis
• Chemical pleurodesis can control difficult or recurrent pneumothoraces (A); but, since surgical options
are more effective, it should only be used if a patient is either unwilling or unable to undergo surgery.
(B)
• Chemical pleurodesis for pneumothorax should only be performed by a respiratory specialist. (C)
Referral to Thoracic Surgeons
• In cases of persistent air leak or failure of the lung to re-expand, an early (3–5 days) thoracic surgical
opinion should be sought. (C)
• Open thoracotomy and pleurectomy remain the procedure with the lowest recurrence rate for difficult
or recurrent pneumothoraces. (A)
• Video-assisted thoracoscopic surgery (VATS) with pleurectomy and pleural abrasion is better
tolerated but has a higher recurrence rate of approximately 5%. (A)
• Surgical chemical pleurodesis is best achieved by using 5 g sterile graded talc, with which the
complications of adult respiratory distress syndrome and empyema are rare. (A)
Tension Pneumothorax
• Tension pneumothorax is a medical emergency that requires heightened awareness in a specific range
of clinical situations. (D)
• Treatment is with oxygen and emergency needle decompression. (D)
• A standard cannula may be sufficiently long if used in a second intercostal space. (D)
Pneumothorax and Pregnancy
• Pneumothorax recurrence is more common in pregnancy, poses risks to the mother and fetus, and
requires close cooperation between chest physicians, obstetricians, and thoracic surgeons. (C)
• The modern and less invasive strategies of simple observation and aspiration are usually effective
during pregnancy, with elective assisted delivery and regional anesthesia at or near term. (C)
• A corrective surgical procedure (VATS) should be considered after delivery. (D)
Catamenial Pneumothorax
• Catamenial pneumothorax is underdiagnosed in women with pneumothorax. (C)

• A combined surgical intervention and hormonal manipulation requires cooperation with thoracic
surgeons and gynecologists. (D)
Pneumothorax and AIDS
• The combination of pneumothorax and HIV infection requires early intercostal tube drainage and
surgical referral, in addition to appropriate treatment for HIV and PJP infection. (C)
Pneumothorax and Cystic Fibrosis
• The development of a pneumothorax in a patient with cystic fibrosis requires early and aggressive
treatment with early surgical referral. (C)
• Pleural procedures, including pleurodesis, do not have a significant adverse effect on the outcome of
subsequent lung transplantation. (D)
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58
Mechanics and Fluid Dynamics of Lung
and Pleural Space
Giuseppe Miserocchi ■ Egidio Beretta ■ Gabriele Simone Grasso
Extracellular fluid plays a vital role in the normal function of the lung. This discussion will be divided
into lung mechanics and the pleural space.
THE PULMONARY INTERSTITIUM

In order to optimize the diffusive process, the thickness of the air–blood barrier (ABB, see chapter
“Mechanics of Breathing and Pulmonary Gas Exchange”) is to be kept as low as possible (0.2 to 0.3
microns), a feature which involves a substantial dehydration of the interstitial space. This condition is
assured through the combined action of a powerful lymphatic drainage and a very low microvascular
permeability of the capillary endothelium1 reflecting the specific structure of the extracellular matrix.
As a result, pulmonary interstitial pressure (Pi) is kept subatmospheric ( −10 cm H2O). The existence of
negative pressure has clear mechanical implications: in the lung, the endothelium of the capillary wall
appears functionally tightly glued to the epithelial wall.
FIGURE 58.1 Cross-section schema of the pulmonary interstitial space to show the macromolecular organization of the
extracellular matrix as well as the microvascular–interstitial fluid filtration and drainage that maintain an interstitial pressure of
−10 cm H2O.
Figure 58.1 represents a cross-section schema of the pulmonary interstitial space and highlights the
macromolecular organization of the extracellular matrix as well as the microvascular–interstitial fluid
dynamics. The matrix includes a fibrillar and a nonfibrillar component. The fibrillar component
essentially includes collagen I and elastic fibers. The nonfibrillar component includes molecules
belonging to proteoglycans (PG) family. Perlecan is an intermediate-weight heparan sulfate (HS)-PG
(Molecular weight 0.1 to 0.5 KDa) present in the basal membrane that, assembled with the laminar
collagen IV, contributes to the control of microvascular permeability through its steric hindrance. Versican
is a high-molecular-weight (>0.5 KDa) chondroitin sulfate (CS)-PG, which is present in the interstitial
space bound to hyaluronan, a random coiled molecule, that provides rigidity to the tissue by establishing
multiple noncovalent links with other molecules of the matrix and with cells.2 Moreover, versican is
carrying numerous chains of glycosaminoglycans (in pink) that are highly reactive with other molecules
and water.
MICROVASCULAR–INTERSTITIAL FLUID DYNAMICS

Fluid filtration across biologic barriers (e.g., capillary endothelium as well as pleural mesothelium) is
defined by the revisited Starling equation:
where Kf is the filtration coefficient; P and π refer to hydraulic and colloid osmotic pressures,
respectively; subscripts c and i refer to capillary and interstitial compartments, respectively; and σ is the
protein reflection coefficient.
The filtration coefficient Kf is equal to the product Lp · S, where Lp is the water hydraulic permeability
and S is the total surface available for filtration. Lp is the intrinsic permeability of the endothelial wall
and reflects the distribution of small pores (5-nm diameter) opening on the paracellular membrane barrier
through which most of the water flows. Proteins also move across barriers, dragged by water through a
pore system that allows their passage. The protein reflection coefficient σ defines how easy it is for a
given protein to cross a barrier. The value of σ varies from 1 (the barrier is totally impermeable to
proteins) to 0 (no restriction to protein passage). Pores allowing protein transport are larger (30 to 50 nm
diameter) but their average density is low (0.006/µm2); accordingly, they provide only a minor share of
water transport.3,4
Figure 58.1 shows in red the direction of microvascular filtration that amounts to 1 · 10−8 mL/cm2 in
24 hours, a very low value, reflecting the low microvascular permeability in physiologic conditions;
filtration is totally drained by lymphatics.
MECHANISMS OF CONTROL OF EXTRAVASCULAR WATER

The lung appears to be quite resistant to edemagenic conditions such as capillary recruitment and an
increase in blood flow, both conditions occurring when the request for oxygen delivery is increased. Such
conditions include exercise and hypoxia (see chapter “Mechanics of Breathing and Pulmonary Gas
Exchange”). The volume of the extravascular water is in fact strictly controlled in order to prevent further
accumulation of fluids in the interstitial space. At least three mechanisms cooperate to allow for only
minimal variations in extravascular water volume relative to the steady state condition.1
1. The glycosaminoglycan chains of PGs are highly hydrophilic and can bind excess water in the
interstitial space to form gel-like structures; this results in an increase in the steric hindrance of PG and
in a corresponding decrease in the porosity of the basement membrane, and thus in microvascular
permeability.
2. The particular assembly of PG5 makes the extracellular matrix extremely rigid, thus providing a low
tissue compliance. This implies that a minor increase in extravascular water (<10%) in response to
increased microvascular filtration (a condition occurring in early phase of interstitial edema), causes a
marked increase in interstitial pressure (e.g., from −10 to 5 cm H2O), buffering further microvascular
filtration.1 This represents an important “tissue safety factor” in order to prevent the development of
lung edema.
3. Finally, precapillary arteriolar vasoconstriction is triggered in lung regions at risk of developing
edema: indeed, limiting blood flow also limits microvascular filtration. Precapillary vasoconstriction
has been described in response to conditions causing an increase in microvascular permeability.6,7
PATHOPHYSIOLOGY OF LUNG EDEMA

The development of severe edema is known as a tumultuous event taking place in minutes. Experimental
models in animals allowed to attribute the sudden increase in extravascular lung water to the abolition of
the “tissue safety factor” due to the loss of integrity of the PG components of the extracellular matrix.5
Fragmentation/degradation of these link proteins results indeed in an increase in matrix compliance and
microvascular permeability. The loss of integrity of PG is due to the combined action of several factors:
the sustained increase in parenchymal stresses, the weakening of the noncovalent bonds of the matrix PG
due to increased water binding, the activation of tissue metalloproteinases,5 and the action of reactive
oxygen species (ROS). Gel filtration chromatography (Fig. 58.2) of lung tissue extracts allows to partition
the three main families of PGs based on molecular weight: the largest PGs (CS matrix proteoglycans, CS-
PG, peak 1), the intermediate size ones (HS-PG, peak 2), and the smallest PGs (peak 3). Figure 58.2
allows to compare, relative to control, how the molecular weight–based profile of PG families is altered,
depending upon the prevailing pathophysiologic factor causing their fragmentation. In case of the so-
called “cardiogenic” edema there is a major destruction of CS-PG, leading, as shown in the middle panel,
to the disappearance of their native peak 1 with a corresponding increase of the peaks of intermediate-
and low-weight PGs (peak 2 and 3, respectively) due to accumulation of their fragments. The destruction
of CS-PG is responsible for the loss of rigidity of the interstitial matrix and therefore loss of “tissue
safety factor.” Hypoxia exposure (Fig. 58.2, right panel) also led to a major fragmentation of HS-PG of
the basement membrane (thus a huge decrease in peak 2), all fragments accumulating under peak 3. The
loss of integrity of HS-PG is a cause of increase in microvascular permeability. In all forms of lung
edema, a severe condition develops when the loss of integrity of the interstitial matrix proceeds beyond a
critical threshold. Proinflammatory cytokines (TNF-α, IL-6, thrombin, histamine, TNF-alpha, IL-8, and
IL-1) are all increased8,9 in the fragmentation phase.
FIGURE 58.2 Gel filtration chromatography of lung tissue extracts to partition the three main families of PGs based on their
molecular weight: the high chondroitin sulfate matrix proteoglycans, CS-PG (peak 1), the intermediate size heparan sulfate
proteoglycans (HS-PG, peak 2), and the smallest PGs (peak 3). The figure allows to compare relative to control (left panel),
how the molecular weight–based profile of PGs families is altered, depending upon the prevailing pathophysiologic factor causing
their fragmentation. In “cardiogenic” edema (middle panel) a major destruction of CS-PG occurs (disappearance of peak 1and
accumulation of fragments under peak 2 and 3) leading to loss of “tissue safety factor.” Hypoxia exposure (right panel) caused
greater fragmentation of HS-PG of the basement membrane (decrease in peak 2 and accumulation of fragments under peak 3)
leading to an increase in microvascular permeability. cpm, counts per minute.
THE RECOVERY FROM LUNG EDEMA
Interstitial edema represents a sharp edge between tissue repair and severe disease; furthermore, edema
characteristically shows a patchy distribution, revealing regional differences in the efficiency of control
of extravascular water volume. Cellular activation for remodeling of various matrix components has been
characterized by differential expression of signaling-transduction platforms on the plasma membrane
(lipid rafts or caveolae10–15). Lack of clearance of the matrix fragments, neutrophil and macrophage
activation,16 production of ROS leading to diffuse alveolar damage, and inhibition of the active alveolar
fluid reabsorption17 hinder the reparative process.
Excessive deposition of interstitial matrix leads to fibrosis. The progression toward fibrosis depends,
in part, on how lung cells interact with the surrounding extracellular matrix microenvironment. Epithelial
cells and fibroblasts (or myofibroblasts) contribute to the deposition of a provisional matrix at sites of
injury and the balance in the activity of metalloproteinases (MMP-2 and 9) and corresponding TIMP is
critical in this phase.18 In particular, the increased MMP-9 activity was found to contribute to
redeposition of a rigid matrix, a critical point to allow reabsorption of edema fluid.19,20 Rapid recovery
of the epithelial barrier and proteolysis of provisional matrix are likely to limit fibro-proliferation. It still
remains to be clarified how exogenous signals from matrix, cytokines, chemokines, and growth factors
induce an altered response in the reparative process leading to fibrosis.21 The histologic pattern of
idiopathic pulmonary fibrosis is a patchy distribution of fibro-proliferative process sparing some
respiratory units but affecting others nearby. Since fibrosis mainly occurs in regions where edema
develops, it appears tempting to put forward the hypothesis that a chronic condition of high permeability
barrier may underlie the fibro-proliferative process.7
PLEURAL SPACE
The pleural space, schematically presented in Figure 58.3, is delimited by the visceral pleura wrapping
the lung and by the parietal pleura covering the rib cage and diaphragmatic surfaces. Pleural membranes
include a layer of mesothelial cells, 4 μm thick, connected to each other by tight junctions on the luminal
side and by desmosomes in the subpleural basal portion. Microvilli 1 to 3 μm long are seen on
mesothelial cells, varying in density from 2/μm2 to 30/μm2. They trap high concentrations of
glycoproteins and hyaluronic acid.22,23 In humans, the thickness of the visceral pleura can attain 100 μm
while that of the parietal pleura is 5 times less.23–25 The parietal pleura is richly supplied with
lymphatics that open directly on the mesothelial surface (lymphatic stomatas). Stomatas (Fig. 58.3A), with
an average diameter of 1 μm (range from <1 μm to 40 μm), have density from 100/cm2 on the intercostal
surface up to 8,000/cm2 on the diaphragm. In the mediastinal region, the density of stomatas is so high that
the mesothelium appears cribriform (Kampmeier foci). Stomatas are frequently grouped in clusters and
connect to an extensive network of submesothelial lacunae.22,26
The lymphatics of the parietal pleura drain the pleural fluid as well as particles reaching the pleural
cavity, for example, asbestos. The lymphatics of the visceral pleura do not connect directly with the
pleural space and are therefore involved only in the drainage of pulmonary interstitial space.
The blood supply to the parietal pleura comes from the systemic circulation, while venous drainage is
through the intercostal veins.27–29 In the visceral pleura the blood supply originates from the systemic
circulation via the bronchial arteries30 and drains mainly into the pulmonary veins.
FIGURE 58.3 A: Transmission electronic microscopy image of parietal lymphatic stomata. (Adapted with permission from
Wang NS. Mesothelial cells in situ. In: Chrétien J, Bignon J, Hirsh A, eds. The Pleura in Health and Disease. New York: M.
Dekker; 1985:23–42.) B: Schematic drawing of pleural space delimited by parietal and visceral pleura.
PLEURAL LIQUID PRESSURE

Pleural liquid pressure is gravity-dependent and therefore varies with height in the cavity. At the end of
expiration it is 0 cm H2O at the bottom of the cavity and becomes subatmospheric with increasing height
in the chest by about 1 cm H2O per cm height.31,32 In supine humans, at mid-heart level, pleural liquid
pressure is in the range of −10 cm H2O. The vertical distribution of pleural liquid pressure does not
reflect a static hydrostatic situation, but rather a continuous top-to-bottom flow. A gravity-dependent flow
of pleural fluid may also be observed upon changing body position. Furthermore, for a given height within
the cavity, pleural liquid pressure is more negative in the mediastinal compared to the costal region,
causing a costal to mediastinal flow.33 Pleural liquid pressure becomes more negative at all sites during
inspiration, and in fact pressure oscillations during the breathing cycle are the cause of fluid recirculation
among the pleural compartments. Flow resistance within the pleural space is relatively high.34
PLEURAL FLUID DYNAMICS

The pleural space contains a tiny amount (≈0.3 mL · kg−1) of hypo-oncotic fluid (≈1 g · dL−1 protein);
thus in physiologic conditions, the permeability of the pleurae to water and proteins is very low. Pleural
fluid turnover is estimated to be ≈0.15 mL · kg−1 · h−1,35 which assures complete fluid renewal in 1 hour.
Figure 58.4 shows the polarization of filtration/drainage for pleural fluid. Fluid is produced mostly in
the less-dependent regions of the parietal pleura and is mostly drained by the lymphatic stomata of the
parietal pleura in the diaphragmatic, costal, and mediastinal regions.35,36 Flow velocity in initial
lymphatics is of the order of 2 mm·min−1. 31 It is then noteworthy to recall that pleural liquid pressure
distribution reflects both a gravity-dependent gradient as well as the intrapleural flows of liquid from the
filtration toward the drainage sites.32–34,37,38 Some data suggest that active water transport operated by
mesothelial cells plays a potential role in pleural fluid turnover.39 The lymphatic conductance (Kl) is
about 10 times higher36 than the filtration coefficient of the parietal pleura (Kf). The visceral pleura is
essentially excluded from pleural fluid turnover in physiologic conditions because, due to its greater
thickness, its permeability is about 10-fold lower compared to that of the parietal pleura.40,41
FIGURE 58.4 Polarization of filtration/drainage for pleural fluid. Fluid is mainly produced in the less-dependent regions of the
parietal pleura and is drained by the lymphatics in the most dependent regions (diaphragmatic, costal, and mediastinal).
CONTROL OF PLEURAL FLUID VOLUME

Lymphatics act as an efficient negative feedback system to regulate pleural fluid dynamics36 through two
mechanisms:
1. they set a rather sub-atmospheric pressure thanks to their powerful draining action; and
2. they can markedly increase draining flow in response to increased filtration.35,36
Figure 58.5 presents a sensitivity analysis depicting the features of the control mechanism on pleural
liquid volume (the controlled variable) operated by lymphatics when facing an increase in microvascular
filtration.36 The chequered area represents the extension of the range of control operated by lymphatics
when their capacity is normal (equal to 1) or progressively decreased due to functional limitation. Point A
corresponds to the physiologic condition. Point B shows how, for a 10-times increase in filtration rate
(due, e.g., to an increase in hydraulic permeability), the volume of the liquid would not even be doubled
due to the possibility of lymphatics to increase the draining flow well within their maximum capacity.
Point C shows that reducing the maximum lymph draining down to 1:10 of normal (e.g., for mediastinal
lymphatic compression or mesothelioma) the volume of the liquid would only increase by 1.5-fold. Yet,
for such a limitation to lymphatic drainage, any increase in filtration rate could not be met, resulting in
pleural fluid accumulation (point D, falling outside the chequered area). The features of the control
mechanisms have been developed using data from animal model31,36; thus, it appears reasonable to
question whether the same mechanism operates in humans. An important role of parietal lymphatics in
humans is demonstrated by the epidemiologic finding of the “black spots,” namely the accumulation of
particulate, for example, asbestos fibers, around the parietal pleural lymphatic stomata.42
FIGURE 58.5 Model of control of pleural liquid volume operated by parietal lymphatics. For explanation see text.
PATHOPHYSIOLOGY OF PLEURAL EFFUSION

Pleural effusion is favored by: (1) an increase in systemic capillary pressure and an increase in
permeability of the parietal/visceral pleura, and (2) a strong limitation to draining lymphatic flow. As
described above, point D in Figure 58.5, is a case where lymphatic control cannot match the filtration rate
largely exceeding the maximum lymphatic drainage capacity. In this condition, pleural effusion will ensue
and the increase in pleural fluid volume will purely reflect a new equilibrium between the pressures
acting across compartments. Pleural effusions are classified as exudates when the fluid/serum total
protein ratio (TPR) exceeds 0.5.43–45 However, this distinction may just result from the definition of a cut-
off value for protein concentration.
It appears justified to relate the degree of mesothelial lesion to the pleural fluid absolute concentration
of lactic dehydrogenase43 (indicated as free lactate dehydrogenase [FLDH]). A cut-off for FLDH has been
proposed at 163 to 200 U · L−1 for diagnostic separation between transudates and exudates43–46 and that
would then correspond to σ 0.5 that implies a considerable increase in protein permeability. It is now
of interest to interpret some clinical observations concerning the occurrence of pleural effusion of various
origin. Pleural effusion is more frequent in left heart failure (it is present in 15% of class IV
patients),47,48 and should be regarded as the result of a marked increase in permeability of the visceral
pleura; thus, in this condition pleural cavity and lung extravascular space are no more functionally
independent, as they actually are in the physiologic condition. The critical importance of increased
permeability in causing pleural effusion is recognized.49 The combined action of hypoxia and
inflammatory state can contribute to the increase in permeability of the visceral pleura. Furthermore,
interstitial lung edema, by generating positive interstitial pressure, may favor fluid filtration into the
pleural cavity.
The increase in right atrial pressure and central venous pressure should entrain a corresponding
increase in filtration rate at capillary level from the parietal pleura. However, pleural effusion is rarely
detected even when right atrial pressure exceeds 20 mm Hg48; the interpretation is that the corresponding
increase in filtration rate of the parietal pleura can be compensated by lymphatic drainage.
RECOVERY FROM PLEURAL EFFUSION

Full recovery from pleural effusion is a long process mainly due to the fact that the lymphatic drainage,
although being able to increase flow rate by 20- to 30-fold, might not match the increase in filtration rate.
Recovery ranges from weeks (for postmyocardial infarction and postcoronary artery by-pass) to months
(for tuberculosis and asbestosis).50 A decrease in pleural fluid volume can only occur when the
inflammation brings the filtration/drainage ratio below unity; this occurs when the physiologic low
microvascular permeability is restored. The Starling mechanism could provide, in principle, fluid
reabsorption in the initial phase, although the pressure gradient to sustain it remains quite poor because of
the high compliance of the pleural space. Lymphatics will progressively contribute to liquid drainage at a
later phase when the Starling-dependent absorption is waning on progressively decreasing pleural liquid
pressure.
MECHANICAL COUPLING OF THE CHEST WALL AND LUNG

The subatmospheric pleural liquid pressure ( −10 cm H2O in the supine posture at the level of the right
atrium) operates as a mechanical link between the chest wall and lung; this allows that changes in chest
volume imposed by the action of the respiratory muscles are exactly followed by the lung. Note that the
opposing lung and chest wall recoil pressure at the end-expiratory volume amounts only to approximately
−4 cm H2O (Fig. 58.6), thus is less negative than pleural liquid pressure; this implies that the parietal and
visceral pleurae are actually pushing one against each other. Despite this mechanical disposition, no
friction of reciprocally sliding pleural membranes is encountered. This occurs because pleural
membranes are covered by phospholipids adsorbed and stratified in multiple layers on their surfaces
(Fig. 58.6 right).51 These molecules (Fig. 58.7) have hydrophobic tails carrying negative charges so that
the parietal and visceral pleura are not really touching each other due to reciprocal repulsive forces of
charges of the same sign (negative) carried by phospholipids. In doing so, these molecules provide an
efficient lubrication system allowing easy reciprocal sliding of the pleural membranes by keeping the
coefficient of friction down to a minimal value ( 0.02, as for ice sliding on ice).
FIGURE 58.6 Left: Schematic drawing of lung-chest wall coupling depicting the difference between pleural liquid pressure and
the so called “pleural surface” pressure, that defines the opposite elastic recoil of lung and chest wall. Right: Enlarged drawing
of the pleural space to show in pink the layers of surfactant molecules stratified on the pleurae.
FIGURE 58.7 The lubrication mechanism operated by repulsive forces of charges carried by the hydrophobic tails of
phospholipids covering the pleurae.
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59
Benign Pleural Effusion
Cliff K. C. Choong ■ Siddharth Padmanabhan
PATHOPHYSIOLOGY
In the normal pleural space, there is a dynamic equilibrium between pleural fluid production and pleural
fluid absorption leading to a constant volume of fluid within the pleural space. At any one time, the
average amount of fluid in the pleural space in a healthy patient is approximately 0.3 mL/kg or
approximately 21 mL in a 70-kg patient.1 The fluid provides a thin layer of lubrication between the
visceral pleural surface (lung) and the adjacent parietal pleural surfaces (chest wall, diaphragmatic, and
mediastinal surfaces). Production of pleural fluid is by filtration from the systemic microvasculature
through the parietal pleura into the pleural space. Absorption and drainage of pleural fluid out of the
pleural space is through the parietal and visceral lymphatic channels.2 Pleural effusion occurs when there
is an imbalance in the equilibrium between production and absorption; that is, when there is an excessive
production of fluid, or decreased absorption of fluid, or both pathologies occurring simultaneously.
EPIDEMIOLOGY
Pleural effusion is a very common clinical condition. Pleural effusions affect over 1 million patients
yearly in the United States alone.3 The leading causes are congestive cardiac failure 500,000 patients,
followed by parapneumonic effusion 300,000 patients, and malignancy 200,000. Other causes include
pulmonary embolism (PE) 150,000 patients, viral disease 100,000 patients, postcardiac surgery 50,000
patients, gastrointestinal abdominal pathology 25,000 patients, tuberculosis 2,500 patients, malignant
pleural mesothelioma 2,704, and asbestos exposure–related benign pleural diseases 2,000.
ETIOLOGY
The etiology of pleural effusion is multiple, and includes diverse clinical conditions.3 Pleural effusion is
firstly classified as either benign or malignant. This chapter focuses on benign pleural effusion. The
etiologies of benign pleural effusion are best considered as medical disorders with “systemic”
manifestations versus “local” pleural disorders.
Pleural effusion is a noted manifestation of several systemic medical diseases, which do not
necessarily affect the pleura directly, but have effusions as a secondary consequence of the systemic
disease. A typical example is a patient with congestive cardiac failure where pleural effusion is one of
the systemic clinical manifestations among other features such as peripheral edema and raised jugular
venous pressure (JVP). Common medical conditions with pleural effusion as one of its systemic
manifestations include cardiac failure, renal failure, hepatic failure, and hypoproteinemia, etc. These
patients generally have bilateral pleural effusions.4 The management of these pleural effusions generally
revolves around therapy aimed at treating the underlying primary medical condition, for example, the
routine medical therapy for heart failure. The pleural effusions in these patients seldom require thoracic
intervention as it generally improves with a good response to medical therapy.5 Occasionally, simple
drainage by aspiration or small intercostal chest drain to relieve large effusions is indicated where the
patient is markedly dyspneic due to the large effusion causing compression and collapse of the lung. This
may sometimes be useful as an initial, temporary measure until the medical therapy kicks in and becomes
effective in managing the primary medical condition and control of its systemic issues (e.g., pleural
effusion and peripheral edema in patients with cardiac failure).5
The second category of pleural effusion etiology is those effusions that are a result of local pleural
disorders or diseases. Local pleural disorders include parapneumonic effusions, empyema (infection of
pleural effusion fluid), inflamed parietal pleura, chylothorax, hemothorax, pleural infection (e.g., TB
pleuritis) among many others. The underlying disorder in these patients with “local” effusion relates to
pleural disease (such as inflamed parietal pleura), lung disease (pneumonia with parapneumonic
effusion), or a pleural space problem itself (trapped lung or reduced lung volume resulting in pleural dead
space being filled by effusion fluid).
Inflamed parietal pleura leads to vasodilatation and increased vascular permeability allowing
increased fluid filtration and leakage into the fluid space. At the same time, the inflammatory process can
impair lymphatic absorption thereby decreasing fluid reabsorption. The end result is development of a
pleural effusion, due to increased leakage as well as decreased drainage.2 The histopathologic analysis of
parietal pleural biopsies from video-assisted thoracic surgery (VATS) can reveal acute changes, chronic
inflammatory changes, or both. Sometimes, these patients may have pneumonia complicated by
parapneumonic effusion, while others may have connective tissue disorders such as rheumatoid arthritis
however presenting as unilateral pleural effusion with associated inflamed pleura. Some may have
asbestos-related pleuritis, and there are other patients with idiopathic causes.
The most common clinical presentation is dyspnea. The shortness of breath is due to the pleural effusion
causing compression and collapse of the adjacent lung. The most common part of the lung affected is the
lower lobe due to the fluid being dependent and accumulating at the basal pleural space when the patient
is standing or sitting up, and the posterior pleural space when the patient is lying down. Generally, most
pleural effusion fluid is free flowing and will accumulate at the dependent part of the chest. Some pleural
effusions may be loculated or multiloculated as seen in advanced parapneumonic effusion or empyema.3
Small to moderate pleural effusions will compress the lower lobe lung however large effusions can
compress and cause collapse of the entire lung. Massive pleural effusions are occasionally encountered
and can lead to tension pleural effusion with mediastinal shift and other tension features. The degree of
shortness of breath, apart from being related to the volume of effusion and degree of lung compression and
collapse, is also dependent on the underlying pulmonary reserve of the patient. In patients with poor
pulmonary reserve (e.g., patients with severe emphysema), a small- to moderate-sized effusion can lead
to significant dyspnea. On the other hand, patients who have good pulmonary reserve (nonsmoking, fit,
healthy patients) may have minimal or no symptoms even in the presence of a large pleural effusion. It is
important to realize shortness of breath may also be related to the underlying medical condition such as in
patients with cardiac failure in addition to the mechanical and physiologic effects of the pleural effusion.6
Other symptoms may include cough, chest wall discomfort or pain. Patients will often have clinical
manifestations of the underlying etiology. For example, peripheral edema and raised JVP in patients with
cardiac failure, jaundice and ascites in patients with hepatic failure, productive sputum and fever in
patients with pneumonia complicated by parapneumonic effusion, traumatic chest wall injuries in patients
with hemothorax, etc. Some patients may have no shortness of breath (asymptomatic) and the pleural
effusions are found incidentally. Other patients may have presented with cough or chest wall discomfort
and therefore undergo investigations that lead to the diagnosis of pleural effusion.
Clinical examination will reveal typical examination findings of pleural effusion. The affected
hemithorax will have asymmetrical decreased chest expansion, decreased tactile fremitus, dullness to
percussion, diminished or inaudible breath sounds.6 This is due to the presence of the pleural effusion
occupying the pleural space thereby displacing the lung away from the chest wall and diaphragm. The
pleural effusion has now caused a separation of the visceral pleura and lung away from the parietal pleura
and chest wall. Pleural friction rubs can sometimes be heard. Generally, small effusions less than 300 mL
will not show signs on physical examination. Most pleural effusions will not have a mediastinal shift
away from the effusion-affected side. In massive effusions, mediastinal shift and tension effects can
sometimes occur. It is however, an uncommon occurrence, as most patients would have sought medical
attention prior to arriving at such an extreme physical state. The volume of pleural fluid required to cause
a mediastinal shift and tension effects depends on the intrathoracic volume, the underlying cause, the rate
of fluid production, the patient’s pulmonary and physical reserves, and timing of clinical presentation. A
small thin frail patient with a small intrathoracic space may have mediastinal shift with 1,000 mL of fluid
while a taller or bigger patient with a large chest wall size (large intrathoracic space) may not have
mediastinal shift until the effusion has exceeded 3,000 mL or more.
INVESTIGATIONS
History taking and clinical examination will provide a clear clinical diagnosis in some patients. Patients
with a known history of cardiac failure with clinical findings of congestive cardiac failure and its
associated systemic manifestations have a clear etiology for their pleural effusion. A chest x-ray will
reveal radiologic features of cardiomegaly, pulmonary edema, and pleural effusion. A plasma BNP test
and transthoracic echocardiography will further confirm the diagnosis of cardiac failure. Patients with
renal failure will have clinical features of uremia and blood tests will reveal elevated urea, creatinine,
and a diminished eGFR confirming renal impairment. Patients with hepatic failure may have a history of
liver cirrhosis or previous liver failure. Clinical findings will include jaundice, ascites, peripheral
edema, and other stigmata of liver failure. Liver function tests will reveal markedly deranged results.
Patients with parapneumonic pleural effusion will have symptoms and signs of pneumonia including
cough, yellow or green productive sputum, fever, chest physical examination findings of pneumonia and
pleural effusion.7 The chest x-ray and computed tomography (CT) of the chest will reveal areas of lung
consolidation and pleural effusion. The inflammatory markers including CRP will be elevated. The
sputum culture may provide microbiologic diagnosis and in febrile patients, there may be positive blood
cultures.
The history taking, physical examinations, and investigations (blood and radiologic tests) are important
in confirming or excluding medical illnesses with systemic manifestations causing pleural effusion.3
Patients with medical illnesses such as cardiac failure, renal failure, hepatic failure, hypoproteinemia and
the like require medical management of the underlying condition. When the underlying medical condition
has responded to therapy, the pleural effusions, often bilateral, will improve. For instance, up to 20% of
patients with nephrotic syndrome suffer from pleural effusion due to the complex interaction between
decreased oncotic pressure, increased aldosterone and vasopressin, and increased inflammatory
mediators.8,9 In patients where medical illnesses have been excluded, a thoughtful and logical stepwise
approach to investigations and management is required. These patients with “local” pleural disorders
often present with a unilateral moderate-to-large pleural effusion. These patients may not have clinical
features of cardiac failure, renal failure, or other, more systemic medical illnesses. The blood tests will
have excluded cardiac (BNP), renal (U&Es, eGFR) and hepatic (LFT) dysfunction. Transthoracic
echocardiography is sometimes necessary in excluding a cardiac cause in patients with pleural effusion.
This is useful in patients with a cardiac history and the echocardiography investigation will provide
useful information on biventricular function and pulmonary pressures. In patients with a cardiac history,
an unremarkable echocardiographic finding will suggest the pleural effusion is not cardiac related and is
due to other etiology.
A CT of the chest is very useful in the evaluation of pleural effusion. It allows for an accurate
assessment of the size and location of the pleural effusion and the degree of adjacent lung compression.
Dependent “free flowing” pleural effusions can be seen as opposed to loculated or multiloculated pleural
collections. CT is also a useful radiologic tool for the evaluation of a patient’s airways. Endobronchial
lesions, intrabronchial masses, airway narrowing, or other abnormalities will often require further
bronchoscopic evaluation to determine further management. Intrinsic airway obstruction or narrowing
needs to be differentiated from extrinsic compression of the airway due to a large pleural effusion.
Presence of infective lung changes in the form of lung consolidative changes can be well appreciated on
CT in patients with pneumonia.10 The pleural effusions present in these patients are therefore likely to be
parapneumonic in nature. The lung parenchyma is assessed on the CT chest and allows for detection of
other pulmonary pathology. Pulmonary emphysema, fibrosis, lung mass, cavitation, bronchiectasis, and
other pathology can be appreciated using this modality. These findings are not always detected on CXR as
the CT provides a better resolution and imaging clarity. Cardiomegaly seen on CT can suggest a possible
underlying cardiac disorder and further cardiac investigations including echocardiography may be
warranted. Patients with congestive cardiac failure may have features of increased pulmonary venous
congestion, pulmonary edema, and cardiomegaly seen on CT chest with associated pleural effusions. In
patients where the clinician is suspicious of PE or would like to exclude it, a computed tomography
pulmonary angiography (CTPA) is utilized to confirm or exclude PE. In patients with renal impairment, a
noncontrast CT chest can provide useful intrathoracic evaluation and assessment of the pleural effusion.8
If PE is suspected and investigation is also required in these patients, a ventilation perfusion (VQ)
scan can be additionally utilized so as to avoid intravenous contrast and the risks of worsening the renal
function. The combined information from a noncontrast CT chest and VQ scan allows the clinician to
make appropriate diagnosis and manage patients with renal failure appropriately. Pleural effusions
associated with PE usually occupy less than one-third of the hemithorax and can be bilateral in up to 46%
of cases.11 Dyspnea is usually out of proportion to the size of the effusion.
In patients with pleural effusion, a careful evaluation of the pleura is important. The presence of
pleural thickenings, pleural plaques, pleural nodules, or larger pleural mass can be detected. Benign and
malignant pleural conditions can lead to pleural effusion. Malignant pleural mesothelioma related to
previous asbestos exposure and metastatic pleural malignancy cause malignant pleural effusion. Patients
with malignant mesothelioma may recall a past history of asbestos exposure, may have presence of
calcified pleural plaques seen on CXR or CT, and may have suspicious irregular pleural thickenings or
pleural masses seen on CT on the same side as the unilateral pleural effusion. Patients with metastatic
pleural malignancy may have a past treatment of cancer or a known history of metastatic cancer. The CT
may have an associated spiculated lung mass (primary lung cancer) or multiple lung nodules (metastatic
cancers). There may be associated pleural nodules or irregular pleural thickenings or pleural soft tissue
masses. The pleural fluid cytology may yield malignant cells; however, it is very important to note that
diagnosis on aspiration of potentially malignant pleural fluid has sensitivity and specificity rates varying
between 65% and 90%.12,13 The false negative rate is therefore high. A negative fluid cytology therefore
does not completely exclude a malignant effusion. If there is a high index of suspicion, further
investigation often in the form of thoracic intervention is required in these patients.
Tuberculous pleuritis can also lead to pleural effusion. There may be associated pleural thickenings or
pleural masses on a chest CT. It is an uncommon condition in the western world where there is
widespread access to modern health care and a relevant immunization program for appropriate
individuals (e.g., patients at higher risks of TB contact or contracting TB etc.). TB is however, still an
important disease in third world countries or markedly lower socioeconomic communities.
Approximately 3% to 25% of patients with tuberculosis have TB pleuritis.14
Travel and migration also leads to TB infection and transmissions in modern society. Patients with TB
pleuritis may have had contact with TB patients, may have recently travelled to TB prevalent geographic
locations or might be an immigrant from one of several countries with known incidence of TB. Patients
with TB pleuritis will often have the clinical stigmata and investigation results of TB infection (malaise,
weight loss, fever, relevant travel history, positive skin and blood tests, and CT features).15
In the appropriate clinical setting, aspiration of the pleural effusion may provide useful information. In
patients with unilateral effusion, where it is uncertain whether the etiology of the effusion is related to
primary “systemic” medical illness (e.g., heart or renal failure) or a local pleural disorder (e.g.,
empyema), the pleural effusion is aspirated and sent for analysis to differentiate between transudative
versus exudative fluid. Transudative fluid is generally produced by medical conditions with systemic
manifestations such cardiac failure, renal failure, or other medical conditions and further management is
aimed at treating the underlying primary medical illness. Exudative fluid is often related to inflamed
pleura, infective or malignant process. Light’s criteria is the most commonly accepted method of
categorizing these effusions.16 Most of these patients present with fever, productive cough, chest pain,
leukocytosis, and increased inflammatory markers.17 Further investigation and management are aimed at
treating the relevant condition and dealing with the pleural effusion complication. Apart from analysis for
the transudative versus exudative of the fluid, the aspirated sample is also sent for microbiologic analysis
and including acid-fast bacilli (AFB), TB, and fungal analysis. Samples are also sent for cytology
analysis looking for malignancy.
MANAGEMENT
The management of medical illnesses with systemic manifestations is primarily medical therapy such as
the appropriate medical treatment for cardiac failure, renal failure, or hepatic failure, etc.3 These patients
usually have bilateral pleural effusions. Generally, the pleural effusion does not require drainage as it
will improve and resolve following response to medical therapy. Occasionally, if the pleural effusion is
large and the patient is experiencing significant respiratory compromise due to marked compression and
collapse of the lung, drainage of the effusion by needle aspiration or placement of a small drain can be
useful in relieving the lung compression and improving lung ventilation. These patients usually have
bilateral pleural effusions and the side with the larger effusion is chosen for drainage. If the effusions
appear equal on both sides, the right side may be chosen for drainage, as the right pleural cavity and lung
are larger than the left side and also the cardiac structures are closer to the left chest wall being at higher
risk to injury.18
Prior to the drainage of the pleural effusion, it is important to have CT or ultrasound imaging to
confirm the effusion. CT is the best radiologic investigation for effusion providing important information
of the size and location of the effusion, and additional information on the pulmonary, airway, pleural,
cardiac, and chest wall structures. CXR alone is not sufficient in confirming pleural effusion as
sometimes lung consolidation or other intrathoracic pathology can mimic pleural effusion. Drainage of a
pleural effusion can be performed under local anesthesia with or without sedation. At the time of
drainage, it is useful to have ultrasound to localize the effusion and guide the entry point of drainage.
Ultrasound provides information on thickness of the chest wall, depth of effusion and direction for
drainage, distance to diaphragm, lung, and mediastinal structures. Ultrasound can be utilized immediately
before drainage or may be utilized as a real time during the procedure. Drainage can be performed by
aspiration or placement of a small chest drain (size 14 F or smaller drain). The chest drain can provide a
longer duration of drainage and potentially a better and more complete drainage of the effusion.19 It can
also be connected to a drainage system which allows for negative suction which may potentially aid in the
re-expansion of the compressed collapsed lung.
“Local” pleural disorders (parapneumonic effusions, empyema, inflamed parietal pleura, chylothorax,
hemothorax, pleural infection) usually cause a unilateral pleural effusion. Management is aimed at
drainage of the effusion and correction of its consequences (compressed displaced collapsed lung,
trapped lung, loculated or multiloculated collections) as well as any associated underlying etiology, such
as treatment of the pneumonia causing the effusion. Small to moderate local pleural effusions can be
initially drained by aspiration or placement of a small chest drain. The fluid must be sent for analysis. In
patients with benign pleural effusion, no further pleural intervention is required if there is full re-
expansion of the lung and no recurrent pleural effusion.20 Keyhole chest surgery in the form of VATS is
required in patients with recurrent pleural effusion, trapped lung (i.e., lack of satisfactory lung re-
expansion following effusion drainage), loculated or multiloculated pleural collections, or in patients
where parietal pleural tissue biopsies are required for diagnosis to guide subsequent management.
The benefits of VATS are both diagnostic and therapeutic. They are fourfold and include (1) complete
drainage of the pleural effusion (therapeutic), (2) parietal pleural biopsies (diagnostic), (3) re-expansion
of lung and decortication if necessary (therapeutic), and (4) pleurodesis (therapeutic). VATS are
associated with a high safety record and high success rate. In patients undergoing VATS, some may
require a thoracotomy when extensive pleural adhesions or severely trapped lung are encountered during
the VATS. Once a recurrent pleural effusion has occurred following an earlier drainage, patients should
be considered for VATS for definitive treatment rather than recurrent drainage by aspiration or chest drain
as recurrent drainage can be associated with increased potential complications such as bleeding,
pneumothorax, infection, pain, and trapped lung.
Patients with a very large unilateral pleural effusion, following a thorough discussion with the patient
on treatment options (drainage alone vs. VATS), can be offered a VATS for definitive treatment as large
effusions have a higher recurrence rate and malignancy must be excluded in such patients.
Patients with a tension pleural effusion must have the pleural effusion drained immediately to relieve
the tension effects. Subsequent investigation and management can then take place once the patient is
stabilized.
CONCLUSIONS
Pleural effusion is a common clinical disorder and can be either benign or malignant in nature. Benign
pleural effusion can be secondary to a medical illness such as cardiac failure, renal failure, or hepatic
failure, with “systemic” manifestations, of which pleural effusion is one. Pleural effusion can also be due
to “local” pleural pathology such as a parapneumonic effusion, empyema, pleuritic, chylothorax, or
hemothorax. Clinical examinations combined with appropriate blood and radiologic investigations are
important in the workup of patients with pleural effusion. The management of benign pleural effusion
depends on the cause of the effusion and its effects. A logical approach with appropriate stepwise
treatment plans usually results in a successful management, regardless of the type of effusion present.
REFERENCES
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2. Kuzdzal J, Asamura H, Detterbeck F, et al., (eds.). ESTS Textbook of Thoracic Surgery. Vol 1. European Society of Thoracic
Surgery. Medycyna Praktyczna (2014), Liskzi:186.
3. Light RW. Pleural Diseases. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
4. Edwards JE, Race GA, Scheifley CH. Hydrothorax in congestive heart failure. Am J Med 1957;22:83–89.
5. Quinn T, Alam N, Aminazad A, et al. Decision making and algorithm for the management of pleural effusions. Thorac Surg Clin
2013;23:11–16.
6. Yalcin NG, Choong CK, Eizenberg N. Anatomy and pathophysiology of the pleura and pleural space. Thorac Surg Clin 2013;23:1–10.
7. Varkey B, Rose H, Kutty K, et al. Empyema thoracis during a 10 year period. Arch Internal Med 1981;141(13):1771–1776.
8. Light RW. Update: management of the difficult to diagnose pleural effusion. Clin Pulm Med 2003;10:8.
9. Light R. Physiology of pleural fluid production and benign pleural effusion. In: Shields TW, LoCicero J, Ponn RB, et al., eds. General
Thoracic Surgery. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:806–817.
10. Porcel JM, Pardina M, Bielsa S, et al. Derivation and validation of a CT scan scoring system for discriminating malignant from benign
pleural effusions. Chest 2015;147(2):513–519.
11. Coche EE, Müller NL, Kim KI, et al. Acute pulmonary embolism: ancillary findings at spiral CT. Radiology 1998;207:753–758.
12. Johnston WW. The malignant pleural effusion. Cancer 1985;56(4):905–909.
13. Hsu C. Cytologic detection of malignancy in pleural effusion: a review of 5,255 samples from 3,811 patients. Diagn Cytopathol
1987;3(1):8–12.
14. Light RW. Update on tuberculous pleural effusion. Respirology 2000;15:451–458.
15. Agha MA, El-Habashy MM, Helwa MA, et al. Role of thoracentesis in the management of tuberculous pleural effusion. Egypt J Chest
Dis Tuberc 2015;64:97–102.
16. Light RW. Clinical practice. Pleural effusion. N Engl J Med 2002;346(25):1971–1977.
17. Chu MW, Dewar LR, Burgess JJ, et al. Empyema thoracis: lack of awareness results in a prolonged clinical course. Can J Surg
2001;44:284–284.
18. Shields TW. General Thoracic Surgery. 6th ed. Vol 1. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
19. Cooke DT, David EA. Large-bore and small-bore chest tubes: types, function, and placement. Thorac Surg Clin 2013;23:17–24. v.
20. Thomas R, Lee YCG. Causes and management of common benign pleural effusions. Thorac Clin Surg 2013;23:25–42.
60
Parapneumonic Effusion, Empyema, and
Fibrothorax
David Waller ■ Sara Tenconi
INTRODUCTION
The overall incidence of pleural infection is increasing worldwide, both in adult and pediatric
population.1 Pleural infection is a frequent clinical problem with an approximate annual incidence of up
to 80,000 cases in the United Kingdom and the United States.2 In a multicenter randomized study set in the
United Kingdom,3 the observed mortality rate from pleural infection was reported to be up to 22%. Since
conservative treatment seems to fail in approximately one-third of patients who develop parapneumonic
empyema, surgery is required to achieve debridement of the pleural space, infection control, and lung re-
expansion.4 The median length of stay of these patients ranges from 12 to 15 days and the overall hospital
costs due to empyema per annum in the United Kingdom and the United States combined is around 320
million US dollars.5
Primary empyema occurs as a complication of intrinsic infection of the lung (Fig. 60.1).
Secondary empyema results from extrinsic sources, that is, invasive procedure to the chest or traumatic
damage. Patients at most risk include the young, the elderly, and those with intrinsic lung disease, mainly
chronic obstructive pulmonary disease (COPD). In addition, diabetes mellitus, immunosuppression
related to chronic corticosteroid use, gastroesophageal reflux, alcohol misuse, intravenous drug abuse, or
poor oral hygiene should be taken into consideration as possible contributing factors. Although risk
factors for pleural space infections mirror those for low respiratory tract infections, micro-organisms
responsible for complicated effusions often differ from those isolated from sputum cultures. In fact, the
difference in oxygen level and pH between the lung and the pleural space can explain why anaerobic and
Streptococcus spp. were traditionally known to be the most common pathogens in pleural infections.
Etiologic agents causing infection of the pleural space have changed since the introduction of antibiotics
and spread of pneumococcal vaccine; they also depend on geographical distribution and clinical setting.
Before the era of antibiotics, Streptococcus pneumoniae was the most frequent organism, but today
Staphylococcus aureus is the most common bacterium leading to empyema.6 Community-acquired
infections are usually caused by gram-positive organisms; the majority are streptococcal, among which
Streptococcus milleri and Streptococcus pneumoniae are the most common. Anaerobic cultures are also
positive in more compromised patients. Hospital-acquired infections are mostly due to Staphylococcus
spp. or gram-negative bacteria. Unfortunately, up to 70% of all Staphylococcus aureus nosocomial
infections in the United Kingdom are methicillin-resistant (MRSA),7 which is also a cause of raising
concern associated with the spread of LRTI and empyema.
FIGURE 60.1 Pathogenesis of parapneumonic effusions.
In the absence of therapeutic intervention, pleural infections represent a progressive process able to
turn a self-resolving parapneumonic pleural effusion into a “complicated” multiloculated brinopurulent
collection associated with clinical and biochemical features of sepsis. An untreated pleural infection can
lead to fibrosis of the lung, contraction of the hemithorax (fibrothorax), necrosis, spontaneous drainage of
pus through the chest wall (empyema necessitatis) or into the bronchial tree (bronchopleural fistula),
pericarditis, mediastinitis, osteomyelitis, and metastatic spread of the infection (e.g., cerebral abscess).
The clinical presentation of pleural empyema recalls and often accompanies symptoms of pneumonia or
sepsis, including cough, fever, shortness of breath, and chest pain. The gold standard to diagnose an
infectious effusion is pleural fluid aspiration: the main differential diagnosis of an exudative effusion is a
malignant effusion to be confirmed either by cytology or histology.
Decision making with regard to treatment is complex and not well standardized (Fig. 60.2). The choice
of the best treatment option depends on the etiology of empyema (primary vs. secondary), the stage of
disease, and the general conditions of the patient. Up to 20% of patients finally require surgery for both
proper evacuation of the infection and re-expansion of the so-called “trapped lung.”7 This is a condition
with a significant impact on patients’ quality of life, causing ventilatory restrictive syndrome with
impairment of the lung perfusion and finally dyspnea. Thoracotomy was the mainstay of surgery until
increasing experience in video-assisted thoracoscopic surgery (VATS) worldwide allowed considering
thoracoscopic debridement and decortication as a valid, less invasive alternative with wider indications.8
FIGURE 60.2 Decision making in Empyema Treatment.
PNEUMONIA AND PARAPNEUMONIC EFFUSION

Community-acquired pneumonia (CAP) is a parenchymal acute condition occurring in a person living in a
community, which has little contact with the health-care system. CAP is an important public health
problem and cause of death9 with an annual incidence of between 207 and 233 per 100,000 population in
the United Kingdom. Up to 20% of affected patients require hospitalization and present a risk of death
within the 30 days from diagnosis which is 46 times higher than the normal population.10
Hospital-acquired pneumonia (HAP) is an infection contracted within the hospital at least 48 hours
after admission. HAP is the second most common nosocomial infection and accounts for 15% to 20% of
the total of infections contracted in hospitals every year. It is the most common cause of infective death
among inpatients and is the primary cause of death in intensive care units. Ventilator-associated
pneumonia (VAP) is a sub-type of HAP which occurs in people who are receiving mechanical ventilation.
VAP is defined as pneumonia diagnosed at least 48 hours after intubation. The mortality rate of VAP has
been reported to be as high as 50% and therefore it is recommended to search for and possibly prevent all
risk factors, including endotracheal and nasogastric tubes; tracheostomy; reintubation; enteral nutrition;
corticosteroid administration; gastric pH-modifying agents; supine positioning; prior antibiotic usage;
poor infection control practice; and contaminated respiratory equipment, medications, or water.11
Health-care-associated pneumonia (HCAP) is an infection that occurs in patients within the
community, but who have frequent contact with the health-care environment. The etiology and prognosis
of nursing home pneumonia appear to be different from CAP, with studies reporting a worse prognosis
and higher incidence of multidrug-resistant organisms as causative agents.12
A parapneumonic effusion (PPE) is a pleural effusion that occurs in patient with concurrent LRTI or
pneumonia; it is normally an exudate and creates a new and different infected space that accompanies and
often worsens the ongoing parenchymal disease.
The development of an empyema in association with pneumonia is a dynamic three-step process in
which failure of treatment can escalate to the subsequent stage (Fig. 60.3).
The “triphasic” nature of the disease was first described in 1962 by the American Thoracic Society:
the whole process involving the development of an empyema takes about 4 to 6 weeks, involving
progressive changes in the pleural cavity, appearance of the effusion, and need for treatment.
STAGE I: EXUDATIVE PHASE

The distinctive feature of this phase is a PPE characterized by the presence of clear, free-floating fluid in
the pleural space. The pathophysiology normally involves an altered balance between pleural fluid
production and reabsorption due to inflammatory mechanisms, increased vascular and pleural
permeability, and neutrophil chemotaxis. Most of these changes are due to increased production of
proinflammatory cytokines (IL-8, TNFα). The pleural fluid is normally sterile and the pH and glucose
level are normal.
STAGE II: FIBRINOPURULENT PHASE

In this phase the effusion is complicated with loculations. A fibrinopurulent empyema represents a
complex pathologic process within the pleural space with variable presentation: the collection can be
uniloculated or multiloculated involving most or the whole pleural cavity. Septa are commonly present
within the collection due to increasing fibrin deposit, activation of the coagulation cascade, and
downregulation of the local fibrinolytic pathway. Micro-organisms are often present due to favorable
chemical alteration of the pleural fluid (pH <7.2, LDH >1,000 U/L) and therefore glucose levels tend to
decrease (<60 md/dL). Bacterial invasion accelerates the immune response and promotes further
migration of neutrophils that, by causing microorganism death, increase CO2 and lactate levels thus
instigating a self-maintaining pathologic mechanism.
FIGURE 60.3 Three-step dynamic process of empyema.
STAGE III: CHRONIC ORGANIZING PHASE

An organizing empyema results from a thick, rigid pleural cortex. Pleural fluid is turned into frank pus by
fibroblast chemotaxis. The pleural thickening encases the lung causing decreased ventilation and a
perfusion–ventilation mismatch (restrictive syndrome) which can lead to a fibrothorax with severe
dyspnea. This is the final stage of an untreated PPE. Bacteria are normally present but this stage of the
disease is nonreversible and functional impairment remains even after eradication of the infection.
The basic principles for the treatment of empyema are: (1) systemic treatment of the underlying cause
of infection; (2) removal of infected fluid and debridement of pleural space; (3) full re-expansion of the
lung; (4) supportive measures to improve patient’s condition and prevent complication including
physiotherapy, nutritional support, and thromboembolic prophylaxis.
TREATMENT
Antibiotic selection is problematic because bacteriology of pleural infection differs significantly from
pneumonia and ongoing treatment may no longer be effective when empyema develops. In addition, up to
40% of patients with suspected complicated effusion have no pathogens isolated with standard cultures.
In a multicenter study of 454 patients from 52 centers in the United Kingdom treated for empyema,
microbiology has been analyzed and results have been correlated with survival.13 The majority of them
had community-acquired postpneumonic empyema (87%), 6% had hospital-acquired infections, and in all
the other cases secondary empyema was diagnosed. Gram-negative bacteria, Staphylococcus aureus, and
mixed aerobic bacteria were all associated with significantly higher mortality rate at 1 year (44% to
46%); furthermore, hospital-acquired infections are reported to have higher mortality rates if compared
with community-acquired infections in patients with Staphylococcus spp. (p = 0.04) and mixed aerobic
bacteria (p = 0.05) (Fig. 60.4). Appropriate antibiotic treatment based on the results from Gram stains
and culture is the key. In the absence of positive cultures, empirical antibiotics should be chosen to cover
likely pathogenic organisms. Penicillin in combination with beta-lactamase inhibitors or clindamycin
(especially in case of penicillin allergy) is the first choice, the latter either alone or in combination with
ciprofloxacin or cephalosporin. Chloramphenicol, carbapenems, third-generation cephalosporins, and
broad-spectrum antipseudomonal penicillins, such as piperacillin, are alternative agents. In all cases,
antibiotic regimens should be adjusted according to the subsequent culture results. Due to a significant
increase in MRSA infection causing HAP and empyema, empirical antibiotics covering resistant strains
should initially include cover for MRSA until microbiologic results are available.
ROLE OF IMAGING
Imaging is useful to confirm the suspicion of a pleural effusion as a complication of pneumonia when
clinical symptoms and signs indicate the presence of fluid in the chest. Furthermore, in combining the
different techniques available we can also obtain information on the effectiveness of treatments, the need
for more invasive procedures, and finally guide drainage.14
FIGURE 60.4 Microbiology of pneumonia.
Standard chest radiography can explore the entire pleural space, is easily available, can be portable
with low radiation exposure for the patient, and can estimate the amount of fluid and indicate the need for
thoracentesis. According to the American College of Chest Physicians, a large effusion that occupies
more than 50% of the hemithorax, the presence of loculations, and signs of pleural thickening all indicate
poor prognosis from medical management and therefore require surgical drainage.15
To evaluate loculation or pleural thickening further investigations are needed: chest ultrasonography
(US) allow the characterization of septation better than computed tomography (CT) scan (Fig. 60.5), is
more sensitive than decubitus radiography (can detect a minimum of 5 mL of fluid), and portable US
examination can be particularly useful in supine critically ill patients.16 In fact, the utility of portable
sonography has been well investigated in Emergency Departments and Intensive Care Units: Tu and
colleagues17 demonstrated that, in critically ill patients, the ultrasonographic features of effusion can
indicate whether thoracentesis is mandatory or could be safely deferred. US suggests the nature or the
stage of the effusion. Yang et al.18 described four different patterns of imaging observable in a
sonographic evaluation: homogeneous anechoic (mainly transudative effusions), complex nonseptated
with internal echogenic foci, complex septated (fibrinopurulent phase empyema), and homogeneously
echogenic (presence of blood or frank pus) (Fig. 60.6).
Intravenous contrast CT scan allows visualization of pleural membranes (Fig. 60.7) and, with
scanning of the adjacent chest, including chest wall, rib, spine, diaphragm, and sub-phrenic space, is ideal
in determining the extent of pleural infection and the presence of underlying parenchymal abnormities,
including differential diagnosis with malignancies.19 Nevertheless, septations within an infected effusion
are less readily imaged as compared with US.20
FIGURE 60.5 US anechoic pleural effusion with septae.
Difficulties of obtaining high quality, movement-free images in severely ill patients and the superior
resolution of CT scan have limited the application of MRI to detect spinal or rib involvement in very
advanced sepsis, while PET scan does not currently have a role in empyema workup.
A key role of imaging is nowadays played in guiding percutaneous Seldinger drainage of pleural
effusions: thoracentesis guided by US decreases the rate of complications, including pneumothorax, and
improves the amount of fluid collected.21
The predictive value of imaging in determining the need for surgery in patients suspected to have poor
prognosis is debatable. Expert opinion advises that the presence of septations within the effusion on CT
or US scan images is a marker of possible failure of chest drain, while nonloculated anechoic collections
are more likely to resolve with image-guided drainage,22 but this will need evaluation in blinded
prospective studies. In fact, the use of CT scan as a guide to indicate the need for VATS debridement has
demonstrated that up to 30% of patients were understaged by preoperative imaging and required
intraoperative conversion to thoracotomy23 to achieve decortication. The role of US has also been
evaluated in monitoring the effectiveness of drainage or replacement of nonworking drains: real-time
follow-up with this harmless, easy-to-access procedure allow better visualization even in critical
patients, improving the outcome of conservative management.22
FIGURE 60.6 US echogenic pleural effusion with lung atelectasis.

FIGURE 60.7 CT visualization of pleural cortex.
STAGE I
Symptoms in the exudative phase of a PPE may vary according to the cause of chest infection: aerobic
infections generally present as septic exacerbations including temperature, leukocytosis, purulent sputum
production; pleural effusions associated with anaerobic or atypical LRTI have a more silent presentation.
Dullness of percussion and an attenuated murmur especially in basal areas of the chest can raise the
suspicion of a pleural effusion. Posteroanterior and lateral chest radiographs usually confirm the presence
of a pleural effusion but, if doubt exists, ultrasound or CT scans are useful in detecting small effusions and
differentiate pleural fluid from pleural thickening.
At this stage bacteria might not be present and analysis of fluid only reveals high levels of proteins and
neutrophils. Infection of this fluid or failure of reabsorption will lead to the following stage of empyema.
Therefore, the challenges in the treatment of stage I PPE are early diagnosis and treatment of infected
effusions, focusing on optimization of pleural sampling and/or chest drain positioning. In early empyema,
especially while patients are receiving antibiotic treatment for underlying lung infections, Gram stain and
culture can fail to show the presence of pathogens. To establish when chest drainage is needed in these
patients, the American College of Chest Physicians (ACCP) in 2000 has suggested a scoring system based
on prognostic factors for poor outcome15: in case of small to moderate effusion, no evidence of pleural
infection, and pH greater than 7.2, drainage might be considered only if repeated thoracentesis has to be
performed. In the case of large or loculated effusion, positive cultures, or pH lower than 7.2, the risk of
poor outcome has to be considered moderate and therefore there is a recommendation for pleural drain
and possibly fibrinolytics or surgical debridement (Fig. 60.8). Macroscopic pus in the pleural space is a
high-risk condition that should be managed aggressively with fibrinolysis and surgery. The British
Thoracic Society (BTS) guidelines,7,24 based on literature review, also recommend chest drainage in the
presence of organisms identified on Gram stain or culture, poor clinical resolution during antibiotic
course, large effusions, pH lower than 7.2, and purulent effusion.
FIGURE 60.8 ACCP criteria for risk stratification.
Size of Drain
The need for chest tube drainage is controversial and depends not only on the amount of fluid but also on
the characteristic of the effusion: Heffner,25 in a meta-analysis, demonstrated that increased acidity
detected in a pleural aspirate (pH level below 7.2) correlates with infection with an accuracy of 92%,
thus suggesting the need for tube thoracostomy. The use of antibiotics in stage I disease is part of routine
treatment of suspected infection and data supporting the use of systemic therapy only in this stage report a
success rate of about 82%. Nevertheless, the BTS evidence-based guidelines issued in 2010 recommend
the use of chest drainage in case of positive Gram stain or cultures, pleural fluid pH lower than 7.2, poor
clinical progress during antibiotic course, or large effusions. A systematic review has shown that tube
thoracostomy as primary treatment of empyema had a failure rate of 40%, which may be stage dependent.
During the exudative phase adequate drainage can be achieved by chest drain insertion while in later
stages ultrasound- or CT-guided insertion may be more effective because of loculations. When drainage is
performed, the tube diameter can vary greatly among series: the clinical outcome of patients treated with
different sizes of chest drain has not been addressed in randomized trials. According to BTS guidelines a
small catheter (10F to 14F) can be adequate to successfully drain most of pleural infections: the
procedure should be image guided whenever possible and regular saline flushing is recommended in
smaller sizes to avoid blockage.7 A larger drain (>28F) has traditionally been used for draining thick pus;
however, there is no consensus on the optimal size, due to the lack of randomized trials. In fact, a review
of chest drain sizes used in patients included in the randomized Multicenter Intrapleural Sepsis Trial
(MIST 1) revealed almost no difference in the primary outcome (death or need for surgery) related to the
type of drain.26 Furthermore, in patient with purulent effusion, there was a borderline statistically
significant difference in the rate of failure, favoring the use of small-bore drains (<15F). It has to be
noticed that the criteria to choose small- or large-bore drains are not standardized but analysis of
demography, bacteriology, and prognostic factors shows acceptable homogeneity among groups. Pain is
also significantly reduced in patients receiving small chest tubes, especially during insertion and while
the drain was in place. The frequency of chest tube blockage or displacement is reported together with the
rate of tube repositioning: despite no significant difference, small chest drains are 2.4-fold more likely to
require replacement.27
STAGE II
The fibrinopurulent stage of empyema can present in many different ways that range from free-floating
turbid fluid with proven bacterial colonization to frank pus organized in multiloculations. Treatment can
vary accordingly from chest drain alone to an aggressive surgical approach. Chest drainage alone has
been reported to have high chance of failure,28,29 while the association of intracavitary fibrinolysis or
VATS debridement is still controversial. The American College of Chest Physicians in 2000 reviewed
stage II empyema patients treated with (1) no drain, (2) thoracentesis, (3) chest tube, (4) fibrinolytics, (5)
VATS, and (6) thoracotomy: they reported a failure rate of 40% for chest drain alone, 15% for chest drain
in association with fibrinolytics, 10% for thoracotomy, and none for VATS debridement. Risk factors for
unsuccessful chest drainage in stage II were also identified as large, loculated, or frankly purulent
effusions with positive cultures.15
Intrapleural Fibrinolytics
Fibrinolytic enzymes are instilled into the pleural cavity to break the septa of the empyema cavity and
degrade the necrotic debris, thereby facilitating drainage of multiloculated effusions. In 2008, a Cochrane
review analyzed the usefulness of fibrinolytics versus saline flushing in 702 randomized patients. Six of
the studies considered actually demonstrated that pleural fibrinolysis decreased the need for surgery;
nevertheless other studies reported no impact of the treatment on overall mortality rates.30 The role and
the efficacy of conservative treatment with fibrinolytics have been evaluated in multicenter randomized
studies with controversial outcomes. Although the large first MIST 1 showed no benefit of the use of
intrapleural streptokinase, the strong clinical and observational support for the use of fibrinolytic agents
inspired the MIST 2, using recombinant tissue plasminogen activator (TPA) and DNase. The results show
that combining TPA and DNase improves the drainage of empyema in patients with infected pleural
effusions and reduces the length of hospital stay and the need for surgery. The timing for intracavitary
treatments is also debatable, but one could advocate early fibrinolysis in stage I parapneumonic empyema
to balance the impairment generated by the inflammatory process and prevent the formation of septa.31
The impact of repeated intracavitary treatments and, potentially, multiple drainages on the length of stay
and the overall cost has yet to be conclusively analyzed.32 However, Wait and colleagues33 in 1997
published a small randomized trial comparing the two approaches: VATS had 91% success rate in treating
stage II empyema, while fibrinolysis only worked in 41% of patients; the remainder had to be
subsequently and successfully treated by VATS. The mean hospital stay in the VATS group was also
shorter (8.7 vs. 12.8 days) with obvious cost saving. These suggested benefits for early VATS have yet to
be replicated in larger trials.
STAGE III
Stage III empyema typically occurs 4 to 6 weeks from the development of a pleural effusion and is
characterized by a rigid cortex encasing the lung, the chest wall, and the diaphragm. The progressive
thickening of the pleura involving all pleural surfaces define a condition named “fibrothorax.” The
narrowing of the intercostal spaces and the secondary atelectasis produce a unilateral loss of volume of
the chest culminating in a restrictive ventilatory syndrome with ventilation–perfusion mismatch and finally
dyspnea.34 The diaphragm can also be involved with limited movements thus decreasing the overall lung
capacity. In addition to this, the recent (and often unresolved) underlying parenchymal infection can
change the consistency of the lung, which is significantly more fragile and therefore limits surgical
manipulation because of increased risk of bleeding, air leak, and bacteremia. Nevertheless, at this stage
chest drain and antibiotics can remove fluid and control infection, but respiratory impairment requires
surgical removal of the peel to restore physiology. Identification of the transition from the purely
fibrinopurulent stage into the formation of an organized pleural cortex may not be easily achieved
preoperatively. Imaging techniques including thoracic ultrasound and CT may not accurately identify the
thickness of the visceral cortex as there will inevitably be a layer of exudate over any cortical rind. The
actual chronicity of the pleural sepsis may not therefore become apparent until VATS debridement has
been performed. The surgeon must then assess whether full lung re-expansion can be achieved by VATS
decortication or whether an open procedure is necessary.
VATS Versus Open Decortication

VATS and open thoracotomy (OT) have been compared in term of effectiveness in treating infected
pleural space and postoperative complications. Lardinois and colleagues35 reviewed the role for VATS in
328 patients with stages II and III empyema: VATS approach was successful in patients with
fibrinopurulent effusion, with a conversion rate of 44% in unexpected stage III disease. VATS approach is
therefore recommended in patients who are promptly referred for surgery after failure of conservative
treatments (less than 2 weeks since admission) and when gram-negative organisms are not involved. In all
other cases open decortication (OD) should be preferred, even with intraoperative conversion if pleural
cortex is identified. The need for early referral in order to achieve successful VATS debridement has been
emphasized before by Waller et al.36 in a retrospective study reporting a conversion rate of up to 59% in
patients with longer preoperative hospital stay (23.9 days vs. 16.6 days, p = 0.04) which had a significant
impact on surgical outcome. The main reason for conversion was failure to obtain satisfactory VATS
decortication with parenchymal re-expansion in more advanced stages. Most recently, Tong et al.37
presented data on 420 patients undergoing VATS (n = 326) or OD (n = 94) for the treatment of benign
pleural disease including empyema, complex pleural effusions, and retained hemothorax. The percentage
of patients with empyema (stage III) or prior surgical management was significantly higher in OD group
(p = 0.007) if compared with patients undergoing thoracoscopic procedures. The conversion rate was
11.4% in a very experienced surgical team, with a reported overall percentage of initial VATS approach
up to 90% in dedicated thoracic surgeons (but less than 44% in mixed-practice cardiothoracic surgeons)
thus confirming that VATS is becoming more effective as operator experience increases. Reasons for
conversion are not indicated; however, the authors state that OD may become necessary whenever
adequate decortication cannot be accomplished thoracoscopically. VATS decortication in stage III
empyema is feasible but requires progression through a learning curve (Fig. 60.9).38 Most of these studies
confirm a superior outcome of VATS versus thoracotomy in terms of length of stay, chest tube duration,
postoperative complications, pain, and mortality; nevertheless, the patient population is somehow
differently distributed between groups, with higher incidence of advanced stage empyema in patient
requiring upfront thoracotomy or intraoperative conversion. In addition, it has to be observed that the term
“decortication” is used inaccurately in many reports of VATS, when the procedure actually described is a
“debridement” (Fig. 60.10).
FIGURE 60.9 Successful one-stage VATS debridement and decortication.
Decortication Versus Empyemectomy

Once the decision has been made to proceed to thoracotomy the surgeon may directly enter the empyema
cavity, complete the debridement, and then separately remove the parietal and visceral cortices (Figs.
60.11 and 60.12). Alternatively, an attempt can be made to excise the chronic empyema cavity in toto
(Fig. 60.13). This is commenced by entering the extrapleural plane on the parietal surface until the
superior extent of the cavity is identified. Then, by blunt dissection, the plane between the visceral pleura
and cortex must be entered and followed inferiorly to the diaphragm. Undoubtedly, empyemectomy is
more technically challenging but does prevent the unwanted exposure of the potentially infected cavity.
Thoracostomy
In the more frail patient who may not tolerate a thoracotomy and either decortication or empyemectomy,
the objective of surgery should be merely debridement and drainage of the infected cavity. This can be
achieved by a small rib resection, the creation of a thoracostomy, and VATS debridement via the stoma.
This procedure can also be achieved in the spontaneously ventilating patient.39
The Timing of Surgery in Stage III

Decortication is associated with perioperative morbidity including transient bacteremia, hypotension, and
persistent air leak. There is evidence that the need for decortication may be less than traditionally
assumed.40 The need for decortication may be determined by the ability of the underlying lung to remodel
the empyema cavity and re-expand naturally after debridement of the infected space. The features likely to
determine the efficacy of natural remodeling include the duration of the disease process and the extent of
the host inflammatory response. It may be advisable to adopt an initial minimally invasive strategy aimed
at debridement of the infected space to shift the balance toward natural remodeling of the empyema cavity.
More aggressive OD is probably best a “dish served cold.” Delaying a reconstructive surgical
remodeling of the chest wall is likely to be less morbid once the resuscitative debridement and antibiotic
therapy has dampened down the infective process (Fig. 60.14). It is also likely to be technically more
satisfactory when the cortex is more developed and the underlying pneumonic lung is resolving.
Inappropriate expedition of OD in the presence of a persistent pneumonic process can result in a
worsening of the septic phenomenon and failure to re-expand the lung. Further drainage procedure may
then be required (Fig. 60.15). It is important to consider that the treatment does not end with the
decortication. Postoperative physiotherapy is imperative to maintain re-expansion of the collapsed and
consolidated parenchyma.
EFFECTS OF DECORTICATION ON LUNG FUNCTION AND CHEST WALL

REMODELING
The effects of decortication on chronic empyema-induced restrictive syndrome have been analyzed in
small retrospective series (23 to 104 patients) with variable surgical approach and follow-up duration (3
to 58 months postoperatively). Pulmonary function tests have increased significantly after OD in most
treated patients41 with an effect on chest wall remodeling (enlargement of intercostal spaces) assessed
with diameter measurements on CT scan.42 Yang et al.43 demonstrated, with CT densitometry, an increase
in volumes in both operated and nonoperated lung in patients affected by tuberculous chronic empyema
due to an overall improvement of the chest wall elasticity.
FIGURE 60.10 Operative technique: VATS debridement/decortication.
When comparing the surgical approach to decortication, VATS seems to have a better impact on the
personal perception of dyspnea assessed with the Medical Research Council (MRC) questionnaire44
together with reduced postoperative morbidity and mortality45; nevertheless, Chan et al.46 found no
difference between time to return to work and perception of exercise capacity in patients treated with
VATS versus thoracotomy in comparable series.
Twenty-six patients with multiloculated pleural effusion, pleural enhancement, mediastinal shift,
elevation of the diaphragm, and narrowing of the intercostal spaces were prospectively evaluated in 35
weeks to assess changes in perfusion scintigraphy, blood gas values, and spirometry.47 More than 70% of
patients had impaired VC and FEV1 values (less than 70% of predicted) preoperatively, all patients
showed severe reduced perfusion of the affected side on scintigraphy, and blood gas parameters were
abnormal in 88% of patients undergoing surgery for chronic empyema. Postoperatively all parameters
significantly improved, although 11 patients still had abnormal arterial blood gas values at 6 months
follow-up.
FIGURE 60.11 The thickened parietal peel is incised and the pleural cavity evacuated of fluid and debris.
All studies demonstrated a significant improvement in lung volumes and function after decortication
for stage III empyema, irrespective of the surgical approach. A proper and more extensive decortication
seems to balance the impairment of a thoracotomy in patients treated with an open procedure. In fact,
when correctly reported, patients undergoing VATS procedures presented with earlier stage empyema and
received debridement rather than decortication.45 The uniformity of results confirms that the natural
healing processes associated with less invasive procedures can achieve good functional repair of the
chest cavity as well as the parenchyma.
FIGURE 60.12 Unlike parietal decortication, the plane of visceral decortication lies between the visceral pleura and the fibrous
peel. The plane of dissection is initiated with a blunt spatula-type instrument. The peel is firmly grasped and gentle traction
applied. Blunt dissection is executed with Kittner dissectors or gauze-covered fingers.
CONCLUSIONS
Modern management of the parapneumonic phenomenon should center on “prevention rather than cure.”
But earlier, minimally invasive measures should be encouraged. Early image-guided drainage of PPE,
possibly with the addition of fibrinolytics, may affect resolution at an early stage. Close monitoring and
early VATS debridement if there is unsatisfactory resolution in sepsis may prevent progression into the
chronic phase. Even in more long-standing cases, do not bypass the merits of VATS assessment since
improvement can be obtained with experience without resorting to thoracotomy. The development of a
chronic pleural cortex or a fibrothorax should be rarely seen in modern practice except in extreme
neglect. The surgeon should facilitate a swing in the balance between the infective process and the natural
healing mechanisms and may be needed to redress a physiologic deficit at a late stage. Inappropriate
overinvasive measures based on radiologic parameters alone should be avoided.
FIGURE 60.13 Blunt dissection of the parietal peel occurs in the plane between the endothoracic fascia and the parietal pleura.
FIGURE 60.14 Successful VATS debridement (A), relief of sepsis (B), delayed decortication to relieve restriction (C).
FIGURE 60.15 Early thoracotomy decortication with failure of lung re-expansion and recurrence.
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21. Diacon AH, Brutsche MH, Soler M, et al. Accuracy of pleural puncture sites: a prospective comparison of clinical examination with
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23. Potaris K, Mihos P, Gakidis I, et al. Videothoracoscopic and open surgical management of thoracic empyema. Surg Infect (Larchmt)
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61
Postsurgical Empyema
Lisa M. Brown ■ Eric Vallières
INTRODUCTION
The reported incidence of empyema after VATS or open lobectomy is 0.4% to 1.5%.1–3 The incidence
after pneumonectomy is greater and ranges from 2.0% to 7.5%.4–6 In a large series of 328 consecutive
extrapleural pneumonectomies, the incidence of empyema was 2.4%.7 Though these numbers are
relatively low, empyemas complicating pulmonary procedures, operations, or penetrating trauma account
for 30% to 40% of all cases of empyema, second only to those complicating pneumonias, or primary
infections of the mediastinum, chest wall, or subphrenic space.8
An important distinction in the approach to the patient with a perioperative empyema is whether there
is an associated bronchopleural fistula (BPF). This is especially true after pneumonectomy. Empyemas
after lobectomy are often a result of a prolonged peripheral air leak in the setting of a persistent pleural
space. On the contrary, more than 75% of empyemas after pneumonectomy occur as a result of a stump
BPF.9,10 In one study of BPF after pneumonectomy for nonsmall cell lung cancer (NSCLC), empyema
patients with a BPF had a much higher incidence of respiratory and cardiac complications, 61.5% versus
11.4% in those without, and mortality, 30.8% versus 3.9% in those without.4 The presence of a BPF is an
independent predictor of mortality11 and the most frequent cause of death is pneumonia in the contralateral
lung. BPFs complicating lung resections are considered early if they occur within 30 days of surgery,
which usually carries a higher mortality rate. In a series of 684 patients who underwent pneumonectomy
for NSCLC, the overall incidence of BPF was just under 5%, nearly evenly split between early and late
occurrences. The reported mortality rates associated with early BPF are 11.6% to 18% and 0% to 7.1.%
with late BPF.12,13
This chapter reviews the preoperative, intraoperative, and postoperative risk factors associated with
empyema and BPF after lobectomy and pneumonectomy. Given the higher incidence of these
complications after pneumonectomy and more devastating consequences, the majority of the thoracic
surgical literature focuses on postpneumonectomy empyema, especially BPF associated. Prevention of
this complication is of the utmost importance; some preoperative risk factors are modifiable while others
are not. Lastly, detection, treatment, and outcomes of postresection empyema and BPF will be discussed.
PREOPERATIVE RISK FACTORS

Age
In general, age is an independent predictor of morbidity and mortality in both medical and surgical
patients. In one report, age ≥70 years was considered a risk factor for BPF after pneumonectomy.12 In
another, age ≥60 years predicted the occurrence of early BPFs.13
Diabetes
Diabetes causes a microangiopathy that alters vascular beds throughout the body, including the bronchial
circulation at the stump and that may impair healing after resection. Patients with insulin-dependent
diabetes mellitus undergoing lung resection for NSCLC are 2.7 times more likely to experience a
postoperative complication than those without.14 Moreover, diabetes is an independent predictor of
postpneumonectomy BPF.12
Benign Lung Disease

The risk of empyema and BPF are greater after pneumonectomy for benign disease (primarily infectious)
as opposed to malignant disease.6 Most of the literature is based on studies of completion
pneumonectomy, as primary pneumonectomy for benign disease is not common.6,15–17 The odds of a major
perioperative complication, including empyema and BPF, are 2.8 times greater in those with benign
disease compared to those with lung cancer.18 The most common complication after pneumonectomy for
resistant TB and other mycobacterial infections is BPF, occurring in 20% to 22.5%.19,20 The largest series
of pneumonectomies comparing benign versus malignant indications reported that the morbidity and
mortality rates were 53%/2.5% for benign and 38.9%/0.2% for malignant.21 However, it is important to
examine factors beyond indication for resection that may contribute to poor outcomes in patients with
benign lung disease. In that series, 37.4% of the benign pneumonectomies were completion compared to
7.5% of malignant. Moreover, 37.1% of all pneumonectomies for benign disease were done as urgent or
emergent procedures, which is a risk factor for complications. Only 1.6% of the operations in the
malignant group were nonelective procedures.21
A major technical challenge in thoracic infectious disease is the associated dense adhesions in the
pleural cavity. This is oftentimes compounded by surgical scarring from prior lung resection.6,20,22
Moreover, these adhesions are usually highly vascularized leading to the potential for significant blood
loss.22,23 Extrapleural dissection may be favored to minimize contamination of the pleural cavity.
According to experts in this field, residual space after lobectomy or segmentectomy is generally not an
issue since the resected lung parenchyma is significantly consolidated and collapsed.20 If not previously
divided, it is advisable to spare the latissimus dorsi as it may be useful as a space filler or to cover the
bronchial stump.20
There are other important technical considerations when undertaking lung resection for infectious
disease. Preoperative diagnostic and toilet bronchoscopy should be performed. In addition, one may
consider a toilet bronchoscopy post resection, prior to extubation, and as needed during recovery. Prior to
chest closure, thorough irrigation of the pleural space including pulsed lavage followed by prolonged tube
thoracostomy drainage until the pleural space is proven sterile is recommended.15 Planned repeated
betadine packing as described by Schneiter and colleagues24 (see below) may also be considered,
particularly if there was significant spillage and contamination during resection.
Induction Chemotherapy
It is unclear whether induction chemotherapy increases the risk of postoperative empyema and BPF. In a
large series from MD Anderson, the incidence of empyema and BPF was zero in those who received
induction chemotherapy followed by surgery (lobectomy or greater lung resection), and 1.2% in those
undergoing surgery alone.25 In two randomized trials comparing induction chemotherapy plus surgery
versus surgery alone, the incidence of BPF was 2% and 1.3% versus 1% and 0%, respectively.26,27
However, in a large series of patients undergoing pneumonectomy (n = 684), induction therapy, either
chemotherapy or radiation therapy was the strongest risk factor for BPF.12
Induction Radiation Therapy

Multiple factors may contribute to the risk of BPF and associated empyema after induction radiation
therapy. First, radiation therapy induces ischemia of the bronchial mucosa.28,29 However, the effect is
variable and unpredictable and it is unclear which patients are more susceptible to the ischemic effects of
radiation therapy than others.29 Interestingly, the bronchial mucosal blood flow recovers within 8 to 10
days after induction radiation therapy followed by surgery.29 Early after radiation therapy, edema and
inhibition of capillary proliferation lead to ischemia, but later on, fibrosis of small vessels is the main
cause of ischemia.28 Second, surgical resection is often times coupled with radical lymphadenectomy that
may further contribute to ischemia from the associated bronchial vessel disruption.
INTRAOPERATIVE RISK FACTORS

Prophylactic Antibiotics
The use of preoperative prophylactic antibiotics is focused primarily on reducing the rate of surgical site
infections. However, it remains controversial whether prophylactic antibiotics are indicated to prevent
perioperative pneumonias and subsequent empyemas. A randomized controlled trial from Spain
comparing cefazolin with placebo found that patients in the cefazolin group had a significantly lower rate
of surgical site infection, 1.5% versus 14%. Also, there was a lower incidence of empyema (7% versus
14%) and pneumonia (4% versus 9%) in the cefazolin group, a clinically important difference that did not
reach statistical significance.30 One group from France decreased the incidence of postoperative
pneumonia 40% by changing the prophylactic antibiotic to an agent that was active against not only
bacteria involved in surgical site infections but also bacterial colonizers of the airways.31
Right Pneumonectomy
Most series have demonstrated that the incidence of BPF after right pneumonectomy is greater than after
left4,5,13,32–38; others have not.12,39–41 In one of the largest series of pneumonectomies (n = 713, right
49.2% and left 50.8%) from the Mayo Clinic, right pneumonectomy was a risk factor for both empyema
and BPF in univariate analyses, but when compared alongside other risk factors was not an independent
predictor of either.5 In another large series (n = 267), right pneumonectomy was an independent predictor
of BPF in addition to COPD, ppoFEV1, bronchial stump length, coverage of bronchial stump, and
mechanical ventilation.4 Darling and colleagues reported a 13.2% incidence of BPF after right
pneumonectomy and 5% after left, and 10.3% incidence of empyema after right pneumonectomy and 5.9%
after left. Moreover, the mortality of a right BPF was higher than left, 44% versus 33%.33
There are several potential explanations for this greater risk after right pneumonectomy. First, the right
pneumonectomy stump is less protected than the left, the latter retracts in the mediastinum after division.
Second, the right stump has a poorer blood supply as it is supplied by only one bronchial artery as
opposed to two on the left. This blood supply is likely further compromised by the often more extensive
right-sided mediastinal lymph node dissection. Lastly, the right main bronchial orifice is larger and
therefore the stump closure may be under greater tension.32
Technique of Bronchial Stump Closure

Over 50 years ago, Sweet42 published an article detailing the principles of bronchial closure including:
(1) minimize trauma to the end of the bronchus, (2) preserve the blood supply all the way to the end of the
cut bronchus, (3) carefully approximate the cut edges of the bronchus, and (4) provide adequate tissue
reinforcement of the bronchial closure. With the use of modern day staplers, there is no difference in the
rate of BPF as long as these principles are adhered to.43 The rates of BPF after stapled and sutured
bronchial closure for lobectomies and pneumonectomies, are both 1.0% and 5.0%.36,44,45 Pitfalls of the
stapling technique need to be recognized: The short bronchus and thickened or calcified bronchial walls
are two scenarios where a hand-sewn technique may be more appropriate.
Beyond the stapled versus sutured debate, modifications of the stump closure have been made in an
attempt to ensure the safest closure possible. A long bronchial stump leads to accumulation of mucus and
secretions and this increases the risk of BPF.4 For this reason, some surgeons have attempted to modify
the closure in ways that eliminate the stump entirely. One of the earliest successful reports of this concept
included 1,100 lung resections with only one BPF (6 months postoperative), published by Jack in 1965.46
There were 450 pneumonectomies, many of which were indicated for tuberculosis and bronchiectasis.
The closure involved dividing the main bronchus 1 cm distal to the carina and trimming the bronchus to
produce a short and mobile bronchial flap, which is sutured to the opposite bronchial wall flush with the
proximal carina thereby avoiding tension and leaving no stump behind.46 Similarly, another group
decreased the incidence of BPF after right pneumonectomy from 11.6% to 3.9% by switching from
bronchial closures (stapled or sutured) to carinal closures; they hypothesized that the improvement may be
due to decreased tension on the suture line and better blood supply.32 Furthermore, BPF is more likely to
occur at either edge (medial or lateral) of the bronchial stump.36,45 The use of a pledgeted horizontal
mattress suture on either end of the stump proximal to the staple line (as well as a row of interrupted
sutures 2 to 3 mm apart proximal to the staple line) has been reported to reduce the incidence of BPF to
1.0%.45
Buttressing the Bronchial Stump

The efficacy of buttressing the bronchial stump with autologous tissue flaps to reduce the rate of BPF after
pneumonectomy remains controversial. A meta-analysis of modern studies from 1999 to 2012 did not
attempt to compare patients undergoing bronchial stump coverage with those who did not due to the
nonrandomized assignment to treatment groups and an inherent bias toward bronchial stump coverage in
patients thought to be at high risk for BPF.47 In the pooled series of patients receiving coverage, the
incidence of BPF was 6.3%, and in patients not receiving coverage, the incidence was 4.0%.47 In the only
randomized controlled trial of bronchial stump coverage with an intercostal muscle flap in 68 diabetic
patients undergoing pneumonectomy, there was an 8.8% incidence of BPF in patients without bronchial
stump coverage and there were no BPFs in patients with coverage.48 Moreover, the incidence of empyema
in those without bronchial stump coverage was 7.4% and there were no empyemas in patients with
coverage.48 Lastly, a porcine study of left pneumonectomy with vascular denuding of the bronchial stump
followed by standard closure the investigators performed muscle flap coverage in half and compared
them at 2 weeks to those without.49 Not surprisingly, coverage of the bronchial stump with a muscle flap
restored the blood supply to the denuded bronchial stump, but interestingly, in those without coverage,
direct contact of the bronchial stump to adjacent mediastinal tissue allowed proper restoration of the
blood supply even without additional coverage.49
The common practice of bronchial stump coverage impairs our ability to scientifically determine
whether it truly does reduce the incidence of BPF. However, most surgeons would agree that it seems
prudent to cover the bronchial stump especially after right pneumonectomy as the risks of some of the
coverage techniques is extremely low and the benefits potentially large. There are many options for
coverage including: muscle flaps (latissimus dorsi, serratus anterior, intercostal),50 parietal pleura,51
pericardium,52 pericardial fat,53 pericardiophrenic graft,53 azygos vein51 on the right side, and
omentum.54,55 In one of the earliest animal studies of the use of an omental pedicle flap, the omentum
rapidly revascularized the bronchial autografts.56 This angiogenic property of omentum is unique and
makes it well suited for bronchial stump coverage. However, one disadvantage is that the most common
method of harvest involves a laparotomy,54 although others have described harvesting this flap from the
chest using a transdiaphragmatic approach.57
The best surgical approach remains to use every means possible to prevent postoperative
complications. If there is a large residual space at the time of lobectomy, particularly when associated
with a parenchymal air leak, maneuvers to minimize the space will expedite closure of the air leak and
thereby reduce the risk of empyema. These maneuvers include: creation of a pleural tent (after upper
lobectomy)58 and elevating the diaphragm by either injecting the phrenic nerve with local anesthetic59,60
or creating a pneumoperitoneum (after lower lobectomy).61
POSTOPERATIVE RISK FACTOR

Mechanical Ventilation
The incidence of BPF in patients requiring mechanical ventilation after pneumonectomy is 19%.35,37 The
need for postoperative mechanical ventilation is an independent risk factor for early BPF.4 It is important
to differentiate cause from effect though. The incidence of BPF may be higher in ventilated patients
because those patients are critically ill. Mechanical ventilation may be a surrogate for critical illness.
DIAGNOSIS
It is paramount to have a high index of suspicion for empyema and BPF in the postoperative period for
any patient whose course is off trajectory; this is especially true after pneumonectomy as the related signs
and symptoms can be nonspecific and the consequences severe. The presence of fever, leukocytosis,
pleural effusion on imaging, and purulent fluid on thoracentesis or thoracostomy are classic findings of
empyema. If purulent fluid is present, the diagnosis is confirmed. If not, the pleural fluid should be sent
for gram stain and culture to confirm the diagnosis. Regardless, the pleural fluid should be analyzed in the
microbiology laboratory in order to accurately tailor the antibiotic regimen.
After lobectomy, a continued air leak is usually due to parenchymal injury, but for large and/or
persistent air leaks it is important to rule out a stump leak. Alternatively, pneumothorax on chest
radiograph should raise suspicion for BPF and lead to further investigation to determine whether one is
present (Fig. 61.1). The classic presentation for postpneumonectomy BPF is a decreasing air fluid level
on sequential chest radiographs (Fig. 61.2) coupled with a productive cough and possibly pneumonia of
the contralateral lung. However, those who are quite remote from the time of operation tend to present
with a more insidious clinical picture including malaise, low-grade fever, anorexia, or unexplained
weight loss. All patients suspected of having a BPF should undergo computed tomography of the chest and
flexible bronchoscopy to make a definitive diagnosis. During bronchoscopy it is helpful to instill a small
volume of saline to see if bubbles form at the bronchial stump closure. If the clinical suspicion persists
but the endoscopic and radiology findings are not diagnostic, a thoracoscopic evaluation of the
pneumonectomy cavity may allow evaluation of the hilar area on positive pressure ventilation while the
area is submerged under water (stump leak test).
TREATMENT
Postlobectomy Empyema With and Without BPF
Empyema after lobectomy is most often associated with a prolonged parenchymal air leak in the setting of
a residual space. The principles of management include adequate drainage, elimination of the space,
antibiotic therapy, and time. In situations where conservative management fails, the options are either for
tissue transfer into the persistent cavity (muscle flaps, thoracoplasty, omentopexy) or creation of an open
window thoracostomy, depending on the overall health of the patient, his or her comorbidities, nutritional
state and on the local expertise of the treating team, the location of the persistent space, and the
availability of transferable vascularized flaps. Open window thoracostomy involves removing a portion
of two to three ribs and undermining the subcutaneous tissues circumferentially so that they can be sutured
down to the endothoracic fascia (marsupialization).60,62 Closure of the window can be attempted at a later
date when the pleural cavity is rid of all gross exudates and granulation tissue begins to form. Serial
computed tomography scans of the chest are important to monitor treatment progress and document
resolution of the infection and obliteration of the space. In contrast to treatment of chronic parapneumonic
empyema, decortication of the entrapped lung is rarely indicated because the remaining lobes do not have
the compliance to fill the residual space.63
There are very few published series on management and outcomes of empyema after partial lung
resections (less than pneumonectomy). Massera and colleagues63 analyzed a small cohort of patients (n =
19) who developed empyema after bilobectomy, lobectomy, or segmentectomy; five of these patients had
an associated BPF. Initial management for the 14 patients with empyema only was tube thoracostomy and
only two of these patients were successfully treated with chest tube alone. The other five patients with
empyema and BPF underwent immediate reoperation including closure of the bronchial stump and open
window thoracostomy; all of these patients had resolution with this approach.63 The success rate of open
window thoracostomy for patients undergoing partial lung resection is 64% to 90%.63–65
FIGURE 61.1 A 54-year-old man with remote history of mediastinal radiation therapy for a right upper lobar small cell lung
cancer with vena cava obstruction presented with a new 5-cm right upper lobe squamous cell lung cancer. He underwent right
upper lobectomy with intercostal muscle flap coverage of the bronchial stump (pT2aN0M0R0) and was discharged home on
postoperative day 4: Chest radiograph at discharge (A). He returned to clinic 2 weeks after discharge with a pneumothorax:
upright chest radiograph (B); lateral chest radiograph (C); chest computed tomography (CT) (D). He was readmitted to the
hospital and bronchoscopy revealed a 2-mm defect within an otherwise healthy bronchial stump (E). A CT-guided pigtail catheter
and antibiotic therapy led to successful resolution of the BPF: chest radiograph (F) and chest CT (G).
Although completion bilobectomy is an option for patients who have undergone right upper or lower
lobectomy and completion pneumonectomy is an option for patients who have undergone left upper or
lower lobectomy, these options should be a last resort. Extending the resection can be associated with
increased mortality and may also prevent necessary lung resections in the future.
Postpneumonectomy Empyema With and Without BPF
Once empyema with or without BPF is suspected in a patient who has undergone pneumonectomy,
aggressive treatment measures should be enacted to protect the remaining lung, given the high mortality
associated with these complications. First, the patient should be upright at least 45 degrees at all times
and if able, should lie in decubitus position with the remaining lung side up to minimize spillage into the
contralateral side. A chest tube should be placed in the pneumonectomy space at or above the level of the
original thoracotomy and while doing the procedure care should be taken to maintain the patient in a
position that avoids spillage of empyema into the remaining lung. The chest tube should be placed to
water seal as suction may cause mediastinal shift especially in patients that have had recent resection.
Antibiotics should be started.
As soon as the pneumonectomy space has been drained and the patient stabilized, bronchoscopy should
be done to assess the quality and length of the stump. If it is unclear whether a BPF is present, a VATS
approach can be done at the time of bronchoscopy to check for bubbles under water during sustained
breathhold with positive pressure.
If there is no BPF, the pleural cavity can be debrided and drains positioned to optimize evacuation of
the pleural space. In certain scenarios where the cavity is well drained without gross contamination, one
may opt to fill the space with antibiotic solution.66
If a BPF is identified, an aggressive operative tactic should be undertaken for both early and late BPF
in patients who are stable and whose contralateral lung is not consolidated or contaminated.37 Factors to
consider when reoperating under these circumstances are whether this is early or late stump dehiscence,
size of the defect, length of the bronchus, quality of bronchial wall and its blood supply, presence or
absence of malignancy at the resection margin, whether or not the mediastinum is fixed, and the extent of
contamination of the space.
FIGURE 61.2 A 70-year-old woman underwent left pneumonectomy with intercostal flap coverage of the bronchial stump for
spindle cell carcinoma (pT2bN1M0R0) and was discharged home on postoperative day 6: upright (A) and lateral chest
radiographs (B) at discharge. She returned for scheduled follow-up 9 days after discharge and was found to have a decreased
air fluid level on upright (C) and lateral chest radiographs (D) and a chest CT was done (E). She was taken back to the OR and
bronchoscopy demonstrated no obvious BPF. A videoscope was inserted into the left chest and when the bronchial stump was
tested under saline a small BPF was identified. At redo left thoracotomy the bronchial stump was covered with a thymic flap; the
left hemithorax was packed with betadine-soaked kerlix. She underwent one subsequent chest exploration followed by definitive
closure: chest radiograph after closure of BPF (F).
Early dehiscence may lend itself to revision and repair. Late dehiscence is technically more
challenging to revise. If the stump is long, it should be shortened. If not, the defect should be sutured
closed with absorbable, pledgeted, monofilament sutures and buttressed with a tissue flap. If direct suture
repair is not possible, a tissue flap alone can be parachuted down onto the BPF, a strategy often favored
when re-exploring for late dehiscence as dissection to revise the stump may be risky. Once the repair is
completed, it should be checked using another saline test. If the pleural cavity is clean the chest can be
closed at that time. However, if there is any concern regarding contamination, drainage or open window
thoracostomy should be done. The use of an irrigation system to manage this clinical scenario has also
been described.67
If the patient is unable to withstand major reoperative surgery, after initial chest tube drainage, one
should have a low threshold to create an open window thoracostomy. The ideal open window
thoracostomy should be anterior enough and large enough to facilitate dressing changes. In addition, the
window should be created over the most dependent portion of the pleural cavity, but avoid making the
window too low as the diaphragm rises after pneumonectomy and can block the window. Sometimes with
adequate drainage and resolution of the ongoing infection and inflammation, small fistulae may close
spontaneously. An aggressive strategy that includes early open window thoracostomy soon after empyema
is detected may lead to faster resolution.68
In a frail patient, where a surgical attempt at closing the BPF is not an option, a novel approach to
control and close a large symptomatic BPF after creation of open window thoracostomy is the deployment
of an Amplatzer septal occluder.69 This Nitinol device was designed for closure of atrial septal defects.
The distal disc is deployed beyond the end of the fistulous opening and then pulled against it while the
proximal disc is deployed within the main bronchus. Early success rates of over 90% have been
reported.69
These approaches to the management of postpneumonectomy empyema and BPF have been around for
over 50 years. The original description of the two-stage procedure for managing postpneumonectomy
empyema was by Clagett and Geraci in 1963.62 The first stage consisted of creation of an open window
thoracostomy and the second stage was instillation of antibiotic solution into the pleural space and
definitive chest closure. The method was successful but oftentimes resulted in significant morbidity and
long hospitalizations. Pairolero and colleagues70 modified the procedure by closing the bronchial stump
and reinforcing it with a muscle flap during the first stage. In the initial report, 28 patients with
postpneumonectomy BPF underwent the first stage of the Clagett procedure with the muscle flap
transposition and once the pleural cavity was clean and BPF healed, the pleural cavity was filled with
antibiotic solution and the chest closed definitively; the success rate was 86%.70 Others have, however,
reported lower success rates.71
Schneiter and colleagues24,72 from Zurich have introduced a modification of these traditional treatment
paradigms with the aim of decreasing time to permanent chest closure. In the initial report, 20 patients
with empyema after pneumonectomy underwent redo thoracotomy, radical debridement of the pleural
space, and closure of BPF if present. At the end of the operation, the pleural cavity was packed with
povidone–iodine-soaked sponges and a chest tube set to 5 cm H2O suction was placed. If the surgeons
were unable to repair the BPF directly, they parachuted an omental pedicle onto the stump and the packing
provided counter pressure during coughing or Valsalva until the flap became adherent. Every 48 hours, the
patient was taken back to the operating room for debridement, irrigation, and repacking until the pleural
cavity was macroscopically clean. Once this was achieved, the pleural space was filled with antibiotic
solution and the chest was closed. The mean number of operations per patient was 3.5, in all patients the
chest was definitively closed within 8 days, and the success rate was 100% with zero mortality in the first
3 months. The advantages to this approach are many: (1) no painful dressing changes at the bedside for the
patient, (2) the temporary packing and chest closure prevent the mediastinum from shifting and do not
impair respiratory mechanics, and (3) the patient can avoid a prolonged outpatient course that involves
daily wound care and the psychologic effects associated with the burden of having an open window
thoracostomy.
As an extension to this accelerated treatment for postpneumonectomy empyema, several case reports
and small series describing the use of negative-pressure wound therapy (NPWT) as an adjunct to surgical
therapy have emerged.73–77 Key benefits to the use of NPWT include increased blood flow and
granulation tissue formation as well as decreased wound edema and tissue bacterial counts.78–79 As
previously described, the first step in management of postresection empyema is open surgical
debridement and repair of BPF including muscle flap coverage. Even in the absence of BPF, muscle flap
coverage of the bronchial stump in the setting of severe infection and inflammation can protect the stump
and enhance wound healing.75 Once the muscle flap(s) are in position, sterile gauze is loosely applied to
cover all mediastinal structures. This is an important step as it prevents adherence of the NPWT sponge to
vital structures.74–76 The subcutaneous tissues and skin are loosely approximated to prevent loss of
domain as the ultimate goal is permanent chest closure. A pressure of -50 to -75 mm Hg is applied and
this is initiated while the patient is under general anesthesia to monitor for hemodynamic instability due to
mediastinal shift. The patient is brought to the OR every 2 to 3 days for debridement and NPWT dressing
change under general anesthesia. It is important to saturate the NPWT sponge and sterile gauze with saline
prior to removal. Most surgeons send tissue cultures at each debridement, but successful closure prior to
achieving negative cultures is possible as long as there is sufficient granulation tissue.74–75 After an
average number of NPWT days of 19 to 26 and 5 to 6 dressing changes, the success rate as measured by
definitive chest closure is approximately 90%.74–75
FIGURE 61.3 A: A full median sternotomy incision has been made and the anterior pericardium is open exposing the great
vessels (SVC, superior vena cava; PA, pulmonary artery). B: A wide incision of the posterior pericardium exposes both bronchi
and the lower trachea. (Reprinted from Ginsberg RJ, Saborio DV. Management of the recalcitrant postpneumonectomy
bronchopleural fistula: The transsternal transpericardial approach. Semin Thorac Cardiovasc Surg 2001;13:20–26. Copyright ©
For main bronchial stump dehiscence, particularly late occurrences, left-sided and associated with
long stumps, the transternal transpericardial approach to the carina (Fig. 61.3) is ideal. It provides an
untouched operative field that is not infected nor inflamed. This exposure is preferable when a redo
thoracotomy is contraindicated or may be too treacherous, or after multiple failed attempts at BPF
closure.80 The earliest description of this approach was by Padhi and colleagues81 via anterior
thoracotomy and division of several costal cartilages allowing access to the pericardium and the carina,
and the first to introduce this exposure using a transternal approach was by Abbruzzini and colleagues.82
After median sternotomy, the superior vena cava (SVC) is retracted to the right and the aorta to the left
followed by incision of the posterior pericardium. Care is taken to preserve as much vascularized thymus
tissue as possible at this stage in case it is needed to buttress the stump. The carina is identified and the
stump can either be amputated and closed with interrupted sutures or stapled. If possible, the distal stump
is completely excised, but if unable to do so, after separating it from the sutured or stapled revised
closure, the mucosa in the detached bronchus should be cauterized to minimize mucus secretions. Lastly,
the new stump is covered with a vascularized tissue flap.80 This approach may be difficult after left
pneumonectomy if significant mediastinal shift has already occurred.80 In Ginsberg’s experience with 25
cases, there was only one recurrence.80 One group even favored this approach over redo thoracotomy in
patients who had undergone prior coronary artery bypass grafting.83
Small BPF defects (<5 mm) with an indolent course can sometimes be managed using endoscopic
therapy including fibrin glue84,85 and silver nitrate.86,87 Mixed outcomes occur with fibrin glue that may be
attributed to details of the technique. One group used rigid bronchoscopy to de-epithelialize the fistula
with a brush or laser followed by fibrin sealant only for BPF <3 mm or spongy calf bone molded to match
the shape of the BPF and then sprayed with fibrin for BPF >3 mm; BPF closed in only 36%.84 When used
exclusively for fistulae <5 mm, aerosolized fibrin can have a 100% success rate after an average of 2.75
applications.85 The success rate of BPF closure with silver nitrate is 82% to 100%.86,87 This technique
entails continuous aspiration of the mucus to ensure a dry mucosal surface. Silver nitrate (1%) on an
applicator is then passed through the working channel of the bronchoscope and rubbed against the
mucosal borders of the fistula until blanching and edema occurs.87 Serial bronchoscopies are required,
but one group reported success after an average of 2.5 procedures.87
Empyema and BPF after extrapleural pneumonectomy with prosthetic patches in place can be
catastrophic.7 There are very few large volume mesothelioma centers thereby limiting the evidence
available to make treatment recommendations. In the early postoperative period with empyema alone, a
VATS approach can be used to drain, debride, and irrigate the chest cavity without patch removal.7 If
VATS is unsuccessful, the patient presents late, or there is an associated BPF, an open window
thoracostomy is created. Early in the postoperative period, the diaphragmatic and pericardial patches
should be left in place until at least 2 weeks after surgery to allow the mediastinum to fix. Once this time
frame has passed, the patches should be removed.7 Using the serial betadine packing protocol as
described by the Zurich group above, one may be able to sterilize the extrapleural pneumonectomy cavity
without needing to remove the diaphragmantic and pericardial patches, particularly in the absence of a
BPF.
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44. Asamura H, Kondo H, Tsuchiya R. Management of the bronchial stump in pulmonary resections: a review of 533 consecutive recent
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46. Jack GD. Bronchial closure. Thorax 1965;20:8–13.
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62
Tuberculous and Fungal Infections of the
Pleura
Gilbert Massard ■ Anne Olland ■ Nicola Santelmo ■ Pierre-Emmanuel Falcoz
Mycobacterial and fungal infections of the pleural space, especially tuberculosis (TB), are a leading
cause of worldwide morbidity and mortality, and TB is also on the rise in the western world.1 Pleural TB
is considered a form of extrapulmonary TB and is most often a secondary phenomenon of primary
infection. It requires pleural biopsy for diagnostic purposes. Approximately 5% of patients with TB will
develop a pleural effusion. Empyema caused by reactivation of TB rarely occurs in patients who have
received adequate medical treatment, but it represents a real challenge to the thoracic surgeon. In a series
of 380 empyema patients reported by Weissberg and Refaely,2 no case of fungal infection was mentioned.
Fungal empyema typically occurs in residual pleural spaces after previous resection or radiation therapy
but also following sequelae of pulmonary TB; these cases are particularly difficult, marked by chronic
illness and consumption. With the resurgence of HIV infection and the interaction with Mycobacterium
tuberculosis, these cases are often complex and hard to treat.
There are no general guidelines for the treatment of any empyema caused by tuberculous and/or fungal
empyema. However, a first step is to eliminate gross contamination, either with tube thoracostomy or
open-window thoracostomy. Usually, drainage of the pleural space combined to medical treatment of the
M. tuberculosis or of the fungal infection is sufficient, and there is no need for complete decortication or
thoracostomy. Nevertheless, the latter must be achieved in case of further relapse of the infection. The
procedure of choice should be an open pleural window, either an Eloesser flap or a modification of this
technique. A decortication should not be done in a patient who has active TB.3 Open-window
thoracostomy may be a lifesaving procedure in acutely ill patients; permanent loss of function must be
expected when the lung remains trapped below an armor of fibrotic scar tissue. The common feature of
chronic mycobacterial and fungal infections is that often the underlying lung cannot be reexpanded to fill
the pleural space, either because of previous partial resection or diffuse fibrosis. In the latter case, the
goal of treatment may be achieved either with thoracoplasty or various pedicled flaps developed from the
chest wall muscles as well as use of the greater omentum.
PLEURAL TUBERCULOSIS
Tuberculous infection of the pleura is a disease of the past. However, there is an upswing in incidence in
third world and developing countries because it is often associated with HIV infection.4 Most of the
principles of treatment that were defined during the 1950s and 1960s are still valuable today.5 Langston
and colleagues6 stated that TB of the pleura may manifest itself clinically and pathologically in a variety
of ways. It varies from a thin idiopathic effusion that may yield acid-fast bacilli with difficulty, if at all, to
a thick purulent exudate that has positive results on direct smears. In the literature, all combinations of
extent as well as characteristics of pleural involvement or bacteriologic content are observed, as noted by
Langston and associates.6 Nevertheless, for clarification, we subdivide the subsequent discussion into
four groups defined by the history of disease: (1) During primary TB, pleural effusions appear in
approximately 5% (4% United States, 23% Spain) of patients.7,8 The fluid is usually serofibrinous, and
this condition should be called tuberculous pleuritis; (2) During reactivation of TB, pleural infection
turns into a true empyema, characterized by an opaque, purulent effusion. Such tuberculous empyemas may
be either pure or mixed. In the case of bronchopleural fistula, other microorganisms can infect the pleura
together with M. tuberculosis; (3) The particular setting of late complications secondary to collapse
therapy for TB, which is infrequently encountered today, presents varying complex problems.
Therapeutic pneumothorax can end up with an exsudate blowing the pleural or extrapleural space. The
latter may present as sterile exsudate, aspecific empyema, or tuberculous empyema. Plombage therapy can
result in infectious complications or migration of plombage material; (4) The incidence of TB pleural
effusions in HIV/AIDS has been reported from 15% to 90%, with the effusion being more common in
patients with higher CD4 cell counts.9,10 Especially in HIV patients, differential diagnosis of a pleural
effusion also includes pleural Kaposi’s disease or lymphoma.11
TUBERCULOUS PLEURITIS
According to Jereb and colleagues,12 the pleural space is the second most common site of extrapulmonary
TB, the first being the lymphatic system. Pleural infection, as noted by Weir and Thornton,13 is supposed
to originate from subpleural pulmonary lesions, with the rupture of these subpleural caseous foci in the
lung into the pleural space. The clinical presentation is well known.5 General signs include low-grade
fever, weakness, weight loss, and night sweats. Respiratory symptoms are nonproductive cough, pleuritic
chest pain, and dyspnea correlated with the extent of effusion, which arises from increased capillary
permeability and the impairment of lymphatic clearance of proteins and fluid from the pleural space. TB
pleuritis often manifests itself with an acute onset of pain and nonproductive cough.12 Chest radiography
shows a pleural effusion (Fig. 62.1); computed tomography (CT) can also be helpful in assessing pleural
thickening and fluid buildup (Fig. 62.2). Concomitant parenchymal disease is observed in approximately
one-third of cases. At the early stage of disease, the tuberculin skin test result is positive in 75% of
patients, but—according to Berger and Mejia14—it should be positive in virtually all patients by 2 months
with the exception of patients with AIDS.
FIGURE 62.1 23-year-old female with a pleural effusion and thickening of the pleura that required biopsy for diagnosis.
Positive diagnosis relies on direct sampling of the pleural fluid and on pleural biopsies with either a
closed technique or a video-assisted thoracic surgery (VATS) procedure. Gross analysis of pleural fluid
reveals an exudative fluid with a protein level in excess of 40 g/L and a white cell count of 1 to 6 g/L,
with predominant lymphocytes. Absence of desquamated mesothelial cells suggests TB, as reported by
Weir and Thornton.13 Determination of glucose level is not really useful. Cultures take 3 to 6 weeks, and
the results are inconsistently positive. Only 30% of cultures became positive in Berger and Mejia’s
experience.14 In the study of Caminero and colleagues,15 determination of IgG antibody levels to
mycobacterial antigen 60 with a cutoff value of 150 U/mL had a sensitivity of 50% and a specificity of
100%. The sophisticated determination of adenosine deaminase (ADA) has been found by Berenguer and
associates16 to have a poor sensitivity and specificity. A meta-analysis of ADA analysis has been
published.17 Falk18 noted that cultures from sputum or gastric content are expected to be negative unless
there is radiologic evidence for parenchymal disease. Therefore the most reliable investigation is pleural
biopsy.
FIGURE 62.2 CT scan showing pleural thickening with fluid trapped in the pleural space. The patient underwent a VATS
procedure for drainage and biopsy of her disease.
Since 2010, the world health organization (WHO) recommends the wide use of Xpert MTB/Rif test for
diagnosis of TB and rifampicine resistance at the same time. The test is based on nucleic amplification
assay for TB and rifampicin resistance and results are obtained in less than 2 hours. It is fully automatized
and does not depend on technicians or biologists expertise. The updated recommendations of the WHO as
of 2013 recommend the use of the Xpert test including for diagnosing extrapulmonary TB in specific
nonrespiratory tissues such as lymph nodes or pleural biopsy, for patients presumed to have extra
pulmonary tuberculosis (EPTB).19
Bates4 and Berger and Mejia14 reported that pleural biopsy with the Abrams needle or a similar
device yields a positive result in 60% to 80% of patients. According to Yim,31 VATS achieves a high
level of specificity because multiple biopsies increase the diagnostic threshold. Given the remarkably
low operative risk, it seems reasonable to proceed with thoracoscopy when direct examination of
bacteriologic samples is negative, rather than waiting several weeks for the result of cultures. Histologic
evidence of caseating epithelioid granulomas is indicative of TB (Fig. 62.3). Levine and colleagues22
recommended that immediate antituberculous therapy be commenced, although only identification of acid-
fast bacilli is completely diagnostic.
In summary, the diagnostic criteria defined by Langston and associates6 are still valuable today.
Tuberculous pleuritis is diagnosed with pleural fluid positive for M. tuberculosis, and pleural disease is
consistent with tuberculous granuloma on histologic study of biopsied or resected tissue.
The natural history of tuberculous pleuritis is usually benign, with spontaneous resorption even if
untreated. Usual management includes antituberculous treatment and close observation. Most often,
patients respond favorably. However, depending on the individual patient’s immunologic status, excessive
production of exudative material may start a diffuse thickening of the visceral pleura, leading to an
entrapment of the lung, regardless of whether adequate antituberculous treatment is used. Such residual
pleural disease may pave the way to reactivation of TB or further development of a bronchopleural
fistula; therefore, pleural drainage or decortication should be considered (Table 62.1).
FIGURE 62.3 Pleural biopsy obtained via a VATS procedure. A hematoxylin and eosin stain shows multiple granulomata in a
23-year-old female.
TABLE 62.1 Treatment Plan for Chronic Mycobacterial or Fungal Empyema

I. Decortication
A. Lung expandable
No extensive circumferential calcifications
No cavitations or cystic bronchiectasis
B. Previous resection
Add thoracoplasty or open pleural window
C. When is additional resection necessary?
Multidrug resistance present
Hemoptysis
Aspergilloma
Cystic bronchiectases/infected
Avoid pneumonectomy whenever possible
D. When is additional resection not indicated?
Reactivated tuberculosis, converted sputum, asymptomatic destroyed lung, drug-resistant strain
E. What to do when poor expansion of lung is present during decortication?
Consider immediate thoracoplasty and/or open pleural window
May elect prolonged drainage plus pneumoperitoneum
F. What to do when there is poor expansion postoperatively?
Consider deferred thoracoplasty
II. Open-window thoracostomy
A. Lung not expandable
Circumferential calcification
Bronchopleural fistula
HIV infection
B. Poor-risk patient
C. Previous resection complicating IIA or IIB
Consider isolated thoracoplasty for apical space
Indications for decortication rely on careful examination of medical imaging. Previously, the indication
for decortication was confirmed with lateral chest radiography. It was assumed that pleural disease seen
on a posteroanterior projection but not visible on lateral films was diffuse around the pleural sac, and that
a minor thickness of the pleural peel occurred. Such cases were expected to clear progressively. On the
other hand, an effusion visible on both anteroposterior and lateral views corresponded to a large
posterior pocket with a relatively thick pleural peel by virtue of dependent accumulation. Such
encapsulated pleural processes are not likely to resolve completely unless they are small at the onset. In
cases with a thick pleural peel, Langston and colleagues6 recommend decortication. CT has confirmed
this approach for assessment of the underlying lung.
Determination of the appropriate timing of surgical intervention was clearly defined in 1967,9 and no
obvious reason exists to change these criteria: (a) decortication is indicated when thoracentesis fails to
yield fluid or fails to alter radiographic appearance; (b) the extent of pleural involvement should be
equivalent to one-third or one-fourth of the hemithorax and cast a clearly discernible shadow in the
posterior basal gutter; and (c) decortication should be made as early as is consistent with good judgment
(i.e., after 2 to 4 months of drug therapy).
A thoracoscopic (VATS) procedure should also be considered even in the presence of pleural
thickening since it allows multiple biopsies and drainage in the costovertebral angles with minimal
invasiveness. The same caveats apply to an open procedure which is aimed at obtaining complete lung
expansion, minimal trauma to the lung, and no residual cavities. Yim21 and others have reported that
isolated cases have been managed successfully by VATS techniques. The diagnostic yield seems to be
100% on histology and 76% positive on culture.
TUBERCULOUS EMPYEMA
Pleural reactivation of TB has been a threat in patients who did not receive major antituberculous drug
therapy. Moreover, chronic empyema is frequently complicated by bronchopleural fistula, leading to a
mixed empyema or complicated tuberculous pleural effusion, characterized by contamination with both
M. tuberculosis and common pyogenes. Chronic empyema following TB adequately treated with
antituberculous antibiotics is seldom associated with reactivation of TB in the pleural space. None of the
22 patients treated by Garcia-Yuste and coworkers23 had any evidence of ongoing mycobacterial
infection.
Diagnosis is easy in patients with known sequelae of TB. Low-grade fever, constitutional complaints,
and increasing dyspnea with or without chest pain are the major symptoms. Abundant sputum suggests
presence of a bronchopleural fistula. On chest radiography, the obvious finding is an increase in the extent
of the pleural involvement. The appearance of an air–fluid level heralds a bronchopleural fistula.
Thoracentesis yields purulent fluid, which should be sent routinely for both bacterial and fungal cultures,
but it may be difficult to perform in the patient with calcified pleura.
As soon as empyema is confirmed, adequate drainage should be instituted. In this setting, our
preference is an open pleural window, whereas others prefer immediate thoracostomy. In patients with
documented reactivation of TB, the classic principle—convert sputum cultures with medical treatment
before resection—remains valid, as recommended by Treasure and Seaworth.24 The next step is to plan
for definitive treatment, which implies major thoracic surgery with often complicated outcomes (Table
62.1).
The first question is to determine whether the underlying lung is reexpandable. Ideally, one would
prefer the most conservative approach, which consists of reexpanding the lung with decortication. The CT
scan is most helpful in the evaluation of the entrapped lung. Areas with cavitations or large cystic
bronchiectases obviously will not reexpand. Conversely, Mouroux and associates,25 as well as Treasure
and Seaworth,24 have found that a patent bronchopleural fistula does not preclude decortication.
The second question is to determine whether parenchymal resection is required. Tuberculous lungs are
relatively stiff, and loss of volume leads to residual pleural space, a factor for persistent empyema
postoperatively. Therefore, combined parenchymal resections should adhere strictly to the classic
indications as reported by Pomerantz26 and Mouroux25 and their colleagues as well as by Treasure and
Seaworth24: multiple drug–resistant disease, threat of hemoptysis, and infectious complications such as
bronchiectasis or aspergilloma. The current criteria for drug resistance are clinical or radiologic
evidence of progressive disease and persistent mycobacteria on sputum examination after 3 months of a
four-drug treatment. At an earlier stage, bacillar casts may be visible on direct examination of smears but
fail to grow in culture. When the remaining lung is extensively destroyed, extrapleural pneumonectomy is
to be considered as a last resort. One should raise some admonitions against this difficult and potentially
dangerous procedure. Publications by Halezeroglu27 and Conlan28 and their associates as well as by
Odell and Henderson29 conclude that both previous TB and coexistent empyema are significant risk
factors for pneumonectomy morbidity and mortality.
Nevertheless, in nonoperated patients, overall mortality in presence of destroyed TB lung will rise to
28% and median survival will not exceed 39 months.30 In recent reports, the mortality following
pleuropneumonectomy is maintained at a lower range averaging 2.9% in adults patients, in comparison to
the spontaneous prognostic cited above.31 In pediatric patients, no postoperative deaths occurred.32 A
striking point is the particular relationship of outcome after surgery and prevalence of TB in the
geographical area where surgery is performed. Morbidity and mortality will be lower in countries with
high prevalence of TB.31,33,34
The postoperative course after decortication with or without additional parenchymal resection may be
complicated mainly by pleural space disease. Prolonged air leaks ultimately seal with long-term drainage
provided that the lung is completely expanded. Persistent pleural spaces after decortication may be
managed either with muscle flaps, plombage, thoracoplasty, or open pleural window. Thoracoplasty has
an unwarranted bad name and should be considered in patients with marked malnutrition; a four-rib
thoracoplasty with a stable and retracted mediastinum may be expeditiously carried out, as noted by
Hopkins and associates,9 compared with the preparation and transfer of two or three muscle flaps. Rather
than performing an immediate thoracoplasty as in former years, the authors prefer to test the expansion
potential of the remaining lung and to proceed with second-stage thoracoplasty only when it proves to be
necessary. Creating an open-window thoracostomy initially is an important decision, because
decortication cannot be performed in a second stage. However, Garcia-Yuste and colleagues23 suggest
that two-stage management with thoracostomy and subsequent muscle plombage of the cleaned residual
space is a reasonable alternative in cases unsuitable for decortication. Poor general health status and
extensive calcifications precluding decortication are indications for this type of management (Fig. 62.4).
In the case of a largely destroyed but asymptomatic lung, two-stage myoplasty may help avoid the
temptation to proceed with extrapleural pneumonectomy. Regardless of the type of surgical management,
adjuvant antituberculous treatment is mandatory in cases of documented reactivation of TB. Besides, in
all cases of EPTB, according to WHO recommendations, HIV testing should be offered to the patients. In
case of associated HIV infection, if not already taken by the patient, antiretroviral treatment should be
given to yield better outcome in combination with TB multidrug therapy.
FIGURE 62.4 Aspergillus empyema caused by bronchopleural fistula complicating an intrapleural pneumothorax. Note the
apical pneumothorax and basal effusion, determining a midthoracic air–fluid level. Extensive pleural calcifications are visible;
translucent trapped lung is packed against the hilum.
LATE PLEURAL AND EXTRAPLEURAL COMPLICATIONS OF COLLAPSE

THERAPY
Until the early 1960s, when major antituberculous drugs became available and began the end of a long-
standing plague, the only active treatment for TB was the so-called collapse procedure. The common
objective of these procedures was to collapse cavitated lung tissue and to obtain scarring of the
tuberculous area progressively. Most physicians familiar with these treatments have retired and few of
their patients still survive. Thoracic surgeons of the younger generation have had virtually no exposure to
such patients.
The first stage of collapse therapy was creation of an artificial intrapleural pneumothorax. Because of
the spontaneous resorption of the intrapleural air, reinjections of air were required at 2-week intervals.
The first indication for thoracoscopic surgery was apical adhesiolysis to promote apical collapse, as
reported by Dumarest and coworkers in 1945.35 When extensive apical adhesions precluded adequate
collapse with intrapleural pneumothorax, extrapleural pneumolysis was the preferred treatment. Similarly,
as carried out by Roberts,36 the collapse space was maintained by periodic injections of air. After 2 to 3
years of treatment, the injections of air were discontinued, and the space progressively filled with serous
fluid and retracted to a small and permanent residual space.
The considerable burden of pneumothorax and the infectious risk from repeated thoracenteses led to
the concept of extramusculoperiosteal plombage, which was most popular between 1948 and 1955, as
reported by Armada and coworkers37 and Shepherd.38 In this operation, the periosteum and intercostal
muscles were stripped off the ribs, similar to thoracoplasty, and pushed inside the chest cavity to collapse
the underlying cavity. The collapse was maintained with methyl methacrylate balls packed between the
denuded ribs and the surface of pneumolysis. Initially, extraperiosteal pneumolysis was believed to avoid
thoracoplasty. However, the many infectious complications, as well as the frequently reported migrations
of material, necessitated that the plombage be removed several months later and thoracoplasty be
performed to obliterate the extraperiosteal space.39 In Chicago and some areas of the Pacific Northwest
of the United States, the use of paraffin as the plombage material became common during the same time
period. Lees40 and Fox41 and their associates reviewed their extensive experience with this material.
Infectious complications were rare, but migration of the wax plomb occurred in more than 25% of the
patients from as early as 5 to 6 months to as late as 10 years or more. A thoracoplasty was rarely
necessary after removal of the migrated plomb, in contrast to the Lucite plombage. All these procedures
rapidly vanished with the advent of antituberculous chemotherapy.
Late infectious complications at the site of previous intrapleural or extrapleural pneumothorax present
as either progressively acquired swelling of the residual pocket or appearance of an air–fluid level
because of a bronchopleural fistula. Half of the patients are symptomatic and complain of fever,
increasing dyspnea, pain, or hemoptysis; productive cough usually indicates bronchopleural fistula. In
asymptomatic patients, the diagnosis is made when consecutive surveillance chest films are compared, as
pointed out by us and our associates.42 Surprisingly, the pleural fluid is sterile on culture in more than half
the patients. Furthermore, though none of those patients received proper multidrug therapy at that time, the
incidence of proven tuberculous empyema is relatively low. Schmid and De Haller43 observed a single
case of reactivated TB in a series of 15 patients. Massard et al. observed four cases of reactivated TB
among 28 patients.43,44 These observations are consistent with earlier data reported by Neff and
Buchanan,45 which showed that tuberculous empyema was a rather unusual early complication of collapse
therapy but did not contribute significantly to the late morbidity. The main hypothesis is that the exsudate,
as a late complication of collapse therapy, is rather consecutive to a transient nearby parenchymal
infection. If not, the presence of bronchopleural fistula can also lead to Aspergillus sp. infection
consecutive to colonization.
COMPLICATION OF THERAPEUTIC PNEUMOTHORAX

The preferred mode of treatment of late empyema is decortication. The underlying lung is expected to
reexpand because no previous parenchymal resection has been performed. Simple open-window drainage
is not satisfactory per se but is a fair treatment for debilitated and otherwise inoperable patients. At the
other extreme, the risk of extrapleural pneumonectomy is certainly prohibitive in this particular setting.
Both sequelae of TB and coexisting empyema are significant risk factors.27,46 Furthermore, these patients
are in their seventh decade of life and frequently present with significant respiratory or cardiovascular
comorbidity. Thoracoplasty should be restricted to either space problems following decortication or
diffuse and heavy calcifications obliterating the extrapleural dissection plane.
Decortication is well tolerated, although it is complicated by prolonged air leaks in most patients.
Drainage time was increased to a mean of 20 days in symptomatic patients and in patients with positive
microbiology results. The reexpansion potential of such chronically entrapped lungs is surprising but may
be anticipated from careful inspection of CT of the underlying lung (Fig. 62.5). Technical details do not
diverge from those of any decortication. Briefly, double-lumen tube intubation is mandatory to prevent
flooding of the opposite lung. The parietal pleura is freed up to the mediastinal reflections, which
requires considerable strength in case of extensive calcifications. The lung is identified ideally at the
anterior mediastinal recess. However, when this adequate cleavage plane is not easily found, the pleural
pocket should be entered and the visceral pleura incised directly over the lung; the thickened pleura is
then progressively freed and excised from the center to the periphery. One should refrain from resecting
any lung, because the previous tuberculous areas have scarred over the years. Because compliance of
such lungs is decreased, strong suction is required to shift the mediastinum and elevate the diaphragm.
Antituberculous therapy is mandatory and should be guided by sensitivity studies. Functional recovery
after such procedures is debated.
COMPLICATIONS OF PLOMBAGE THERAPY

Most often, complication of plombage therapy is a pyogenic infection or a tuberculous infection of the
plombage space. The consecutive swelling of the plombage space induces pressure on the devitalized
ribs followed by fracture of the ribs and migrations of the balls to the muscles layers and thoracotomy
scar. The balls can then be felt just beneath the skin of the patient: from that point on, fistulization to the
skin has been described.47 Besides, though much more scarce, various case descriptions of erosive
complications due to the plombages balls migrating to the mediastinum have been described (esophageal
migration, swallowing, and intestinal obstruction; aortic or intercostal erosions and pseudoaneurysm of
the plombage space).48,49 In the end, another scarce complication is the malignant transformation into
histiocytofibroma, chondrosarcoma, or lymphoma starting from the plombage space.50,51
FIGURE 62.5 Aspergillus empyema caused by bronchopleural fistula complicating an intrapleural pneumothorax. Same patient
as in Fig. 62.4. A: Mediastinal window: thickened parietal and visceral pleura with extensive calcifications. B: Parenchymal
window: the trapped lung tissue is nearly normal and reexpanded after decortication.
Surgical treatment of the standard case of infectious complication in the plombage space will require
reopening of the thoracoplasty incision, removal of devitalized ribs, and of the plombage material.39
Fluoroscopy should be used during the removal, to be sure all balls are removed as some of them may be
hidden in calcified tissues. In case of aortic erosion, cardiopulmonary bypass may be initiated in
peripheral femorofemoral as the aortic arch may not be that easily cross-clamped through the
thoracotomy; proper aortic repair may even need hypothermic circulatory arrest.
ASPERGILLUS EMPYEMA
Pleural infection with Aspergillus fumigatus is a rather infrequent disease. Kearon and colleagues52
listed only 30 cases in an exhaustive review of the literature. Even in the immunodeficient setting of lung
transplantation, Aspergillus empyema remains rare. In a series of 31 graft recipients with positive
Aspergillus culture results reported by Westney and colleagues,53 only one patient developed Aspergillus
empyema. Contamination of the pleural space with Aspergillus spores or hyphae results either from direct
intrapleural seeding during surgery or by aspiration of aerosolized particles through a bronchopleural
fistula. Fungal growth requires a persistent pleural space, which provides excellent atmospheric
conditions, with an ambient temperature of 37°C, a moisture of 100%, and abundant proteins readily
available for digestion by fungal catalase or chymotrypsin.
Pleural aspergillosis presents as two clinical pictures that differ considerably. Acute Aspergillus
empyema develops usually during the immediate postoperative course after an intrapleural thoracic
procedure and presents with findings similar to any postoperative pleural infection. Late Aspergillus
empyema presents as a chronic process of the saprophytic type, similar to pulmonary aspergilloma.
ACUTE ASPERGILLUS EMPYEMA

As noted by Herring and Pecora,54 acute Aspergillus empyema most often occurs after a surgical
procedure undertaken to treat an aspergilloma. Nowadays, this affirmation needs to be nuanced by the
increasing number of patients undergoing lung transplantation. During lung transplantation, a substantial
number of patients may be chronically infected or colonized by Aspergillus sp.; in these patients, the
opening of the bronchial tract to the pleura during the removal of the native lung may spill Aspergillus sp.
into the pleura. As immunocompromised hosts, these patients may also develop empyema later on
following lung transplantation: the immunosuppression required to keep the lung graft in function is the
strongest in the field of solid organ transplantation and the lung is an organ that is continuously in contact
with the surrounding world. Aspergillus sp. are a recognized pathogen that is feared all along the follow-
up of lung transplant recipients and that may express in various ways: invasive aspergillosis,
aspergilloma, or pleural aspergillosis/empyema.55
Nevertheless, the most common operation preceding acute Aspergillus empyema is partial lung
resection, such as lobectomy or segmentectomy for Aspergilloma. One case, reported by Purcell and
Corris,56 was a patient with bronchopulmonary aspergillosis who developed A. fumigatus empyema
subsequent to a spontaneous pneumothorax. Nakanishi and colleagues57 noted that percutaneous
instillation of antifungal agents into a parenchymal cavity hosting a mycetoma is also known to foster
pleural seeding.
The most common clinical finding of acute Aspergillus empyema after partial lung resection is
prolonged air leak and persistent drainage of fluid; in addition, fever and weight loss are usual. The
residual pleural space hosting the infection is not always apparent on standard chest radiography, and
anterior spaces most often require CT studies to be identified. After pneumonectomy, the signs of
empyema are well known to all thoracic surgeons: general malaise, fever, and pallor identify the patient
at risk. Infection is confirmed by an elevated white blood cell count and persisting high levels of C-
reactive protein, as reported by Icard and associates.58 Chest radiography shows a rapid increase of the
pleural air–fluid level because of increased exudation of pleural fluid; the mediastinum is occasionally
shifted toward the contralateral lung.
Diagnosis of Aspergillus empyema is easily confirmed by appropriate analysis of pleural fluid
samples. Serodiagnosis is less reliable because it may be negative at the early stages of the disease.
Cure of acute Aspergillus empyema requires sterilization and complete and definitive obliteration of
the pleural space. Various strategies such as pleural lavage through a chest tube, surgical debridement,
and open-window thoracostomy achieve a satisfactory gross cleaning of the pleural space. But the final
decision as to how to obliterate the space depends on the reexpansion potential of the remaining lung.
After resections less than lobectomy, expansion is clearly possible as soon as air leaks have sealed. In
such patients, conservative management with antifungal treatment has a fair chance for success. According
to Chatzimichalis and coworkers,59 because of the hyperemia of the acutely infected pleura, the tissue
penetration of itraconazole is satisfactory and sufficiently high local concentrations are easily obtained,
similar to invasive pulmonary aspergillosis. A single case of successful treatment with aerosolized
liposomal amphotericin B has been reported by Purcell and Corris.56 High local tissue concentrations are
expected in the presence of a bronchopleural fistula.
The problem is different in patients who have undergone a lobectomy. Clearly, intraoperative seeding
results from parenchymal tears because of a difficult dissection. This means that such patients had
complex aspergilloma, as pointed out by Daly and colleagues,60 and that the remaining lung is expectedly
sclerotic with reduced reexpansion potential. In favorable cases, institution of a pneumoperitoneum
increases the diaphragm sufficiently to obtain contact of the pleural surfaces. In the event of larger pleural
spaces, aggressive management is mandatory to shorten the spontaneous evolution. In our opinion, apical
spaces are best dealt with by thoracoplasty. Muscle flaps are often disappointingly thin in emaciated
patients marked by chronic illness; further, the largest flap (i.e., the latissimus dorsi) has usually been
sacrificed during the initial thoracotomy.
Management of Aspergillus empyema after pneumonectomy does not differ from management of
postpneumonectomy empyema in general. Once the diagnosis is established, the pleural space must be
drained. Aggressive management is mandatory to obtain quick cleaning of gross purulent material. Most
authors proceed with an open-window thoracostomy, as described by Clagett and Geraci.61 It is
questionable whether a tedious cleaning by VATS techniques offers any advantage over a short
thoracotomy in this situation. To obliterate the cleaned pleural space, the debate is between the
proponents of muscle plombage procedures—as advocated by Shirakusa62,63 and Pairolero and their
colleagues64 as well as by Ali and Unruh65—versus the partisans of thoracoplasty, including Horrigan and
Snow,66 Grégoire,67 and Hopkins and their associates.9
There are several recommendations to prevent from aspergillus empyema during surgery of
aspergilloma. Pneumonectomy should be avoided whenever possible in the setting of an Aspergilloma of
the lung as it carries the highest risk for later septic complications with an empyema rate in excess of
25%.68 Segmentectomy or wedge resection should also be avoided whenever possible as it determines a
high risk of opening the cavitation and spill the aspergillus content into the pleura. It is the opinion of the
authors that the ideal resection should be anatomic encompassing the mycetoma and the surrounding
cavitation. As a consequence, lobectomy is the most frequent resection performed to cure aspergilloma. If
the patient is unfit for an anatomic resection, or the only acceptable resection possible is pneumonectomy,
then a radical but acceptable alternative consists of a direct approach of the cavitation to remove the
mycetoma, followed by immediate thoracoplasty to collapse the cavitation. An intermediate step with
cavernostomy may be helpful in severely ill patients to reduce the inflammatory and septic burden, give
time to metabolic recovery (re-nutrition, functional rehabilitation) before thoracoplasty for closure.
CHRONIC ASPERGILLUS EMPYEMA

Chronic Aspergillus empyema is fostered by a residual pleural space communicating with the bronchial
tree. The cavity is penetrated by aerosolized fungal material similar to parenchymal cavities. Further
development of the fungus is favored by progressive erosion of the surrounding structures by its
proteolytic enzymes. The most frequent setting is previous partial lung resection for TB or lung cancer.
Adjuvant or neoadjuvant radiation therapy has been retrospectively identified in 4 of our 6 patients
operated for lung cancer69 and, as suggested by Utley,70 might be a contributing factor. In addition,
occasional Aspergillus empyemas are encountered in patients with sequelae of previous collapse therapy,
as previously noted.
The common problem in these patients is that medical therapy with itraconazole is likely to fail. The
first reason is that tissue penetration in chronic lesions surrounded by fibrotic scar tissue is expected to be
low, as pointed out by Chatzimichalis and associates.59 The second reason is that the possibility of
infection persists as long as a residual pleural space exists. The obligate operative management is one of
the most challenging situations in general thoracic surgery. The precarious health status of patients with
Aspergillus empyema is best described by Krakowka and colleagues,71 who reported five deaths during
treatment in a series of 10 patients.
Two clinical presentations are discussed, corresponding to postresectional empyema and empyema in
previous collapse spaces. Chronic postresectional empyema may be detected on routine chest
radiography but is usually symptomatic. The symptoms are similar to those of pulmonary aspergilloma:
hemoptysis, bronchorrhea, dyspnea, and chest pain. Chest radiography shows either a partial
hydropneumothorax indicating a bronchopleural fistula or a progressive thickening of known pleural
sequelae that was noted by Libshitz and associates.72 True intrapleural megamycetomas are uncommon.
Empyema in previous intrapleural or extrapleural collapse spaces or residual pockets after tuberculous
pleurisy may be silent and appear as an enlargement of the pleural thickening on sequential surveillance
chest radiography. Otherwise, fever and chest pain are the usual symptoms. Cough and increased sputum
indicate bronchopleural fistula, which is characterized by an air–fluid level on chest films.
A positive diagnosis relies on direct identification of Aspergillus species or serodiagnosis. Sampling
of pleural fluid is easy in patients with hydropneumothorax only. Fortunately, serodiagnosis is most
reliable because it is nearly always positive in patients with chronic infection. Our current criteria for
Aspergillus infection are the following: either at least two precipitations on immunoelectrophoresis or a
single precipitation with positive catalase activity.
Treatment options differ between postresectional and postcollapse empyema. In any event, the
underlying lung should be left in place when feasible, because a significantly increased risk for mortality
and major morbidity exists after pneumonectomy in patients with preoperative empyema. This has been
estimated to be close to 40% by Halezeroglu27 and Conlan28 and their associates as well as by Odell and
Henderson.29 Furthermore, according to McGovern and colleagues,73 the risk of completion
pneumonectomy in this situation is prohibitive. The operative mortality of 9.4% after completion
pneumonectomy for cancer was increased to 27.6% after completion pneumonectomy for benign disease
in the Mayo Clinic experience (reference). Similarly, the prevalence of empyema was 20.7% and 9.3%,
respectively, for benign and malignant disease, and the prevalence of bronchopleural fistula was 17.2%
and 3.1% (reference). Therefore, further resection is warranted only when persisting infectious lesions
such as lung abscess or bronchiectases would otherwise jeopardize the outcome. In extreme situations,
completion pneumonectomy and immediate thoracoplasty have been advocated by Utley.70
In postresectional empyema, the remaining lobe is usually fibrosed because of previous TB or
radiation therapy. Therefore, decortication is likely to fail. Muscle transfers are less than optimal in these
malnourished patients with marked chronic illness; besides, as previously noted, the latissimus dorsi
muscle has usually been sacrificed during the initial thoracotomy. Although some successes have been
obtained with omental transfer, as reported by Shirakusa and associates,63 the authors would add some
caveats to this technique. In malnourished patients, the tissue volume is spare. Harvest of the omentum
exposes the patient to the additional risk of laparotomy. When the omentum is used, one should avoid a
direct passage through the diaphragm to prevent herniation of abdominal viscera. It is mandatory to use
indirect tunneling, either through Morgagni’s hiatus or through the phrenohepatic ligaments, as suggested
by Jurkiewicz and Arnold.74
The most appropriate management should include careful curettage of all fungal material, followed by
a retailoring of the chest wall with thoracoplasty. Many authors, such as Grégoire and colleagues,67
recommend leaving the first rib in place to avoid scoliosis. However, others, including Loynes,75 believe
that scoliosis is determined by extensive rib resections and resection of the transverse processes of the
vertebra. One should routinely resect the first rib, as do Hopkins and colleagues9 and Horrigan and
Snow.66 Incomplete apical collapse is a concern when the first rib is left in place. Of course, such
operations are risky because of the disabled status of these patients. In our experience, mortality of
thoracoplasty has been 7%, caused by respiratory infection. More than half the patients in our series69
experienced major perioperative bleeding (>1,500 mL) because of the usual hypervascularization of
aspergilloma cavities. Preoperative embolization, as suggested by Hughes and associates,76 usually fails
to reduce intraoperative bleeding because the perilesional vascular network is supplied by multiple
pedicles, as pointed out by Chen and colleagues.10 The authors suggest generous rib resection because
more than 40% of our patients had persistent space problems after thoracoplasty (see below).
The postoperative course is usually prolonged, with an average hospital stay of 49 days in our
experience; this is the result of the disease rather than of the procedure used. However, long-term results
show no evidence for recurrent infection at a mean follow-up of 7 years. Thoracoplasty offers the
possibility for a one-stage cure (are these unpublished data? If they are, this should be specified).
Management with open-window thoracostomy followed by muscle flap transfer or omentoplasty to fill the
residual space seems less aggressive than thoracoplasty, but completion of the treatment plan takes at
least 6 months, as reported by Shirakusa and colleagues.62
Treatment of long-term complications of residual collapse spaces is initiated with tube thoracostomy
and irrigations. CT scan reveals some expandable underlying parenchyma in most cases, although
perfusion scan shows a dramatic decrease of perfusion (Fig. 62.5). Knowing the risk of pneumonectomy
through an empyema,42 the authors advocate decortication in the latter cases. Inexperienced surgeons
might be frightened by the sight of the residual lung with multiple parenchymal leaks at the conclusion of
the operation. Triple drainage with strong suction and a good deal of patience lead finally to sealing of the
leaks and cure of the patient. One should remember that postoperative drainage is significantly prolonged
in symptomatic patients and patients with positive microbiology findings.44
MISCELLANEOUS CONDITIONS
Several other fungal diseases—such as blastomycosis, histoplasmosis, cryptococcosis, and
sporotrichosis—may occasionally involve the pleura during acute pulmonary infection with pleural
perforation. Patients with AIDS are particularly prone to such infections. The main problem in these
patients is appropriate microbiologic diagnosis. With adequate antifungal treatment, the infection should
resolve with no need for surgical management except to drain large effusions.
Two agents, Coccidioides immitis and Candida albicans, are of particular interest.
Coccidioidomycosis may cause diffuse lung destruction similar to TB and result in similar surgical
problems. The presence of yeast cells within a pleural effusion suggests the presence of an
esophagopleural fistula.
COCCIDIOIDOMYCOSIS
Pleural infection with C. immitis seldom has been referred to in the literature. A review published by
Drutz and Catanzaro78,79 describes two situations depending on the natural history of disease. An acute
infection appears in 40% of infected patients and mimics an influenza-like acute respiratory infection. The
pleural effusion that may appear simultaneously to the pulmonary infiltrate is usually sterile.
Approximately 5% of patients develop irreversible pulmonary lesions, such as cavitations or
bronchiectases. Rupture of a cavitation into the pleural space leads to a coccidioidal or mixed empyema.
Amphotericin B is the basis of treatment. Surgical indications are the same as the guidelines for pleural
TB. Acute infection with C. immitis usually mimics M. tuberculosis infections; often a pleural biopsy is
the only way to get histologic confirmation of the disease.
The difficulties of chronic pulmonary coccidioidomycosis with empyema are perfectly illustrated by a
case reported by Utley.70 This patient presented with bronchopleural fistula and simultaneous
granulomatous infection of the lung and pleural space, 10 years after a left lower lobectomy for
coccidioidomycosis. Operative intervention was prompted by major hemoptysis. Completion
pneumonectomy was required because of cavitations in the remaining lobe. A mass closure of hilar
vessels and bronchus with transfixing mattress sutures was used because of inability to individually close
the vessels and bronchus secondary to fibrous scarring of the hilum, and the pleural space was obliterated
by an immediate thoracoplasty.
CANDIDA ALBICANS
Though usually seen in immunocompromised individuals, such as patients with AIDS or transplant
recipients, as noted by Emery and associates,80 empyema with yeast cells should suggest an esophageal
fistula. Typically, microbiology reveals combined infection together with saprophytic oropharyngeal
bacteria or gram-negative bacilli. Jones and Ginsberg81 noted that diagnosis of an esophagopleural fistula
is usually simple in case of spontaneous or iatrogenic disruption.
Sehti and Takaro reported that an esophagopleural fistula complicates approximately 0.5% of
pneumonectomies.82 This complication is relatively unknown, although Takaro and colleagues reported its
occurrence in their collective review in 1960.83 Intraoperative injury, causing a direct tear or
devascularization with subsequent necrosis, leads to an early fistula that becomes apparent during the
postoperative recovery period. The empyema is managed by insertion of a chest tube and the diagnosis is
often established by simple observation of draining saliva or food particles. Recurrent cancer or
inflammatory change is the cause of late esophagopleural fistulas and is revealed by the occurrence of an
empyema. We observed the presence of tiny sinuous tracts that are sometimes tedious to close and require
careful barium swallow studies in various positions, especially lateral decubitus with the pneumonectomy
space in the dependent position.84 Curative treatment may be offered to any patient without recurrent
cancer and requires two steps: closure of the esophageal defect by direct repair, reinforced with a
myoplasty or omentoplasty, and eradication of the empyema by definitive obliteration of the
pneumonectomy space. This is achieved with either thoracoplasty or muscle flap transfers, as Massard84
and Engelman85 and colleagues have suggested.
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67. Grégoire R, Deslauriers J, Beaulieu M, et al. Thoracoplasty: its forgotten use in the management of non-tuberculous post-
pneumonectomy empyema. Can J Surg 1987;30:343.
68. Massard G. Treatment of suppurative lung disease. Eur Respir Monogr 2004;29:168–180.
69. Massard G, Roeslin N, Wihlm JM, et al. Pleuropulmonary aspergilloma: clinical spectrum and results of surgical treatment. Ann Thorac
Surg 1992;54:1159–1164.
70. Utley JR. Completion pneumonectomy and thoracoplasty for bronchopleural fistula and fungal empyema. Ann Thorac Surg
1993;55:672–676.
71. Krakowka P, Rowinska E, Halweg H. Infection of the pleura by Aspergillus fumigatus. Thorax 1970;25:245–253.
72. Libshitz HI, Atkinson GW, Israel HL. Pleural thickening as a manifestation of Aspergillus superinfection. Am J Roentgenol Radium
Ther Nucl Med 1974;120:883–886.
73. McGovern EM, Trastek VF, Pairolero PC, et al. Completion pneumonectomy: indications, complications and results. Ann Thorac Surg
1988;46:141–146.
74. Jurkiewicz MJ, Arnold PG. The omentum: an account of its use in the reconstruction of the chest wall. Ann Surg 1977;185:548–554.
75. Loynes RD. Scoliosis after thoracoplasty. J Bone Joint Surg 1972;54:484–498.
76. Hughes CF, Waugh R, Lindsay D. Surgery for pulmonary aspergilloma: preoperative embolization of the bronchial circulation. Thorax
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77. Chen JC, Chang YL, Luh SP, et al. Surgical management for pulmonary aspergilloma: a 28-year experience. Thorax 1997;52:810–813.
78. Drutz DJ, Catanzaro A. Coccidioidomycosis. Part I. Am Rev Respir Dis 1978;117:559–585.
79. Drutz DJ, Catanzaro A. Coccidioidomycosis. Part II. Am Rev Respir Dis 1978;117:727–771.
80. Emery RW, Graif JL, Hale K, et al. Treatment of end-stage chronic obstructive pulmonary disease with double lung transplantation.
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82. Sehti GK, Takaro T. Esophagopleural fistula following pulmonary resection. Ann Thorac Surg 1978;25:74–81.
83. Takaro T, Walkup HE, Okano T. Esophagopleural fistula as a complication of thoracic surgery. J Thorac Cardiovasc Surg
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84. Massard G, Ducrocq X, Hentz JG, et al. Esophagopleural fistula: an early and long-term complication after pneumonectomy. Ann
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85. Engelman RM, Spencer FC, Berg P. Postpneumonectomy esophageal fistula. Successful one-stage repair. J Thorac Cardiovasc Surg
1970;59:871–876.
63
Thoracoplasty: Indications and Surgical
Considerations
Marco Alifano ■ Antonio Bobbio ■ Christine Lorut ■ Jean-François Regnard
GENERALITIES
Thoracoplasty is a surgical procedure that allows treatment of complicated pleuro-pulmonary conditions.
After resection of several adjacent ribs, leaving in place their periosteal beds, chest wall loses its rigidity
and can collapse a lung caverna or obliterate a pleural space. The periosteal beds left in place will form
rods of re-ossification which will secure the collapsed cavities in their new position in a few weeks.
However, this collapse is sometimes incomplete, even if a wide thoracoplasty has been performed. In
some cases, in spite of a substantial volume reduction, the residual space may require iterative surgical
procedures.
Thoracoplasty was conceived to collapse cavities of lungs affected by tuberculosis and gained
worldwide acceptance in the pre-antibiotic era. Thoracic empyema represented the other, less frequent,
indication. At present, persistent pleural space in postresectional empyema and refractory primary
empyema with trapped lung are the more common, albeit rare, indications for thoracoplasty. Other
indications include treatment of aspergilloma and empyema associated with necrotizing pneumonia.1
HISTORICAL BACKGROUND
Thoracoplasty in the Treatment of Pulmonary Tuberculosis
In 1882, Forlanini, having observed that clinical improvement sometimes followed when spontaneous
pneumothorax occurred in cavitary pulmonary tuberculosis, proposed and used artificial pneumothorax to
collapse and compress these cavities. Induction of pneumothorax was frequently unsuccessful because of
adhesions induced by the need of frequent pneumothorax insufflation. Thoracoscopic intrapleural
pneumolysis was developed by Jacobeus in 1913 and often allowed pulmonary collapse, but success rate
was variable, especially if repeated procedures were necessary. Other methods used to collapse the lung
—such as phrenic nerve exeresis and pneumoperitoneum—were inconsistently successful. As early as in
1885, de Cerenville had collapsed tuberculous cavities by resecting portions of the second and third ribs.
In 1907, Friedrich resected ribs 2 through 9 in one stage. This procedure had an unacceptable level of
morbidity and mortality even in its modifications by Sauerbruch.2 It remained for John Alexander, in
19373 (Fig. 63.1), to analyze the shortcomings of prior procedures and develop the three-stage operation
(extra-musculo-periosteal rib resection) which constitutes the basis for the modern one-stage extra-
musculo-periosteal thoracoplasty. Andrews thoracoplasty (based on extraperiosteal rib resection and
opening of pachypleuritis (heavily thickened pleura) which is then invaginated and used to close
bronchial fistulas and fill the cavity) was described a couple of decades later.4 It represents an evolution
of Alexander thoracoplasty and may be considered an alternative surgical technique. Both Alexander and
Andrews thoracoplasties can collapse pleural or pulmonary cavities. With time the indications shifted
from treatment of tuberculosis to treatment of postresectional empyema.
“Plombage thoracoplasty” represented an alternative to conventional thoracoplasty in the treatment of
pulmonary tuberculosis. The term plombage is derived from the French verb plomber, meaning to seal.
Plombage was mainly used in patients considered too ill for conventional thoracoplasty. The main
advantages of this procedure were prevention from paradoxic ventilation and potential sequential
bilateral procedures. Furthermore, it was thought that plombage would cause less detrimental, long-term
effect on lung function. The procedure is directly descended from extrapleural and extrafascial
pneumolysis, procedures that were frequently ineffective in pulmonary tuberculosis. Formerly, a variety
of materials were inserted into the extrafascial space, including oil, fat, blood, and paraffin, often with
dismal late sequelae. In an effort to find a more biocompatible material, Woods and colleagues5 used
methyl methacrylate spheres, similar to ping-pong balls, as the “plombe,” inserted in a plastic bag to
prevent migration and to facilitate later removal (Fig. 63.2). Subsequently, they used only sheets of
polyethylene as the plombe. Plombage thoracoplasty is very rarely performed today, although its use was
advocated one decade ago in the treatment of multidrug resistant tuberculosis.6
Thoracoplasty in the Treatment of Pleural Empyema

With respect to pleural infections, wide decostalization of the chest wall was employed by Schede7 for
the treatment of chronic empyema in the late nineteenth century, and this procedure was used until the mid-
twentieth century. The operation was accompanied by massive blood loss and a mortality rate
approaching 50%. Undesirable late sequelae included paradoxic chest wall motion, paresis of the
abdominal wall, and a grotesque cosmetic defect. The procedure consisted of creating a U-shaped flap of
all the soft tissues of chest wall overlying the empyema cavity and then resecting the ribs, intercostal
muscles, and thick parietal pleura (Fig. 63.3). The previously elevated soft tissue flap was then allowed
to fill the pleural space over packing. Dissatisfaction with these procedures, however, led to the
development of other methods of treatment of chronic empyema, especially decortication. In 1990,
Horrigan and Snow8 modified Schede thoracoplasty, closing the chest over drains and achieving early
healing and more acceptable cosmetic and functional results.
FIGURE 63.1 Degrees of lung collapse after sequential stages of thoracoplasty for tuberculosis.
FIGURE 63.2 Extraperiosteal plombage. A: The ribs are denuded and the periosteum, intercostal bundles, and pleura are
depressed over the cavity. B: The plombe is inserted into the extraperiosteal space.
During the 1950s and 1960s, thoracoplasty for tuberculosis became obsolete with the introduction of
antituberculous chemotherapy and the advent of procedures of muscle transposition to fill pleural spaces.
Moreover, it was considered a mutilating operation, leading to undesirable anatomic, functional, and
cosmetic sequelae (Figs. 63.4 and 63.5). However, despite the bad reputation, there remain a few cases
of chronic pulmonary/pleural infections in which thoracoplasty is indicated. Available studies in the last
30 years have shown that thoracoplasty can be an excellent therapeutic option, in selected patients, used
alone or in combination with muscle flap transposition.1,8–16
INDICATIONS
Patients with postresectional empyema or primary empyema in which the lung fails to reexpand are
potential candidates for thoracoplasty.8–16 Furthermore, in the setting of lung infections, thoracoplasty can
be used as a primary surgical treatment (almost exclusively in the case of a limited aspergilloma in a
patient not tolerating resection) or as a step in a complex management of some lung infections, to
obliterate a pulmonary (often after cavernostomy) or pleural (often after thoracostomy) cavity.1
INDICATIONS IN POSTRESECTION EMPYEMA
Although management of postresectional empyema is described in detail elsewhere in this book, some
aspects of current practice are discussed below, since thoracoplasty may represent, in most cases, a step
in the complex management of patients with this condition.
FIGURE 63.3 Technique of Schede thoracoplasty. A, B: Vertical incision in the midaxillary line and excision of the draining
sinus. C: The incision is carried through the muscles to the chest wall and the muscles are reflected. The empyema cavity is
entered and unroofed by excising the ribs and intervening intercostal muscles and neurovasculature structures. The cavity is
completely saucerized. Intercostal vessels are controlled with suture ligatures. D: The cavity is packed with gauze and
subsequently the chest wall muscles are allowed to approximate the visceral pleura.
Postresectional empyema is the most common indication for thoracoplasty, and postpneumonectomy
empyema represents the largest group.12–14 In postresectional empyema, thoracoplasty does not represent
primary treatment, because of frequent general and respiratory repercussions in already severely ill
patients. On the other hand, thoracoplasty is generally well tolerated once clinical conditions have
already been stabilized by adequate pleural drainage (closed or open) and medical treatment.12–14,17 Thus,
routine policy after diagnosis of postresectional empyema, especially if associated with a broncho-
pleural fistula, is urgent intercostal drainage, possibly followed by open-window thoracostomy (e.g.,
Eloesser flap), especially if a bronchopleural fistula is present.12–14,17,18 Appropriate antibiotics as well
as ventilatory (if needed) and nutritional support are employed, and attention is directed to associated
medical illness; in some circumstances, bronchopleural fistula may close with this treatment.13 Only
occasionally, an urgent thoracoplasty—following evacuation of pleural fluid by tube drainage or open-
window thoracostomy—may be indicated in the presence of a large fistula responsible for extreme loss of
tidal volume incompatible with mechanical ventilation in case of associated contralateral
pneumonia/ARDS requiring intubation (Fig. 63.6).18
FIGURE 63.4 Seven-rib thoracoplasty for extensive cavitary disease. Note the scoliosis.
In postresectional empyema without bronchopleural fistula, when sepsis persists, a

videothoracoscopic debridement can be attempted (possibly associated to a period of irrigation-
cleansing) followed by open-window thoracostomy in the event the debridement procedure fails to
control symptoms.18–20 In addition, open-window thoracostomy is performed in the majority of patients
with postresectional empyema (especially after pneumonectomy) associated with bronchopleural fistula
since closed drainage often fails to achieve control of a permanently contaminated space (Fig. 63.7).13–18
Once infection is controlled and the cavity is reduced, management of residual space depends on the
presence or absence of a bronchopleural fistula. In the absence of bronchopleural fistula, and if the
residual cavity is clean, closure of cavity edges by direct approximation of skin flaps may be indicated.
This procedure is simple and safe, but the results can vary (because of high rate of recurrent infection)
and it is obviously unsuitable when bronchopleural fistula is present.21 Either muscle or omental flap
transposition has been reported as safe and effective in filling a postresectional cavity and, possibly,
sealing a bronchopleural fistula.22–29 However, there are clinical scenarios, especially after
pneumonectomy, in which the cavity is too large to be filled with muscles or in which there are no
muscles or omentum available. In such circumstances, thoracoplasty may be indicated to obliterate these
cavities (Figs. 63.7 to 63.9).13–15,17,18 The obliteration may be complete (immediately after the operation
or in the subsequent weeks) and associated to closure of a possibly coexisting bronchopleural fistula (Fig.
63.8), or may require a final step by muscle/omental transposition to fill the residual cavity (Fig.
63.9).13,17,18
Although some have proposed a more aggressive approach to postpneumonectomy empyema with
bronchopleural fistula,30,31 the authors advocate the above-described multistep treatment, as this approach
limits surgical risks in severely ill patients and because bronchopleural fistula can close
spontaneously13,17,18 or with endoscopic treatments which can be used in association with the multistep
treatment.32,33 Among available techniques, the use of Amplatzer occluders has been popularized in recent
years because of increased stability and probable increased effectiveness in terms of fistula occlusion.33
FIGURE 63.5 Schede thoracoplasty with massively deformed chest wall.
However, this multistep management of postpneumonectomy empyema should be regarded as flexible

and the decision of undertaking a subsequent surgical procedure should be taken on an individual basis,
taking into account infection control, the anatomy of the surgical field, the general and cardiorespiratory
conditions, and the disease-free interval from cancer recurrence. In an institutional 10-year experience,13
19 patients needed open-window thoracostomy to control infection and bronchopleural fistula of 28
patients with postpneumonectomy empyema. Moreover, 4 patients underwent subsequent myoplasty which
alone was adequate to obtain complete closure of the cavity, whereas 13 patients had a thoracoplasty
(43%) associated with a further filling procedure in 8 cases. The remaining two patients maintained their
thoracostomy and never underwent subsequent obliteration procedure because of poor general conditions
and uncontrolled infection. In no cases did postpneumonectomy thoracostomy close spontaneously. In this
series, Alexander thoracoplasty was performed in all but one patient; however, the choice of the
thoracoplasty and its timing with respect to previous drainage procedures are variable according to
different institutional experience. Although Alexander thoracoplasty is used by the majority of surgical
teams for this indication,13,14 in most cases after open-window thoracostomy, others suggest Andrews
thoracoplasty,12,16 generally after close drainage. These procedures’ respective technical aspects,
advantages, and limitations will be discussed below.
In some patients, the surgical anatomy may dictate choice of the technique: as an example, in case of
small, late, infected postpneumonectomy spaces, open-window thoracostomy may be not feasible, and
closed drain followed by Andrews thoracoplasty may be the only reliable surgical treatment option (Fig.
63.10).
FIGURE 63.6 Andrews thoracoplasty employed in an emergent setting in a patient with postpneumonectomy empyema. Initial
treatment was chest drainage followed by open-window thoracostomy (A). Extreme loss of tidal volume in spite of compressive
dressing indicated urgent Andrews thoracoplasty, which obtained control of leaks and important reduction of the
postpneumonectomy space, as observed in axial (B) and coronal (C) CT scan.
In cases of postlobectomy empyema, the indications for thoracoplasty are less frequent, as
bronchopleural fistula is more rarely observed than after pneumonectomy and an empyema without fistula
is an exceptional occurrence. Because of a smaller cavity and the presence of residual lung, treatment
with drainage, thoracoscopic debridement, or open-window thoracostomy might be more successful.
Bronchoscopic sealing of small fistulas is increasingly used, although the supporting evidence derives
from only few studies with a limited number of patients.33 Repeat thoracotomy, complete lung
mobilization, and, bronchial re-suturing with muscle flap buttressing may constitute an alternative in
patients in good general conditions, but this strategy is rarely employed.34 A more aggressive approach,
including completion pneumonectomy and myoplasty, has also been suggested but should be regarded as
an exceptional indication.35 In the above-mentioned 10-year surgical series,13 an open-window
thoracostomy was necessary in 17 of the 19 patients with postlobectomy empyema. The open-window
thoracostomy closed spontaneously in two patients, was filled by a muscular flap in seven cases, and
required a thoracoplasty in eight cases (Fig. 63.11). Thus, the percentage of thoracoplasty is relatively
high (42%) and indicates that spontaneous closure of thoracostomy occurred rarely and simple filling
with a flap is not always feasible, even in cases of postlobectomy empyema.
INDICATIONS IN PRIMARY EMPYEMA

Thoracoplasty for primary empyema is an accepted procedure albeit extremely uncommon.1,13,14 In fact,
thoracoplasty can be an option if the pleural infection is asymptomatic despite persistent infection of the
pleural space, the lung does not reexpand and decortication has either failed or it is not indicated because
of poor cardiorespiratory reserve, or anticipated failure of the lung to reexpand. In the event that open-
window thoracostomy is necessary to control infection, a subsequent myoplasty is usually successful and
should be taken into consideration since the residual space is often small and easy to fill.25 If myoplasty is
not feasible or has failed, thoracoplasty may be indicated (Fig. 63.12).
FIGURE 63.7 Management of a patient referred for postpneumonectomy empyema with broncho-pleural fistula. Bedside chest
x-ray (A) shows the postpneumonectomy cavity associated with parietal empyema. After failure of close chest drain, open
window thoracostomy was rapidly performed (B). Subsequent management (C) included Alexander thoracoplasty (see text).
In a recent surgical series,13 341 patients underwent surgery for primary empyema; of these, 216 were
carried out by video-assisted thoracoscopy (pleural debridement) and 122 by thoracotomy (pleural
debridement with/without lung decortication). Only three patients required a thoracoplasty (0.8%) which,
in one patient, was associated with myoplasty (thoracomyoplasty).
INDICATIONS IN FUNGAL AND NON-FUNGAL INFECTION OF THE LUNG

Aspergilloma
The best treatment option for pulmonary aspergilloma is pulmonary resection. However, a small
percentage of patients with aspergilloma do not tolerate resectional surgery and have to be managed by
medical treatment or, in most instances, by non-resectional surgery.1 The majority of this subset of patients
non-susceptible to treatment by resectional surgery have large or bilateral lesions and require
cavernostomy and subsequent filling by muscular flap transposition. In these patients, thoracoplasty may
be indicated before (or as an alternative to) flap transposition, as an intermediate step to facilitate
reduction of pulmonary space if this is too large to prevent filling with available muscular flaps (Fig.
63.13).13
FIGURE 63.8 Management of a patient with broncho-pleural fistula occurring after completion pneumonectomy performed for
broncho-vascular fistula complicating a right upper lobectomy. Axial CT scan showing the large broncho-pleural fistula (A).
Treatment involved open-window thoracostomy (CT scan, coronal view, B), followed by Alexander thoracoplasty, which resulted
in rapid reduction in the volume of pleural space (C), which was almost completely filled at 6-week follow-up (D). Complete
filling and definitive skin closure were observed at subsequent out-patient visit.
In a small percentage of patients with localized postero-superior lesions not candidates for resectional
surgery, Andrews thoracoplasty may be indicated as first line of treatment. The localization of these
lesions contraindicates cavernostomy (which would be posterior in the interscapulo-vertebral space) but
their small volume allows their almost complete filling (after removal of the fungus ball) with
pachypleuritis and intercostal muscles, during the same operative time (see later for technical details, Fig.
63.14).1
FIGURE 63.9 Chest x-ray (A) of a patient treated by open-window thoracostomy followed by thoracoplasty for late
postpneumonectomy empyema. Residual space was filled by serratus anterior transposition (B).
Multidrug Resistant Tuberculosis

The appearance of drug-resistant organisms and AIDS have rekindled interest in thoracoplasty and its
application.6 As many as two-thirds of patients with multidrug-resistant tuberculosis are not candidates
for resection because of extent of disease or poor pulmonary function.6 Plombage thoracoplasty has been
studied in this setting in small retrospective series with interesting results.6
Necrotizing Pneumonia
Thoracoplasty is also indicated for the treatment of a persistent infected pleural space in the setting of a
necrotizing infection of the lung after necrosectomy (performed by either thoracotomy or direct open-
window thoracostomy).1,37 Thoracoplasty may be used to obliterate the residual space after
cavernostomy, open-window thoracostomy, or thoracotomy, if intrathoracic flap transposition or Clagett
procedure is not possible or not indicated (Fig. 63.15).1,37
SURGICAL TECHNIQUES
Nowadays, improved surgical and anesthesiologic techniques, as well as perioperative care, allow
thoracoplasty to be safely performed in one stage.13–18 Patients with satisfactory general and
cardiorespiratory conditions can in fact tolerate extensive (eight or nine) rib resection. For more fragile
patients, it was suggested to perform thoracoplasty in two or three stages to reduce surgical trauma,3 but
this attitude seems out of date: if a patient is considered to have a too high surgical risk for a one-stage
thoracoplasty, alternative solutions are probably best suited. Furthermore, in the event of
postpneumonectomy empyema (currently the most frequent indication), the absence of lung under the
thoracoplasty prevents the effects of chest wall paradoxic motion.
The operation is performed in patients who have their infected space already drained by either chest
tube (“thoracoplasty on drain”) or open window thoracostomy/cavernostomy,13–18 ideally placed lower
on the chest wall so as not to interfere with subsequent thoracoplasty. An afebrile status and normalized
markers of systemic inflammation prelude control of the sepsis which is mandatory before performing a
thoracoplasty.
TECHNIQUES OF THORACOPLASTIES IN POSTPNEUMONECTOMY

EMPYEMA
In the treatment of a postpneumonectomy empyema, thoracoplasty is performed by a posterior approach.
The patient is placed in the lateral decubitus, leaning forward (“Paulson” position), so that the frontal
plane of the patient does with the table a 60° angle (Fig. 63.16). In this way, the inter-scapular-vertebral
region is optimally exposed. The skin incision is that of a conventional posterolateral thoracotomy,
extended upwards in the inter-scapular-vertebral region, up to the level of the spine of the scapula. When
performed in a patient with open-window thoracostomy, which is usually located in the lateral chest wall,
the incision extended backward and upward from the posterior limit of the thoracostomy.
After iterative section of the latissimus dorsi and the trapezius, serratus muscles and rhomboid are
separated from the inter-serrato-rhomboid fascia to expose the costo-intercostal plan.
Subsequent maneuvers will depend on the type of thoracoplasty: in this chapter, only Alexander and
Andrews thoracoplasties will be described since intrapleural thoracoplasty (according to Schede) is no
longer used in the treatment of postpneumonectomy empyema.
Alexander Thoracoplasty
In the so-called Alexander thoracoplasty, the costal resection is done in extra-musculo-periosteal manner,
that is, by resecting only the bony portion of the ribs. To achieve an optimal collapse, the first eight or
nine ribs should be resected; however, in some instances, less extensive rib resection is sufficient: this
should be individualized on the basis of preoperative chest x-ray and CT scan, by careful evaluation of
the anatomy of postpneumonectomy space with respect to thoracic skeleton.
FIGURE 63.10 Late postpneumonectomy empyema with persistent bronchopleural fistula. After close drainage (A), and
because of contraindication of open-window thoracostomy (small, postero-superior space [B: CT scan, axial view; C: CT scan,
coronal view]), an Andrews thoracoplasty was performed with rapid obliteration of pleural space and closure of fistula (D).
The rib resection begins at the sixth rib level and proceeds cranially; if necessary, after resection of
the first six ribs, it can be extended caudally. A 3-cm incision is made in the periosteum on the upper
border of the sixth rib; this flap of periosteum is then elevated, thus allowing a flange of a Finocchietto rib
spreader to be inserted (Fig. 63.17). The rib spreader is opened and the upper flange elevates and fixes
the scapula, thus freeing the assistant for other duties. The attachments of the serratus anterior to the
second and third rib are visualized and transected 1 cm from their insertion on each rib using cautery.
Subsequently, the periosteum is incised with electrocautery at middle of the external aspect of each rib,
and then the rib is dissected using the appropriate tools (Fig. 63.18). To this purpose, a Farabeuf
periosteal elevator is used at the external aspect of the ribs,; then, Maurer periosteal elevators for upper
and lower costal edges, and, finally, small and then large raspatories for the deep surface of the rib are
utilized. The limit of the posterior section of each rib is the transverse process; in fact, costovertebral
disarticulation does not contribute to the collapse of the pleural space. In case of previous open
thoracostomy, rib resection should include the posterior portion of previously resected ribs. Anteriorly, a
sloping resection of the costal arches is generally performed, with progressively less anterior rib being
removed as the resection progressed upward, in order to prevent excessive thoracic deformity.
FIGURE 63.11 Management of a patient referred for empyema with bronchopleural fistula occurring after right upper
lobectomy for aspergilloma. Treatment involved close chest drainage (CT scan, axial view, A; and coronal view, B) followed by
Andrews thoracoplasty with immediate obliteration of pleural space and bronchial fistula (C). Chest x-ray performed 15 days
postoperatively (D).
With respect to the dissection of first two ribs, one should be particularly careful because of their
intimate relationship with the subclavian vessels (Fig. 63.19). The outer edge of periosteum of the second
rib, which is generally easily palpable, is incised with electrocautery and then released from the bony
portion of the lower aspect of the rib with the Farabeuf periosteal elevator. The upper aspect of the bony
portion of the rib is freed by the Maurer periosteal elevator and then by the Maurer small raspatory,
pushing the periosteum inwards together with insertions of middle scalene muscle. The movement of the
raspatory will also be protected by the finger index of the contralateral hand placed on the lower aspect
of the ribs, up to encircle a segment of the whole rib under digital control. Subsequently, the periosteum of
the whole rib is released by the Maurer large raspatory. Once the bony portion of the second rib is
released, it is cut with a costotome for first rib a few millimeters from the transverse process posteriorly
and at the junction between the middle and anterior arch, anteriorly. With the progression of the rib
resection, the collapse of pleural cavity will become more and more obvious (Fig. 63.20), providing
sufficient exposure of the first rib which will be dissected in a sub-periosteal manner according to the
same technique described for the second rib. With dissection of the superior aspect of the rib, lower roots
of brachial plexus, anterior scalene muscle, and subclavian vessels will be pushed upwards, allowing
safe posterior (few millimeters from the costo-transversal junction) and anterior (at middle arch level)
section of the bony portion of the rib.
FIGURE 63.12 Management of an immunocompromised patient referred for pyogenic empyema. Because of failure of
thoracoscopic debridement and open decortication, open window thoracostomy was performed. Because of unavailability of
sufficient muscular or omental flap, inferior thoracoplasty (associated with a limited myoplasty) was performed with obliteration
of pleural space, as seen at CT scan (A, coronal view; B, axial view).
Controversy exists as to whether the first rib should be resected.10,11 Most teams believe that excision
of the first rib allows for good collapse of the apex without causing significant shoulder abnormality or
scoliosis and should be performed whenever an apical space is present.13,38 However, whether or not the
first rib is resected, extrafascial apicolysis is fundamental to collapse the apex and should always be
performed.13 Apicolysis, as described by Semb,39 consists of extrapleural division of adhesions between
the pleural dome at the apex and the soft tissues to achieve vertical collapse and to approximate the soft
tissues to the mediastinum.
FIGURE 63.13 Management of a patient with right upper lobe aspergilloma, poor general conditions, and repiratory
insufficiency. Treatment involved cavernostomy (A) followed by upper Alexander thoracoplasty (B) to reduce space. Complete
filling was finally achieved by transposition of a small pectoralis major flap.
Controversy also exists with respect to resection of the transverse processes of different vertebrae in
order to maximize paravertebral collapse,3,8,9 since such procedure has been also related to the
development of severe scoliosis.40 The authors as well as others,11,12 obtain a satisfactory posterior
collapse even if the transverse processes are left in place.13 However, special care should be taken to cut
ribs close to the costo-vertebral joints and, more importantly, to perform at each level the dissection of
the thickened pleura from the whole transverse process, following the extrapleural plane.
FIGURE 63.14 Management of a patient with left upper lobe aspergilloma (CT scan, axial view [A] and coronal view [B]), and
poor respiratory reserve contraindicating resective surgery. Treatment involved upper Andrews thoracoplasty (C) to remove the
fungus ball and obliterate space.
If the resection of the seventh rib is not required for the collapse, the lower third of the scapula is
resected subperiosteally in order for it to not impinge on the seventh rib. Omitting this maneuver will
result in painful shoulder girdle motion, often associated with a palpable “click.” Furthermore, the
impingement of the scapular tip up on the seventh rib acts as a strut, increasing scoliosis. A Gigli saw or
an electric saw is adequate to perform this resection; the angle of resection should parallel the upper
border of the seventh rib.
Once rib resection, apicolysis, and posterior extrapleural dissection are finished, the quality of
collapse can be appreciated. In most instances it is satisfactory, leaving a small post-pneumonectomy
space drained by the open-window thoracostomy (in rare instances by chest drainage). In case of thick,
partially calcified pachypleuritis, the collapse can be less satisfactory, and the decision to convert to an
Andrews thoracoplasty (see below) can be made. Alternatively, the subscapular space is drained by a
large-bore chest tube and the chest wall closed in a standard manner by approximating the divided
muscular, subcuticular, and cutaneous layers.
FIGURE 63.15 Management of a patient with necrotizing pneumonia (CT scan, coronal view, A) with refractory sepsis in spite
of resuscitation, antibiotic treatment, and pleural drainage. Treatment involved open necrosectomy with progressive improvement
of respiratory failure and CT scan appearance (B, C). Weaning from mechanical ventilation and inotropic drugs was rapidly
possible, but persistent infection of apical space in spite of prolonged drainage (D) and antibiotics necessitated upper
thoracoplasty with symptom controls and rapid obliteration of apical space (E), which was complete some weeks later.
FIGURE 63.16 Periscapular incision through the muscles of the chest wall.
Postoperative chest radiograph will demonstrate the reduction in volume of pleural space, which will
continue in the following days (Fig. 63.21). The authors usually perform thoracoplasty and a filling
procedure of residual open-window thoracostomy (when indicated) at different times to limit surgical
trauma in weak patients.13,17,18 Flap transposition, after thoracoplasty, should be proposed as soon as
permitted by the patient’s general and local condition.
FIGURE 63.17 A rib spreader elevates the scapula. Lower flange is maintained in position following an incision elevating the
periosteum of a lower rib. The serratus muscles are removed from the ribs using cautery.
FIGURE 63.18 Essential surgical instruments: from top to bottom, then from left to right: Maurer raspatory, large model;
Maurer raspatory, small model; Maurer rib’s upper margin periosteal elevator; Collin costotome; first-rib costotome; Farabeuf
periosteal elevator; Maurer rib’s inferior margin periosteal elevator.
FIGURE 63.19 Neurovascular and muscle relations to the first and second ribs.
FIGURE 63.20 Operative view: progressive collapse becomes evident with ongoing upward rib resection. Sixth, fifth, and fourth
ribs have been resected in a subperiosteal manner.
Andrews Thoracoplasty
Andrews thoracoplasty is performed in a fashion similar to Alexander, with the only difference being that
after rib resection, apicolysis, and, dissection of posterior pachypleuritis, a “thoraco-mediastinal”
plication of the thickened pleura, endothoracic fascia, intercostal bundles, and periosteum is performed
(see later) to further obliterate the cavity and possibly seal an associated bronchial fistula.4 To perform
this plication, the infected cavity is opened through an incision overlying a rib bed (Fig. 63.22). The
whole cavity is exposed and a careful debridement of the empyema cavity is performed. At the level of
the parietal pleura the debridement is more vigorous by means of extensive curettage of the granulations.
The aim is to create two (above and below the pleural incision) pliable and cleansed external parietal
flaps, made of vascularized pleural peel, intercostal muscles, endothoracic fascial, and periosteum. These
flaps are then placed in juxtaposition to the mediastinal surface of the empyema space, and both are
secured by absorbable sutures. In the presence of a fistula, its closure is attempted by direct bronchial
suture and buttressing with pleuro-musculo-periosteal flap (Fig. 63.23). The bulk of flaps is sometimes
sufficient to obliterate the entire empyema space, or at least to significantly reduce its volume (Fig.
63.24).
FIGURE 63.21 Radiographic aspects of progressive obliteration of an infected postpenumonectomy space treated by Alexander
thoracoplasty: chest x-ray taken preoperatively (A); immediately after operation (B); at discharge (12 days postoperatively) (C);
at 1-month follow-up (D).
Alternatively, muscle flaps (serratus anterior or pectoralis major) can be used as patches to close the
fistulas; in this case, the flap is sutured around the fistula which is left open. This maneuver can largely
contribute to cavity filling but requires significant mobilization of muscles with possible spreading of the
infection in the subcutaneous/subfascial areas.12
The subscapular space, which communicates after opening of the pachypleuritis with the collapsed
empyema space, is drained by a large-bore chest tube and the chest wall closed in a standard manner by
approximating divided muscular, subcuticular, and cutaneous layers.
Since the Andrews thoracoplasty results in communication of the empyema cavity with the subscapular
space, this procedure exposes the patient to the risk of chest wall infection.12 Indeed, the problem arises
particularly in the case of a previously positioned chest tube drain (without open-window thoracostomy),
which, in the absence of thoracostomy, may not be sufficient to evacuate purulent debris. Perioperative
targeted antibiotic prophylaxis seems essential and can reduce the risk of surgical site infection.
FIGURE 63.22 Operative view: opening pachypleuritis after extraperiosteal rib resection.
Mobilization of the shoulder and arm is not allowed during the early postoperative days; thereafter,
physical rehabilitation to ensure shoulder mobility is started.
THORACOPLASTIES FOR POST-LOBECTOMY EMPYEMA: “TAILORING

THORACOPLASTY” AND THORACOMYOPLASTY
Tailoring thoracoplasty (prior to lobectomy for tuberculosis, concomitant with or subsequent to the
primary operation) was suggested in 1930, when it was believed that incomplete expansion of remaining
lung would occur and persist, as in instances when an upper lobectomy and superior segmentectomy were
combined.41–43 These “tailoring thoracoplasties” (subperiosteal resection of the first five to six ribs
according to the previously described technique) fell into disrepute: the need for preresectional
thoracoplasty was not reliably predictable, thus adding a potentially useless procedure and making
resection more difficult as well as incurring the risk for post-thoracoplasty spread of tuberculosis.
Concomitant thoracoplasty had an adverse effect on postoperative ventilation since it can generate
retained secretions, atelectasis, and pneumonia (“drowned lung”).41–43 Nowadays, “preventive”
thoracoplasties (either before lobectomy and concomitant with it) are no longer performed. In fact,
thoracoplasty may be seldom indicated in the treatment of rare post-lobectomy empyemas. Postoperative
apical space problems, if anticipated before surgery, may be prevented by pleural tenting or
intraoperative pneumoperitoneum.44 Persistent basilar spaces may also be managed by
pneumoperitoneum.
Postoperatively, in case of persistently infected apical spaces resilient to more conservative
maneuvers, a limited upper thoracoplasty with resection of the first four to six ribs (according to the local
anatomy, as assessed on CT scan) is probably the best treatment option (Fig. 63.11).13 The choice of
thoracoplasty will depend on institutional preference, quality of collapse observed preoperatively, and
associated bronchopleural fistula. If the collapse seems satisfactory and the risk of a likely associated
bronchopleural fistula is minimal, Alexander thoracoplasty is generally preferred. Conversely if the
pachypleuritis is very thick thereby preventing a satisfactory collapse and/or in the presence of a large
bronchopleural fistula, Andrews thoracoplasty may present the advantage of inducing a better collapse
and predisposing to both an intraoperative closure of bronchopleural fistula and an almost complete
intraoperative filling of the space (Fig. 63.11).
Persistently infected basilar spaces, generally treated by open drainage until cleansing, are best
managed by flap transposition. A previously undivided latissimus dorsi generally provides sufficient bulk
to completely obliterate the residual basal cavity and seal the possibly associated bronchopleural
fistula.45 In the case of previous muscular transection, omental transposition may represent an excellent
alternative.17 In both cases, while performing transposition, if the cavity cannot be entirely filled by the
flap, a limited intrapleural thoracoplasty can be added to totally obliterate the cavity in one stage (Fig.
63.25). In this operation, called thoracomyoplasty by Garcia-Yuste and colleagues,35 thoracoplasty
consists of the resection of the costal bony extremities of the thoracostomy borders and resection of the
two ribs above and below the thoracostomy, together with the intercostal muscles, neurovascular bundles,
and parietal pleura.
In any case, closed drainage of the pleural space has to be continued until total obliteration of the
space.
THORACOPLASTIES FOR PRIMARY PLEURAL EMPYEMA

When chronic empyema persists for months, without definitive treatment, the parietal wall becomes so
thick and rigid that it cannot be brought into apposition with the visceral pleura or mediastinum by
conventional extrapleural thoracoplasty.
After discontinuation of Schede thoracoplasty, in 1946 Grow,46 and, independently in 1953, Kergin,47
described an intrapleural thoracoplasty in which the thickened parietal pleura was resected but the
intercostal muscles and neurovasculature were preserved and allowed to fall into the empyema space
after resection of the ribs overlying the space (Fig. 63.26). As described by Grow, the operation includes
resection of sufficient length and number of ribs to completely unroof the empyema cavity for a distance
of 3 cm beyond all borders of the cavity. One rib above and one rib below the cavity is resected. The
intercostal bundles are separated in the plane of the endothoracic fascia and retracted so that the entire
thickened parietal pleura overlying the empyema cavity is exposed and resected. The intercostal bundles
are then allowed to fall into the cavity. An intercostal bundle is sutured over the site of a bronchial fistula,
if one is detected. The chest is drained and the wound closed with a large pressure dressing. The
extrafascial space and the empyema space are drained if a fistula is present.
In the presence of an open-window thoracostomy, this operation is generally not feasible (except for
very small open-window thoracostomy). Thoracomyoplasty (performed as described in the previous
paragraph) can be considered an excellent treatment option, especially in patients with preserved
extrathoracic muscles which will be available for flap transposition (Fig. 63.12).35
THORACOPLASTIES IN FUNGAL AND NON-FUNGAL INFECTION OF THE

LUNG
Pulmonary Aspergilloma
Patients with large cavitary lesions complicated with aspergilloma not amenable to resectional surgery
require medical treatment and, in several instances, cavernostomy.1,48,49 This is effective in control of
both local and systemic septic symptoms. Spontaneous closure of cavernostomy is rare, in spite of
prolonged daily change of dressing, because of nature of cavity—pulmonary and not pleural: in fact,
pachypleuritis may not contribute to direct obliteration; frequently associated poor nutritional status; and
multiple bronchial and bronchiolar fistulas responsible for the continued bacterial contamination of the
space.1 Accordingly, subsequent filling by muscle flap transposition (generally by pectoralis major and,
more rarely, serratus anterior, depending on the surgical anatomy) is generally indicated. However,
space may be too large to be filled with available muscular flaps which often present a reduced bulk in
these sick patients. Thoracoplasty is thus performed, before flap transposition, as an intermediate step to
reduce the volume of the hemithorax.1,13 Subsequently, a one-step Alexander thoracoplasty is carried out
according to the previously described technique (Fig. 63.13). Since the cavity is generally limited to the
apex, the thoracoplasty usually involves the first four to six ribs. Preoperative CT scan will guide the
exact extent of resection.

FIGURE 63.23 Andrews thoracoplasty. A: Ribs overlying the empyema space are resected and the thick fibrous track is
excised. B: The parietal flap is thinned by sharp dissection. C: The mediastinal pleura is curetted. D, E: The mattress sutures
approximate the parietal flap to the mediastinal pleura. (Reprinted from Andrews NC. Thoracomediastinal plication. J Thorac
Surg 1961;6:809. With permission.)
In a small percentage of patients with aspergilloma not tolerating resectional surgery, this three-step
procedure may be not indicated, because of the localization of the lesion preventing the possibility of a
satisfactory cavernostomy. In these cases (small postero-superior lesions), a primary Andrews
thoracoplasty may be indicated (Figs. 63.14 and 63.27).1
Multidrug Resistant Pulmonary Tuberculosis

Conventional thoracoplasty is completely abandoned in the treatment of pulmonary tuberculosis. In the
setting of multidrug resistant tuberculosis, plombage thoracoplasty has been proposed decades ago.6 The
operation, as initially described, consists of denuding the ribs overlying the cavity of their periosteum,
depressing the soft tissues, and then inserting the plombe in the “bird cage” of the denuded ribs. In 4 to 6
months the collapsed extraperiosteal tissues form a stable bony plate, thus preventing paradoxic
ventilation. At that time the plombage material and the atrophied ribs are removed, leaving the first rib
and transverse process.5
Armada and colleagues50 proposed one-stage plombage in which the prosthesis is not removed.
Despite Wilson’s misgivings about leaving the plombe in situ, the one-stage procedure was embraced by
other surgical groups and was more frequently performed than the original procedure. Thus complications
related to the implant were recorded years later. These complications include infection, migration of the
plombage material, mediastinal compression, erosion into the esophagus or bronchus, and development of
cancer.51,52 Although they have become increasingly rare, these complications continue to be recorded in
current clinical practice, as they may occur several decades after the initial procedure. The development
of more physiologically inert plombage materials, notably tissue expanders and breast prostheses, has
given impetus to plombage therapy for pulmonary tuberculosis, since these devices have been
successfully used for treating the postpneumonectomy syndrome and can be left in place for decades
without significant side effects.53,54
FIGURE 63.24 Rapid obliteration of an infected postpneumonectomy cavity with large broncho-pleural fistula, requiring open
window thoracostomy (A). Immediate results of Andrews thoracoplasty are shown in panel (B).
MORBIDITY AND MORTALITY AFTER THORACOPLASTY
Postoperative complications of thoracoplasty relate directly to the underlying disease, associated medical
illness, and possible technical misadventure such as injury to subclavian vessels and brachial plexus.
Pulmonary complications of atelectasis and pneumonia can be minimized by vigorous chest physical
therapy. Wound infection is not common, and subscapular wound infection may be avoided by meticulous
hemostasis and wound drainage.
Multiple ribs resection allows the contralateral intercostal muscles to function unapposed, often
leading to scoliosis and convexity to the operated side (Figs. 63.4 and 63.5). First-rib resection may lead
to elevation of the shoulder girdle. These deformities are more marked in patients <40 years of age and
less marked in those >60, in whom the spine is less mobile. If the first rib and transverse processes (as
usually) do not require resection, the degree of scoliosis is cosmetically more acceptable and it, as well
as shoulder girdle dysfunction, is ameliorated by physical therapy.40
FIGURE 63.25 Preoperative (A) and postoperative (B) CT scan (coronal view) of a patient with empyema with bronchopleural
fistula after right lower lobectomy. Thoracomyoplasty allowed space obliteration and fistula closure.
FIGURE 63.26 Grow–Kergin thoracoplasty. A: The intercostal bundles are mobilized following the rib resections. B: The thick
parietal peel is excised. C, D: The intercostal bundles are allowed to fall into the cavity. (Reprinted from Kergin FB. An
operation for chronic pleural empyema. J Thorac Surg 1953;26:430. Copyright © 1953 The American Association for Thoracic
Surgery. With permission.)
Mortality is similarly related to underlying disease rather than to the operative procedure.
Perioperative deaths are more common in lung cancer cases and when there is a bronchopleural fistula. In
the study of Peppas et al.,11 operative mortality was 25% (4/16); ultimate control of the infection was
obtained in 10 patients, with therefore a success rate of 62.5%. Nevertheless, Icard and colleagues12
achieved a mortality rate of 4.3% with the Andrews thoracoplasty and healing of empyema in 20 of 23
cases. The remaining cases healed after a second procedure. More recently, in the mono-institutional
experience of the authors,13 26 patients underwent thoracoplasty. Postoperative mortality was 3.8%: one
patient (who had empyema after extrapleural pneumonectomy for mesothelioma) died 21 days after
thoracoplasty of adult respiratory distress syndrome. Five patients (19%) experienced postoperative
complications, in all cases after extramusculoperiosteal thoracoplasty with resection of more than five
ribs. In addition, acute pneumonia developed in two patients, whereas subscapular abscess, atelectasis,
and blood loss were recorded in one patient each.
FIGURE 63.27 Preoperative CT scan (A) and postoperative (2-month follow-up) chest x-ray (B) of a patient with aspergilloma
complicated by a destroyed lobe after bilobectomy and chemo-radiotherapy for lung cancer. Treatment involved Andrews
thoracoplasty with fungus ball removal and achieved complete space obliteration.
Thoracoplasty was successful in 20 patients, alone in 6 and combined with a procedure to fill the
residual space in 14. The overall success rate was 80%. With respect to the indications, thoracoplasty
was successful in 17 of 21 (81%) postresectional empyemas (11 of 13 postpneumonectomy and 6 of 8
postlobectomy), in all primary empyemas, and in 1 case of cavernostomy. Regarding techniques,
extramusculoperiosteal thoracoplasty showed a 77% success rate and thoracomyoplasty a 100% success
rate. Andrews thoracoplasty was successful in the only case in which it was performed. Combined
thoracoplasty and filling procedures were successful in all 14 cases.13 Similar results were reported by
Hysi et al.15 in a mono-institutional experience in 90 postpneumonectomy empyemas managed in a 10-
year period. Open-window thoracostomy was performed in all the cases and achieved infection control in
all but 1 case; 7 open-window thoracostomy spontaneously healed, and 24 were never closed. The
remaining 59 patients with open-window thoracostomy underwent Alexander thoracoplasty. Mortality
after thoracoplasty was 5%. Empyema recurred in three patients. Overall success rate (infection control)
after thoracoplasty was 91.5%.
Botianu et al.16 reported on their 25-year experience on Andrews thoracoplasty in the treatment of
post-pneumonectomy empyema. Among the 30 patients, 22 had associated one-stage flap transposition.
Bronchial fistula was present in 14 cases and was closed and reinforced. Overall mortality was 6.7% (2
cases) and two patients (6.7%) presented with recurrence of the empyema requiring an open-window
procedure.
An experience with both post-pneumonectomy and postlobectomy empyema is reported in the study by
Krassas et al.14: thoracoplasty was performed for post-pneumonectomy empyema in 20 patients
(bronchial fistula was associated in 11 cases); 14 of them had previous open window thoracostomy; 12
required associated intrathoracic muscle transposition. Mortality was 15% (3/20). In the eight patients
with postlobectomy empyema (always associated with bronchial fistula; one of them had previous open
window thoracostomy), thoracoplasty was almost always associated with intrathoracic muscle
transposition (7/8 cases) and no death occurred. All the patients (post-pneumonectomy and post-
lobectomy) discharged from the hospital except one were cured and did not complain of symptoms of
secondary lung function or shoulder impairment.
The topic of late sequelae of thoracoplasty was also studied by our team.13 At late follow-up, all
patients present with some degree of thoracic deformity and scoliosis, but in 88% of cases morphologic
sequelae were neither severe nor symptomatic and the cosmetic result was considered acceptable by the
patients. In only 1 out of 26 patients was the thoracic deformity severe, and in another patient scoliosis
was symptomatic: both patients had extramusculoperiosteal thoracoplasty with resection of ribs 1 to 9.
All patients complained of a restriction in shoulder mobility during the early postoperative period, which
progressively improved with intensive physical rehabilitation. A residual reduction in shoulder mobility
was generally well accepted by the patients. Only one patient experienced a frozen shoulder syndrome,
with disability and chronic pain (resection of ribs 2 to 8). No patient showed progressive pulmonary
failure related to thoracoplasty. Overall 5-year survival from the date of thoracoplasty was 76%; cancer-
specific 5-year survival was 78% and 80% from the date of thoracoplasty and pulmonary resection,
respectively.
CONCLUSIONS
It is obvious that thoracoplasty, a hoary antiquity that served to elevate thoracic surgery to the status of a
recognized specialty, remains an occasionally useful operation. It still is a safe and effective solution for
difficult intrathoracic space problems, especially in combination with other filling procedures and
provided that infection is controlled. Postresectional empyema, mostly postpneumonectomy, with or
without bronchopleural fistula, represents the main indication today. To paraphrase Alexander: In the last
analysis, thoracoplasty is used to close a space that no other operation can close.3
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64
Anatomy of the Thoracic Duct and
Chylothorax
Moritz C. Wyler von Ballmoos ■ David W. Johnstone
EMBRYOLOGY AND HISTOLOGY

The lymphatic system is derived from the endothelium of the venous system1 as a bilateral structure at the
end of the fifth week, following development of the cardiovascular system. Six distinct lymph sacs form
from the anterior cardinal vein, both iliac veins, the posterior cardinal vein, as well as in the
retroperitoneal space. The cisterna chyli forms by fusion of two lumbar trunks and the intra-abdominal
trunk; from these structures lymphatic vessels spread in the tissue planes along veins into the periphery.
The thoracic duct is initially a bilateral structure with many bridging vessels but usually joins to form a
single duct system.2 The final thoracic duct develops as the left jugular sac grows caudally and the right
thoracic duct extends from the cisterna chyli rostrally, while the upper part of the right-sided duct and the
lower part of the left-sided duct obliterate, resulting in a thoracic duct crossing the midline. This pattern
of maturation leads to anatomic variations; the standard pattern is found in only 65% of humans.3
The capillary system of the lymphatics has an endothelium without a distinct basement membrane
allowing the absorption of large molecules. Filaments anchor the capillaries to the extracellular matrix
providing structural support. The thoracic duct has a typical three layer composition consisting of intima,
media, and adventitia surrounded by a basement membrane. The muscular media aids with propulsion of
chyle through the thoracic duct in conjunction with frequent valves. Other factors contributing to lymph
flow are positive abdominal pressure, negative intrathoracic pressure, and Bernoulli effect at the junction
of the duct and the venous system.
THORACIC DUCT ANATOMY

The usual course of the thoracic duct is illustrated in Figure 64.1. The thoracic duct is the common
channel draining lymphatic fluid from the lower body and the left upper body to the venous system. The
thoracic duct originates in the cisterna chyli anterior to the second lumbar vertebra (range T10–L3) and
on the right of the aorta, passes along the spine through the aortic hiatus (T10–T12), and ascends posterior
to the esophagus, anterior to the intercostal vessels and between the aorta and the azygos vein, to the right
of the midline (Fig. 64.2). At the fifth or sixth thoracic vertebra, the duct crosses to the left posterior to the
aortic arch and origin of the left subclavian artery, and passes through the thoracic inlet along the left side
of the esophagus. The duct receives tributaries from the bronchomediastinal trunk before exiting the
mediastinum. Once the duct enters the neck, it arches laterally at the C7 level anterior to the subclavian
artery, vertebral artery, and thyrocervical arteries. It continues superficial to the phrenic nerve and the
scalenus anticus muscle, passes behind the left carotid sheath and jugular vein, and usually terminates into
the posterior confluence of the left jugular and subclavian veins at the medial margin of the anterior
scalene muscle. This termination may be as single (80%) or multiple trunks (20%).4,5 The duct has valves
at various points along its course, the most consistent being the valve at the entry into the venous system
preventing reflux of blood into the duct.
Lymph from the right head and neck, arm, chest wall, right heart, right lung, lower half of the left lung,
right diaphragm, and convex surface of the liver drains into the right lymphatic duct. This duct also carries
lymph from the heart and the dome of the liver and from the right diaphragm. The right lymphatic trunk
typically has its major drainage into the posterior junction of the right subclavian and jugular veins; this
duct is small and rarely seen.6
FIGURE 64.1 Usual anatomic pattern of the thoracic duct.

FIGURE 64.2 Surgical anatomy of the thoracic duct in the right suprahepatic location.
MAJOR VARIATIONS OF THE THORACIC DUCT

Variations occur in nearly half the cases studied, generally consisting of multiple thoracic trunks (25% to
33%), variable crossover levels, and variable drainage of accessory trunks from the right chest, arm, and
head.3,7,8 Multiple studies of the duct termination indicate that variation is the rule: less than 40% join the
left venous confluence, with most other variations consisting of termination into the left innominate,
jugular, vertebral or right internal jugular vein, or bilateral termination (2%), and rare azygos vein
termination.9 The duct may also pass posterior to the vertebral and subclavian arteries en route to its
venous termination.
COMPOSITION OF CHYLE
Of the fluid traversing the thoracic duct in a healthy person, 95% originates in the intestines and liver. The
primary physiologic role of the cisterna chyli and thoracic duct is to deliver digestive fat to the venous
system. Medium- and long-chain fatty acids cannot be absorbed directly into the blood stream and form
micelles that are transported in the chyle. Approximately 60% of ingested fat reaches the venous system
via the thoracic duct. Fat from intestinal absorption gives chyle its characteristic milky appearance.
Consequently, chyle appears serous in the fasting state.
The composition of chyle is summarized in Table 64.1. Concentrations of fat, protein, and lymphocytes
vary considerably depending on the timing, composition, and amount of food ingested.
The fat in thoracic duct lymph is composed of neutral fat, free fatty acids, sphingomyelin,
phospholipids, cholesterol, and cholesterol esters. Fatty acids shorter than 10 carbon atoms are absorbed
directly into the portal system and therefore largely bypass the lymphatic circulation. For that reason, a
diet restricting fat to short-chain triglycerides has been used to reduce thoracic duct flow. Ingested fat
passes from the intestine to the systemic circulation over approximately 1.5 hours, with peak absorption 6
hours after ingestion.
TABLE 64.1 Composition of Chyle

Component Amount (per 100 mL)
Total fat 0.4–5.0 g
Cholesterol 65–220 mg
Protein 2.2–5.9 g
Albumin 1.2–4.1 g
Globulin 1.1–3.6 g
Fibrinogen 16–24 g
Antithrombin ¼ plasma concentration
Prothrombin ¼ plasma concentration
Fibrinogen ¼ plasma concentration
Sugar 48–200 g
Electrolytes Similar to plasma
Cellular elements
Lymphocytes 400–6,800/L
Erythrocytes 50–600/L
From Maskell NA, Butland RJA. BTS guidelines for the investigation of a unilateral pleural effusion in adults. Thorax 2003;58(suppl 2):ii8–
ii17; Selle JG, 3rd, Snyder WH, Schreiber JT. Chylothorax: indications for surgery. Ann Surg 1973;177(2):245–249; Helin RD, Angeles STV,
Bhat R. Octreotide therapy for chylothorax in infants and children: A brief review. Pediatr Crit Care Med 2006;7(6):576–579.
Extracellular protein, electrolytes, and glucose from the interstitial space are transported in lymphatic
fluid and returned to the venous system. The protein concentration is about half and the electrolyte
concentration almost equivalent to that of plasma.10
The main cellular elements of thoracic duct lymph are lymphocytes, predominantly T-lymphocytes
(90%).11 Thoracic duct lymphocytes differ from peripheral blood lymphocytes in their reactivity to
antigenic stimulation. Fat-soluble vitamins, antibodies, enzymes, and urea nitrogen are present in thoracic
duct lymph. Chyle is bacteriostatic, probably due to its high lecithin and fatty acid content, and typically
prevents empyema formation.
PHYSIOLOGY OF THE THORACIC DUCT

The flow of lymph in the thoracic duct has been estimated to be 1.38 mL/kg/hr of body weight per hour,
varying between 30 and 190 mL/hr.9 Flow increases after ingestion of food and water and during
abdominal massage.12 Hepatic lymph increases by 150% after meals, whereas the basal intestinal lymph
flow may increase 10-fold after fatty meals.6 Volumes up to 2,500 mL of chyle in 24 hours have been
collected from the cannulated human thoracic duct. Starvation and complete rest decrease the flow of
thoracic duct lymph.
The inflow of chyle into the lacteal system is driven by absorption of intestinal food and liquid and is
augmented by intestinal contractions. The negative transdiaphragmatic pressure gradient helps upward
flow of chyle. Muscular contractions of the duct wall occur every 10 to 15 seconds independent of
respiratory movements. The intraductal pressure ranges from 10 to 25 cm H2O, and with obstruction may
increase to 50 cm H2O.13 The thoracic duct valves, located throughout its course but mostly in the upper
portion, promote upward flow.
CAUSES OF CHYLOTHORAX
A chylothorax is the presence of lymphatic fluid in the pleural space resulting from a laceration of the
lymphatics; its causes can be broadly grouped into congenital, traumatic, infectious, and neoplastic (Table
64.2).
TABLE 64.2 Etiology of Chylothorax

Developmental anomalies
Traumatic
Birth trauma
Blunt
Penetrating
Surgical
Cervical
Excision of lymph nodes
Radical neck dissection
Thoracic
Ligation of patent ductus arteriosus
Excision of coarctation
Esophagectomy
Resection of thoracic aortic aneurysm
Resection of mediastinal tumor
Left pneumonectomy
Abdominal
Sympathectomy
Radical lymph node dissection
Diagnostic procedures
Lumbar arteriography
Subclavian vein catheterization
Neoplasms
Miscellaneous
From Chernick V, Reed MH. Pneumothorax and chylothorax in the neonatal period. J Pediatr 1970;76(4):624–632.
CONGENITAL CHYLOTHORAX
Congenital, or primary, chylothorax is the most common cause of pleural effusion in the neonatal period.14
It presents at birth or during the first weeks of life as respiratory distress. Most cases are idiopathic.
Chylothorax is associated with syndromes which involve abnormal lymphatic development. The thoracic
duct may be absent or atretic, or may have multiple, dilated lymphatic channels with abnormal
communications including fistulae to the pleural space; lymphedema and polyhydramnios can occur as a
result. Birth trauma, including hyperextension of the neck, and conditions elevating pressure in the
superior vena cava, may be causes as well.15
Treatment of congenital chylothorax is generally conservative, with expectation of resolution in 4 to 5
weeks. Continued breast feeding has not prevented resolution in many cases, though MCT diet or
parenteral nutrition may be needed in refractory cases. Thoracentesis is appropriate for initial relief of
respiratory distress; pleuroperitoneal shunting is preferred in absence of ascites; thoracic duct ligation
and/or pleurodesis may be required in some cases.15
TRAUMATIC CHYLOTHORAX
Chylothorax may occur following blunt or penetrating trauma. The most common form of nonpenetrating
injury to the thoracic duct is produced by sudden hyperextension of the spine with rupture of the duct just
above the diaphragm. Sudden stretching over the vertebral bodies may be enough in itself to tear the duct,
but usually the duct has been fixed as a result of prior disease or malignancy. Vomiting or violent coughing
also can result in tearing of the thoracic duct.16 Penetrating trauma to the thoracic duct is unusual and is
typically of lower priority than other associated injuries.
IATROGENIC INJURIES
Injury to the thoracic duct can occur during any operation in the vicinity of the mediastinum or lower neck.
Chylothorax has been reported following most types of thoracic procedures. The duct is at particular risk
during esophagectomy, first rib resection, aortic operations, coarctation repair, ligation of patent ductus
arteriosus, left pneumonectomy, removal of posterior mediastinal tumors, and sympathectomy.
Chylothorax may also complicate radical neck dissections, surgery or cannulation of the subclavian
vessels, abdominal sympathectomy, and lymph node dissections. Occasional chylothorax following
central venous cannulation may be due to venous occlusion rather than direct injury to the duct.17
Awareness of the typical ductal anatomy and its variability combined with vigilance when working in
areas at risk is the best strategy for avoiding damage. Injury to the duct is often unrecognized
intraoperatively because patients have not had oral intake for many hours and the duct lymph is serous.
Preoperative ingestion of a fat-containing liquid with or without addition of a marker has been proposed
by some surgeons to identify the thoracic duct if an intraoperative injury occurs, and in order to facilitate
duct ligation when necessary.18 Injuries to the duct below the T6 level tend to present on the right, and
those above that level tend to present on the left.
The incidence of chylothorax following esophagectomy varies between 0.5% and 3.4% in large
contemporary reports, and does not clearly depend on the approach chosen. Orringer et al.19 reported less
than 1% incidence in 1,085 patients undergoing transhiatal esophagectomy. Dugue et al.20 reported a 2.7%
incidence among 850 patients undergoing Ivor-Lewis esophagectomy. A report of 1,787 esophagectomies
performed with a 1.1% incidence of chylothorax found no difference between transthoracic and
transhiatal approaches (1% of 1237 patients vs. 1.3% of 464 patients, respectively).21 A meta-analysis of
44 published reports found a 2.1% incidence among 2,675 transhiatal esophagectomies and a 3.4%
incidence among 2,808 Ivor-Lewis esophagectomies.22 Prophylactic duct ligation at the time of
esophagectomy has been proposed by some authors. The evidence from several studies, mostly
retrospective cohorts, is mixed regarding the effectiveness of prophylactic duct ligation but suggests it can
be done safely and without significantly prolonging operative time.23 In 255 patients resected via a left
thoracoabdominal approach, Dougenis et al.24 reported a lower incidence of chylothorax among those
who had prophylactic duct ligation (2.1%) versus those who did not (9%). Merigliano et al.,21 reporting
1,787 esophagectomies, found no chylothoraces in 106 consecutive patients since adopting a policy of
routine thoracic duct ligation during transthoracic resection. Another series of 850 Ivor-Lewis
esophagectomies with routine duct ligation reported a 2.7% incidence of chylothorax.20 These rates are
not substantially lower than large recent series that do not employ routine ligation.
One randomized clinical trial with 653 patients reported a reduction in the incidence of chylothorax
from 2.1% to 0.3% after a priori duct ligation in esophagectomy patients.25 In a large, single institution
series, Shah et al.26 demonstrated that chylothorax after esophagectomy substantially increases morbidity,
length of stay, and perioperative mortality after esophagectomy. Since it adds little operative time and can
be done safely, preventative duct ligation should be considered especially if a more extensive mediastinal
dissection is performed or thoracic duct injury is deemed likely due to other intraoperative findings.
Chylothorax following pulmonary resection is unusual. In a large retrospective study from the Mayo
Clinic, over 11,000 patients who underwent thoracic surgical procedures included 47 (0.42%) who
developed a postoperative chylothorax.27 Thirteen of these patients had undergone a pulmonary resection.
Sarsam et al.28 reported that chylothorax developed in 9 of 1,800 patients (0.5%) who underwent
pneumonectomy. Terzi et al.29 reported 13 chylothoraces occurring among 1,744 patients after
pleuropulmonary surgery (0.74%). The majority of cases occur after pneumonectomy, extensive
lymphadenectomy, sleeve resections, or other resections involving more extensive dissection in the hilum
and paratracheal area.30,31
NEOPLASTIC CHYLOTHORAX
Invasion, compression, or tumor embolism of the thoracic duct by malignancies can result in rupture of
distended tributaries with resultant chylothorax, or more rarely, chylopericardium.32 Neoplasms account
for about half of all chylothoraces in adults and a malignancy is the diagnosis of exclusion in every patient
with a new, unexplained chylothorax. Lymphoma is the most common culprit ( 50% of cases), followed
by lung cancer and retroperitoneal sarcoma, but metastatic disease from virtually every organ system has
been described in association with chylothorax.33 Chylothorax has also resulted from mediastinal
radiotherapy for malignant disease and can occur during therapy or late in the course of disease without
necessarily signaling the development of a recurrence.
MISCELLANEOUS CAUSES
Infections (tuberculosis, fungal, mediastinitis), filariasis, vasculitides, and thrombosis of the jugular and
subclavian veins can cause chylothorax. Benign lymphangiomas arising in the thoracic duct also may
produce single or multiple cystlike spaces filled with chyle. Pulmonary lymphangioleiomyomatosis is a
rare cause of chylothorax in women of reproductive age presenting also with pneumothorax and
hemoptysis. Chylothorax is seen in 20% of cases and is due to infiltration of lymphatics by smooth muscle
cells.34,35
Secondary chylothorax can occur because of chylous ascites resulting from abdominal surgery, a
malignancy, pancreatitis, pancreatic pseudocysts, cirrhosis of the liver, or exudative enteropathy.
PATHOPHYSIOLOGY
If the initial leak from the thoracic duct remains contained within the mediastinum, the only sign may be a
widened mediastinum on chest x-ray. With rupture of the mediastinal pleura, lymphatic fluid rapidly
accumulates in the pleural space.
When chyle accumulates in the pleural space, or more rarely, in the pericardium, it presents with the
signs of a large pleural effusion (dyspnea, cough, hypoxemia) or pericardial effusion (tachycardia,
pericardial tamponade). Onset of these symptoms is typically gradual, but the course can be rapid with
presentation as a tension chylothorax. Without external drainage net losses of fluid, fats, lymphocytes, and
protein do not occur. The success of pleuroperitoneal shunts in infants with chylothorax illustrates this
point, as does conservative management of patients with lymphoma who often respond to treatment of the
underlying disease. However, significant fluid shifts from intravascular to extravascular can still result in
hemodynamic compromise.
Often drainage is necessary to alleviate symptoms and ongoing external drainage of a chylothorax may
rapidly deplete nutritional, fluid, electrolyte, and lymphocyte reserves. The volume of lymph can exceed
2.5 L/day, and in most postoperative cases drainage exceeds 1 L/day. The resulting malnutrition,
immunosuppression, and coagulopathy carry a high morbidity and mortality unless corrected. Spontaneous
healing of a nonsurgical fistula may be expected in less than half of patients within 2 weeks, and death
generally ensues in the remaining patients unless the fistula is surgically closed.
DIAGNOSIS
Diagnosis of a chylothorax is suggested, via thoracentesis or catheter drainage, by the presence of
nonclotting, milky fluid in the pleural space. Whereas chyle can be clear in the fasting state, it becomes
milky after oral intake that includes fats. Even in the fasting state the fat content of thoracic duct fluid is
significant. Biochemical and microscopic examinations of the fluid confirm the diagnosis. The
concentration of triglycerides is higher and the protein concentration less than half that of plasma; fluid
with a triglyceride level of more than 110 mg/dL has a 99% chance of being chylous as opposed to a 5%
chance when less than 50 mg/dL.36 The presence of chylomicrons in the fluid is specific for the diagnosis
of chylothorax, and should be sought if triglyceride levels are equivocal. On microscopic examination, the
presence of fat globules that clear with alkali and ether, or that stain with Sudan-3, is diagnostic. Gram
stain can be helpful for making the diagnosis, typically showing more lymphocytes than
polymorphonuclear leukocytes and no bacteria. A cell count with differential resulting in 90%
lymphocytes essentially makes chylothorax the diagnosis of exclusion.
Chylothorax should be distinguished from pseudochylothorax, which results from the accumulation of
cholesterol crystals in a long-standing pleural effusion. In these cases the pleura is usually markedly
thickened and fibrotic.37 The most common causes of a pseudochylous effusion include chronic
rheumatoid pleurisy, tuberculosis, and artificial pneumothorax.38,39 Chylothorax and pseudochylothorax
can be discriminated by lipid analysis of the fluid. In a pseudochylothorax the cholesterol level is >200
mg/dL, chylomicrons are not found, and cholesterol crystals are often seen.40 If the diagnosis is still in
question, a fatty meal containing green No. 6 dye will stain a chylous effusion in about 1 hour after
ingestion.
The rate of fluid accumulation is often characteristic for a true chylothorax. A chylous fistula averages
700 to 1,200 mL/day in a 70-kg adult. Postoperatively, this may not become evident for several days,
depending on the patient’s oral intake, fluid balance, or type of surgery. An abrupt increase in chest tube
drainage or rapidly filling pneumonectomy space should raise suspicion of a chyle leak and prompt
appropriate diagnostic tests. Diagnosis of a postpneumonectomy chylothorax may be delayed because the
pleural space is either not drained, or drained for a brief period postoperatively. The development of a
pleural effusion is expected and its rate of increase may vary. Patients may present with a tension
chylothorax, causing contralateral mediastinal shift and related symptoms. A high index of suspicion is
needed to make a timely diagnosis.
In cases of nontraumatic chylothorax, the underlying cause must be sought and in adults must raise the
suspicion for a malignancy. A complete history and physical examination is performed, and computed
tomography of the chest and abdomen is typically obtained to identify lymphadenopathy, mediastinal
masses, primary tumors of the lung, and other suspected lesions.
Albeit laborious, lymphangiography provides useful information regarding the lymphatic anatomy and
fistula site. It is generally reserved for refractory chylothoraces that have failed initial surgical closure.
Other methods used to locate the leak intraoperatively include preoperative subcutaneous injection of 1%
Evans blue dye in the thigh or enteral administration of a fat source like cream or olive oil. Methylene
blue may be added to the fat source to highlight the site of the fistula, but it widely stains the mediastinal
and pleural surfaces.
CONSERVATIVE MANAGEMENT
Conservative (nonsurgical) management of chylothorax is usually appropriate as an initial strategy,
particularly in the first few days following surgery or trauma, or in cases of malignant chylothoraces
which may respond to treatment of the underlying neoplasm (particularly lymphoma). The principles of
conservative management are adequate respiratory function, obliteration of the pleural space, reduction of
chyle flow, maintenance of hydration, and provision of adequate nutrition. This is successful in roughly
25% to 50% of all patients with chylothorax within 2 weeks of treatment.
Evacuation of the pleural space is most commonly achieved by tube thoracostomy. This provides lung
re-expansion and obliteration of the pleural space. Close attention must be paid to tube patency, position,
and changes in drainage as prolonged drainage can lead to tube obstruction or loculation away from other
portions of the pleural space. Since chyle is bacteriostatic, infection from the indwelling tube is
uncommon. Alternatively, repetitive thoracocentesis or a pleuroperitoneal shunt can be used. Repetitive
thoracocentesis can result in hemothorax, empyema, and incomplete drainage, thus further complicating
the situation. Pleuroperitoneal shunting may be appropriate in cases of malignant chylothorax, since
nutritional losses are minimized and dyspnea is improved. Pleuroperitoneal shunting is a reasonable
option when thoracotomy is contraindicated, and may be the best choice when the lung is entrapped.
Implantation is simple, safe, and effective in properly selected patients. Occlusion with fibrinous debris
occurs in about 10% of patients and requires replacement. Chylous ascites is a contraindication. Success
has been reported to be 75% to 90% in treating pediatric chylothoraces and up to 80% in adults.41–43 The
procedure is associated with minimal discomfort, but the subcutaneous chamber must be compressed up
to several hundred times per day to shunt an adequate volume. In debilitated cancer patients, this is not a
useful solution. Intermittent external drainage, either with thoracentesis or a semi-permanent catheter, may
be a reasonable palliative alternative.
Maintenance of nutrition, prevention of dehydration, and reduction of chyle flow are closely related.
Large losses of fluid, electrolytes, protein, fat, fat-soluble vitamins, and lymphocytes result in severe
metabolic and immunologic derangement. A reduction in enteral intake and specifically in the dietary
intake of long-chain fatty acids is associated with a significant reduction in lymphatic flow. The
substitution of dietary fat with medium chain triglycerides is widely practiced. Short- and medium-chain
fatty acids bind to albumin and pass directly into the portal circulation. Yet, success of this strategy is
limited. Any oral intake increases chyle production and endogenous triglycerides contribute up to 80% of
chylous triglycerides even when an MCT diet is used. As a result most authors prefer complete bowel
rest and TPN as the optimal means of nutritional support while minimizing chyle production.
Traumatic chylothoraces that will close with conservative management typically do so within 2 weeks.
When the chest drainage is low, the pleural space is evacuated, and the lung is expanded, oral intake can
then be resumed. Once the patient is eating a normal diet with no evidence of persistent chyle leak, the
chest tube can be removed.
It is probable that chylous fistulae close by obliteration of the adjacent pleural space rather than by
healing of the lymphatic vessels themselves. To accelerate pleural symphysis, various chemical
sclerosants have been applied to the pleural space. These include antibiotics (tetracycline, doxycycline),
antineoplastic agents (bleomycin), biologic modifiers (OK-432, interferon, and interleukins), and talc.
Chemical pleurodesis may be most appropriate for patients with malignant chylothoraces, in whom direct
closure of the leak is impossible, but rarely is successful in absence of complete drainage and with high
fistula output. Aggressive pulmonary toilette and if necessary further support, including invasive
ventilation, are imperative in all patients with chylothorax to ensure adequate respiratory function and full
expansion of the lung. Positive pressure ventilation modes can be used to reduce chylous leak in patients
already receiving mechanical ventilation.
When the chylothorax is secondary to lymphatic obstruction by tumor, treatment of the primary
condition with radiotherapy and/or chemotherapy may control the chyle fistulae, either by promoting local
fibrosis or by relieving lymphatic obstruction. Thoracotomy for duct ligation should be offered only after
careful consideration of the patient’s prognosis and likelihood of successful closure. Poor results have
been reported in this setting.44,45 In the occasional chylothorax patient undergoing thoracotomy for
diagnosis, duct ligation and pleurectomy should be performed if feasible.
Several pharmacologic interventions have been tested to reduce chyle production including
somatostatin, octreotide, and etilefrine. Somatostatin is a polypeptide hormone that has predominantly
inhibitory effects on gastrointestinal and endocrine function.46 Octreotide decreases the volume of foregut
secretions, therefore reducing the volume and protein content of fluid within the thoracic duct; it may also
act directly on the splanchnic circulation to reduce lymph production.47–49 Somatostatin has been used
successfully in adults, infants, and children with chylothoraces. For postoperative chylothoraces, it may
have utility as an adjunct in initial conservative management. The use of somatostatin is better
documented in the literature compared to octreotide; however, evidence for both drugs as well as
comparison between them is still very limited. Etilefrine has been suggested as another adjunct. Its
sympathomimetic action may increase contraction of smooth muscle cells in the thoracic duct and thereby
reduce the chyle leak.
Other methods of conservative management include positive pressure ventilation, inhaled Nitric Oxide
(NO) at 20 ppm, and percutaneous embolization of the thoracic duct. The institution of positive pressure
ventilation and/or NO has reportedly resulted in a marked reduction in chest tube drainage and has even
stopped the chyle leak. It is believed that systemic venous hypertension may be a significant contributing
factor to a persistent chyle leak. NO, a predominately pulmonary arterial vasodilator, may decrease
systemic venous pressures by augmenting forward flow through the right side of the heart.
Radiation therapy has been reported in select cases of postoperative chylothorax as a palliative
treatment in patients that cannot tolerate a surgical intervention.
SURGICAL MANAGEMENT
There is general consensus that failed conservative management warrants surgical intervention. There is
less agreement on clinical parameters that constitute failed conservative management, which is also
uniformly used in addition to any surgical intervention. The following indications have been proposed in
the literature. Idiopathic chylothorax in neonates and nontraumatic chylothorax should be managed
nonoperatively. Indications for thoracic duct ligation in traumatic chylothorax are an average daily loss of
greater than 1,500 mL/day in adults or greater than 100 mL/yr of age in children over a 5-day period;
persistent leak for more than 2 weeks despite conservative management; and nutritional or metabolic
complications. If the lung is entrapped and pleural symphysis cannot be achieved by tube thoracostomy,
then early surgical intervention is also indicated.44 Dugue et al.20 tried to identify predictors of successful
conservative management in patients with chyle leaks after esophagectomy and suggested that chyle output
of <10 cc/kg/day on the fifth postoperative day predicted success with medical management alone (12/14
patients), whereas output above this level was seen in all of their patients requiring surgical ligation of
the thoracic duct. Other authors have advocated immediate reoperation, citing the low likelihood of early
closure of the fistula.21,27 In our experience, a postesophagectomy chylothorax that has not resolved within
5 days warrants prompt re-exploration and duct ligation. At that point the pleural space is relatively free
of adhesions and the gastric conduit can be mobilized without difficulty to expose the suprahiatal area.
Drainage usually subsides promptly thereafter.
Compared to chyle leaks occurring after esophageal resection, those following pulmonary resection
may be handled more conservatively. In the Mayo Clinic study cited above, 89% of postesophagectomy
chylothoraces required re-exploration compared to 38% following pulmonary resection.27 The decision
to continue medical management or proceed with surgery must be based on the type of pulmonary
resection performed, the volume and duration of chyle drainage, and the nutritional and immunologic
status of the patient. Following lobectomy, a conservative approach may be suitable if the remaining lung
fills the pleural space and drainage rates are not excessive. Factors associated with failure of this
approach are drainage >500 cc/day and extensive lymphadenectomy.29 Other authors have not found
response to an initial trial of conservative management to be predictive of its eventual success, and favor
early surgical intervention.50 Chylothorax following pneumonectomy often poses additional challenges,
when drainage is complicated by the shifting mediastinum, the possibility of empyema, and the absence of
residual lung to provide tissue apposition to seal the fistula. Factors reported to predict successful
conservative treatment include absence of contralateral mediastinal shift and related symptoms, drainage
less than 300 cc/day, presentation after the first postoperative week, and absence of a demonstrable leak
on lymphangiography associated with opacification of the lymphatic system all the way to its venous
termination in the neck.28,51,52
FIGURE 64.3 (A) Lipiodol injection in both inguinal areas for lymphatic uptake and delineation of the thoracic duct leak. With
time, the dye migrates into the thoracic duct and demonstrates a leak to the left side in this case. (B) Thoracic duct micro-
catheter placed via direct puncture of cisterna chili, with contrast demonstrating a chyle leak to the left in the mid chest. (C)
Thoracic duct embolized with coils at the level of the leak, and n-BCA glue occlusion of the entire thoracic duct inferior to the
coils. This resolved the left chylothorax, which was a postoperative complication following esophagectomy.
The goals of a surgical intervention are reduction in chyle leak, maximizing lung expansion, and
obliteration of the pleural space. The surgical options for control of chylothorax are direct ligation of the
thoracic duct, mass ligation of the thoracic duct, thoracoscopic ligation of the thoracic duct, pleurectomy,
application of fibrin glue, and placement of a pleuroperitoneal shunt. If the chyle leak can be identified,
direct ligation with nonabsorbable ligatures should be performed on either side of the leak. If the leak
cannot be identified, extensive dissection should be avoided. Mass ligation of all tissue between the
aorta, spine, esophagus, azygos vein, and pericardium is most easily performed above the diaphragmatic
hiatus via the right pleural space.53,54 This procedure has a success rate of approximately 80% even if the
thoracic duct cannot be identified. Mass ligation has been traditionally performed via a right thoracotomy
through the sixth or seventh interspace with division of the inferior pulmonary ligament. Parietal
pleurectomy may promote pleural symphysis and should be considered when control of the duct is
uncertain. Pulmonary decortication may be necessary if the lung is entrapped in a benign peel and may be
supplemented with a chemical pleurodesis. Importantly, pleural and lymph node biopsies should be
obtained in patients that have an unknown or suspected malignant etiology underlying the chylothorax.
Unilateral chylothorax should be explored through the involved side. In bilateral cases, it is prudent to
perform mass ligation via the right chest, as this will often resolve both sides. If the left chylothorax
persists, preoperative lymphangiography may be useful to clarify the ductal anatomy before exploring the
left chest. Access to the thoracic duct through the left chest is usually complicated by the course of the
descending aorta.
Since its introduction in the early 1990s, thoracoscopic ligation of the thoracic duct has become a
therapeutic option and is now widely accepted as the recommended initial surgical intervention.55–57
Enteral administration of a fat source (50 cc of heavy cream or 100 cc of olive oil) given shortly before
surgery has been proposed to help identify the chyle leak. Thoracoscopy is performed under general
anesthesia using single lung ventilation. A trocar is placed in the right 6th or 7th intercostal space in the
mid-axillary line. A 30-degree scope is inserted and the pleural space is evaluated. A second port in the
right 8th posterior intercostal space is used for dissection and division of the inferior pulmonary ligament.
A third port is placed in the anterior axillary line superiorly for retraction of the lung. The pleura is
incised above the diaphragm. In roughly 60% of patients the thoracic duct is a single structure between T8
and T12. If the duct can be identified easily then it is dissected free. Both ends are clipped and a portion
may be sent for pathologic confirmation. If the thoracic duct cannot be easily identified, mass ligation of
all tissue in the position previously described is performed using clips or endoscopic ligation. Adjuncts
that have been described in the setting of VATS duct ligation include the use of chemical pleurodesis,
intrapleural fibrin glue, and ultrasonic coagulation. Chest drainage is established. The chest drain is
removed when chyle drainage has ceased with the patient on a normal diet. The reported success of
surgical interventions has ranged from 60% to 100%.
With the growing experience of Interventional Radiology, percutaneous transabdominal duct
catheterization and embolization can be a safe and effective alternative treatment for persistent
chylothorax (Fig. 64.3). It may be warranted not only in patients too frail to undergo duct ligation, but also
in any patient who has had recent surgical procedures. However, patients with previous major abdominal
surgery involving retroperitoneal organs may not be suitable for this intervention as they may have
occlusion of the major retroperitoneal lymphatic ducts and cisterna chyli. In experienced centers and with
suitable candidates, the success rate of this technique can be up to 70%.
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65
Solitary Fibrous Tumors and Other
Uncommon Neoplasms of the Pleura
Joel Miller Sternbach ■ Anjana Yeldandi ■ Malcolm M. DeCamp
INTRODUCTION
The pleura consists of a matrix of collagen, elastic fibers, lymphatics, and blood vessels underlying a
single layer of mesothelial cells, with primary pleural tumors arising from any of these components.
Approximately 90% of these neoplasms are malignant mesotheliomas, with half of the remaining 10%
made up of solitary fibrous tumors of the pleura (SFTP) and the other half consisting of other, less
common, tumors.1 Originating from submesothelial mesenchymal cells, SFTP occur most commonly as
well-circumscribed, pedunculated masses arising from the visceral pleura and generally follow a benign
course with excellent long-term survival following complete resection. However, an unpredictable
malignant potential in 10% to 15% of cases, including patterns of dedifferentiation, aggressive clinical
behavior, and late recurrences, currently require long-term follow-up for all patients. The clinical
presentation, imaging findings, operative management, and histopathologic features of benign and
malignant SFTP are reviewed and a variety of clinical and pathologic scoring systems are presented in an
attempt to better inform postoperative surveillance protocols. Finally, less common benign and malignant
primary pleural tumors are reviewed.
HISTORICAL PERSPECTIVE/BACKGROUND
The first report of a primary localized pleural tumor is attributed by Lieutaud in 1767 and, more
specifically, the first report of a pleural neoplasm believed to be a solitary fibrous tumor (SFT) was by
Wagner in 1870.2 Klemperer and Rabin3 provided the first pathologic distinction for pleural tumors in
1931, dividing them into diffuse and localized mesotheliomas and proposing a submesothelial
mesenchymal origin for the localized type. A decade later, Stout and Murray4 described the classic
histologic feature of solitary fibrous tumors (SFTs), the so-called “patternless pattern,” but erroneously
attributed the neoplasm to a mesothelial cell origin and referred to it as a localized fibrous mesothelioma.
Further characterization of the histologic and ultrastructural features of SFTP5–10 firmly established the
neoplasms as arising from the mesenchymal tissue below the mesothelial lining of the pleura. This
evolution in the understanding of the cellular basis, clarification of immunohistochemical features and,
more recently, the identification of a common driver mutation in SFTP has resulted in an extensive history
of nomenclature changes and reclassifications. A list of previously used terminology for SFTP is
provided in Table 65.1; use of these historic terms should be avoided due to the potential for confusion
with the pathologically and clinically distinct entities of localized malignant mesothelioma and the
sarcomatous variety of diffuse malignant mesothelioma. Since the initial discovery and characterization of
these tumors in the pleural space, SFT have also been identified as arising in virtually every part of the
body.11
Our understanding of the pathogenesis of these rare tumors was fundamentally changed by the
discovery of a common driver mutation for pleural and extrathoracic SFTs and hemangiopericytomas
(HPCs) in 2013. Studies by Robinson12 and Chmielecki13 and colleagues, utilizing next-generation genetic
sequencing techniques including whole-exome and transcriptome sequencing, demonstrated the consistent
presence of an inversion of adjacent genes located on chromosome 12q13. The inversion results in the
attachment of the early growth response 1 (EGR1)-binding domain of NGFI-A-binding protein 2 (NAB2)
to the activation domain of signal transducer and activator of transcription 6 (STAT6). This fusion
effectively converts a transcriptional repressor (NAB2) into a constituent activator (NAB2-STAT6) of
EGR target genes. EGR-responsive genes include NAB2 (resulting in a feed-forward cycle), insulin-like
growth factor 2 (IGF2), fibroblast growth factor 2 (FGF2), and platelet-derived growth factor D
(PDGFD), as well as a variety of receptor tyrosine kinases. This discovery led to refinement of the
immunohistochemical diagnosis of SFT and identified an array of potential molecular targets for novel
adjuvant therapies. Identification of the NAB2-STAT6 gene fusion in other tumor types previously thought
to be distinct clinical entities has supported the inclusion of what were formerly known as giant-cell
angiofibromas, HPCs, and lipomatous HPCs as morphologic variants of SFT. Similar genetic discoveries
include the identification of a high incidence of fusion between the WW transcription regulator 1
(WWTR1) and calmodulin-binding transcription activator 1 (CAMTA1) genes in epithelioid
hemangioendothelioma (EHE),14,15 a characteristic translocation t(X;18)(p11;q11) causing fusion of the
synaptotagmin (SYT) and synovial sarcoma, breakpoint X (SSX) genes in synovial sarcoma16 and
amplification of mouse double minute 2 homolog (MDM2) in dedifferentiated liposarcoma.17
TABLE 65.1 Historical Nomenclature for Solitary Fibrous Tumors of the Pleura (SFTP)
Historical Term Current Term
Localized mesothelioma
Fibrous mesothelioma
Localized fibrous mesothelioma
Benign fibrous mesothelioma
Solitary fibrous mesothelioma
Benign mesothelioma
Solitary fibrous tumor of the pleura (SFTP)
Pleural fibroma
Subpleural fibroma
Submesothelial fibroma
Submesothelioma
Localized benign fibroma
Localized fibrous tumor of the pleura
Fibrosarcoma of the pleura Malignant SFTP
Hemangiopericytoma Hypercellular variant of SFTP
Lipomatous hemangiopericytoma Fat-forming variant of SFTP
Giant-cell angiofibroma Giant-cell variant of SFTP
BENIGN SOLITARY FIBROUS TUMORS OF THE PLEURA
Despite being the most common nonmesothelial primary pleural neoplasm, SFTP remain relatively rare;
to date, less than 2,000 cases have been reported in the literature, almost exclusively in retrospective,
single-center series.18
Cases of SFTP have been reported in patients ranging from early childhood to octogenarians but the
majority occur between the fifth and seventh decades of life with most series reporting an equal frequency
in both men and women,19 and a slight female preponderance in the remainder.20 No consistent, causative
environmental factors such as smoking or asbestos exposure have been identified. Although historical
series reported up to two-thirds of patients presenting with intrathoracic or paraneoplastic symptoms,21
the proportion of asymptomatic patients diagnosed with SFTP has increased with the rising prevalence of
chest imaging and most recent series report 50% to 60% of masses are found incidentally.22 When
symptomatic, patients most commonly report chronic cough (22% to 33%), chest pain (19% to 23%), and
dyspnea (11% to 22%).6,23,24 Chest pain has been reported more commonly with tumors arising from the
parietal pleura. Rarely, in patients with large tumors, symptoms arising from bronchial compression and
airway obstruction have been reported, including atelectasis, obstructive pneumonitis, and hemoptysis.6,19
A rare case has been reported of cardiac decompensation due to compression and displacement of the
right side of the heart and inferior vena cava by a large, right-sided SFTP.25,59
PARANEOPLASTIC SYNDROMES
Hypertrophic Pulmonary Osteoarthropathy (Pierre Marie–Bamberger Syndrome)
Hypertrophic pulmonary osteoarthropathy (HPO) describes a rheumatoid-like disease of the bones and
joints. In addition to clubbing of the fingers and toes, the classic findings in HPO include stiffness of the
joints, edema over the ankles and occasionally of the hands, arthralgia, and pain along the surfaces of the
long bones, especially the tibia. The joint and bone pain is typically bilateral and can be severe. The
distal ends of the ulna and radius are frequently involved, and radiographic evidence of periosteal
thickening is most commonly seen at those sites. The bones of the hands, ankles, knees, elbows, and
shoulders are involved in that approximate order. Finger pressure on the anterior surface of the distal
tibia often elicits pain in advance of any radiologic changes. Despite the association of digital clubbing
and HPO with a variety of intrathoracic disease processes, when attributed to a paraneoplastic process, it
is referred to as Pierre Marie–Bamberger syndrome, after the two physicians that initially described the
symptom complex in the late 1800s.26,27 Harrison-Phipps and colleagues28 reported HPO in 23% of 86
patients with SFTP seen over a 30-year period at the Mayo Clinic, with digital clubbing observed in 20%
of the patients as well. Additional series have similarly reported rates of Pierre Marie–Bamberger
syndrome in up to 20% of patients.24,29,30 Briselli et al.,21 in their collective review of 368 patients,
reported an incidence of HPO of 22%, and found the syndrome to be more commonly associated with
larger tumors (>7 cm). The clinical significance of HPO is greater in its diagnostic rather than its
therapeutic implications. Removal of the pulmonary lesion for the most part gives dramatic remission of
the arthralgia and peripheral edema. Osseous changes regress much more slowly, with radiographic
resolution between 2 and 5 months after resection.22 Tumor recurrence is often heralded by a return of the
symptoms present with the original osteoarthropathy.
HPO is also seen in nonneoplastic conditions that cause significant shunting in the pulmonary
circulation, which has been proposed to allow unfragmented megakaryocytes to reach the distal
circulation where they stimulate the local production of growth factors including PDGF and vascular
endothelial growth factor (VEGF).31,32 Santini and colleagues33 were able to demonstrate significantly
reduced circulating levels of VEGF and PDGF in cancer patients after administration of the
bisphosphonates zoledronate and pamidronate. More recently, the resolution of bone pain was reported in
a patient with HPO following treatment with zoledronate,34 providing additional support for the role of
growth factors in the pathophysiology of HPO. In addition to the implication of growth factors in the
pathophysiology of HPO,35 Hojo and colleagues36 have suggested abnormal production of hepatocyte
growth factor as responsible for digital clubbing. Recent studies using high-resolution magnetic resonance
imaging (MRI) have confirmed the hypervascularization of the distal phalanges that occurs in clubbing37
while the periostitis that is a hallmark of HPO has been demonstrated using 18F-fluorodeoxyglucose
(FDG) positron emission tomography (PET).38
Hypoglycemia (Doege–Potter Syndrome)

The association of hypoglycemia with mesenchymal tumors has been referred to as the Doege–Potter
syndrome, since both physicians separately reported cases of hypoglycemia associated with a fibrous
intrathoracic tumor in 1930.39,40 In Briselli et al.’s21 review of 360 cases of fibrous tumors of the pleura
the incidence of hypoglycemia was 4%. Historically, hypoglycemia had been associated with larger and
histologically malignant tumors6 and in tumors with high mitotic rates41; however, a recent review42 found
an equal distribution of Doege–Potter syndrome between benign and malignant SFTs. In their case report
and review of the literature from 1979 to 2011, Meng and colleagues identified 45 cases of SFTP
associated with nonislet cell tumor hypoglycemia (NICTH), with 22 occurring in patients with benign
histology according to England’s criteria. There was no gender predilection and the mean age at
presentation was 60.8 and 64.1 years for the benign and malignant groups, respectively. The authors note
that more than 85% of the cases occurred in patients between 50 and 70 years old. For the 38 cases in
which tumor size was reported, 37 (97%) were >10 cm. All but two cases ( 10%) in each group were
cured of their hypoglycemia following resection and were free from recurrence at a mean follow-up of 35
months (range 1 to 288 months).
As with hypoglycemia from other causes, patients with Doege–Potter syndrome can present with
varying symptoms of central nervous system glucose deprivation. Convulsions, syncope, and coma may
occur, with death resulting from profound hypoglycemia if not identified and corrected promptly. The
spontaneous and often severe hypoglycemia seen in patients with NICTH is attributed to excessive
production and secretion of a partially processed, high molecular-weight form of IGF2.43 This
prohormone is known as “big-IGF2” and has been observed in elevated blood levels, as well as in high
concentrations within tumor cells, in several studies of patients with NICTH.44,45 Big-IGF2 stimulates
glucose uptake by the tumor and by insulin-responsive tissues such as muscle and fat. Hepatic glucose
production and insulin secretion are decreased by hypoglycemia and by the direct inhibitory effects of big
IGF2 on the pancreatic beta cells. Big-IGF2 also inhibits compensatory mechanisms including
glucogenesis in the liver and lipolysis in adipose tissues resulting in refractory hypoglycemia.46 This
understanding of the pathophysiology of NICTH fits with upregulation of the IGF2 gene as one of the EGR
genes targeted by the activation domain of the NAB2-STAT6 fusion product. Complete resection of the
responsible neoplasm provides immediate resolution of NICTH.29,47
Other Paraneoplastic Conditions

Galactorrhea has been found in association with SFTP.21 The clinical abnormalities that result in its
occurrence remain obscure. Similarly, β-hCG production with associated perimenopausal symptoms was
reported in association with a clinically aggressive intrathoracic SFT.48
RADIOGRAPHIC FEATURES
Chest Roentgenogram
The appearance of SFTP is for the most part indistinguishable from that of other masses of the lung. A
circumscribed mass of varying size is usually located in the lung periphery or in the projection of an
interlobar fissure. The larger neoplasms may have irregular shapes, although the margins are usually
sharply defined (Fig. 65.1). These tumors arise most often from a pedicle from the visceral pleura, but
this latter feature is rarely recognized on the chest radiograph. Occasionally, movement of the mass may
be demonstrated with changes in position when the tumor is on a stalk,49 a finding that has also been
reported on computed tomography (CT)50; such changes in shape or location with respiration or
repositioning of the patient are highly suggestive of pedunculated tumors.51
Computed Tomography
The appearance on CT is of a well-defined, occasionally lobulated mass with soft-tissue attenuation
(Hounsfield units [HU] between 25 and 40) that displaces, rather than invades, surrounding structures
(Figs. 65.1B and 65.2). Cardillo and colleagues52 found homogenous, low enhancement (<15 HU) on
contrast-enhanced CT to be suggestive of a benign tumor. Larger tumors may be associated with
heterogeneous enhancement patterns and density related to hemorrhage, necrosis, and/or areas of cystic
degeneration (Fig. 65.1B).53,54 Given the rarity of lymphatic metastases, the presence of regional
adenopathy is suggestive of an alternative diagnosis.18 Contrast-enhanced CT may also reveal a vascular
pedicle and can assist in delineating parietal or visceral pleural origin.
Magnetic Resonance Imaging

MRI findings include variable appearance and enhancement based on the morphologic heterogeneity of
the tumor. The classic, hypocellular SFTP typically shows low-to-intermediate signal intensity on T1 and
heterogeneously low intensity on T2-weighted sequences with areas of high T2-weighted signal intensity
often corresponding to hemorrhage, necrosis, cystic degeneration, or increased vascularity.53–55 MRI can
be particularly helpful in determining relationship to surrounding structures in the thoracic cavity as well
as establishing intrathoracic origin in the case of tumors that abut the diaphragm or those in a paraspinous
location.54
FIGURE 65.1 A: Chest x-ray showing a large, left-sided solitary fibrous tumor of the pleura (SFTP). B: Computed tomography
axial image of the same tumor from a computed tomography scan showing the heterogeneous density corresponding to areas of
cystic degeneration and necrosis characteristic of larger tumors.
FIGURE 65.2 Computed Tomography (CT) scan of a benign solitary fibrous tumor of the pleura. Axial (A), Coronal (B), and
sagittal (C) images showing an SFTP arising from the visceral pleura of the right lower lobe. Of note, the mass forms an acute
angle with the posterior and diaphragmatic parietal pleura and the mass is compressing, rather than invading, the parenchyma of
the surrounding right lower lobe.
Positron Emission Tomography

The published experience with the use of PET in the diagnosis of SFTP is limited and studies have
presented conflicting findings regarding the utility of this modality in differentiating benign from malignant
tumors. Cardillo and colleagues52 typified these mixed results in their study of 10 cases in which PET
was part of the preoperative evaluation. In eight “negative” studies (maximum Standardized Uptake Value
(SUVmax) <2.5), seven cases were ultimately confirmed to be benign with one malignant histologically.
The two positive studies came from one benign and one malignant case, providing a negative predictive
value of 87.5%, with a small sample size. Hara and colleagues56 reported a case where focal, increased
FDG uptake (SUVmax = 3.0) corresponded to a discrete area of malignant transformation within a large,
otherwise benign appearing SFTP; a similar case is depicted in Figure 65.3. Kohler et al.57 reported on
the ability of FDG PET to predict malignant histology in three patients with positive studies, all of whom
met malignant criteria on pathologic analysis. Dong and colleagues58 reported a similar case in which
increased uptake (SUVmax = 17.3) was seen on FDG PET in a patient with a CT-guided biopsy consistent
with benign SFTP but a clinically aggressive course, including multiple intraparenchymal metastases,
ultimately consistent with the malignant variety. Robinson and Reilly59 presented early cases
demonstrating the absence of uptake on FDG PET to predict benign histology, with similar results in the
study by Cortes and colleagues.60
Ultrasound
The role of ultrasound in the evaluation of SFTP is limited although some utility has been reported in
differentiating abdominal versus thoracic origin for tumors that abut the diaphragm.53 When viewed on 2D
ultrasound via an intercostal window, the characteristic appearance of a viscerally based SFTP is that of
a homogenous, hypoechoic mass that compresses the neighboring lung, distorting the visceral pleural line
and demonstrates respiratory movement relative to the chest wall.61
FIGURE 65.3 Positron emission tomography (PET) scan in focally dedifferentiated solitary fibrous tumor of the pleura. Coronal
(A) and sagittal (B) reformatted images show a focal area of increased uptake within an otherwise bland appearing tumor arising
from the visceral pleura of the left upper lobe.
DIAGNOSIS
Definitive diagnosis of SFTP relies on pathologic analysis of resected surgical specimens. Fine-needle
aspiration (FNA) biopsy has been found to be unreliable for suggesting the diagnosis of SFTP, which
relies heavily on identification of characteristic histology. While a few early studies reported diagnostic
utility,20 most published series have shown that FNA biopsies frequently provide insufficient tissue for a
definitive diagnosis.19,62,63 Cardillo and colleagues52 found that FNA performed in 23 cases provided a
generic diagnosis of unspecified “mesenchymal tumor” in 40% and were nondiagnostic in the remaining
60%, with similar results reported in other contemporary series.57,64 The limited available evidence does
suggest a higher diagnostic yield with core-needle biopsies. In their series of five patients, Weynand and
colleagues65 reported a 100% diagnostic accuracy using a transthoracic cutting needle. Needle biopsy
performed with the guidance of FDG PET to target hypermetabolic areas has been suggested to improve
the adequacy of tissue sampling for diagnosis as well.66 There is no specific role for bronchoscopy in the
diagnosis of SFTP (outside of ruling out other lesions in symptomatic patients), although exceptionally
rare endobronchial SFTs have been reported.67,68
TREATMENT
The mainstay of treatment for SFTP is surgical resection. Tumors considered benign on the basis of
location and morphology may ultimately be found to be malignant, both histologically and clinically, so
adequate removal of the original lesion must be ensured. There has been no evidence to suggest that
lobectomy is preferable to local resection of a pedunculated lesion arising from the visceral pleura.
Stapled wedge resection of 1 to 2 cm of lung parenchyma around the base of the tumor is generally
sufficient (Fig. 65.4); simple transection of the pedicle is inadequate and should be discouraged given that
tumor cell invasion of the stalk and recurrences following pedicle transection have both been described.52
If the lesion is within the lung parenchyma, however, anatomic resection is advisable. A segmentectomy is
occasionally sufficient, but even a bilobectomy may be necessary when the lesion is located within a
fissure.
SFT of the mediastinal, diaphragmatic, and parietal pleura should be excised as widely as can be
accomplished satisfactorily since these locations are more often associated with a malignancy. Radical
resection of SFT arising from the parietal pleura, including extrapleural dissection and chest wall
resection, was described in 11 of 60 patients in the series by Magdeleinat and colleagues.64
FIGURE 65.4 Video-assisted thoracoscopic surgery (VATS) excision of a benign solitary fibrous tumor of the pleura. Coronal
(A) and sagittal (B) reformatted images revealed a small mass (black arrows) appearing to arise from the diaphragm and
projecting into the interlobar fissure of the left lung. C: Thoracoscopic image showing the mass arising on a stalk entirely from
the visceral pleura of the left upper lobe. D: A stapled wedge resection was performed with a 1- to 2-cm margin. E: The
specimen was placed in a retrieval bag prior to removal from the chest cavity. Final pathology was consistent with a benign
SFTP.
Removal can be accomplished via a standard open thoracotomy; however, a video-assisted thoracic
surgery (VATS) approach has been successfully utilized in selected patients in almost all contemporary
case series. Sanguinetti69 described a case with successful thoracoscopic resection of an SFTP in 1996.
Cardillo et al.70 reported the use of VATS in 39 of their 55 patients (70.9%). The standard open approach
was reserved for patients with very large tumors, with multiple synchronous lesions, with inverted
fibromas, and with obvious malignant lesions. An update by the same authors a decade later reported
attempting VATS in 69 of 110 patients (63%) with a 14.5% conversion rate.18 Kohler et al.57 highlighted
the potential benefits of the thoracoscopic approach, successfully completed in 15 of 27 patients in their
series. Patients undergoing VATS had a shorter mean length of stay (4.5 vs. 7.5 days) and although the
tumors extirpated by VATS were smaller (mean 4.9 cm vs. 12.4 cm for those removed by anterolateral
thoracotomy), the masses in the former group ranged from 2 to 9.5 cm. Lu and colleagues,71 in their series
of 13 cases, also reported a shorter length of stay for the four patients undergoing VATS, all of whom had
smaller tumors and a prominent pedicle. It would appear that either approach is satisfactory as long as
one does not impede the ability to achieve complete resection.
It should be emphasized that the resection of any of these tumors must be microscopically complete.
The recurrence of a benign lesion is a potentially dangerous event and risks the development of a
subsequently malignant tumor. Mahesh et al.72 recorded such a development at the time of a third
recurrence of an initially benign tumor. The fourth recurrence was likewise malignant. Contact metastasis
has also been reported at the site of tumor extraction70,73 and highlights the importance of the use of a bag
during specimen removal (Fig. 65.4E).
Tapias and colleagues74 noted that preoperative embolization of feeding arteries for large tumors (>20
cm) can reduce intraoperative blood loss and that a thoracoabdominal approach facilitates removal of
large tumors. Palleschi and colleagues75 described a similar case as did Weiss and Horton,76 who
reported having to abort an attempted resection via median sternotomy of a massive SFTP from the left
hemithorax of a 69-year-old female; the authors subsequently employed percutaneous angiography and
embolization of the supplying vessel arising from the left costocervical trunk to facilitate a safer
resection. Overall, an operative mortality rate of 1% has been reported,52 with the rare deaths described
more commonly following resection of massive SFTP.
PATHOLOGIC CHARACTERISTICS
Gross Features
Most benign tumors arise from the visceral pleura on a stalk and project into the pleural space in a
pedunculated manner. Sessile attachment to the pleura occurs, and inward growth into the lung
parenchyma may be seen infrequently (the so-called inverted fibroma). Yousem and Flynn77 reported three
cases of intraparenchymal SFTs, only one of which was attached to the visceral pleura. They theorized
that the other two may have arisen from mesenchymal cells in the interlobular septa or even de novo in the
lung tissue. SFTP may also occasionally develop within a fissure as well as arise from the mediastinal,
diaphragmatic, or costal portions of the parietal pleura. Tumors in these locations, including those arising
within a fissure or growing into the lung, often prove to be malignant.70 Although many SFTs arising from
the parietal pleura have a broad base, some larger tumors may feature a vascular pedicle.21 This may be
associated with increased vascularity of the lesion. Even with some smaller benign tumors, vascular
adhesion between the tumor and the adjacent visceral or parietal pleura is not uncommon and may be
troublesome at the time of operation. Grossly, benign SFTP are almost always ovoid or round. The
external surface may be smooth or bosselated, with a thin, membranous capsule present in approximately
half of the cases.6 The size can vary greatly from a small nodule to a mass completely filling a
hemithorax. Regardless of the size, on cut section, the tumor is nodular and composed of dense, whorled
fibrous tissue (Fig. 65.5A) that may, in 10% to 15% of cases, contain cyst-like structures filled with a
clear viscid fluid. Calcifications are not characteristic but may occasionally be present within the tumor.
Histologic Features
Microscopically, one or more histologic patterns may be seen. The most common pattern seen is the
“patternless pattern” described by Stout.78 Fibroblast-like cells and connective tissue are observed in
varying proportions and are arranged in a disorderly or random pattern (Fig. 65.5B). The tumor cells are
spindle or plump ovoid cells with round to oval nuclei and small nucleoli. Collagen and elastin bundles
are readily identified. Pleomorphism and mitoses are seen infrequently. The second most common pattern
is the hypercellular variant, previously known as HPC, featuring closely packed tumor cells arranged
around open or collapsed, irregular branching capillaries (Fig. 65.6). Other uncommon patterns, always
mixed with one of the aforementioned patterns, are described as storiform, herringbone, leiomyoma-like,
or neurofibroma-like.
FIGURE 65.5 Benign solitary fibrous tumor of the pleura. A: Gross: Well circumscribed mass, 6 cm in greatest dimension, with
a firm white whorled cut surface. B: Micro: “patternless pattern” of dense strands of collagen with interspersed spindle cells.
FIGURE 65.6 Microscopic view of a benign SFTP with the hemangiopericytoma-like pattern of tumor cells surrounding open
capillaries and small- to medium-sized blood vessels with the classic “stag horn” appearance.
Ultrastructural Features
Ultrastructurally, single to clusters of fusiform to round cells are found interspaced between focal or
abundant collagen. The spindle cells most closely resemble mesenchymal cells of fibroblast or
myofibroblastic type with dilated rough endoplasmic reticulum.7,8,10,21,79 Keating et al.29,80 noted that no
basal lamina, intracellular junctions, or microvilli are seen.
Immunohistochemical Features
The characteristic immunohistochemical staining for SFTP and other pleural tumors is summarized in
Table 65.2. CD34 reactivity is characteristically described as present in hematopoietic stem cells,
endothelium, vascular tumors, and smooth muscle tumors. Bcl-2 oncoprotein (a regulator of cell death)
has been identified in both benign and malignant spindle cells of these pleural tumors as well as in tumors
of this cell type in other locations.81–83 The lack of keratin reactivity and positive CD34 antigen and bcl-2
oncoprotein differentiate SFTP from desmoplastic mesothelioma.
Since the discovery of the NAB2-STAT6 fusion gene, multiple studies have assessed the utility of
immunohistochemical staining for the presence of the predicted NAB2-STAT6 protein fusion product,
with the majority concluding that strong nuclear staining for STAT6 is a highly sensitive and specific
marker to differentiate SFTP from its histologic mimics. More recent studies have looked at the role of
specific combinations of NAB2-STAT6 exon fusions in determining the histology, clinical presentation,
and behavior of SFTs.84–87 The NAB2 exon 4–STAT6 exon 2/3 fusion variant has been associated with
pleuropulmonary SFTs85 and less aggressive behavior.86
Demicco and colleagues,87 in an analysis of growth factor pathways and potentially targetable
biomarkers, found that the various histologic presentations of the different SFTP morphologies were
related to specific patterns of growth factor production potentially attributable to specific combinations of
the NAB2 and STAT6 genes. In the hypercellular variants (formerly HPCs) there was a predominance of
VEGF and PDGF-beta, while the hypocellular (or classic) SFTP highly expressed EGFR and metastatic
tumors overexpressed PDGFR-alpha. Confirmatory studies of gene expression in SFT have consistently
demonstrated the overexpression of STAT6 but also frequently identifying GRIA2 expression, a gene
sequence not normally seen in cells with fibroblastic differentiation. GRIA2, found in 89% to 93% of
SFTs, encodes for a glutamate receptor subunit known as GLUR2 that is normally found in the nervous
system and is hypothesized to have tumorigenic properties by mediating increased cell proliferation.88,89
GRIA2 positivity has been shown to differentiate SFT from other CD34+ tumors, notably, dedifferentiated
liposarcomas and deep fibrous histiocytomas, suggesting a potential complimentary role for GRIA2 with
STAT6 in resolving challenging diagnostic cases. Similarly, Creytens and colleagues90 suggest
immunohistochemical staining for MDM2 in cases where difficulty in discriminating SFT from
liposarcoma is encountered. No studies have yet reported on the application of STAT6 immunostaining to
FNA or core-needle biopsies, but given the high sensitivity and specificity, it is reasonable to infer that
this new tool will increase the diagnostic yield of tissue biopsies performed in any manner.
PROGNOSIS
Almost all patients with benign localized fibrous tumors of the pleura are cured by adequate excision of
the lesion. England et al.6 noted only two recurrences in 98 patients (2%), and in both patients a second
curative resection was possible. A high index of suspicion for malignancy must be maintained in cases of
recurrence.
MALIGNANT SOLITARY FIBROUS TUMORS OF THE PLEURA
INCIDENCE
The relative incidence of malignant SFTs as compared with that of the benign lesions is a matter of
ongoing debate. Thirty-six percent of the fibrous pleural tumors reviewed by England et al.6 were
malignant, but all of the 223 cases had been referred to the Armed Forces Institute of Pathology for study
and represent a biased database. More contemporary series have reported an incidence of malignant
tumors between 12% and 14%.19,21,26,70 The issue has been further complicated by varying definitions of
malignancy; while most studies use the classic histologic criteria set forth by England and colleagues in
1989, clinically aggressive behavior including local recurrence, metastasis, and invasion of surrounding
structures has also been used to classify SFTP as malignant.91
CLINICAL FEATURES
In contrast to those with benign SFTP, most patients with malignant SFTP, approximately three-fourths,
have symptoms (Table 65.3). Chest pain, cough, dyspnea, and fever are the most common symptoms.
Osteoarthropathy rarely, if ever, occurs with localized malignant lesions. Hypoglycemia, however, is
more commonly seen in patients with malignant than with benign fibrous tumors of the pleura. An
incidence of 11% as compared with 3%, respectively, is found.6
TABLE 65.2 Histopathology of Nonmesothelial Primary Pleural Tumors
Benign Characteristic Staining
Solitary fibrous tumor of the pleura + CD34, Bcl-2, CD99, STAT6 (nuclear), GRIA2
− pan-cytokeratin, EMA, SMA, Desmin, CD31, S100
Calcifying fibrous tumor + vimentin, SMA, CD34; calcifications/psammoma bodies
− S100, desmin
Adenomatoid tumor + cytokeratin, vimentin, and calretinin
− CEA, TTF-1, EMA, desmin and CD34
Sclerosing pneumocytoma + EMA, TTF1, vimentin, napsin, surfactant proteins
− CEA, S100, SMA, calretinin, CD34, WT1, CK5/6
Primary pleural lipoma Mature adipocytes without atypia
Primary pleural schwannoma + S100, cytokeratin
+/− CD34
Malignant
Malignant SFTP + p53, bcl-2, CD99, STAT6 (nuclear), GRIA2
+/− CD34, cytokeratin, β-catenin
Desmoplastic small round cell tumor + cytokeratins, vimentin, desmin, chromogranin
− S100
Localized malignant mesothelioma + cytokeratin, SMA
− CD34, bcl-2, STAT6, GRIA2
Primary pleural thymoma + CK19, terminal deoxynucleotidyl transferase
− CD34, vimentin, bcl2
Synovial sarcoma + cytokeratin, EMA, bcl-2, vimentin, TLE1
− S100, desmin, SMA
Liposarcoma + MDM2 (nuclear), vimentin, STAT6 (up to 15%)
− cytokeratin, SMA, desmin
Fibrosarcoma/desmoid tumor + SMA, β-catenin, cyclin D1
− CD34, cytokeratin
Epithelioid hemangioendothelioma + CAMTA1 (nuclear), TFE3, CD31, UEA1, CD34
− Desmin, S100, cytokeratin
Angiosarcoma + CD31, FLI1, ERG, claudin5
− Calretinin, WT1, CK5/6
Epithelioid angiosarcoma + CD31, UEA1, factor VIII-related antigen, vimentin
− Calretinin, WT1
Lymphoproliferative Disorders
Primary effusion lymphoma non-Hodgkin B-cell lymphoma
Pyothorax-associated lymphoma non-Hodgkin B-cell lymphoma
CD, Cluster of differentiation; Bcl-2, B-cell lymphoma 2; STAT6, Signal transducer and activator of transcription 6; GRIA2, Glutamate
receptor ionotropic AMPA type subunit 2; EMA, Epithelial membrane antigen; SMA, Smooth muscle actin; CEA, Carcinoembryonic antigen;
TTF-1, Thyroid transcription factor 1; WT1, Wilms tumor 1; TLE-1, Transducin-like enhancer of split 1; MDM2, Murine double minute 2;
CAMTA1, Calmodulin-binding transcription activator 1; TFE3, Transcription factor E3; UEA1, Ulex europaeus agglutinin-I; FLI1, Friend
leukemia virus integration 1; ERG, ETS-related gene.
IMAGING
The radiographic findings in patients with malignant SFTP are similar to those seen in patients with the
benign variety except that lesions tend to be larger and pleural effusion is seen more often. An incidence
of associated pleural effusion of 32% was recorded by England et al.6 compared to 8% in patients with
histologically benign tumors. Occasionally, rib erosion may occur as the result of invasion of the chest
wall. In larger lesions, CT and MRI often reveal heterogeneity within the mass, reflecting areas of
hemorrhage, necrosis, and/or increased vascularity. Although mixed results have been shown in the few
reports of the use of FDG PET in discerning benign from malignant SFTP, hypermetabolic lesions
(maxSUV >2.5) should be viewed with suspicion.18 In particular, hypermetabolic foci within an
otherwise bland tumor are concerning for areas of dedifferentiation.57
DIAGNOSIS
In most instances, the diagnosis is not apparent until histologic examination of the resected specimen is
completed. Invasion of the chest wall or other adjacent structures within the chest grossly establishes the
malignant nature of the lesion. Recurrence of an SFTP originally thought to be benign must be regarded as
suggesting the true malignant nature of the lesion (Fig. 65.7).
FIGURE 65.7 Gross morphology of a recurrent malignant fibrous tumor in a 60-year-old woman. A, B (cut surface): The
specimen, from a recurrence 6 years after initial diagnosis, shows significant heterogeneity, and focal areas of adipose tissue (fat-
forming variant vs. dedifferentiation).
TABLE 65.3 Features of Solitary Fibrous Tumors Suggestive of Malignancy
Clinical Symptomatic at presentation
Presence of a pleural effusion
Inverted fibroma, intraparenchymal, parietal pleural, or mediastinal origin
Sessile morphology
Fibrous adhesions
Imaging Size >10 cm
Extensive necrosis and hemorrhage
Invasion of chest wall or surrounding structures
Heterogeneous high signal-intensity and contrast uptake on T2-weighted MRI sequences
Maximum SUV >2.5 on FDG PET
Histopathology Classic (England’s criteria)
Hypercellular (overlapping)
Nuclear pleomorphism
Extensive areas of necrosis and/or hemorrhage
>4 mitoses/10 high-powered fields
Dedifferentiation (abrupt transition to high-grade sarcoma)
Immunohistochemical Loss of CD34 expression and overexpression of IGF2
Positive staining for S-100, p16, p53 or cytokeratin
MIB (Ki-67 proliferation index) > 0%
Activation of the akt/mTOR pathway
Overexpression of PDGFR-alpha
SUV, standardized uptake value; FDG PET, 18F-fluorodeoxyglucose positron emission tomography; IGF2, insulin-like growth factor 2;
akt/mTOR, akt pathway mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor.
FIGURE 65.8 Gross morphology of a 15-cm malignant fibrous tumor. Cut section shows a tan, fleshy tumor with areas of
yellow necrosis and hemorrhage. The tumor recurred in 8 months and the patient died after 17 months.
Gross Features
The malignant variety SFTP, as compared with benign tumors, tends to be large (>7 to 10 cm), to be more
often located atypically (arising from the parietal pleura, within a fissure, or to exhibit inverted growth
into the pulmonary parenchyma), and to show areas of necrosis and hemorrhage (Fig. 65.8).
Microscopic Features
Malignant SFTP, according to England et al.,6 reveal (a) high mitotic activity (>4 mitosis per 10 high-
power fields), (b) high cellularity with overlapping and crowding of nuclei, (c) the presence of necrosis,
and (d) pleomorphism (Fig. 65.9). El-Nagger and colleagues7 also noted higher mitotic counts in
malignant SFTP. In addition to the presence of necrosis, extensive areas of myxomatous change and
hemorrhage are commonly seen.
Other Features
Although the immunohistochemical profile of malignant SFTP is essentially the same as that of the benign
variety (Table 65.2), there are a few differences of interest. First, although CD34 is present in most
malignant tumors, it may be absent in a small percentage; particularly in high-grade tumors. Second,
Yokoi and colleagues92 found all malignant SFTP to stain positively for nuclear p53 and that the degree of
p53 expression was correlated with recurrence, nuclear atypia, high mitotic activity and local invasion.
More recently, p53 positivity was shown to be associated with both a shorter disease-free survival (DFS)
and unfavorable histology including higher mitotic rate and presence of nuclear atypia/pleomorphism.86
Finally, increased staining for Ki67, a marker of cellular proliferation, has been demonstrated in
malignant SFTP.93 Ambiguous cases of malignant SFTP, such as those that are CD34-negative or are
suspected of having undergone dedifferentiation, highlight the potential utility of testing for the presence
of the NAB2-STAT6 gene fusion or immunohistochemical staining for nuclear STAT6.94
FIGURE 65.9 Microscopic section of a malignant fibrous tumor of the pleura. Histology demonstrates increased cellularity with
cellular pleomorphism and increased number of mitotic figures.
TREATMENT
Wide local excision, including pulmonary and pleural resections, is performed with the goal of obtaining
negative pathologic margins. Resection of a lesion arising from the parietal pleura should include the
tissue down to the endothoracic fascia when possible. Resection of the adjacent chest wall is done only if
involvement is apparent. Localized recurrence of even malignant SFTP should be evaluated for possible
resection. Incomplete resection of malignant SFTP has been reported to occur in 7% to 11% of cases.95
Operative spillage is to be avoided during VATS removal of any solitary fibrous tumor (benign or
malignant), and each tumor should be protected by a bag as it is extracted through the access port to
prevent seeding of the chest wall.
ADJUVANT THERAPY
Traditional cytotoxic chemotherapy has shown minimal benefit in the treatment of malignant SFT;
Stacchiotti and colleagues96 reviewed the response to anthracycline-based regimens in 30 patients with
malignant or dedifferentiated SFT from various sites (including 13 pleuropulmonary) and found a 20%
partial response rate (RR) with a median progression-free survival (PFS) of 4 months. Similarly, 19
patients treated with high-dose, single-agent ifosfamide therapy had a 10% RR and median PFS of 3
months. The authors did describe a trend toward increased effectiveness in the dedifferentiated cohort
treated with anthracycline (30% RR vs. 11% for malignant SFT). In a subsequent study, the authors
demonstrated improved disease control rate when treating a small cohort of patients with malignant SFT
with pazopanib, a vascular endothelial growth factor receptor (VEGFR) inhibitor.97 Prior to the
discovery of the NAB2-STAT6 mutation, case reports and small case series describing the use of targeted
therapies, including sorafenib,98,99 imatinib,100 sunitinib,101 and the monoclonal antibody against IGF1R,
figitumumab,102 showed variable effectiveness, with limited evidence of antitumor effect in the majority
of patients. Park and colleagues103 found a partial response (PR) in 11 of 14 patients undergoing anti-
VEGFR treatment with temozolomide and bevacizumab with a median PFS of 10.8 months. Le Jeune and
colleagues104 reported a case of refractory NICTH in a patient with an unresectable, metastatic SFT that
was successfully controlled following treatment with sorafenib. Trabectedin (ET-743) has shown
antitumor effects in a variety of translocation-related sarcomas, including myxoid liposarcoma, and more
recently the specific use in malignant SFTP was reviewed by the French Sarcoma Group.105 Eleven
patients with metastatic SFTP, after failing first-line treatment with conventional anthracycline-based or
targeted chemotherapy, received 1.5 mg/m2 of trabectedin every 3 weeks as salvage therapy; the authors
reported a PR in only one patient but a disease control rate of 81.8% and median PFS of 11.6 months. A
similar disease control rate (78%) was seen in nine patients with SFTP receiving trabectedin as second-
or third-line treatment in a recent study describing the multimodality management of advanced SFT.106
Based on their analysis of growth factor and tyrosine kinase receptor (TKR) pathways in 96 SFT,
Demicco and colleagues87 theorized that due to the specific patterns of overexpression, classic,
hypocellular SFTs would be more susceptible to anti-EGFR therapies (such as gefitinib), than the
hypercellular variants, which expressed high levels of VEGF and PDGF-beta. The authors noted that
many tumors overexpressed multiple growth factor and TKR pathways and as a result agents targeting a
broader array of TKR pathways, such as sunitinib, may show increased efficacy over more focused
therapies. For the same reason, the authors suggest that a dual-therapy approach with a combination of
growth factor and TKR inhibitors may also be beneficial. Preclinical studies also support the concept of
using broad TKR inhibitors; agents with a larger spectrum of kinase inhibition, including sunitinib,
sorafenib and regorafenib, showed increased antitumor effect compared to pazopanib and axitinib in a
murine model of dedifferentiated SFT.97
Case reports have described PR to external beam radiotherapy107 and a recent study in soft-tissue
SFTs suggested a potential role for adjuvant radiotherapy in improving local control but additional
research is needed before advocating its use in cases other than incomplete resection.108 In summar y,
patients with incompletely resected SFTP and those with malignant histology should be considered for
inclusion in a clinical trial evaluating the use of targeted molecular therapies. Patients with
dedifferentiated SFTP may respond better to traditional cytotoxic chemotherapy targeting the sarcomatous
component of their tumor.
PROGNOSIS
Inherent to the small sample sizes of published case series, malignant SFTP have shown wide variability
in rates of recurrence (7% to 30%) and long-term survival (12% to 45%).6,24,26,91,96 Boddaert and
colleagues91 performed a meta-analysis of the largest case series published since 2000, including over
700 patients, and found tumor recurrence to be significantly higher in patients with malignant histology
(by England’s criteria, Table 65.3), sessile morphology, and incomplete resection. One of the few areas
of consensus in published series has been that the most important indicator of clinical outcome is whether
the tumor can be totally excised at the initial operation. Van Houdt and colleagues109 found in a series of
81 patients undergoing resection with curative intent from all sites that a positive resection margin was
significantly correlated with local recurrence and that both a high mitotic rate and tumor size >10 cm
were significantly correlated with the development of metastatic disease. Furthermore, the subset of
patients with both an increased mitotic rate and tumors >10 cm were noted to have the shortest overall
survival. Recurrences are typically at the site of excision, however spread to other sites within the thorax
or into the abdomen can occur. Lymph node metastases are rarely seen, but may occur, similar to blood-
borne metastases, in patients with persistent or recurrent disease. The sites of metastases recorded, in
order of decreasing frequency, are the liver, central nervous system, spleen, peritoneum, adrenal gland,
gastrointestinal tract, kidney, intra-abdominal lymph nodes, and bone. Most patients with recurrent
disease survive <2 to 5 years without resection.6
TABLE 65.4 Prognostic Scoring Systems
Staging Characteristics Predicted Clinical Course or Recurrence
System
de Perrot19 Pathologically benign, pedunculated Stage 0 2% recurrence risk

Pathologically benign, sessile Stage I 8% recurrence risk
Malignant pathology, pedunculated Stage II 14% recurrence risk
Malignant pathology, sessile Stage 63% recurrence, 30% mortality rate
III
Multiple, synchronous metastases Stage
IV
Demiccoa,111 Age >55 (1 point) 0–2 low risk; no metastases seen in this group
Size (>5 cm, <10 cm—1 point; 10–15 cm—2 points; >/ = 15 3–4 intermediate risk; 23% with metastases at 5 yrs,
cm—3 points) 36% at 10 yrs
Mitoses/10 high-powered fields (1–3—1 point, >3—2 5–6 high risk; 85% with metastases at 5 yrs, 100% at
points) 10 yrs
Tapiasb,74 Parietal pleural origin (1 pt) 0–2 Low risk; 0% rate of metastases at up to 20 yrs
Sessile morphology (1 pt) 3–6 High risk; recurrence in 77% of patients at 15
yrs
Long-axis >/= 10 cm (1 pt)
Hypercellularity (1 pt)
Presence of hemorrhage or necrosis (1 pt)
>3 mitoses/10 hpf (1 pt)
a Presence of areas of dedifferentiation in this series were associated with a poor prognosis, independent of risk category.
b Predicts risk of recurrence in completely resected tumors.
As larger series of SFTP with longer follow-up have been accumulated, a variety of prognostic
scoring systems have been proposed in an attempt to correlate clinicopathologic features to risk of
recurrence, with the intent of informing follow-up guidelines (Table 65.4). de Perrot et al.110 presented a
comprehensive analysis of recurrence risk and developed a clinicopathologic staging system with
accompanying management algorithm based on tumor morphology and pathologic classification according
to England. Advancing stage was correlated with increased risk of recurrence and suggested the need for
closer follow-up in patients with sessile morphology and/or malignant histology. Demicco and
colleagues111 proposed a clinicopathologic model for assessing risk of metastasis and disease-specific
survival based on age >55, tumor size in 5 cm increments and number of mitoses per 10 high-powered
fields (as a continuous variable). Based on a score from 0 to 6, patients are classified as low (0 to 1),
intermediate (2 to 4), or high (5 to 6) risk; no patients in the low risk group experienced metastasis while
patients with high-risk tumors were found to have rates of metastasis at 5 and 10 years of 85% and 100%.
Tapias and colleagues74 analyzed outcomes for 59 patients over a 33-year-period and developed a six-
point system incorporating the classic histologic and clinical features associated with malignancy to
predict risk of recurrence in completely resected SFTPs. Points are assigned for: parietal pleura origin,
sessile morphology, size (long axis) > or = to 10 cm, hypercellularity, presence of hemorrhage or necrosis
and > or = to 4 mitoses/10 HPFs. A score less than 3 was associated with a 0% recurrence at up to 20
years in the development cohort. The Tapias system was subsequently evaluated in a validation cohort of
113 patients that confirmed the prognostic value in terms of recurrence and overall survival.23 Boddaert
and colleagues91 applied the various prognostic scoring systems to the outcomes of the 80 patients in their
series and found the Tapias system to have the highest sensitivity and specificity (100% and 80%,
respectively). In addition, multiple studies have demonstrated significantly higher rates of metastasis and
disease-specific mortality (100% and 43% respectively) in patients with SFTP containing areas of
dedifferentiation compared to histologically benign tumors.111,112
RARE PRIMARY BENIGN TUMORS OF THE PLEURA
CALCIFYING FIBROUS TUMOR OF THE PLEURA

Pinkard et al.113 first described the occurrence of calcifying fibrous tumors of the pleura in three young
adults in 1996. The pleural lesions were identified on standard chest radiography with calcification of the
masses subsequently demonstrated on CT. On resection, the masses were found to be unencapsulated and
were seen to arise from either the parietal or visceral pleural surface (Fig. 65.10). Suh and colleagues114
reported a multifocal case in a 35-year-old asymptomatic male who underwent thoracotomy with
extirpation of a total of 16 nodules, ranging in size from 0.5 to 3 cm, from the visceral and parietal pleura
in the right chest. The mean age of patients with the pleural-based lesions is 34 years, compared to the
more common occurrence of calcifying fibrous tumors in the soft-tissue of the extremities in the pediatric
population (mean age 14.5 years). Two-thirds of the published cases to date have reported the presence of
multiple tumors at presentation, however no evidence of malignancy has been seen and complete surgical
resection appears to be curative.115
FIGURE 65.10 Gross (A) and microscopic (B) examination of a calcifying fibrous tumor of the pleura. Note the absence of a
discreet capsule (A) and numerous, scattered violet-stained spherical calcifications (B).
ADENOMATOID TUMOR
Adenomatoid tumors are small nodular pleural lesions typically found incidentally on imaging,
intraoperatively or on examination of a resected lung specimen. They have been found in the visceral
pleura as well as in the pulmonary ligament and the published cases have reported sizes from 5 mm to 2.5
cm. The nodules are composed of epithelial cells with mesothelial differentiation present in a fibrous
stroma (Table 65.2).116 These rare tumors are benign, and their bland cytology allows differentiation from
pleural metastatic disease in patients with a synchronous malignancy as well as the adenomatoid growth
pattern of malignant pleural mesothelioma. Surgery appears to be curative, with no reported recurrences
following resection.
SCLEROSING PNEUMOCYTOMA (HEMANGIOMA)

In the 2015 WHO classification,117 sclerosing hemangioma was reclassified from “miscellaneous tumors”
to “adenomas” and the terminology standardized to sclerosing pneumocytoma, reflecting the derivation
from, and presence of, embryonic respiratory epithelium (round cells) and cuboidal surface cells,
resembling type II pneumocytes. Sclerosing pneumocytoma is almost always a benign epithelial tumor,
more commonly found in the lungs, but rare cases have been identified as arising from the pleura.118 A 5:1
female predilection has been reported with an average age at presentation of 46 years.119 These tumors
are typically noted incidentally on imaging as noncavitating, peripheral nodules, <3 cm in diameter. The
treatment of the pleural-based tumors is surgical resection, with enucleation or wedge resection
considered adequate, and the prognosis should be excellent.
PLEURAL LIPOMA
Despite being the most common benign tumor in adults, primary pleural lipomas are extremely rare, with
less than 15 cases reported in the literature.120 Although imaging findings such as nonhomogeneity can be
suggestive of a malignant component, the difficulty in distinguishing pleural lipomas from well-
differentiated liposarcomas preoperatively compels resection of most of these tumors.121
PLEURAL SCHWANNOMA
Thought to arise from the sheaths surrounding autonomic nerve fibers in the pleura, less than 20 of these
benign tumors have been published.122 Characteristically slow growing, the reported cases have occurred
in young adults with a slight male predominance. Rare cases of malignant peripheral nerve sheath tumors
(MPNST) have been reported in patients with neurofibromatosis type 1 and a history of radiation
exposure.123,124 Surgical resection is the treatment modality of choice for both the benign and malignant
variety when possible.
RARE PRIMARY MALIGNANT TUMORS OF THE PLEURA

The overwhelming majority of malignant lesions involving the pleura are either diffuse malignant
mesotheliomas, metastatic lesions involving the pleural surface, or direct invasion of adjacent tumors
from the lung or chest wall. Many of the metastatic and invasive lesions mimic a diffuse malignant
mesothelioma in both their pathologic features and clinical course. The metastatic lesions include
melanomas, thymomas, epithelioid sarcomas, and adenocarcinomas from various sites, primarily the lung.
The latter, also known as pseudomesotheliomatous adenocarcinoma of the lung,125 is typically associated
with older, male smokers, but was also recently described in a 34-year-old nonsmoker with a history of
pleural scarring secondary to tuberculosis infection.126 Rare cases of small-cell carcinoma of the lung
simulating pleural mesothelioma have also been reported.127 Characteristic histology and
immunohistochemical staining (Table 65.2) are usually required to differentiate these secondary tumors
from true diffuse mesotheliomas and the other rare primary malignant pleural lesions described below.
DESMOPLASTIC SMALL ROUND CELL TUMOR

Classically an intra-abdominal tumor, desmoplastic small round cell tumor (DSRCT) has been described
arising primarily from the pleura, typically in younger adults with a nonspecific presentation. The tumor is
composed of small, poorly differentiated cells with a malignant appearance. The t(11;22)(p13;q12)
translocation, characteristic of intra-abdominal DSRCT and resulting in EWSR1-WT1 gene fusion, has
also been identified in the pleural-based variety.128 These tumors typically follow an aggressive clinical
course and despite a multimodality treatment approach of surgical resection, chemotherapy, and radiation,
the life expectancy for patients is in the range of months to a few years.
LOCALIZED MALIGNANT MESOTHELIOMA

Immunohistochemically and ultrastructurally these tumors are identical to the much more common diffuse
malignant mesothelioma, but lack the gross and/or microscopic evidence of widespread tumor on the
serosal surfaces, nodules, a tumorous rind or tumor caking that is characteristic of the latter. The largest
case series of localized malignant mesothelioma describes long-term follow-up (11 to 122 months) for 21
patients.129 After wide surgical resection, 10 of the 21 patients had no evidence of disease, whereas the
other 11 patients had had either a local recurrence or distant metastases. However, none had experienced
diffuse pleural spread. Additional cases of localized malignant mesothelioma of the pleura, variably
amenable to extirpation, have been reported.24,130–133
PRIMARY PLEURAL THYMOMAS

Although it is particularly difficult to differentiate from simple extension of a thymic-based tumor to the
pleural surfaces, rare cases of primary pleural thymomas have been reported.134–136 These ectopic
thymomas are rarely associated with myasthenia gravis137 and radiologically may appear as diffuse
nodular pleural thickening, mimicking malignant mesothelioma. Complete resection of both the primary
tumor and native thymus is recommended, with adjuvant chemotherapy and radiation based on the
histologic grade and stage.138
SYNOVIAL SARCOMA OF THE PLEURA

Seen more commonly as metastatic disease from the extremities, both monophasic and biphasic synovial
sarcomas have been described as arising from the pleura, although <20 of these tumors have been
reported to date.139,140 In the monophasic type, the tumor is composed of plump, spindle-shaped cells
arranged in short fascicles. In the biphasic tumor, glandular epithelium is interspersed with the
aforementioned spindle-shaped cells. Molecular evaluation has significantly aided the diagnosis of
synovial sarcoma. Studies have found 90% to 95% of synovial sarcomas include the t(X;18)
translocation, leading to the SYT–SSX gene fusion. The resulting fusion protein products are thought to
have tumorigenic effects through dysregulation of the cell cycle. The SYT–SSX translocation is not seen
in the sarcomatoid variety of diffuse malignant mesothelioma or other histologically similar malignancies
and identification of the translocation by reverse-transcriptase PCR, FISH, or conventional cytogenetics
provides the most sensitive and specific method of diagnosis.141,142 Aberrant expression of transducing-
like enhancer of split 1 (TLE1) has also been shown to be characteristic of synovial sarcoma.143 These
tumors typically occur in young adults and, while a multimodality approach of surgery and chemotherapy
may prolong survival, are generally rapidly fatal.
PRIMARY PLEURAL LIPOSARCOMA

Liposarcomas of the pleura, thought to arise from residual rests of undifferentiated mesenchymal cells, are
exceedingly rare. Only 15 cases of primary pleural liposarcomas have been reported, including myxoid,
well-differentiated, and lymphocyte-rich subtypes.144,145 The treatment of pleural liposarcoma is complete
surgical resection with care taken to ensure a wide surgical margin and to prevent any rupture of the
capsule of the tumor. Complete removal may be curative, but adjuvant radiotherapy is often added.
FIBROSARCOMAS OF THE PLEURA AND DESMOID TUMORS

Extremely rare spindle-cell neoplasms, 22 primary pleuropulmonary desmoid tumors have been reported
with 12 of those cases identified as having a pleural origin. The tumors have been noted in patients with
familial adenomatous polyposis (FAP) and often display mutations in the adenomatous polyposis coli
(APC) and beta-catenin genes, with nuclear expression of beta-catenin having been shown to correlate
with overexpression of the cyclin D1 genes.146 As with desmoid tumors in other locations, primary
pleural tumors display locally aggressive behavior and wide-local excision is the treatment of choice
when feasible. A 25% recurrence rate in patients with a negative margin suggests a potential role for
adjuvant radiotherapy or hormonal agents such as tamoxifen.147 Desmoid tumors are considered a low-
grade variant of fibrosarcomas, the more malignant presentation of the latter has also been reported and is
associated with an identifiable gene translocation (t[7;16][q33;p11]).148
MALIGNANT TUMORS OF VASCULAR ORIGIN
PLEURAL EPITHELIOID HEMANGIOENDOTHELIOMA

Less than 50 of these rare tumors that markedly resemble malignant mesotheliomas have been identified
as having a primary pleural origin.149 Studies using whole-transcriptome sequencing led to the discovery
of the consistent presence of a WWTR1 and CAMTA1 gene fusion in EHE. The rearrangement was noted
to have a prevalence using FISH of 89% to 100%, with 100% specificity.14,150 The utility of WWTR1–
CAMTA1 fusions in diagnosis of EHE was highlighted in the new 2015 WHO classification.117 More
recent studies have confirmed the high incidence of WWTR1–CAMTA1 as well as gene fusions between
yes-associated protein 1 (YAP1) and Transcription Factor E3 (TFE3) in EHE and described the role of
immunohistochemical staining for nuclear CAMTA1 and TFE3 in the diagnosis of this uniformly fatal
tumor.151 Clinically, the presence of a pleural effusion, symptomatic presentation (cough, hemoptysis or
chest pain), and multinodular disease have been associated with a worse prognosis.152 Pleural EHE is
typically resistant to conventional chemo- and radiotherapy, however there have been mixed reports of
response to novel antiangiogenic agents.153 While EHE are generally considered low- to intermediate-
grade malignancies when found in extrathoracic soft tissues, skin, and viscera, pleural EHE has been
described as rapidly fatal in almost all published reports.154
ANGIOSARCOMA OF THE PLEURA

Chronic inflammation has been suggested as the underlying pathogenesis of this uncommon and highly
malignant neoplasm arising from vascular endothelial cells within the pleura. Cases have been reported in
association with chronic empyema, tuberculous pyothorax, pneumoconiosis, occupational asbestos
exposure, and radiotherapy.154,155 Novel markers include friend leukemia integration 1 (FLI1), a highly
sensitive and specific nuclear transcription factor, and erythroblast transformation-specific related gene
(ERG), a member of the erythroblast transformation specific (ETS) family transcription factors, that is
present in virtually all benign and malignant vascular tumors and negative in most other tumors of
mesenchymal origin.156,157 As with the other pleural-based malignancies of vascular origin, the clinical
course is uniformly poor.
EPITHELIOID (PSEUDOMESOTHELIOMATOUS) ANGIOSARCOMA

The most common variant of primary pleural angiosarcoma is associated with pleural thickening and
hemorrhagic effusion and is readily confused with a malignant mesothelioma.158 Cases with discrete,
localized pleural lesions may be amenable to resection, however the tumor is very aggressive in its
malignant behavior; patients usually succumb within a few months of diagnosis. The use of radiotherapy
is mainly palliative in nature and embolization can be similarly employed to reduce bleeding or prior to
attempted resection.159
OTHER MALIGNANT TUMORS AND PRIMARY PLEURAL SARCOMAS

Additional cases have been reported of exceedingly rare, primary pleural malignancies including:
squamous cell carcinoma,160,161 mucoepidermoid carcinomas,162 adenosquamous cell carcinoma,163 and
primary melanoma of the pleura.164,165 A variety of other malignant sarcomas, more commonly found in
extrathoracic locations, are typically differentiated from diffuse malignant mesothelioma by their lack of
cytokeratin reactivity. These include rare cases of primary pleural osteosarcoma,166,167
carcinosarcoma,168 extraskeletal myxoid and mesenchymal chondrosarcomas,169–172 and primary
rhabdomyosarcoma of the pleura.173 Treatment consists of complete excision when possible but the
prognosis is generally poor.
PRIMARY PLEURAL LYMPHOMA

While involvement of the pleura in patients with lymphoma is common (up to 16% of patients with non-
Hodgkin lymphoma174), primary pleural lymphomas are quite rare. Two main types have been described,
primary effusion lymphomas (PEL) and pyothorax-associated lymphomas (PAL). PEL are non-Hodgkin
lymphomas typically occurring in HIV+ patients and defined by the presence of human herpesvirus-8
(HHV-8). PAL is more commonly associated with Epstein–Barr virus but overall attributed to chronic
inflammatory stimulation of B-cells in the pleura and has been most commonly described in Japanese
patients.175 Chemotherapy using R-CHOP has been shown to produce a complete response in 25% to 50%
of cases.176
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66
Chemotherapy and Alternative Therapies
for Malignant Pleural Mesothelioma
Federica Grosso ■ Giorgio V. Scagliotti
Patients with malignant pleural mesothelioma (MPM) have very poor prognosis with median overall
survival (OS) of 4 to 13 months for untreated and 6 to 18 months for treated patients.1,2 For the majority of
patients who are not candidates for surgery and multimodality strategies, systemic therapy and symptom-
directed treatments represent the only viable options.
CYTOTOXIC CHEMOTHERAPY
Because of the prevalent palliative intent of systemic treatment in advanced MPM, a small study
investigated whether cytotoxic chemotherapy should be initiated immediately after definitive diagnosis or
at the time of symptomatic progression.3 This study showed a trend for better survival and a longer period
of symptom control in those patients receiving chemotherapy immediately after the diagnosis rather than at
the time of symptomatic progression.
A formal demonstration of the superiority of cytotoxic chemotherapy over best supportive care (BSC)
is lacking. The only randomized study that investigated active symptoms control (ASC) versus ASC plus
vinorelbine or mitomycin–vinblastine–cisplatin (MVP) failed to demonstrate a survival benefit for the
two chemotherapy arms compared with ASC with median OS of 8.5 and 7.6 months, respectively.
Patients who received single agent vinorelbine had no statistically significant trend to improved OS (9.4
months).4 Table 66.1 summarizes the state-of-the-art cytotoxic chemotherapy as first- and second-line
treatment in MPM.
The combination of cisplatin and pemetrexed is the only regimen that showed a survival advantage
compared to cisplatin alone in a well-powered phase III randomized clinical trial.5 Cisplatin was
selected as the reference drug since a meta-analysis of phase II studies conducted in MPM from 1965 to
2001 demonstrated it as the most active single agent.6
In this study, 456 chemotherapy-naive patients were randomized to receive cisplatin 75 mg/m2 plus
either pemetrexed 500 mg/m2 or placebo every 3 weeks. The median OS was significantly longer for the
combination regimen over cisplatin alone, 12.1 versus 9.3 months, respectively. Overall response rate
(ORR) and progression-free survival (PFS) also favored the combination regimen, being 41% versus
17% and 5.7 versus 3.9 months, respectively.5 A companion study highlighted that the combination was
associated with improvement in quality of life and symptoms control. The differences in these secondary
endpoints became significant within the first three cycles and remained statistically significant by week
15.7 Furthermore, a later analysis revealed that survival was greater in patients who received folic acid
and vitamin B12 supplementation and the supplemented patients experienced less treatment-related
toxicities and received a greater median number of cycles.8
Unfortunately, there are no proven predictive biomarkers for cisplatin and pemetrexed that can
improve patients’ selection; however, a retrospective study including 60 MPM patients suggested that
lower levels of thymidylate synthase correlate with better PFS and OS.9
Raltitrexed is another thymidylate synthase inhibitor that improves patient efficacy outcomes in
association with cisplatin. In a randomized phase III trial 250 patients were randomized to raltitrexed 3
mg/m2 plus cisplatin 80 mg/m2 every 3 weeks versus cisplatin alone.10 The ORR was 24% versus 14%,
favoring the combination with a clear-cut trend for better outcome for the combination compared to single
agent cisplatin with median OS of 11.4 versus 8.8 months and 1-year survival rate of 46% versus 40%,
respectively.
The quality of life data showed a statistically significant improvement of dyspnea in favor of the
combination, and the overall quality of life was impaired at baseline but did not worsen in both arms in
patients remaining on treatment.11 Raltitrexed is currently licensed for the treatment of MPM in few
European countries but it is not commercially available in the United States.
In order to ameliorate the tolerability profile and, more specifically, the cumulative nonhematologic
toxicities of cisplatin, the replacement of cisplatin with carboplatin has been evaluated in two phase II
studies. The larger one included 102 patients who received carboplatin AUC5 and pemetrexed 500 mg/m2
with vitamin supplementation. The ORR was 19%, with PFS of 6.5 months and median OS of 12.7
months.12 In the second study 76 patients received the same regimen; the ORR was 25% with PFS of 8
months and a median OS of 14 months.13 In the combined analysis of these two studies carboplatin plus
pemetrexed had a similar outcome in younger patients compared to those >70 years, with a higher degree
of hematologic toxicity in the elderly subgroup.14 Furthermore, a large expanded access program of 1704
chemotherapy-naive MPM patients showed a lower rate of objective response for carboplatin plus
pemetrexed compared to cisplatin plus pemetrexed (26% vs. 21%) but the PFS and the 1-year survival
rate were quite comparable, 6.9 versus 7 months and 63% versus 64%, respectively.15
Despite the lack of conclusive evidence from a randomized clinical trial comparing head to head the
two regimens, the combination of carboplatin with pemetrexed may be a suitable therapeutic option in
elderly patients or for those unfit for cisplatin administration.
TABLE 66.1 Cytotoxic Systemic Therapies
Treatment Line of ORR PFS OS Type of Study (Year of References
Therapy Publication)
ASC alone I NR 5.1 7.6 Phase III (2008) 4
vs. vs. vs.
ASC + MVP 5.1 8.5
vs. vs. vs.
ASC + vinorelbine 5.6 mo 9.4 mo
Cisplatin + pemetrexed I 41% 5.7 12.1 Phase III (2003) 5
vs. vs. vs. vs.
cisplatin alone 17% 3.9 mo 9.3 mo
Cisplatin + raltitrexed I 24% 5.3 11.4 Phase III (2005) 10
vs. vs. vs. vs.
cisplatin alone 14% 4.0 mo 8.8 mo
Carboplatin and pemetrexed I 19% 6.5 mo 12.7 Phase II (2006) 12
mo
Cisplatin and gemcitabine I 47% 25 41 wks Phase II (1999) 18
wks
Cisplatin and gemcitabine I 33% 6.4 mo 11.2 Phase II (2002) 19
mo
Pemetrexed + folic acid and vit. I 16.3% NA 13 Phase II (2003) 20
B12 vs. vs.
vs. 9.5% 8 mo
pemetrexed alone
Pemetrexed II 5.5% 3.6 8.4 Phase II (2008) 23
vs. vs. vs. vs.
BSC NA 1.5 mo 9.7 mo
Pemetrexed + cisplatin II 32.5% NA 7.6 Phase IIIb (2006) 24
vs. vs. vs.
pemetrexed alone 5.5% 4.1 mo
Pemetrexed and platinum II 19% 3.8 mo 10.5 Observational study (2011) 25
mo
Vinorelbine II 16% NA 9.6 mo Phase II (2009) 28
Vinorelbine II 15% 2.3 mo 6.2 mo Retrospective study (2014) 29
ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
The optimal length of first-line treatment is still a matter of debate. Although a small non-randomized
Dutch study demonstrated the safety and the feasibility of continuation of pemetrexed until progression
suggesting a survival benefit,16 this strategy has not yet been validated and is not recommended in the
routine clinical practice. A CALGB prospective randomized phase II study is addressing the role of
maintenance in this setting.17
The combination of cisplatin and gemcitabine was tested in two phase II studies and indicated
therapeutic activity and symptomatic benefit.18,19 Nevertheless, in absence of randomized evidence the
first-line use of gemcitabine-based chemotherapy is not fully supported.
Single agent pemetrexed as front-line treatment with or without vitamin supplementation was
investigated in a phase II study.20 A total of 64 patients were enrolled and single agent pemetrexed
resulted in 14% objective responses with median OS about 11 months. Forty-three patients received
vitamin supplementation with a better treatment tolerability and a median OS of 13 months compared to 8
months for nonsupplemented patients. The results of an International Expanded Access Program
confirmed these findings.21 Out of 812 patients treated with single agent pemetrexed, 247 were
chemotherapy naive. The response rate was 10.5% while the median PFS was 6 months and OS 14.1
months. Based on these data, for patients clinically judged unfit for platinum-based doublet, first-line
single agent pemetrexed represents a treatment option.
Unfortunately, almost all MPM patients after a variable period of time develop progressive disease
and currently there is no approved therapy for relapsed MPM. At progression most of the patients still
maintain good clinical conditions with preserved organ function and thus are potential candidates for
second-line therapy. In the pemetrexed registration trial the poststudy therapy was associated to prolonged
survival (HR 0.56; 95% CI: 0.44–0.72).22 Nevertheless, this observation could have been influenced by a
selection bias in favor of patients able to receive further chemotherapy.
In the second-line setting a randomized phase III study of single agent pemetrexed versus BSC was
conducted in 243 pretreated and pemetrexed-naive patients.23 Pemetrexed significantly improved the
disease control rate (59% vs. 19%) and the median PFS (3.6 vs. 1.5 months) but failed to show any
improvement in quality of life and OS, quite likely due to the higher crossover rate in the control arm.
Indeed, 52% of patients in the BSC arm received poststudy chemotherapy and this may have jeopardized
a potential survival benefit. Data from the above-mentioned expanded access program suggested that
pemetrexed alone or in combination with platinum are feasible second-line options in pemetrexed-naive
patients.24 An initial analysis in 153 evaluable patients showed an ORR of 33% for the combination of
cisplatin and pemetrexed and 5.5% for single agent pemetrexed with a disease control rate of 69% and
47%, respectively. Median OS was 7.6 months for the combination and 4.1 months for pemetrexed alone.
In a larger analysis of the same study in 396 pretreated patients who received single agent pemetrexed,
ORR was 12% with median PFS of almost 5 months.21 These data indicate that MPM patients who did
not receive pemetrexed as part of the first-line therapy should be treated with second-line pemetrexed,
alone or in combination with platinum agents.
The rechallenge with pemetrexed at the time of progression either alone or in combination with
platinum agents is clinically pursuable. A small study on 31 patients reported a disease control rate of
48% with median PFS of 3.8 months and median OS of 10.5 months (4). Interestingly, patients with longer
relapsing time (>12 months) had a PFS of 5.5 months with the rechallenge, whereas patients who relapsed
over a shorter time (<12 months) had a median retreatment PFS of 2.5 months. In an Italian multicenter
survey, patients retreated with pemetrexed-based second-line chemotherapy achieved a significantly
longer PFS and OS with higher disease control rate when compared to patients treated with non-
pemetrexed-based second-line regimens.25 Overall, these limited data indicate that the rechallenge with
pemetrexed may be considered mainly for those patients with prolonged tumor control after first-line
pemetrexed and when experimental therapies are not available.
Vinorelbine is often used as a second-line agent. In a phase II study on 63 pretreated MPM patients,
single agent weekly vinorelbine 30 mg/m2 for 6 weeks yielded an ORR of 16% and median OS of 9.6
months with a moderate toxicity profile.26 A recent retrospective study evaluating the activity of
vinorelbine 25 mg/m2 every 3 weeks confirmed an ORR of 15% with a disease control rate of 49% while
median PFS was 2.3 months and OS 6.2 months.27
In vitro data suggest that BRCA1 plays an essential role in vinorelbine-induced apoptosis and the loss
of BRCA1 protein expression was identified in 38.9% out of 144 MPM samples.28 A phase II trial is
testing the efficacy of oral vinorelbine over placebo by measuring levels of BRCA1 expression as a
potential predictive factor of sensitivity.29
Realistically, cytotoxic therapy for MPM has reached a plateau, and targeted therapy tackling
deregulated pathways are urgently needed to improve survival. Because of the lack of straightforward
evidence of activity and regulatory approval for any agent or therapeutic strategy, relapsing MPM patients
are ideal candidates to be entered into clinical studies in order to test the efficacy of new agents and
strategies.
TARGETED THERAPIES
The loss of tumor suppressor genes rather than gain of function mutations in MPM has been recently
described. According to version 71 of the catalogue of somatic mutations in cancer, the most commonly
mutated genes in DMM are cyclin-dependent kinase inhibitor 2A (CDKN2A), neurofibromatosis type 2
(NF2), and BRCA-associated protein 1 (BAP1).30 Recently, high-throughput sequencing technologies
have been developed offering the opportunity to map the type and extent of genetic variations and to
provide a correlation with morphologic and prognostic parameters of potential therapeutic relevance. An
Italian series of 123 paraffin-embedded tissue samples of advanced-stage MPM patients was
retrospectively analyzed through next-generation sequencing technology to explore genomic profiling and
to investigate any potential correlation with clinical pathologic variables and survival outcomes. The
most frequently identified and validated genetic variations were clustered in two main pathways: the
p53/DNA repair and the receptor tyrosine kinase–phosphatidylinositol 3-kinase (PI3K)–AKT pathways.
In the p53/DNA pathway, genetic variations were mainly identified in TP53, SMARCB1, BAP1, and
CDKN2A. In the receptor tyrosine kinase–PI3K–AKT pathway, already known cancer-associated
mutations such as PDGFRA, KIT, and KDR were identified in 38, 26, and 38 samples, respectively.
Mutations in two genes that affect mTOR regulation, STK11 and NF2, were also detected. The results of
this study excluded the presence of a specific mutation in a single driver gene, rather favoring the
hypothesis of the accumulation of several nondriver mutations. Accumulation of mutations in several key
pathways was significantly correlated with shorter PFS and reduced OS.31
NGS and new high-throughput sequencing technologies might represent a good opportunity for
understanding the complex mutational and molecular landscape and also to identify deregulated pathways
providing the rationale for investigating novel targeted approaches.31 Existing data on targeted therapies
in MPM are summarized in Table 66.2.
Arginine Deaminase (ADI-PEG20)

Arginine, a key amino acid for cell survival, and reduced or null levels of argininosuccinate synthase-1
(ASS-1), a rate-limiting enzyme in arginine production, were detected in a significant proportion of MPM
patients.32 Arginine succinate deficiency renders mesothelioma cells sensitive to arginine deprivation,
and this antimetabolite strategy with the arginine-degrading enzyme arginine deaminase (Adi-PEG20) has
been recently proposed for therapeutic use.33 In the multicenter randomized phase II ADAM trial, Adi-
PEG20 plus BSC versus BSC alone was tested in patients with ASS1-deficient MPM, a metabolic status
detected in almost 50% of chemo-naive and relapsed patients. The study met its primary endpoint
showing an improvement of median PFS in the experimental arm with stable disease as best response and
neutropenia, fatigue, and anaphylactic reactions as main G3–G4 toxicity.34 A phase I study of Adi-PEG20
in combination with pemetrexed plus cisplatin (TRAP trial) as first-line therapy in MPM patients with
arginine succinate deficiency is currently ongoing.35
Targeting the Cell Cycle

Most cancer cells exhibit genomic instability (often with mutations in p53 gene) and are therefore,
following DNA damage, dependent for survival on the G2 checkpoint, making cancer cells susceptible to
pharmacologic disruption of the G2 checkpoint. CBP501 is a cell-cycle deregulator that inhibits several
kinases involved in the cell-cycle arrest at G2.36 In in vitro experiments, CBP501 in combination with
chemotherapy showed an increased proportion of cancer cells in G1 and superior cisplatin cytotoxicity
due to its higher influx into tumor cells through an interaction with calmodulin. A phase I trial of CBP501
alone and in combination with cisplatin showed antitumor activity in platinum-resistant patients and, with
the exclusion of a manageable infusion-related rash, no additional toxicities were observed. An open-
label, international, randomized phase II trial in previously untreated patients with advanced MPM has
been recently completed.37 Sixty-three patients were randomized 2:1 to cisplatin and pemetrexed ±
CBP501. In the group treated with CBP501, in 63% of the patients PFS was >4 months versus 39% for
those treated with chemotherapy alone; corresponding figures for median PFS were 5.1 and 3.4 months,
respectively. However, OS (13.3 vs. 12.8 months) did not differ between the two arms.
NF2 Suppression
The NF2/Hippo signaling pathway is altered by mutation or deletion of the NF2 gene in almost 40% of
MPM.38 NF2 is a tumor suppressor gene located on chromosome 22q12 encoding for the protein merlin,
but its role in suppressing tumorigenesis is still poorly defined. The absence of merlin causes activation
of multiple mitogenic signaling pathways, such as HER1/2, mTOR, ERK, and focal adhesion kinase
(FAK); therefore, it has been assumed that merlin inhibits signaling by negatively regulating multiple cell
surface receptors.39 Preclinical data indicate that merlin inactivation plays a critical role in the
pathogenesis of MPM increasing its invasiveness through upregulation of FAK expression, and merlin
deficiency is associated with higher sensitivity to FAK inhibitors40 (Fig. 66.1). A phase I study of the oral
FAK inhibitor GSK2256098 included 23 patients with pretreated MPM and showed a better PFS in
merlin-negative MPM.41 A phase IIB trial (COMMAND) is currently testing the oral FAK inhibitor
defactinib (VS-6063) given continuously as maintenance strategy compared with placebo in advanced
MPM42 using merlin status as a stratification factor.
TABLE 66.2 Targeted Therapies

Targeted Rationale Type of Study References
Therapies
Arginine deaminase Arginine succinate deficiency renders mesothelioma cells sensitive to arginine Phase II 33–35
deprivation; Adi-PEG is an arginine-degrading enzyme ADAM trial
Phase I TRAP
trial
Cell cycle Cancer cells might be susceptible to pharmacologic disruption of the G2 Phase I trial 36,37
checkpoint. CBP501 is a cell-cycle disregulator Phase II trial
NF2 NF2 is a tumor suppressor gene encoding for the protein merlin; merlin Phase I study of 43–45
inactivation plays a critical role in the pathogenesis of MPM increasing its GSK2256098
invasiveness through upregulation of focal adhesion kinase (FAK) expression Phase IIB
COMMAND
trial
Phase II trial
with
Everolimus
PI3K/AKT/mTOR The PI3K/AKT/mTOR pathway is crucial for the regulation of cell growth, Phase I studies 49,50
pathway proliferation, and protein biosynthesis; in vitro studies have shown that its of inhibitors
inhibition may induce apoptosis in mesothelioma cell lines
Tyrosine kinase Many growth factor receptor families such as EGFR, PDGFR, and VEGFR are Phase I and II 55–60
frequently activated in mesothelioma studies of 63,66,67
inhibitor
imatinib
Phase II trial of
inhibitor
dasatinib
Phase II trial of
inhibitor
gefitinib
Phase II study
of inhibitor
erlotinib
Angiogenesis and Vascular endothelial growth factor levels are increased in the serum and pleural Phase III 74
blood vessels fluid of MPM patients NVALT 75–79
study of 80
thalidomide 81–83
Phase I/II trials 84–86
of 87
bevacizumab 88–90
Phase II study 91–93
of nintedanib 96
Phase I/II 94
studies of
sorafenib
Phase I/II
studies of
sunitinib
Phase II study
of vatalanib
Phase I/II trials
of cediranib
Phase II study
of BNC105P
Phase I study of
NGR-hTNF
Phase II
NGR019 trial
of NGR-
hTNF
Phase III
NGR015 trial
of NGR-
hTNF
Heat shock protein HSP90 stabilizes a number of proteins required for tumor growth and survival of Phase I /II 99
90 a variety of tumors including mesothelioma MESO02
Merlin loss results in unregulated mTORC1 signaling pathway that is sensitive to rapamycin inhibition
through a mechanism involving mTORC1 activation.43 However, the results of a phase II study with the
mTOR inhibitor everolimus showed only limited clinical activity.44 An additional phase II trial explored
the role of everolimus in patients selected by merlin status as predictive biomarker; the study has been
recently completed but not yet reported.45
PI3K/AKT/mTOR Pathway
The PI3K/AKT/mTOR pathway is crucial for the regulation of cell growth, proliferation, and protein
biosynthesis, processes that are implicated in tumorigenesis, and its upregulation has been reported in a
variety of solid tumors including prostate, colorectal, breast cancer, and melanoma. In an exploratory
study of 30 treatment-naive MPM, the aberrant activation/expression of partner proteins of the
PI3K/mTOR signaling cascade provided prognostic information.46 and in vitro studies have shown that its
inhibition may induce apoptosis in mesothelioma cell lines.47
mTOR inhibition alone generates compensatory upregulation of PI3KCA that allows restoration of
PI3K function and therefore the downstream signaling on AKT.48 To overcome this mechanism of
resistance, dual PI3K/mTOR inhibitors have been developed. GDC-0980 is a small molecule inhibiting
PI3K, mTORC1, and mTORC2 and preliminary data in 26 MPM patients showed 2 objective
responses.49 LY3023414 is another dual PI3K/mTOR inhibitor currently under evaluation in phase I
studies.50
Tyrosine Kinase Inhibitors (TKIs)

Genetic and molecular studies have confirmed that many growth factor receptor families such as
epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and
vascular endothelial growth factor receptors (VEGFR) are frequently activated in mesothelioma.51
The activity of TKIs tackling these receptors has been explored in several clinical studies. In
mesothelioma cells, PDGFR-α and β are overexpressed and high PDGF serum level has been suggested
as an independent predictor for adverse outcome.52,53 The coexpression of c-kit, reported in 26% of
mesothelioma patients, acted as background information for testing imatinib clinically.54 To date, four
phase II studies of single agent imatinib have been performed, including overall 94 patients. Results
invariably showed no objective responses and a PFS <2 months, therefore failing to show any hint of
activity, and, consequently, no further studies are indicated.55–58 In mesothelioma cell lines, imatinib
enhanced the sensitivity to gemcitabine and pemetrexed.59 A phase I trial investigating imatinib in
combination with cisplatin and pemetrexed in 70 chemo-naive patients has been reported. The median
PFS was 7.9 months and the median OS was 8.8 months. Best response by Response Evaluation Criteria
in Solid Tumors showed one partial response, three minor responses, seven stable diseases, and three
progressive diseases. The combination showed some clinical benefit but was not easily tolerated.60 In
Italy, a phase II study evaluating imatinib in combination with gemcitabine as second-line treatment has
been conducted but results have not been reported.61
FIGURE 66.1 Inhibition of NF2 (merlin)-mediated proliferation. Merlin is present in an open, inactive form and in a closed,
active form; the activation of integrin receptor tyrosine kinase signaling (associated with the cell-matrix adhesion) causes the
activation of PAK (serine-threonine kinase p21-activated kinase). PAK phosphorylates merlin, a mechanism that causes the
inactivation of merlin and the consequent removal of the block to cell-cycle progression in normal cells. When CRL4DCAF1 is
not inhibited by merlin, it regulates the oncogenic program of gene expression. CRL4, cullin-ring E3 ligase 4; DCAF1, DDB1-
and CUL4-associated factor 1.
Dasatinib inhibits PDGFR and the Src family of nonreceptor tyrosine kinase and exerts a cytotoxic
effect in mesothelioma cell lines.62 A phase II trial in 46 pretreated patients tested its activity and overall
disease control rate was 32.6%; PFS at 24 weeks was 23% with no objective response. Inacceptable
pulmonary toxicities precluded further investigation in unselected MPM patients.63
All the studies reported above are negative but some antitumor activity was observed in a limited
minority of the cases suggesting the need for the identification of molecular biomarkers for potential
further developments in a specific subset of patients. However, at the present time the search for potential
biomarkers of activity remains elusive and quite unlikely to be successful in the near future.
Epidermal Growth Factor Receptor Inhibitors

EGFR was considered to be a promising target for systemic therapy of mesothelioma since preclinical
studies showed that this receptor is highly expressed in tissue samples and its overexpression is
associated with favorable prognosis.64,65 In a phase II study gefitinib, a first-generation EGFR-TKI, was
investigated in 43 chemotherapy-naive patients and EGFR overexpression was detected in 97% of
patients. Only one complete and one partial response were observed in patients with epithelioid
histology. Almost 50% of patients had stable disease up to 24 weeks. Median PFS was 2.7 months and no
difference in the outcome between patients with low and high EGFR expression was observed. Median
OS time was 6.8 months, being 3.6 months in patients with low and 8.1 in patients with high EGFR-
expressing tumors.66
Erlotinib, another EGFR-TKI, was evaluated in 63 pretreated MPM patients and no objective
responses were observed with disease stabilization achieved in 42% lasting at least 6 weeks and without
any correlation with EGFR expression. The median OS was 10 months.67 The combination of erlotinib
and bevacizumab was investigated in 24 pretreated patients without showing any antitumor activity, with
median PFS of 2.2 months and median OS of 5.8 months.68 Despite the high level of EGFR expression,
the lack of activity of EGFR inhibitors in mesothelioma is likely related to the almost complete absence
of EGFR-sensitizing mutations in this disease.69
Antiangiogenic and Vascular Disrupting Agents

Vascular endothelial growth factor (VEGF) levels are increased in the serum and pleural fluid of MPM
patients compared to healthy subjects or in patients with other malignancies.70 Elevated levels are more
frequently associated with advanced stages and correlate with microvascular density and, ultimately, with
poor prognosis.71 In vitro studies indicated that VEGF stimulates mesothelioma cells in a dose-related
manner and anti-VEGF antibodies are able to inhibit MPM cells growth.72
Based on these considerations, maintenance strategies targeting angiogenesis have been tested.
Thalidomide displays antiangiogenic properties through the inhibition of VEGF, basic fibroblastic
growth factor (b-FGF), and transforming growth factor alpha (TGF-α).73 The phase III NVALT study
randomized 222 patients with objective response or stable disease at the end of first-line therapy to
thalidomide versus observation as maintenance therapy and did not show any benefit either for PFS or
OS. Median PFS in the thalidomide arm was 3.6 months compared with 3.5 months in the control arm,
with median OS of 10.6 and 12.9 months, respectively.74
Bevacizumab, a monoclonal antibody blocking the ligand VEGF, was evaluated in two single-arm
front-line phase II trials in combination with platinum and pemetrexed followed by maintenance
bevacizumab until progression.75,76 Both studies failed to show hints for superior efficacy in terms of
higher ORR or improvement in other treatment outcomes when compared with historical data.
A double-blind randomized phase II trial investigated cisplatin and gemcitabine with or without
bevacizumab in 115 chemotherapy-naive patients and did not show any benefit. The figures for ORR were
25% and 22%, whereas the ones for PFS and median OS were 6.9 and 6.0 months, and 15.6 and 14.7
months, respectively. A subset analysis suggested a survival advantage in patients with low baseline
VEGF serum levels, independently from the treatment arm, suggesting a prognostic more than a predictive
role.77
A multicenter randomized phase II/III study is currently investigating the combination of pemetrexed
plus cisplatin with or without bevacizumab as initial treatment. A preliminary report showed an ORR of
15% in the triplet combination arm with a percentage of not progressive patients at 6 months, the primary
endpoint of the study, significantly higher compared to the chemotherapy-alone arm (73.5% vs. 43%).78
The accrual has been completed and final results are eagerly awaited.79 Based on the existing evidence
the use of bevacizumab in association with chemotherapy in patients with advanced MPM is not
supported.
Nintedanib is a potent inhibitor of pro-angiogenic pathways. A double-blind, randomized, phase II
exploratory study aimed at evaluating efficacy and safety of this agent versus placebo when combined
with cisplatin and pemetrexed has recently completed the enrolment. Patients who do not develop
progressive disease are allowed to receive maintenance treatment with either nintedanib or placebo until
progression.80
Sorafenib is a potent inhibitor of PDGFR-β, VEGFR-2, VEGFR-3, Raf, and c-Kit81 and in a phase II
study including 50 evaluable patients both chemotherapy naive and previously treated an ORR of 6% was
reported with median PFS and OS of 3.6 and 9.7 months, respectively. Patients who had received prior
chemotherapy had a superior OS compared to those who were chemotherapy naive (13.2 and 5 months,
respectively), quite likely the expression of a patient selection bias.82 Another phase II trial assessed
sorafenib as single agent and enrolled 53 patients pretreated with platinum-containing chemotherapy.
Treatment was well tolerated but antitumor activity was limited.83
Sunitinib is another multitargeted TKI that blocks PDGFR-β, VEGFR-1, VEGFR-2, VEGFR-3, and c-
KIT and in a phase II study 51 patients received this TKI after failing cisplatin and pemetrexed or
gemcitabine. ORR was 12% (6 patients) and 34 patients (65%) had stable disease with median PFS and
OS of 3.5 and 6.1 months, respectively. Correlative biomarkers included mesothelin, VEGF-A, VEGF-C,
interleukin-8, sVEGFR-2, sVEGFR-3, and s-kit but none of them predicted treatment response.84 Another
phase II trial with objective response as primary endpoint failed to meet the criteria for proceeding to the
second step showing only one response among 35 evaluable patients.85 A phase I trial with an expansion
cohort in MPM patients demonstrated that sunitinib at 37.5 mg was not tolerated in combination with
cisplatin plus pemetrexed requiring dose reduction mainly due to myelosuppression following the first
cycle and showed only marginal incremental activity.86
In a phase II study, the VEGF and PDGFR TKI vatalanib at 1,250 mg administered orally once daily
was tested in 47 untreated patients. Responses were in 6% and stable disease in 72% of patients. The 3-
month PFS rate was 55% and the study didn’t meet the specified end point of a 3-month PFS of 75%.
Median PFS and OS were 4.1 and 10 months, respectively. No correlation was found between serum
levels of VEGF, PDGF, TSP-1, or mesothelin and clinical outcomes, suggesting no further development of
this drug in this disease.87
Cediranib, a pan-VEGFR TKI, was evaluated in a phase II study including 54 pretreated patients and
the ORR was 9% with median PFS of 2.6 months and OS of 9.5 months.88 Another phase II study included
51 patients who had received ≤1 prior regimen of chemotherapy. Partial responses were observed in 10%
of patients with stable disease in 34%; median PFS was 1.8 months and OS 4.4 months.89 A randomized
phase II trial comparing cisplatin and pemetrexed with or without cediranib as first-line therapy is
currently enrolling patients.90
BNC105P is a tubulin polymerization inhibitor that acts as a vascular disrupting agent through
selectively shutting down tumor blood vessels without affecting normal vasculature. It generates tumor
regression and, occasionally, tumor clearance in mice bearing xenografts of several human tumor types.91
In advanced MPM, BNC105P was investigated as second-line treatment in a single-arm study including
30 patients. One partial response (3%) and 13 stable diseases (43%) have been observed; median PFS
was 1.5 months and OS 8.2 months.92
NGR-hTNF consists of human TNF-α linked to the tumor homing peptide asparagine-glycine-arginine
(NGR), which selectively binds an aminopeptidase-N-isoform overexpressed on tumor blood vessels. In
a phase II study including 57 pretreated patients, ORR was 2% with median PFS and OS of 2.8 and 12.1
months, respectively.93 A randomized double-blind phase III study in patients pretreated with pemetrexed-
based chemotherapy (NGR 015) compared NGR-hTNF versus placebo plus investigator choice.94
Although the primary endpoint of improving OS was not met in the intent-to-treat population, the study
showed a statistically significant 40% improvement of OS in patients who had progressed during or
shortly after the end of first-line chemotherapy. These patients represent 50% of the intent-to-treat
population and were identified by a prespecified analysis based on prior treatment-free interval. This
clinical parameter will help in identifying patients who derive most clinical benefit from NGR-hTNF in
combination with chemotherapy. Consistent with the OS improvement in this subgroup, a 40% longer PFS
was also reported for the NGR-hTNF–treated patients who had a more aggressive, chemoresistant
disease. NGR-hTNF has already been granted Orphan Drug designation for the treatment of mesothelioma
in both the EU and the United States.95
An ongoing phase II randomized trial (NGR 019) is testing the role of NGR-hTNF versus placebo as
maintenance treatment in patients with nonprogressive disease after six cycles of first-line pemetrexed-
based chemotherapy.96
Heat Shock Protein S90 Inhibitors

Heat shock proteins are a family of proteins produced by cells in response to stressful conditions. HSP90
is a chaperone that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids
in protein degradation. It also stabilizes a number of proteins required for tumor growth and survival in a
variety of different tumors including mesothelioma.97 Ganetespib, a novel HSP inhibitor, showed
promising efficacy when combined with docetaxel as second-line treatment in advanced NSCLC.98 The
phase I/II MESO02 trial is currently exploring the efficacy of ganetespib as maintenance treatment versus
placebo after first-line cisplatin–pemetrexed plus ganetespib.99
IMMUNOTHERAPY
MPM is commonly associated with relevant inflammatory reaction partially secondary to the long-term
retention of asbestos in lung tissue. In a retrospective study including 175 epithelioid mesothelioma
patients, high degree of chronic inflammatory cell infiltration in the stromal component was associated
with improved OS. This study first suggested the prognostic value of inflammatory response but also
provided the rationale for investigating immunotherapy in epithelioid MPM patients.100
The high number of genetic and epigenetic changes in most of cancer cells generates relevant shedding
of tumor-associated antigens that can be recognized by the host immune system. On the other hand, the
ability of malignant cells to escape antitumor T-cell activity in the cancer microenvironment is a crucial
event for cancer progression. Tumor antigen recognition by T cell is dependent on T-cell receptor (TCR)
recognition of a peptide binding major histocompatibility complex (MHC). Following TCR engagement,
T-cell activation requires costimulatory signals mediated by T-cell CD28 binding to a B7 family molecule
(B7.1 or B7.2) on the antigen-presenting cell (APC). As a consequence of this process, inhibitory
receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1
(PD-1) are upregulated and expressed on activated effector T cells and contribute to modulate the immune
response after antigen activation. CTLA-4 competes for binding to B7 ligand on APC and regulates T-cell
activity at an early stage and following CTLA-4 binding indeed T-cell response becomes abrogated. PD-1
receptor is expressed on activated T lymphocytes, including those infiltrating tumors, and mediates
immune suppression through the binding with its ligands, PDL-1 and PDL-2. The tumor can block T-cell
activation and therefore evade immune surveillance by upregulating PD-1 ligands101–103 (Fig. 66.2).
Existing data on immunotherapeutic approaches in MPM are summarized in Table 66.3.
FIGURE 66.2 The T-cell responses to tumor antigens are determined by stimulatory and inhibitory coreceptors. MHC, major
histocompatibility complex; TCR, T-cell receptor; PD-1, programmed cell death 1; PDL-1, programmed death ligand 1; CTLA-4,
cytotoxic T-lymphocyte-associated protein 4; CD28, cluster of differentiation 28. B7 ligands include B7.1 (CD80) and B7.2
(CD86).
IMMUNE CHECKPOINTS
Tremelimumab is a humanized monoclonal Ig2 antibody that binds to CTLA-4 and in a pivotal phase II
single-arm study at the dose of 15 mg/kg intravenously once every 90 days it was tested in 29
chemoresistant advanced MPM patients with progressive disease or severe toxicity from previous
treatments. Objective responses were observed in 2 patients (7%), one lasting 6 months and another one
18 months; disease stabilization was seen in 9 patients (31%) with median PFS of 6.2 months and 1- and
2-year survival rates of 48% and 37%, respectively, and median OS of 10.7 months.104 This study
suggested that although tumor shrinkage was quite limited, immunotherapy induced long-lasting efficacy
possibly resulting in survival advantage. Toxicity profile was manageable with 93% of patients
experiencing mainly grade 1–2 treatment-emergent adverse events (cutaneous rash, pruritus, colitis, or
diarrhea), and in 4 patients (14%) grade 3–4 toxicities (2 gastrointestinal, 1 neurologic, 2 hepatic, and 1
pancreatic) were observed. In a subsequent study tremelimumab at 10 mg/kg on day 1, q4 weeks for 6
doses during the induction phase followed by every 12-week dosing until progressing disease or severe
toxicity, was evaluated in 29 MPM patients progressing on first-line platinum and pemetrexed. At a
median follow-up of 14.5 months 4 immune-related responses were observed, with 11 patients
experiencing stable disease with a median duration of 7.7 months and disease control rate of 52%;
median OS was 11.3 months. Grades 1–2 and 3 treatment-related adverse events (gastrointestinal,
dermatologic, and fever) occurred in 89.6% and 3.4% of patients, respectively.105 A phase 2b multicenter
trial included 564 advanced-stage and pretreated MPM patients and using a 2:1 randomization
investigated tremelimumab, with the same dose schedule reported for the above study, versus placebo,
and recently completed the accrual.106
In two retrospective studies PDL-1 immunohistochemistry expression was assessed using two different
antibodies, 5H1 and E1L3N.107,108 In the largest series, paraffin-embedded samples of 77 mesothelioma
patients were stained with anti-PDL-1 clone E1L3N and tumors with >1% of stained tumor cells were
considered PDL-1 positive. PDL-1 positivity was detected in 20% of patients, associated with
nonepithelioid histology and poor prognosis, with median survival in PDL-1-positive MPM significantly
worse than in PDL-1-negative (4.79 vs. 16.3 months, respectively).108 In the other study the percentage of
positive MPM was 40%.107 The different percentage of PDL-1 positivity in the two series could simply
be the consequence of differences in the cut-off values used for positivity and related to technical
differences in the diagnostic antibodies.
It remains unknown whether PDL-1 expression could act as a predictive marker and whether its
expression can change over time with chemotherapy, since PDL-1 is an inducible protein that can be up-
and downregulated upon certain conditions. This also raises the question if archival tumor samples can be
reliably used for assessing PDL-1 status. In a fashion similar to other cancers, the sensitivity and
specificity of PDL-1 detection can vary by the used test, the quality of tissue samples, and the selected
cut-off points. Intriguingly, objective responses have been seen in NSCLC patients whose tumors were
negative for PDL-1 expression.109 Therapies targeting this pathway are of major interest and under
development for MPM patients (Table 66.3).
TABLE 66.3 Immunotherapy

Immunotherapy Rationale Type of References
Study
Immune MPM is commonly associated with relevant inflammatory reaction partially related to Phase II 104,105
checkpoints asbestos-induced chronic inflammation. Associated protein CTLA-4 and MESO- 108,109
programmed cell death 1 (PD-1) are upregulated and expressed on activated TREM
effector T cells 2008 study
Phase IIB
MESO-
TREM
2012 study
Analysis of
expression
of PD-L1
Mesothelin- Mesothelin is overexpressed by most epithelioid mesothelioma but not in normal cells Phase I trial of 113
targeted amatuximab 115
approaches Phase II trial 117
of 120,122
amatuximab 123
First-line study
of CRS-207
Phase I trials
of SS1P
Preclinical
studies of
anetumab
ravtansine
Oncolytic viruses Oncolytic viruses have the capacity to destroy tumor cells, therefore releasing Preclinical 126
antigens that allow T-cell activation through dendritic cells study 127–129
Phase I trial
WT1 WT1 is a transcription factor highly overexpressed in mesothelioma. WT1 peptides Phase II trials 130–133
can elicit T-cells response against mesothelioma cell lines
Vaccination with Autologous tumor vaccines have been shown to generate tumor regression through Phase II trials 134–139
tumor cell tumor-specific immunity
lysate
MESOTHELIN-TARGETED AGENTS
Mesothelin is a cell surface glycoprotein expressed in pleural and peritoneal mesothelial cells and it is
overexpressed in most epithelioid mesotheliomas but not in normal cells.110 Its biologic role has not been
fully understood but it binds to CA125 and its overexpression is involved in cell adhesion and tumor
invasion.111 Mesothelin-targeted immune approaches combined with host immune depletion as occurs
with chemotherapy have shown encouraging activity in mesothelioma. Three mesothelin-targeted agents
are currently in clinical development: amatuximab (MORAb 009), a chimeric anti-mesothelin monoclonal
antibody; CRS-207, a live-attenuated Listeria monocytogenes vector encoding human mesothelin; and
SS1P, a recombinant immunotoxin.
Amatuximab (MORAb 009) is a high-affinity chimeric monoclonal antibody against mesothelin.112 In a
phase I trial in 24 previously treated patients, including 13 mesotheliomas, single agent MORAb 009 at
200 mg/m2 in a weekly schedule was well tolerated and 11 patients had stable disease after receiving at
least one course of therapy.113 In a single-arm multicenter phase II trial amatuximab at 5 mg/kg was
administered on days 1 and 8 with cisplatin and pemetrexed; responsive and stable-disease patients
received amatuximab maintenance until disease progression. The study included 89 patients and 56 (62%)
received amatuximab maintenance. No overlapping toxicities with chemotherapy were observed and 11
patients experienced amatuximab-related hypersensitivity reactions. Partial responses were observed in
33 (40%) patients and stable disease in 42 (51%). Median PFS was 6.1 and median OS 14.8 months.114 A
randomized, placebo-controlled phase III trial is currently evaluating first-line amatuximab 5 mg/kg,
administered weekly, in combination with cisplatin and pemetrexed in patients with unresectable
mesothelioma.115
CRS-207 is live-attenuated L. monocytogenes strain engineered to express the tumor-associated
antigen mesothelin. CRS-207 stimulates innate and adaptive cellular immunity and when combined with
chemotherapy synergistically acts by modifying the tumor environment to improve immune-mediated
killing.116 In a first-line pivotal study 16 patients received 2 induction vaccinations with CRS-207 every
15 days, and then up to 6 cycles of cisplatin plus pemetrexed and 2 boost CRS-207 vaccinations.
Clinically stable patients received CRS-207 maintenance vaccinations every 8 weeks. No serious
adverse events were observed, except for manageable infusion-related fever, chills/rigors, hypotension,
and nausea/vomiting. Nine patients had confirmed partial response and four had stable disease.117
SS1P consists of an anti-mesothelin Fv (SS1) fused to PE38, a 38-kDa portion of Pseudomonas
exotoxin A. After binding to mesothelin, SS1P is internalized by endocytosis and kills cells by arresting
protein synthesis and with initiation of programmed cell death.118 In preclinical models, cells with high
mesothelin expression, as determined by immunohistochemistry, showed sensitivity to SS1P.119 In a phase
I clinical trial of patients with advanced mesothelin-expressing cancers who had failed standard
therapies, SS1P every other day for three doses was well tolerated. Pleuritis was the dose-limiting
toxicity and the maximum tolerated dose (MTD) was 45 μg/kg.120 The most commonly reported adverse
events were hypoalbuminemia and fatigue, and a limited antitumor activity was observed. In addition
most patients developed SS1P-neutralizing antibodies after one or two cycles. In a subsequent study an
immunosuppressive therapy with pentostatin and cyclophosphamide to deplete T and B cells was
implemented. Out of 10 MPM patients refractory to chemotherapy, 3 had major responses with 2 ongoing
at 15 months and 2 others responsive to chemotherapy after discontinuing SS1P.121 In mice with
mesothelin-expressing human tumor xenografts, SS1P as single agent had modest antitumor activity;
however, when combined with chemotherapy remarkable synergy was observed. These preclinical
findings guided an additional phase I trial of escalating doses of SS1P administered intravenously on days
1, 3, and 5 during cycles 1 and 2 of cisplatin and pemetrexed, and in 20 chemotherapy-naive MPM
patients, marked antitumor activity was noted. Ten out of 13 patients who received the maximal tolerated
dose of 45 μg/kg (77%) had a partial response, 1 had stable disease, and 2 had progressive disease.
Objective radiologic responses were associated with significant decreases in serum mesothelin,
megakaryocyte potentiating factor, and cancer antigen 125.122
Anetumab ravtansine is a fully humanized anti-mesothelin antibody conjugated to microtubule targeting
toxophore DM4 (BAY 94-9343). In preclinical studies it showed selective cytotoxicity against
mesothelioma cells, sparing normal mesothelial cells, and clear activity against mesothelioma cell lines
and xenografts suggesting it as a potent drug candidate for further development.123
Overall these data suggest that immunotherapy is a relatively new therapeutic strategy in MPM, with
manageable toxicity profile. Further definition of predictive factors to improve patients’ selection may
result in additional survival advantage. However, because in MPM tissue, cytokines and regulatory T
cells that suppress an efficient immune response have been detected124 the combination of cancer
vaccines with agents that modulate regulatory T cells, with or without chemotherapy, may result in a
synergistic activity.
ONCOLYTIC VIRUSES
Oncolytic viruses are emerging as a promising cancer therapy as a result of their capacity to destroy
tumor cells while sparing normal tissues, therefore releasing antigens that allow T-cell activation through
dendritic cells (DCs).125 Several oncolytic viruses have been tested in preclinical models of pleural
mesothelioma, among which vesicular stomatitis virus, adenovirus, Newcastle disease virus, herpes
simplex virus, vaccinia viruses, and measles virus (MV) are currently investigated. A preclinical study in
a panel of mesothelioma cells derived from patients with pleural effusion investigated the oncolytic
activity and the immunoadjuvant properties of a live-attenuated MV strain derived from the Edmonston
vaccine lineage. MV strain induced apoptosis of infected mesothelioma cells, which were efficiently
phagocytosed by DCs that showed spontaneous maturation and produced proinflammatory cytokines.
Furthermore, priming of autologous T cells by DCs loaded with MV-infected mesothelioma cells induced
proliferation of tumor-specific CD8 T cells.126 Phase I clinical trials are underway testing the intrapleural
application of measles, herpes, and vaccinia viruses in patients with MPM.127–129
WILMS TUMOR SUPPRESSOR GENE 1 (WT1)

WT1 is a transcription factor highly overexpressed in mesothelioma and its immunohistochemical staining
is routinely used, as part of a panel of appropriate markers for diagnostic purposes, while in
mesothelioma cell lines WT1 peptides can elicit T-cells response.130 The safety and the immunogenicity
of WT1 vaccine plus GM-CSF in patients with thoracic tumors expressing WT1 have been tested. Nine
patients with MPM and 3 with NSCLC were vaccinated; 8 patients received at least 6 vaccinations while
10 patients were evaluable for immune response. One patient with mesothelioma had a prolonged disease
stabilization lasting over 3 years and five had documented immune responses with only minimal
toxicity.131 Randomized phase II trials are currently testing the adjuvant role of the WT1 vaccine in MPM
patients after the completion of a multimodality treatment132,133 (Table 66.3).
VACCINATION WITH TUMOR CELL LYSATE

In experimental models, autologous tumor vaccines have been shown to generate tumor regression through
tumor-specific immunity.134 Similarly, autologous tumor lysate vaccines in melanoma and prostate cancer
patients induce tumor-specific immunity and in some patients tumor regression.135,136 In these studies, the
vaccine was administered with GM-CSF as an adjuvant to improve the recruitment and differentiation of
DCs.
The antitumor immunity of an autologous mesothelioma cell lysate, administered subcutaneously with
GM-CSF, was tested in 22 MPM patients and the laboratory evidence of an immunologic response was
documented in 32% of the treated cases. Clinically, the treatment was tolerated, albeit no complete or
partial responses were observed while 7 patients had stable disease; the median OS time was 11.5
months, and the 1- and 2-year survival rates were 50% and 27%, respectively.137
ISCOMATRIXTM is a particulate adjuvant consisting of cholesterol, phospholipid, and saponin and its
combination with an antigen is known as ISCOMATRIXTM vaccine. It showed the induction of strong
antigen-specific cellular and humoral immune responses to a broad range of antigens of viral, bacterial,
parasite, or tumor origin in a number of animal species including nonhuman primates and humans. In a
phase II study in MPM aimed to evaluate the safety and the activity, ISCOMATRIXTM was combined with
tumor cell vaccines plus celecoxib, used to facilitate DC maturation.138 Another study evaluated the
allogeneic tumor vaccine K526-GM in combination with celecoxib and cyclophosphamide was also used
to decrease the amount of regulatory T cells.139
CELLULAR THERAPIES
Dendritic Cells
DCs play a critical role in presenting tumor-associated antigens (TAA) to T cells and, consequently, in
generating tumor-specific immunity.140 DCs induce activation and proliferation of CD8+ cytotoxic T
lymphocytes (CTL) and helper CD4+ lymphocytes. The goal of DC-based cancer immunotherapy is to
trigger a specific antitumor immunity with the generation of effector cells able to attack and lyse tumors.
The effect of DC-based immunotherapy on the outgrowth of mesothelioma was tested in murine models
using tumor cell lysate as antigens to pulse DCs and induced strong tumor-specific CTL responses leading
to prolonged survival in mice with the efficacy dependent on the tumor load.141 A clinical study in 10
MPM pretreated patients evaluated the efficacy and safety of autologous tumor lysate pulsed DCs
administered intradermally and intravenously, every 2 weeks for a total of three injections. The
vaccination was safe with moderate fever as the only side effect and in four patients the vaccination
induced cytotoxic T-cell response.142
CAR-T
T cells can be redirected to overcome tolerance to cancer by engineering with integrating vectors to
express a chimeric antigen receptor (CAR) that enables T cell to destroy target cells. Genetically
engineered autologous T lymphocytes may indeed increase antigen recognition or alter the
immunosuppressive tumor microenvironment through production of cytokines. As reported above,
mesothelin is a tumor-associated antigen overexpressed in a variety of malignancies with relatively
limited expression in normal tissues. Investigational agents consisting of autologous T cells expressing an
anti-mesothelin CAR have been developed and have shown in vitro and in vivo activities.143 T
lymphocytes can be genetically modified by retrovirus or RNA electroporation. Indeed safety concerns
associated with viral vector production have limited clinical application of T cells expressing chimeric
antigen receptors.144 Mesothelin-specific redirected T cells are currently being tested in early clinical
trials.145
The fibroblast activation protein (FAP)-redirected T cells showed promising in vitro activity and are
currently under investigation. To minimize the risk of on-target off-tissue toxicity and to maximize the on-
target antitumor effect the adoptive transfer is directly performed in the pleural effusion.146,147
PHOTODYNAMIC THERAPY (PDT)

PDT is increasingly being used to treat thoracic malignancies, including MPMs. It is a nonionizing
radiation therapy, but a photosensitizer that accumulates in malignant cells and is activated by a specific
light wavelength. This combination produces reactive singlet oxygen that can exert anticancer activity
through apoptotic, necrotic, or autophagic tumor cell death. PDT may also induce an inflammatory
reaction stimulating a tumor-directed host immune response.148,149
Usually PDT in MPM is part of a multimodality treatment and it can be safely combined with
macroscopically complete surgical resection and other treatment modalities to improve local
control.150,151
INTRAPLEURAL CHEMOTHERAPY
In MPM intrapleural chemotherapy (or hyperthermic intrapleural chemotherapy) after cytoreductive
surgery (pleurectomy and decortication) may be performed afterwards in an attempt to remove all
microscopically residual malignant disease. This approach has been shown to be effective for peritoneal
metastases from appendiceal malignancy, peritoneal mesothelioma, and colorectal cancer.152,153
CONCLUSION
Unlike other solid cancers, very limited improvements in the systemic treatment of MPM patients have
been made in the last years and only limited insights have been gained into the biology of this disease. To
date, the doublet of cisplatin and pemetrexed is still the only evidence-based systemic treatment
associated with clinically significant survival improvement and better quality of life. For patients unfit for
cisplatin, carboplatin may represent a reasonable alternative. Predictive molecular markers unfortunately
have no role in the everyday clinical practice.
Second-line therapies are an unmet clinical need, in the lack of treatment approaches of proved
efficacy. In selected patients with prolonged disease control after first-line pemetrexed-based
chemotherapy, the rechallenge with pemetrexed should be considered while vinorelbine remains a viable
option for palliation in patients early failing pemetrexed. Many targeted agents have been tested so far
with very scanty activity both as single agent and in combination with chemotherapy. Novel
immunotherapeutic approaches, including those assessing the inhibition of immune checkpoints, are being
explored and hopefully may result in therapeutic advances in the management of MPM patients. Whenever
possible, patients should be encouraged to enter in the available clinical trials testing new agents and new
strategies.
The worldwide increase in the incidence of MPM claims for more effective treatment. Oncogenic
driver mutations that have radically changed the management of adenocarcinoma of the lung unfortunately
have not yet been detected in MPM. The future development of targeted approaches is focused on the
exploration of pathways activated as a consequence of the loss of tumor suppressor genes or other targets
associated with the disease phenotype. Biologic therapy addressing angiogenesis and tyrosine kinase
deregulated activity has shown overall disappointing results despite hundreds of patients enrolled in the
clinical studies performed so far.
A promising area of investigation besides immunotherapy includes the NF2/Hippo pathway. Merlin
deficiency leads to deregulation of several pathways such as the PI3K/mTOR, Hedgehog, and FAK
pathways. In preclinical models, targeting these pathways results in inhibitions of tumor growth and
clinical studies are currently testing these approaches.
Further advances in the MPM treatment indeed require well-designed clinical studies addressing the
role of therapeutic agents selected on the molecular profiling of the individual tumor. A critical point in
implementing these types of studies is the availability of adequate amounts of tumor tissue from each
patient. For these reasons, but also for others correlated to diagnostic and staging challenges, patients
with MPM should be referred to centers with expertise and dedicated multidisciplinary teams.
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67
Surgical Approaches for Diffuse Malignant
Pleural Mesothelioma
Bryan M. Burt ■ Shawn S. Groth ■ David J. Sugarbaker
INTRODUCTION
Malignant pleural mesothelioma (MPM) is a rare, locally aggressive, and rapidly fatal tumor of the
thoracic pleural mesothelium, commonly associated with inhalational exposure to asbestos.
Approximately 2,500 to 3,000 new cases, per year, are seen in the United States; however, epidemiologic
studies suggest that the incidence of MPM worldwide is underestimated and increasing.1,2 The disease is
five times more common in males, which is likely reflective of occupational exposure to asbestos. The
clinical presentation is insidious with the most common presenting symptoms being dyspnea and chest
pain.
MPM is refractory to single modality local or systemic therapy. Multimodality approaches
incorporating surgical macroscopic complete resection with chemotherapy and/or radiotherapy, however,
are associated with long-duration disease remission and overall survival in selected patients.3,4 An expert
panel discussed the role of surgical cytoreduction for MPM at the International Mesothelioma Interest
Group Congress in 2012. The panel agreed that surgical macroscopic complete resection and control of
micrometastatic disease played a vital role in the multimodality therapy of MPM. Moreover, there is an
indication of surgical cytoreduction when macroscopic complete resection is deemed achievable.5
Staging in MPM lacks consensus, and various staging systems exist. The classic staging system
described by Butchart et al. in 1976 is relatively simple and descriptive.6 The Brigham staging system,
based upon resectability by extrapleural pneumonectomy (EPP), may not be applicable to patients
undergoing pleurectomy/decortication (PD).7 The Tumor, Node, Metastasis (TNM) staging system,
proposed by the International Mesothelioma Interest Group (IMIG), is the accepted American Joint
Commission on Cancer staging system (AJCC).8
In this chapter, we describe our approach to patient selection, preoperative preparation, surgical
resection and reconstruction, and the postoperative management of EPP and PD for patients with MPM.
SELECTION OF PATIENTS
EPP entails en bloc resection of the parietal pleura, lung, ipsilateral hemidiaphragm, and pericardium,
followed by pericardial and diaphragmatic reconstruction. PD involves resection of the parietal and
visceral pleura while sparing the lung. Pericardial or diaphragmatic resection may be incorporated into
PD when required; in these circumstances, the operation is referred to as an “extended pleurectomy and
decortication.” Proponents of EPP endorse this operation, as it provides a complete oncologic resection
and facilitates delivery of hemithoracic radiation (because of the removal of the lung) with significantly
less toxicity in comparison to PD (because the lung is left in place). Advocates of PD argue that complete
macroscopic resection is, indeed, achievable with this operation and that PD can be performed with less
operative morbidity.
To date, there is no definitive evidence that either cytoreductive operation (EPP or PD) offers a
survival advantage over the other. A retrospective review of 1,494 patients undergoing surgical resection
in the large, multicenter initial analysis of the International Association for the Study of Lung Cancer
(IASLC) Mesothelioma Database found that there is a connection between stage I tumors resected by EPP
and longer median survival (40 months) when compared with those patients managed by PD (23 months).
There were no survival differences found between EPP and PD with higher stage disease (Fig. 67.1).4 In
contrast, a multi-institution retrospective study of 663 patients surgically treated for MPM suggested that
PD may have a long-term survival advantage when compared to EPP.9 Further, a recent meta-analysis of
24 series failed to find differences in 2-year survival in patients receiving either EPP or PD.10 Significant
selection bias confounds each of these studies, and the oncologic efficacy of one operation over the other
remains undefined.
Incorporating pneumonectomy into the resection of pleural mesothelioma will consistently result in
higher postoperative morbidity and mortality. In the first reports of “curative” surgery for MPM, Butchart
et al. performed EPP with a surgical mortality rate of 30%.6 In a nearly 30-year period since this initial
report, advances in patient selection, intraoperative techniques, and postoperative management have
decreased the mortality of this operation substantially, especially in centers that perform a high volume of
mesothelioma surgery. In the largest published series of EPP for MPM, 529 patients with epithelial MPM
underwent EPP with 5% 30-day or in-hospital mortality.11 A recent analysis of the Society of Thoracic
Surgeons Database reported operative morbidity rates of 10.5% for EPP and 3.1% for PD, and major
complication rates of 25.3% for EPP and 4.6% for PD.12 In the meta-analyses of 24 MPM datasets of
1,512 patients undergoing PD and 1,391 patients undergoing EPP, operative mortality rates of 4.5% for
EPP and 1.7% for PD were reported.10
FIGURE 67.1 Overall survival is shown according to type of curative-intent procedure (EPP or P/D) and stage: (A) Stages I to
II and (B) stages III to IV. The 95% confidence interval is shown in parenthesis. EPP, extrapleural pneumonectomy; P/D,
pleurectomy/decortication. (Reprinted from Rusch VW, Giroux D, Kennedy C, et al. Initial analysis of the International
Association For the Study of Lung Cancer Mesothelioma Database. J Thorac Oncol 2012;7(11):1631–1639. Copyright © 2012
All patients undergoing consideration for EPP or PD require a thorough staging and cardiopulmonary
evaluation. Evaluation begins with tumor histology, preferably by evaluation of a thoracoscopically
obtained tissue sample. It is well recognized that patients with sarcomatoid and biphasic histology have
poor prognosis, which is significantly worse than for patients with epithelioid histology.3,4 For patients
with sarcomatoid MPM, it has become our practice to favor operative therapy in the context of a study
protocol.
Our preoperative workup for a patient with MPM being considered for cytoreductive surgery includes
a dedicated chest CT with intravenous contrast to assess the extent of mediastinal involvement. The
patient should also have a PET-CT to assess the extent of nodal disease and to assess for disease
extending outside of the ipsilateral hemithorax. A chest MRI may be superior to other cross-sectional
imaging techniques in assessing discrete foci of chest wall invasion and diaphragmatic muscle
involvement.13 However, it is our experience that MRI may often be misleading in many cases. In
contrast, narcotic-dependent chest wall pain is highly suggestive of unresectable disease. Because of the
limitations of current imaging studies, exploration is performed in some patients with questionable
radiographic evidence of chest wall invasion but without distant disease. Obvious radiologic
demonstration of chest wall invasion or palpable tumor by examination is considered unresectable.
Extrathoracic chest wall invasion discovered at exploration is typically considered unresectable as well.
In rare cases, however, limited chest wall resections will be offered if complete macroscopic resection is
achievable otherwise. If there is a suggestion of transdiaphragmatic invasion on preoperative imaging, or
if there is significant bulky diaphragmatic disease, diagnostic laparoscopy is performed. Lastly, cervical
mediastinoscopy is performed for staging purposes. N3 disease is considered a contraindication to
surgical resection. Induction chemotherapy is offered to patients with N2 disease, and those who have a
measurable response to systemic therapy will be offered surgical resection. Previous talc pleurodesis is
not a contraindication to resection.
To determine the patient’s suitability for EPP, the authors use several preoperative physiologic criteria
outlined in Table 67.1. Pulmonary function measured by a forced expiratory volume in 1 second (FEV1)
of greater than 2 L is considered sufficient for pneumonectomy. If FEV1 is less than 2 L, a ventilation-
perfusion (VQ) scan is obtained to predict postoperative lung function. If the postoperative FEV1 is less
than 0.8 L, we will not offer EPP and will consider PD. Echocardiography with Doppler studies is
performed in all patients to assess for pulmonary hypertension, which, if present, may be further assessed
by right heart catheterization.
TABLE 67.1 Criteria for Selection of Patients for EPP

Extent of Limited to the ipsilateral hemithorax without transdiaphragmatic, transpericardial, extensive chest wall involvement, and
disease N2 or N3 disease
Performance Karnofsky score >70
status
Pulmonary Postoperative FEV1 >0.8 L
function
Cardiac function Left ventricular EF >45%; PA pressure <50
Renal function Creatinine <2
Liver function AST <80 IU/L, total bilirubin <1.9 mg/dL, PT <15 s
EXTRAPLEURAL PNEUMONECTOMY: TECHNIQUE

Right Extrapleural Pneumonectomy
A thoracic epidural is placed preoperatively for intraoperative and postoperative analgesia. Standard
monitoring with telemetry, continuous pulse oximetry, central venous access, and urinary Foley
catheterization are routine. A pulmonary artery catheter is placed for intraoperative and postoperative
fluid management and is especially useful for this purpose in patients undergoing intraoperative heated
chemotherapy with cisplatin, which results in cisplatin-induced diuresis. After the induction of general
anesthesia, a left-sided double-lumen endotracheal tube is placed for single lung ventilation, and the
patient is positioned in the left lateral decubitus position. A nasogastric tube is placed to facilitate
identification of the esophagus during extrapleural dissection and for gastric decompression during the
immediate postoperative course.
EPP is performed in the following steps: incision and exposure of the parietal pleura; extrapleural
dissection to separate the tumor from the chest wall; en bloc resection of the pleura, lung, diaphragm, and
pericardium with division of hilar structures; thoracic nodal dissection; and reconstruction of the
diaphragm and pericardium.
The pleural resection begins with an extended posterolateral thoracotomy. The incision is started
midway between the posterior scapular tip and the spine and extended to the costochondral junction along
the sixth rib. Previous thoracoscopy sites that lie along the planned thoracotomy incision are included in
the thoracotomy incision. Other port sites are excised separately as the disease will often recur in these
areas. The latissimus dorsi and serratus anterior muscles are divided, and the sixth rib is resected. The
posterior periosteum in the bed of the sixth rib is incised to expose the extrapleural plane. Extrapleural
dissection is performed using a combination of blunt and sharp dissection beginning on the anterolateral
aspect of the chest and advancing toward the apex (Fig. 67.2). Anteriorly, the internal mammary arteries
are identified, and care is taken to prevent avulsion. If extended chest wall invasion obliterating the
extrapleural plane is discovered, surgical resection is precluded. In the absence of this, the extrapleural
dissection is continued anteriorly and posteriorly toward the mediastinum and diaphragm to allow two
chest retractors to be positioned for optimal exposure (Fig. 67.3). During extrapleural dissection,
previously dissected areas are packed with surgical pads to assist in hemostasis.
FIGURE 67.2 A: Sagittal section of right lung and pleura. B: Pleurectomy is begun between the endothoracic fascia and the
parietal pleura using blunt dissection. The plane is developed cephalad. (From Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds.
Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright © Marcia Williams. All rights reserved.)
The dissection is then carried over the apex of the lung where great care is given to avoid injury to the
subclavian vessels. The tumor is brought down from the posterior and superior mediastinum (Fig. 67.4)
and sharp dissection is performed to dissect the tumor off of the superior vena cava and azygos vein. The
posterior dissection is next performed, exposing the right upper lobe and right mainstem bronchus. The
nasogastric tube is palpated and the tumor is carefully resected off the esophagus. The thoracic duct is
routinely prophylactically ligated en masse. Anteriorly, the pericardium is opened with dissecting
scissors and the pericardial space is palpated to assess for pericardial invasion (Fig. 67.5). If unexpected
invasion of vital mediastinal structures such as the aorta, vena cava, esophagus, epicardium, or trachea is
identified, the operation is aborted. In the absence of mediastinal invasion, diaphragmatic resection is
initiated.
FIGURE 67.3 Two chest retractors are placed, one anterior and one posterior, to increase the exposure. (From Sugarbaker DJ,
Bueno R, Krasna MJ, et al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright © Marcia Williams.
All rights reserved.)
FIGURE 67.4 A nasogastric tube in the esophagus aids in palpating the esophagus while dissecting the pleura from the
esophagus. (From Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-Hill;
2014. Copyright © Marcia Williams. All rights reserved.)
The insertions of the diaphragm on the chest wall are bluntly avulsed with finger dissection (Fig.
67.6). This dissection begins on the lateral margin of the diaphragm and proceeds circumferentially both
anterior and posterior toward the mediastinum. Although not completely intuitive, this technique results in
a relatively bloodless resection of the diaphragm from the chest wall. The peritoneum is then bluntly
dissected off of the diaphragm using sponge sticks. The dissection then proceeds with the separation of
the muscular attachments of the diaphragm from the mediastinum using a combination of blunt dissection,
electrocautery, and surgical clips placed on diaphragmatic vessels. Caution is taken in the region of the
inferior vena cava and the esophageal hiatus (Fig. 67.7). The previous incision in the anterior
pericardium is then extended toward the junction of the pericardium and diaphragm, and the most medial
aspect of the diaphragm is divided, completing the diaphragmatic resection.
Attention is returned to the anterior pericardial incision that is extended over the superior vena cava to
the level of the hilum. The right main pulmonary artery and the superior and inferior pulmonary veins are
dissected intrapericardially. The pulmonary artery is typically divided first. However, depending on how
well the anatomy lends itself to ease of dissection, it is not uncommon to divide the superior vein first. A
soft-flanged catheter (endoleader) is passed around the pulmonary artery to guide safe passage of an
endovascular stapler, facilitating the division of the artery (Fig. 67.8). The pulmonary artery is clamped
with the stapling device. It is then assured that there is no cardiopulmonary compromise and that there are
no changes in the PA waveform. Changes in the PA waveform could represent inclusion of the PA line
within the stapling cartridge. The superior and inferior pulmonary veins are divided in a similar fashion.
After the division of the vessels, the posterior pericardium is incised, and this completes the pericardial
resection (Fig. 67.9).
FIGURE 67.5 The pericardium is opened anteriorly and the pericardial space is palpated to assess for myocardial invasion.
(From Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014.
Copyright © Marcia Williams. All rights reserved.)
FIGURE 67.6 The diaphragm is separated bluntly or by avulsion from the chest wall muscular attachments. (From Sugarbaker
DJ, Bueno R, Krasna MJ, et al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright © Marcia
Williams. All rights reserved.)
Taking care to avoid devascularization, the right mainstem bronchus is dissected circumferentially and
encircled as close to the carina as possible with a heavy gauge wire bronchial stapler (Fig. 67.10). The
bronchial stump and contralateral main bronchus are visualized by direct bronchoscopic examination to
ensure a short bronchial stump; the bronchus is then divided. The en bloc resection specimen (pleura,
lung, diaphragm, pericardium) is removed from the chest. Pathology performs frozen section analysis of
the bronchial margin. A staging mediastinal lymphadenectomy, with resection of paratracheal, subcarinal,
paraesophageal, and inferior pulmonary ligament lymph nodes, is then performed.
FIGURE 67.7 Dissection around the esophageal hiatus and inferior vena cava. (From Sugarbaker DJ, Bueno R, Krasna MJ, et
al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright © Marcia Williams. All rights reserved.)
FIGURE 67.8 An endoleader is passed around the pulmonary artery to guide the safe passage of the endovascular stapler, and
the right pulmonary artery is divided. (From Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds. Adult Chest Surgery. 2nd ed.
New York: McGraw-Hill; 2014. Copyright © Marcia Williams. All rights reserved.)
FIGURE 67.9 The right pulmonary artery and right superior and inferior pulmonary vein have been divided. The diaphragm and
pericardium have been resected. The bronchus will be prepared for division. Following this, the specimen can be removed. (From
Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright ©
Marcia Williams. All rights reserved.)
FIGURE 67.10 The right mainstem bronchus is encircled as close to the carina as possible before division with a heavy-gauge
wire bronchial stapler. (From Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds. Adult Chest Surgery. 2nd ed. New York:
McGraw-Hill; 2014. Copyright © Marcia Williams. All rights reserved.)
Warm water is instilled into the chest, and handbag ventilation is performed to 30 mm H2O pressure to
check for air leaks along the bronchial staple line. Chest wall hemostasis is achieved with liberal use of
argon beam coagulation. Areas of concern for incomplete resection, if any, are marked with metallic clips
to facilitate adjuvant radiotherapy. An omental flap is fashioned by mobilization of the greater omentum
off of the transverse colon. Next, the vascular supply to the flap is contoured from a pedicle off of the
gastroepiploic arteries along the greater curvature of the stomach (Fig. 67.11). The flap is then tucked
temporarily back into the abdominal cavity.
Gore-Tex (W.L. Gore and Associates, Flagstaff, AZ, USA) patches are used to reconstruct the
diaphragmatic and pericardial defects. The diaphragm is reconstructed using two 20 × 30 cm pieces of 2
mm thick Gore-Tex dual mesh, stapled together in a side-by-side fashion with a slight overlap at the
center. The patch is contoured to the shape of the hemithorax creating (Fig. 67.12) a loose, floppy patch at
the center, resulting in less tension at the suture lines along the chest wall. Such a dynamic patch is less
likely to be complicated by patch dehiscence from the chest wall and abdominal content herniation into
the pneumonectomy cavity. The diaphragmatic patch is approximated to the chest wall anteriorly,
laterally, and posteriorly with nine Ethibond sutures placed through the patch and the intercostal space
(Fig. 67.13). Each suture is passed through a 14 mm polypropylene button and tied down around the
button, buttressing the patch to the chest wall. Seven sutures are placed laterally along the posterior,
medial, and anterior eighth or ninth intercostal space. One suture is placed through the remnant of the
divided sixth rib anteriorly, and one suture is placed through the anterior sixth intercostal space. A
laparoscopic tacking device is then used to place tacks through the patch into the chest wall on both the
anteromedial and posteromedial aspects of the patch to further secure these areas to the chest wall. When
securing the patch posteriorly, care must be taken to avoid undue compression on the IVC. A small
opening is then made in the medial mid-portion of the diaphragmatic patch to permit transposition of the
omental flap into the pneumonectomy space. Medially, the patch is sewn to the inferior cut pericardial
edge and diaphragmatic crus using two or three Ethibond sutures. This step is critical to prevent
herniation of abdominal viscus organ into the chest.
FIGURE 67.11 The omental flap is harvested for later use as a bronchial buttress. (From Sugarbaker DJ, Bueno R, Krasna MJ,
et al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright © Marcia Williams. All rights reserved.)
FIGURE 67.12 The diaphragmatic patch is constructed from two pieces of 2-mm thick Gore-Tex dual mesh. (From Sugarbaker
FIGURE 67.13 Polypropylene buttons (14 mm) (A) are used to buttress the (B) suture that secures the patch of the chest wall.
The pericardium is reconstructed to prevent cardiac herniation into an empty right hemithorax, which
is potentially a fatal complication. A 15 cm × 20 cm, 0.1 mm thick Gore-Tex pericardial patch is
fenestrated to prevent pericardial effusion and sewn to the pericardial edges with interrupted sutures
placed first posteriorly, then anteriorly (Fig. 67.14A). The diaphragmatic and pericardial patches are then
sewn to each other medially (Fig. 67.14B). It is assured that there is no undue tension on the pericardial
patch, which could both restrict the contracting heart and result in pericardial patch dehiscence.
The omental flap is then transposed into the chest and secured with vicryl sutures to the bronchial
stump to provide tissue coverage and separation from the pulmonary artery staple line (Fig. 67.15). A 12
Fr red rubber catheter is placed into the pneumonectomy space and brought out anteriorly through a
separate, inferior stab incision. The thoracotomy is then closed in the standard fashion in multiple layers.
The red rubber catheter is connected to a three-way stopcock; 1,000 mL of air in men and 750 mL of air in
women are removed, positioning the mediastinum to the midline. After the chest is closed, the patient is
gingerly placed in the supine position to avoid rapid shift of the mediastinum. Flexible bronchoscopy is
performed to assess the bronchial stump and to clear secretions, and a contralateral basilar chest tube is
placed to prevent postoperative accumulation of a contralateral pleural effusion. The patient is extubated
in the operating room.
FIGURE 67.14 A: The pericardial patch is fenestrated and sewn to the pericardial edge. B: Both patches are sutured to the cut
edge of the pericardium and onto each other medially. (From Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds. Adult Chest
Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright © Marcia Williams. All rights reserved.)
Left Extrapleural Pneumonectomy

The technique of left EPP is similar to that of right EPP with some key variations. Important differences in
the approach to anesthesia include placement of a right-sided double-lumen endotracheal tube or a left-
sided endobronchial blocker. During posterior extrapleural dissection on a left EPP, it is critical to enter
the preaortic plane to prevent inadvertent injury of the intercostal artery trunks. Also, caution should be
exercised around the thoracic duct and recurrent laryngeal nerve during dissection of the aortopulmonary
window and subclavian vessel takeoff from the aortic arch. During diaphragmatic resection, it is useful to
leave a 2 cm rim of diaphragmatic crus near the gastroesophageal junction if possible (Fig. 67.16).
Placement of sutures to this rim of crus to the prosthetic diaphragmatic patch prevents gastric herniation
into the pneumonectomy space. If this is not possible, the use of a laparoscopic tacking device to secure
the patch to the chest wall anteriorly is beneficial.
FIGURE 67.15 The omental flap is sutured to the bronchial stump. (From Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds.
Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright © Marcia Williams. All rights reserved.)
FIGURE 67.16 Two centimeters of diaphragm is left around the esophagus if possible. (From Sugarbaker DJ, Bueno R, Krasna
MJ, et al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-Hill; 2014. Copyright © Marcia Williams. All rights
reserved.)
Since the left main pulmonary artery is relatively shorter than the right main pulmonary artery, it is
divided extrapericardially (Fig. 67.17). The left mainstream bronchus should be dissected deep to the
aortic arch and as close to the carina as possible to ensure a short bronchial stump after division.
Mediastinal lymph node dissection on the left side also includes level 5 and 6 nodal stations. Although
cardiac herniation associated with the pericardial defect is not an issue on the left side, it is our practice
to reconstruct the pericardial defect after left EPP to prevent restrictive pericarditis. Less air is removed
from the left pneumonectomy space when using a red rubber catheter placed into the left hemithorax in
comparison to the right (750 mL in men and 500 mL in women). The EPP patient is extubated while in the
operating room to avoid positive pressure on the bronchial stump.
FIGURE 67.17 The left pulmonary artery is divided extrapericardially because it is shorter in comparison with the right
pulmonary artery. (From Sugarbaker DJ, Bueno R, Krasna MJ, et al., eds. Adult Chest Surgery. 2nd ed. New York: McGraw-
Hill; 2014. Copyright © Marcia Williams. All rights reserved.)
Postoperative Management of the EPP Patient

Patients undergoing EPP are transferred to the intensive care unit (ICU) at the conclusion of the
procedure. A chest radiograph is obtained immediately to confirm placement of the central line. A PA line
is obtained to confirm the appropriate location of the nasogastric tube and red rubber catheter and to
assess for the position of the mediastinum in the midline. This intrapleural red rubber catheter may be
used to aspirate air or fluid in the setting of mediastinal shift. Pressure measurement through this catheter
may aid in the postoperative management of the pneumonectomy space.14 The authors recommend
aspirating no more than 300 cc per treatment to avoid large swings in the mediastinum. This tube is
removed on postoperative day (POD) 3. Initially, patients are managed in the ICU for 2 to 3 days and then
transferred to the thoracic intermediate care unit. Patients who have undergone heated intraoperative
chemotherapy (HIOC) (see below) receive liberal amounts of intravenous fluids for the initial 24 hours to
facilitate renal protection. Otherwise, fluid is restricted to 1 L per day for 3 to 5 days. When necessary,
colloids and blood product transfusion are administered.
Prevention of pulmonary complications, namely pulmonary embolus and aspiration, is the focus of
postoperative management. A thoracic epidural is maintained for 4 to 5 days postoperatively for
analgesia, and aggressive chest physiotherapy is performed daily. Patients are kept on bed rest on
postoperative POD1, sat up and dangled on the edge of the bed on POD2, and ambulated 2 to 3 times per
day beginning on POD3. Aggressive diuresis begins on POD2 for the next several days until the patients
return to their preoperative weight. Liberal amounts of bedside bronchoscopy with conscious sedation is
performed when required for pulmonary toilet. Daily chest radiographs are obtained to assess the
mediastinal position and infiltrates or effusions in the contralateral lung. Any suggestion of pneumonia is
treated aggressively, and contralateral effusions are treated with thoracostomy tube placement. Deep vein
thrombosis (DVT) prophylaxis is achieved with subcutaneous heparin, and routine surveillance lower
extremity ultrasounds are obtained every 7 days to assess for DVT. Nasogastric tubes are used for gastric
decompression and to prevent aspiration and are typically removed on POD2. Oral diet is advanced
slowly with return of bowel function. The inability to generate a strong cough or hoarseness is suggestive
of recurrent laryngeal nerve injury, which will lead to significant aspiration risk. In these cases, prompt
evaluation with flexible laryngoscopy is recommended, and early vocal cord medialization if vocal cord
paralysis is identified.
PLEURECTOMY AND DECORTICATION: TECHNIQUE

After the induction of general anesthesia, the patient is prepared and positioned for surgery, and an
extended posterolateral thoracotomy with resection of the sixth rib is performed, as described above for
EPP. The extrapleural dissection is similar to that described above for EPP, as well, beginning laterally
and advancing toward the apex of the chest, then proceeding anteriorly, medially, and inferiorly enough to
insert two chest retractors. The extrapleural dissection then continues to mobilize the lung and parietal
pleura completely from the chest wall to expose the superior, anterior, and medial hilar structures, also as
described above for EPP.
A plane between the pericardium and the mediastinal pleura is sometimes present. If it is not, or if
there is malignant invasion of the pericardium, the pericardium should be resected en bloc at a later stage
of this operation. The dissection is carried toward the posterior diaphragmatic sulcus. If superficial
invasion of the diaphragm is found, a partial thickness resection of the diaphragm could be performed. In
this case, the plane between the tumor (diaphragmatic pleura) and the uninvolved diaphragm can be
entered, and the dissection is initiated at the posterior costophrenic angle and carried anteriorly. This can
be facilitated by strong retraction of the pleura away from the diaphragm. In many patients, deeper
involvement into the diaphragmatic muscle mandates either a full-thickness partial resection of the
diaphragm or a complete diaphragmatic resection with reconstruction. In either case, the deep border of
the diaphragm must be dissected free from the peritoneum. Care is taken to not enter the abdomen to
prevent tumor seeding into the abdominal compartment. Violation of the peritoneum, however, is often
unavoidable especially around the central tendon, and any defects in the peritoneum should be closed
immediately. If resection of the pericardium is required, it is opened gradually, and traction sutures on the
cut edge of the pericardium can aid in maintaining the position of the heart and in circumferential
resection of the pericardium (Fig. 67.18).
FIGURE 67.18 The parietal pleura has been stripped from the chest wall, and the lung is ready for decertification. Note the
exposed hilar structures, traction sutures on the pericardium, closed peritoneal defect, and resection of involved diaphragm.
Once the dissection is completed to the hilar structures, the parietal pleura is opened, and the pleural
envelope between the parietal and visceral pleura is entered. Decortication of the visceral pleura then
ensues, which in some respects, is the most technically demanding and tedious portion of the procedure.
The decortication is begun by sharply incising the thickened visceral pleura. The cut edge of the visceral
pleura can be grasped with an Alice clamp or ring forceps. The lung parenchyma is then massaged off the
visceral pleura aided by the use of a sponge stick or folded laparotomy pad, placing pressure
predominantly on the visceral pleura itself. The decortication must extend cautiously into the fissures
because they are often substantially involved with disease (Fig. 67.19). Inflation of the lung will allow
better visualization of the plane between the visceral pleura (tumor) and lung parenchyma and will
minimize bleeding. Therefore, the lung is often inflated and deflated several times during the decortication
portion of the procedure. Communication between the surgeon and anesthesiologist is important because
the blood loss during this portion of the procedure can be significant, and most patients require
intraoperative transfusion. Nodal dissection is completed as described above for EPP.
FIGURE 67.19 Decortication must be performed meticulously in the fissures to remove all gross disease. (From Sugarbaker
After the delivery of the specimen, reconstruction of the diaphragm and pericardium, if required, is
performed. If the diaphragm is largely intact, it can be closed primarily by plication to prevent upward
movement and subsequent compression atelectasis of the lower lobe. Larger defects can be closed using a
small Gore-Tex patch. If the diaphragm was completely resected, it is reconstructed as described above
for EPP. Hemostasis is assured and can be aided by argon beam coagulation to control the diffuse
bleeding that can be seen from the chest wall. Since a substantial degree of postoperative air leak is
expected following PD, adequate lung expansion at the conclusion of the operation is critical to prevent
pleural space infectious problems in the setting of prolonged air leak. Three chest tubes (an anteroapical
tube, a posteroapical tube, and a right-angle tube along the diaphragm) and an apical Blake drain are
placed. The patient is transferred to the ICU intubated.
Postoperative Management of the Pleurectomy/Decortication Patient

The postoperative care of the PD patient is similar to that of the EPP patient, with some differences.
Patients undergoing PD typically remain intubated overnight to benefit from positive pressure intubation
on the pleurectomized lung, which facilitates expansion and minimizes postoperative bleeding. As there is
usually substantial degree of air leak in the immediate postoperative period, chest drains are placed on
suction to facilitate initial lung expansion. The chest tubes are placed to water seal during the first few
postoperative days when the lung is not dependent upon suction for complete expansion. The tubes are
removed in an order depending upon the location of air leaks. On occasion, persistent air leak without
pneumothoraces is treated with a Heimlich valve on an outpatient basis and this is typically removed
during an office visit about 2 weeks following discharge.
MULTIMODALITY THERAPY
Single modality therapy for MPM, whether it is surgery alone, chemotherapy alone, or radiotherapy alone,
does not have a significant impact on recurrence-free or overall survival. As a reference, the median
survival of patients treated with the current standard of care first-line chemotherapy regimen (cisplatin
and pemetrexed) is 12 months.15 The treatment of patients with MPM has therefore evolved to a
multimodality approach that incorporates surgery with chemotherapy and/or radiotherapy. The balance of
the MPM literature, comprised chiefly of retrospective data comparison and prospective single-arm study
comparisons to historical controls, suggests that a multimodal attack on this disease may prolong
recurrence-free survival and overall survival.
The largest series of patients treated surgically for MPM was reported in an analysis of the
international MPM database from the IASLC. In this study, the median survival of 207 patients undergoing
surgery alone was 11 months, compared to 20 months in 1,162 patients undergoing surgery with some
other treatment.4 These data are certainly affected by selection bias and by confounding from various
prognostic factors. For example, one retrospective review of 183 patients who underwent EPP followed
in some cases by chemotherapy and/or radiation determined that non-epithelial histology, involved
extrapleural nodes, and extensive local invasion of the tumor were poor prognostic factors. In that study,
the subgroup of 31 patients who had epithelial histology, negative resection margins, and negative lymph
nodes had a 2-year survival rate of 68% and a 5-year survival rate of 46%.3 Six prospective single-
institution phase II studies have been reported on the role of neoadjuvant chemotherapy, EPP, and
postoperative radiation.16–21 These trials differed in the inclusion of patients with sarcomatoid histology
and N2 status. About 75% of patients included in these trials underwent EPP and about three-fifths
received postoperative radiotherapy. Consequently, it is difficult to make generalizable conclusions. The
median survival of these patients ranged from 16.8 to 25.5 months, and the operative mortality of EPP
ranged from 0% to 5%.
Multimodality therapy with PD can include options such as neoadjuvant and/or adjuvant chemotherapy,
intraoperative chemotherapy, intraoperative or adjuvant radiotherapy, and intraoperative photodynamic
therapy. The largest series incorporating these various modalities has been recently reviewed.22 The
median survival of these 374 patients ranged from 9 to 33 months cumulatively. Recently, a series of 102
patients undergoing PD with heated intraoperative povidone-iodine, followed by prophylactic
radiotherapy to the thoracotomy incision and drain sites, and systemic chemotherapy reported a median
survival of 32 months and a 5-year survival rate of 23.1%.23 A significant problem encountered following
administration of adjuvant radiotherapy after PD (with the lung remaining in situ) is one of severe
radiation pneumonitis. More recent experiences with intensity-modulated radiation therapy (IMRT)
following PD have demonstrated improved (but still significant) toxicity with grade III or worse radiation
pneumonitis in 12% to 20% of patients and fatal pneumonitis in 3% to 8% of patients.24
The tendency for local recurrence in the ipsilateral hemithorax25 has prompted investigators to study
additional modalities to improve local control. During the past decade, a series of phase I and II trials of
hyperthermic intraoperative chemotherapy lavage has been completed, initially using cisplatin as a single
agent.26–28 Data from these three trials were combined and analyzed retrospectively. As a result, patients
identified as having low-risk epithelial MPM undergoing surgical resection and HIOC were found to have
a significantly longer interval to recurrence and overall survival in the comparison group.29 Further,
overall survival and recurrence estimates significantly favored patients receiving low doses compared
with high doses of hyperthermic cisplatin, suggesting a dose-related survival benefit.26
CONCLUSION
Malignant pleural mesothelioma is a devastating malignancy arising in the mesothelium of the pleura. A
surgically centered multimodality approach to physiologically fit patients has the potential to significantly
extend survival.
ACKNOWLEDGMENTS
The authors thank Leslie Nobles and Ellie Biaghoshi for their excellent support with the preparation of
this chapter.
REFERENCES
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2008. Bull World Health Organ 2011;89(10):716–724, 24A–24C.
2. Park EK, Takahashi K, Hoshuyama T, et al. Global magnitude of reported and unreported mesothelioma. Environ Health Perspect
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3. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-
term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg
1999;117(1):54–63; discussion 65.
4. Rusch VW, Giroux D, Kennedy C, et al. Initial analysis of the International Association for the Study of Lung Cancer Mesothelioma
Database. J Thorac Oncol 2012;7(11):1631–1639.
5. Rusch V, Baldini EH, Bueno R, et al. The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting
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Surg 2013;145(4):909–910.
6. Butchart EG, Ashcroft T, Barnsley WC, et al. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the
pleura. Experience with 29 patients. Thorax 1976;31(1):15–24.
7. Sugarbaker DJ, Norberto JJ, Swanson SJ. Surgical staging and work-up of patients with diffuse malignant pleural mesothelioma. Semin
8. Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International
Mesothelioma Interest Group. Chest 1995;108(4):1122–1128.
9. Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of
malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135(3):620–626, 6 e1–e3.
10. Taioli E, Wolf AS, Flores RM. Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in
mesothelioma. Ann Thorac Surg. 2015;99(2):472–480.
11. Sugarbaker DJ, Richards WG, Bueno R. Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma:
novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients. Ann Surg
2014;260(4):577–580; discussion 580–582.
12. Burt BM, Cameron RB, Mollberg NM, et al. Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an
analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg 2014;148(1):30–35.
13. Heelan RT, Rusch VW, Begg CB, et al. Staging of malignant pleural mesothelioma: comparison of CT and MR imaging. Am J
Roentgenol 1999;172(4):1039–1047.
14. Wolf AS, Jacobson FL, Tilleman TR, et al. Managing the pneumonectomy space after extrapleural pneumonectomy: postoperative
intrathoracic pressure monitoring. Eur J Cardiothorac Surg 2010;37(4):770–775.
15. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in
patients with malignant pleural mesothelioma. J Clin Oncol 2003;21(14):2636–2644.
16. Weder W, Kestenholz P, Taverna C, et al. Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural
mesothelioma. J Clin Oncol 2004;22(17):3451–3457.
17. Weder W, Stahel RA, Bernhard J, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in
malignant pleural mesothelioma. Ann Oncol. 2007;18(7):1196–1202.
18. Rea F, Marulli G, Bortolotti L, et al. Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation
in malignant pleural mesothelioma (MPM): feasibility and results. Lung Cancer 2007;57(1):89–95.
19. Batirel HF, Metintas M, Caglar HB, et al. Trimodality treatment of malignant pleural mesothelioma. J Thorac Oncol 2008;3(5):499–
504.
20. Krug LM, Pass HI, Rusch VW, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural
pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27(18):3007–3013.
21. Van Schil PE, Baas P, Gaafar R, et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II
multicentre trial. Eur Respir J 2010;36(6):1362–1369.
22. Lang-Lazdunski L. Surgery for malignant pleural mesothelioma: why, when and what? Lung Cancer 2014;84(2):103–109.
23. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic
radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J Thorac Cardiovasc
Surg 2015;149(2):558–566.
24. Rosenzweig KE. Current readings: improvements in intensity-modulated radiation therapy for malignant pleural mesothelioma. Semin
25. Baldini EH, Recht A, Strauss GM, et al. Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac
Surg 1997;63(2):334–338.
26. Richards WG, Zellos L, Bueno R, et al. Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic
cisplatin lavage for mesothelioma. J Clin Oncol 2006;24(10):1561–1567.
27. Zellos L, Richards WG, Capalbo L, et al. A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic
cisplatin with amifostine cytoprotection for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2009;137(2):453–458.
28. Tilleman TR, Richards WG, Zellos L, et al. Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin
with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study. J Thorac Cardiovasc
Surg 2009;138(2):405–411.
29. Sugarbaker DJ, Gill RR, Yeap BY, et al. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and
survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J Thorac
Cardiovasc Surg 2013;145(4):955–963.
68
Malignant Pleural Effusions
Jessica L. Hudson ■ Varun Puri
Virtually all cancers have been known to metastasize to the pleura. A malignant pleural effusion (MPE)
can be related to malignant progression, disease recurrence, or may be the initial presentation of an
underlying cancer; therefore, it is an important indicator of morbidity and mortality. The most common
presenting symptom of patients with MPE is dyspnea with exertion. Patients with MPE often present with
a moderate to large effusion (500 to 2,000 mL); a small proportion of patients may have complete
opacification of the hemithorax (Fig. 68.1). Malignancy is the most common cause of a massive pleural
effusion. In a retrospective review, nearly 70% of massive pleural effusions were related to cancer.1
Patients with MPE sometimes have chest pain caused by involvement of the parietal pleura, ribs, or chest
wall. However, with malignant mesothelioma, insidious onset of subacute, nonpleuritic chest pain is more
common and it frequently refers to the upper abdomen or shoulder.2 Almost all patients with a malignant
mesothelioma present with symptoms,3 whereas up to 25% of patients with other causes of MPE may be
relatively asymptomatic and the pleural effusion is discovered on a routine chest radiograph performed in
a patient with known malignancy.4,5 Physical examination typically reveals pleural effusion and,
sometimes, lymphadenopathy. The examination may also be unremarkable.4
FIGURE 68.1 A 60-year-old woman with adenocarcinoma of the lung with a massive right pleural effusion on chest radiograph.
Note the contralateral mediastinal shift.
A pleural effusion is subcategorized as malignant when cancer cells are confirmed in the pleural fluid
or tissue. Less than 10% of patients with MPE have an unknown primary site at the time of the initial
diagnosis of the effusion.6 In some patients with known malignancy and an associated pleural effusion,
malignant cells are not demonstrated in either pleural fluid or pleural tissue despite multiple diagnostic
tests. These are subcategorized as paramalignant effusions and are associated with and caused by the
malignancy but do not result from pleural invasion by the tumor.7 From a practical standpoint, both
malignant and paramalignant pleural effusions are managed largely based upon the size of the effusion and
the resulting symptoms.
The most common cause of MPE is lung cancer. The pleura may be involved by direct extension or by
vascular embolization.8 Among solid tumors, breast cancer is the next most common cause of MPE,
accounting for approximately 25% of MPE. Lymphomas account for approximately 10% of all MPE and
are the most common cause of cancer-related chylothorax.6 Ovarian and gastric carcinomas are next in
frequency, with each representing less than 5% of MPE. Although rare, diffuse malignant mesothelioma
and its association with asbestos exposure have been well established and are discussed in Chapters 66
and 67.9
PATHOGENESIS
Adenocarcinoma of the lung is the most common cell type to involve the pleura, presumably owing to its
peripheral location and propensity for vascular invasion. Autopsies in patients with MPE due to lung
cancer consistently found pleural metastasis on both the visceral and parietal pleural surfaces. Rarely was
only the visceral pleural surface involved, and isolated parietal pleural metastases were never
identified.8 The mechanism of action of visceral pleural metastasis in lung cancer is most likely from
contiguous spread or pulmonary arterial invasion with embolization. Malignant cells then migrate from
the visceral to parietal pleural surface along pleural adhesions, hypothesized to be either preformed or
tumor-induced. An alternative theory suggests that free tumor cells exfoliated from the visceral pleural
surface adhere to the parietal pleura and multiply. When bilateral pleural metastases develop in lung
cancer, metastasis to the contralateral lung is due to either hepatic spread or direct parenchymal invasion.
Once contralateral lung metastasis occurs, this usually progresses to pulmonary artery invasion and
subsequent embolization follows. This mechanism is further supported by the relationship between the
laterality of the primary lesion and the resultant MPE.4
Another important mechanism for both paramalignant and malignant pleural effusions is the impaired
lymphatic drainage of the pleural space. Obstruction of the lymphatic system can occur at any point from
the stroma of the parietal pleura to the mediastinal and internal mammary lymph nodes. Pleural tumor
invasion into the structures of the lymphatic system results in an inflammatory response causing increased
microvascular permeability.10 The cytokine vascular endothelial growth factor (VEGF) plays a vital role
in the induction of further vascular leakage, which has been shown not only in pleural effusions but also in
ascites.11 Tumor cells implanted in the pleura of experimental animals secrete VEGF, leading to
microvascular permeability. In vivo modeling of lung adenocarcinoma demonstrated inhibition of pleural
fluid formation after successful blockage of the VEGF receptor.12 Oxygen-free radicals, arachidonic acid
metabolites, proteases, lymphocytes, and immune complexes are suspected to be causative as well.10
With regard to malignant obstruction along the length of the thoracic lymphatic chain, autopsy studies
have shown a consistent association between mediastinal lymph node involvement specifically and the
presence of substantial pleural fluid.4,8 However, these studies did discover reported cases of absent
MPE despite significant pleural tumor burden, lending support to this mechanism of lymph node
metastatic burden. In the same way, pleural involvement by sarcoma does not lead to pleural effusions due
to the lack of lymphatic metastasis.8 Conversely, both Hodgkin and non-Hodgkin lymphomas have been
associated with MPE with variable incidences, although usually through different mechanisms.13
Lymphatic obstruction results in MPE in Hodgkin disease, whereas non-Hodgkin lymphoma MPE tends to
result from a combination of lymphatic obstruction and direct pleural invasion.5,14,15 In malignant
mesothelioma, pleural effusion is a common early manifestation, likely as a result of both increased
capillary permeability from direct pleural invasion as well as impaired pleural lymphatic drainage. As
this tumor progresses and the visceral and parietal pleura fuse, the fluid diminishes or disappears.
Paramalignant effusions have more varied mechanisms: direct local effect of the tumor, systemic
manifestations of the malignancy, or, not infrequently, as a consequence of therapy (Table 68.1).
IMAGING OF THE CHEST

Chest Radiographs
The suspicion for MPE should be high in patients presenting without clinical signs or symptoms of an
infection or systemic inflammatory disease but in whom a large pleural opacification without
contralateral mediastinal shift is found. Chest radiographs may also demonstrate circumferential pleural
thickening, a meniscus sign along the lateral chest wall, or hemidiaphragm elevation. In addition to
effusion, the following differential diagnoses should be considered: (1) atelectasis due to carcinoma of
the ipsilateral mainstem bronchus, (2) a fixed mediastinum due to malignant lymph nodes, (3) malignant
mesothelioma (the opacification is actually mostly tumor with a small effusion), and (4) extensive tumor
infiltration of the ipsilateral lung, radiographically mimicking a large effusion.
Bilateral effusions despite a normal heart size on chest radiograph are also suggestive of malignancy,
most commonly carcinoma (Fig. 68.2). However, it should be noted that nonmalignant effusions with
similar presentation can occur with lupus pleuritis, esophageal rupture, hepatic hydrothorax, nephrotic
syndrome, and constrictive pericarditis.16
TABLE 68.1 Causes of Paramalignant Pleural Effusions
Cause Comment
Local Effects of Tumor
Lymphatic obstruction Important mechanism for accumulation of pleural fluid
Bronchial obstruction Pneumonia with a parapneumonic effusion; does not exclude operability in lung cancer
Bronchial obstruction with Transudate; does not exclude operability in lung cancer
atelectasis
Lung entrapment Due to extensive tumor involvement of visceral pleura; usually excludes pleurodesis; candidate for
indwelling catheter
Chylothorax Disruption of thoracic duct; non-Hodgkin lymphoma most common cause
Systemic Effects of Tumor
Pulmonary embolism Hypercoagulable state from an adenocarcinoma
Hypoalbuminemia Serum albumin <1.7 g/dL; associated with anasarca
Complications of Therapy
Radiation therapy
Early Pleuritis 6 weeks to 6 months after radiation completed; loculated, exudative effusion
Late Fibrosis of mediastinum; constrictive pericarditis
Chemotherapy
Abraxane Associated with interstitial disease, especially when combine with gemcitabine
Atatinib Associated with interstitial disease, especially in Asian patients
Bleomycin Associated with interstitial disease
Crizotinib Associated with interstitial disease; pneumonitis
Cyclophosphamide Pleuropericarditis
Docetaxel Severe fluid retention with effusion or tamponade
Doxorubicin Congestive heart failure; effusion
Erlotinib Associated with interstitial disease
Gemcitabine Pulmonary edema; pulmonary fibrosis; interstitial disease
Getitinib Associated with interstitial disease
Methotrexate Pleuritis or effusion ± blood eosinophilia
Mitomycin Associated with interstitial disease; acute respiratory distress syndrome
Nivolumab Pneumonitis
Procarbazine Fever and chills; blood eosinophilia
Vinorelbine Associated with acute respiratory distress syndrome
Modified from Sahn SA. Malignant pleural effusions. Clin Chest Med 1985;6:114. Copyright © 1985 Elsevier. With permission. Supplemented
by National Cancer Institute (www.cancer.gov).
FIGURE 68.2 A 64-year-old woman who presented with progressive dyspnea on exertion. She had an amylase-rich pleural
effusion. Note the chest radiograph with bilateral pleural effusions, a cardiac silhouette at the upper limits of normal, and no
evidence of congestive heart failure.
As stated above, pleural effusions associated with lung cancer are ipsilateral to the primary lesion.
They can occur bilaterally but virtually never occur solely in the contralateral pleural space. With the
exception of breast cancer, other primary cancers that result in MPE do not appear to have an ipsilateral
predilection, and bilateral effusions are quite common. This is because pleural involvement in these cases
usually results from bilateral mediastinal lymph node metastasis. Regardless of the origin of the primary
cancer, bilateral parenchymal metastasis, thoracic duct involvement, or malignant ascites can result in
bilateral malignant effusions.4
It should be noted that, in contrast to the diffuse lymphadenopathy and parenchymal infiltrates see in
Hodgkin lymphoma, non-Hodgkin lymphoma rarely results in intrathoracic lymphadenopathy despite the
manifestations of pulmonary disease or pleural effusions.14,17,18 Interestingly, patients with sarcoma may
present initially with a pneumothorax rather than pleural effusion.19
In the case of malignant mesothelioma, the initial chest radiograph may demonstrate only a moderate to
large unilateral pleural effusion. In order to help distinguish mesothelioma from carcinoma, the following
radiographic clues are sought: pleural nodularity, absence of contralateral mediastinal shift with an
apparent large effusion, a tendency for loculation, and evidence of interstitial lung disease by way of
pleural plaques in the contralateral lung and pleura suggestive of asbestos exposure. However, even a
trained radiologist may not be able to appreciate pleural thickening or nodularity until after therapeutic
thoracentesis.20
Ultrasonography
Increasingly, ultrasonography is being utilized to evaluate patients with pleural effusions and to improve
characterization of the pleural surface including invasion. It provides real-time and dynamic information
not attainable by computed tomography. As it pertains to predicting malignancy in pleural effusion,
ultrasound has been shown to have 70% to 80% sensitivity, 84% to 100% specificity, and 82% to 100%
positive predictive value, and 79% to 82% negative predictive value.21 Features suggestive of
malignancy include, but are not limited to, pleural thickening greater than 1 cm, diaphragmatic thickening
more than 7 mm, or pleural/diaphragmatic nodules.22 These findings were reproducible when radiologists
were blinded to clinical and radiologic details or when there was diagnostic uncertainty.21,22
Additionally, ultrasonography can assist with performance of pleural fluid sampling and for image-guided
placement of temporary or indwelling drainage catheters.23 Ultrasound guidance has been shown to
drastically decrease the incidence of postthoracentesis pneumothorax, especially in smaller effusions.23,24
However, it has been suggested that the high negative predictive value of ultrasound dictates that more
advanced imaging is needed if a cytologic diagnosis is not achieved.25
Advanced Imaging Modalities

The most diagnostic information can be obtained by computed tomography (CT) or positron emission
tomography (PET) as these also provide information about primary tumors, sites of metastatic disease,
and metabolic activity of these lesions (Fig. 68.3). CT can also identify anatomic causes of paramalignant
pleural effusions such as superior vena cava or bronchial compression. When performed before large
volume paracentesis, CT also allows for evaluation of both the visceral and parietal pleura (Fig. 68.4).
There are several findings on CT that are suggestive of MPE. These include, but are not limited to: (1)
circumferential pleural thickening, (2) nodular pleural thickening, (3) parietal pleural thickening greater
than 1 cm, and (4) mediastinal pleural involvement with evidence of a primary tumor. Each of these
findings on CT have a specificity of 22% to 56% and a sensitivity of 88% to 100%.26,27 On PET (Fig.
68.5), the sensitivity for malignant pleural disease has been reported to be 93% to 100%, with a
specificity of 67% to 89%, positive predictive value of 63% to 94%, and negative predictive value of
94% to 100%. The risk of a false positive is increased in the setting of uremia, parapneumonic effusions,
and after pleurodesis.28
Magnetic resonance imaging (MRI) provides less diagnostic information of the lung parenchyma when
compared to contrast CT though is superior in detection of soft tissue invasion, including chest wall or
diaphragm. Therefore, MRI is rarely performed for pleural effusions.26,27
CHARACTERISTICS OF PLEURAL FLUID

MPE may be serous, serosanguinous, or grossly bloody. A grossly bloody effusion suggests direct pleural
involvement, whereas a serous effusion implies increased lymphatic permeability due either to lymphatic
obstruction or an endobronchial lesion with associated atelectasis. Light et al. suggested that, in the
absence of trauma, if the red blood cell count in the pleural fluid is greater than 100,000/μL, then
malignancy is likely. Pleural fluid usually contains 2,500 to 4,000 nucleated cells per microliter, of which
most are lymphocytes, macrophages, and mesothelial cells. Usually, more than half of the cell population
are lymphocytes while lymphomatous pleural effusions are typically composed of 80% lymphocytes.
Neutrophils usually comprise less than 25% of the cell sampling but, on rare occasions such as intense
pleural inflammation, a neutrophilic predominance may be seen.29–31 Eosinophilia in pleural fluid is rare;
in a prospective study, it occurred in 7.8% of patients with MPE but was nonspecific because malignancy
was equally prevalent among eosinophilic and noneosinophilic effusions.32
FIGURE 68.3 A 66-year-old woman with left lung squamous cell carcinoma. A: Posterior–anterior chest radiograph showing
opacification of the left hemithorax. B: Computed tomography depicting the same large left-sided pleural effusion with
compressive atelectasis resulting in left lung collapse.
FIGURE 68.4 A 75-year-old man with metastatic pancreatic adenocarcinoma. Computed tomography in A axial and B coronal
views. Note the pleural-based metastatic disease in the right hemithorax and moderate pleural effusions with adjacent atelectasis.
FIGURE 68.5 A 60-year-old woman with mixed small-cell and non–small-cell right lung cancer and loculated pleural effusion.
Positron emission tomography-computed tomography (PET-CT) image fusion in two axial views (A,B). Note the multiple right-
sided FDG-avid pleural-based metastases as well as FDG-avid mediastinal, right axillary, and retroperitoneal lymphadenopathy.
Carcinomatous pleural effusions typically are exudative with protein concentrations ranging from 1.5
to 8.0 g/dL. Up to 5% of MPE are transudates; however, these transudative MPE are caused by early
stages of lymphatic obstruction, atelectasis from bronchial obstruction, or most often by a concomitant
disease, such as congestive heart failure. In an effusion that would be characterized as transudative except
for violation of only the lactate dehydrogenase (LDH) Light criterion, malignancy should be suspected.29
At presentation, approximately one-third of the patients with MPE have a pleural fluid pH less than
7.30 (range 6.95 to 7.29) and a low glucose concentration (<60 mg/dL or ratio of pleural fluid to serum of
<0.5). These effusions are usually chronic and are suggestive of large volume of tumor burden and some
degree of fibrosis of the pleural surface. It is hypothesized that local acidosis is a result of reduced
glucose entry into the pleural space via the abnormal pleural membrane and impairs efflux of glucose end-
products, including CO2 and lactic acid. Prognostically, compared with normal pH–normal glucose MPE,
low pH—low glucose malignant effusions are associated with shorter survival, higher cytologic
diagnostic yield on initial thoracentesis, and a poorer response to chemical pleurodesis.33
MPE due to lymphoma are characteristically similar to those of carcinoma of the pleura except that
they tend to be less hemorrhagic and less likely to result in pleural fluid acidosis and low glucose
concentrations. In contrast to pleural carcinoma, malignant mesothelioma MPE are more likely to have a
low pH–low glucose content and greater protein and LDH concentrations.7,34 Because of an overlap of
values, however, these data are not independently predictive or helpful in differentiating carcinoma from
mesothelioma in an individual patient.
DIAGNOSIS
By definition, an MPE is one in which cancerous cells are confirmed in the pleural fluid or tissue, either
by aspiration or biopsy. Conventionally, these samplings result from thoracentesis, percutaneous biopsy,
thoracoscopy, or thoracotomy. However, a pleural effusion in the setting of known malignancy has a 50%
positive predictive value and, therefore, further invasive diagnostic testing should only be undertaken if
the information obtained will change the clinical staging or therapy options, or, alternatively, if the patient
requires symptomatic relief. It should be noted, however, with the evolution of personalized treatment and
increased utilization of targeted cancer therapies, additional tissue sampling of the pleural tumor for
mutation analysis or genome sequencing may provide an opportunity for management decision-making and
palliative treatment of the effusion.
Techniques for Initial Diagnosis
The question of initial diagnostic modality of choice usually centers around analysis of either pleural fluid
or pleural tissue. A prospective study in over 200 patients compared the diagnostic yield of pleural fluid
cytology, percutaneous needle biopsy, and thoracoscopy. Cytology had a 62% sensitivity and needle
biopsy a 44% sensitivity, with a combined sensitivity of 74%, compared with the 95% sensitivity of
thoracoscopy.35 From a compilation of several larger series of cases of malignancy, similar results were
seen: pleural fluid cytology had a diagnostic yield of 66% whereas percutaneous pleural biopsy had a
diagnostic yield of 46%. When both procedures were conducted, a positive diagnosis was obtained in
73% of cases.6 The sensitivity of the pleural fluid analysis was independent of the sampling volume, with
similar diagnostic accuracy across volume ranges from 10 to 1000 mL of pleural fluid.36 For patients with
a proven malignancy, using a standardized approach to thoracentesis and an experienced cytopathologist,
diagnostic yields on the initial pleural fluid examination are as high as 90%, with only an additional 2%
to 4% yield gained by analyzing a second sample.37–39 From thoracoscopy data, the yield of percutaneous
pleural biopsy could theoretically be increased by undertaking the procedure as close to the midline and
the diaphragm as possible. This is based on the conventional pattern of pleural metastases, which tend to
originate near the diaphragm, spreading cephalad toward the costal pleura. However, even with these
improvements, the sensitivity in randomized control trials of percutaneous pleural biopsy still range
widely from 7% to 72%.40,41 More recently, implementation of ultrasound- or CT-guided percutaneous
pleural biopsies for lesions greater than 20 mm in diameter has increased the sensitivity to 86% to 87%
with a corresponding 100% specificity, positive predictive values of 100%, and negative predictive
values of 80%.41,42 However, these modalities are not available at every care center. Several
observations can be made from these data:
a. The diagnostic yield is dependent on the extent of disease and primary malignancy.
b. Pleural fluid cytology is more sensitive than pleural biopsy.
c. Attempts should be made to perform cytologic testing on the initial pleural fluid from either diagnostic
or therapeutic thoracentesis.
d. Conventional percutaneous pleural biopsy adds little to cytologic examination.
e. The lower yield from pleural biopsy results from the pattern of pleural metastasis, sampling error, and
operator technique, although these can be modulated with skilled image guidance.
f. The wide range of sensitivities with both diagnostic modalities likely relates to imprecise handling of
specimens, expertise of the cytopathologist, and the possibility that the pleural effusion was
paramalignant at the time of the procedure.
Management of Inconclusive Cytology or Pathology Results

Nevertheless, some patients with suspicious pleural effusions will remain without a diagnosis despite a
repeat cytologic examination with or without pleural biopsy. Options at this time include observation,
thoracoscopy, or open pleural biopsy. Recommending an invasive procedure in order to obtain a
definitive diagnosis is often easier psychologically for the physician than accepting diagnostic uncertainty.
However, one cannot ignore the additional morbidity and economic burden created for the patient. Of the
invasive options, thoracotomy is not indicated in patients with MPE because it confers ninefold higher
odds of postoperative complications when compared to thoracoscopy.43 Thoracoscopy is a highly
effective diagnostic procedure with minimal morbidity and essentially no mortality; it can be performed
by skilled pulmonologists or by surgeons and does not require creation of a pneumothorax so it may be
better tolerated by patients with advanced lung disease. The sensitivity of thoracoscopy in diagnosing
MPE is 90% to 100%.44 However, this modality is less effective for nonmalignant diagnoses and,
therefore, utilization should be driven by the pretest probability of malignancy.44–46 Importantly,
bronchoscopy should be done before thoracoscopy with pleural biopsy when concern is raised for a more
central parenchymal or even bronchial lesion. Features that should prompt bronchoscopy include a large
effusion without contralateral shift, ipsilateral volume loss, a pulmonary lesion in addition to the effusion,
or hemoptysis. In the absence of the aforementioned conditions, the value of bronchoscopy in an
undiagnosed pleural effusion is limited.47
An alternate approach to diagnostic uncertainty is observation with repeat cytology and pleural biopsy
at a later time if the effusion has not regressed. An increase in the size of the pleural effusion or
reaccumulation after evacuation heightens the suspicion of malignancy. If effusions are malignant, they
rarely resolve spontaneously. Furthermore, in the setting of a high pretest probability of MPE, a few-week
delay in diagnosis does little disservice to the patient who already has widespread, incurable disease
with a poor prognosis. However, the diagnosis of a malignancy that characteristically is responsive to
therapy—such as breast, prostate, thyroid, small-cell lung, or germ cell cancer and lymphoma—should be
pursued more aggressively in the appropriate clinical setting. Additionally, a prolonged delay in draining
the effusion may lead to a trapped lung and must be avoided.
Diagnostic Utility of Tumor Marker Analysis of Pleural Fluid

There is no practical diagnostic value to the measurement of pleural levels of carcinoembryonic antigen,
cancer antigen 125, carbohydrate antigen 15-3, cytokeratin 19 fragments, hyaluronic acid, and LDH
isoenzymes. Chromosomal analysis of pleural fluid is expensive and not available in all laboratories but
may be helpful in the diagnosis of lymphoma and leukemia. Similarly, flow cytometry is most helpful with
lymphocyte-predominant effusions when lymphoma is a consideration but should not be routinely
employed for MPE.48–50 An additional exception may be breast cancer, where steroid receptors
determination may lead to possible hormonal therapy.
Special Considerations
The diagnosis of malignant mesothelioma requires both clinical and histologic observations. Diagnosis
from pleural cytology is problematic, and its value is questioned.51 Even when general malignancy is
diagnosed, it may be impossible to differentiate metastatic adenocarcinoma from a malignant
mesothelioma. Because of small-volume tissue yield, percutaneous needle biopsy does not consistently
provide a definitive diagnosis and, instead, frequently prompts a misleading diagnosis of
adenocarcinoma. High levels of hyaluronic acid were historically thought to aid in diagnosing
mesothelioma. However, most patients with mesothelioma have intermediate levels, which again do not
distinguish from metastatic carcinoma and other inflammatory diseases.52 Cytology and percutaneous
needle biopsy have a diagnostic yield in malignant mesothelioma of 26% and 21%, respectively.
Alternatively, experienced thoracoscopists report a 98% diagnostic yield in malignant mesothelioma.53
However, when considering invasive diagnostic procedures, it is important to remember that
mesotheliomas tend to invade surgical sites. Prophylactic irradiation should be given postoperatively.54
Sarcomas and mixed histology mesothelioma lesions can be diagnosed by most pathologists but it is
difficult to differentiate the epithelial form from the more common metastatic adenocarcinoma. Special
tissue stains, newer immunologic techniques, and electron microscopy aid in the diagnosis of patients
with the epithelial variety of mesothelioma (see Chapter 66).
PROGNOSIS
The diagnosis of an MPE foreshadows a poor prognosis that has persisted despite advancements in
oncologic therapies.55 Survival for patients with carcinoma of the lung, stomach, or ovary is generally
measured in terms of weeks to a few months from the time of diagnosis of the MPE. The notable exception
is in patients with breast cancer who may survive several months to years, depending on their response to
chemotherapy. Patients with lymphomatous pleural effusions tend to have intermediate survival between
breast cancer and other carcinomas.55 In a meta-analysis of 417 patients, median survival from the time of
MPE diagnosis was only 4 months, with a 31% survival at 6 months and 18% at 1 year.56
The subset of patients with low pH–low glucose MPE have significantly shorter survival—on the
order of a few months—compared to those with a normal pH and glucose, whose survival approximates 1
year. Thus, the biochemical findings in the pleural fluid provide helpful information for determining a
rational plan of palliative treatment. However, the pleural fluid pH and glucose alone should not guide
palliative therapy; it should be used only in conjunction with other parameters such as primary tumor,
performance status, and comorbid disease.55
It is imperative to note that, while the presence of a pleural effusion is an ominous sign in lung cancer
that usually precludes operability, approximately 5% of these patients actually have a paramalignant
effusion or effusion from another cause and may be operative candidates.57 Circumstances suggesting that
the pleural effusion in lung cancer is paramalignant and that the patient may still be cured by resection are
squamous cell type, radiographic volume loss, serous effusion, transudate, and parapneumonic effusion.
The oncologic team must diagnose the cause of the pleural effusion before prohibiting possible curative
surgery. If the cause of the effusion cannot be established clinically, diagnostic thoracoscopy should be
considered.
TREATMENT
When a pleural effusion, either malignant or paramalignant, has been documented in a patient who is not a
surgical candidate, palliation must be considered, taking into account the patient’s general condition,
symptoms, and expected survival. The goal in management of an MPE in the nonsurgical patient should be
lung reexpansion. An unexpandable lung in the setting of malignancy may be the result of an endobronchial
obstruction or direct malignant involvement of the visceral pleura.58 Malignancy involving the visceral
pleura may prevent apposition of the pleural surfaces following pleural space drainage and may manifest
as a hydropneumothorax following thoracentesis or chest tube placement for the malignant effusion (also
known as trapped lung). Most asymptomatic patients eventually develop progressive pleural effusions,
producing dyspnea that requires therapy, while the minority reach a new steady state of pleural fluid
formation and absorption and do not progress to a symptomatic stage requiring intervention.
Management options in the literature range from observation in the asymptomatic patient to
thoracotomy with pleurectomy. Thoracotomy and decortication should generally be avoided in this
population as retrospective data reveal unacceptably high morbidity and mortality after the operation.43
Therapeutic thoracentesis may be the only approach necessary in patients with very slow rate of
reaccumulation, with cancers that respond to chemotherapy, or with limited expected survival (<45 days).
In the debilitated patient with a short expected survival but persistent symptoms, it may be more prudent
to perform either a therapeutic thoracentesis periodically or to place a smaller bore indwelling catheter
than to recommend hospitalization with tube thoracostomy or Video-assisted thoracoscopic surgery
(VATS) with pleurodesis, given their associated morbidity and cost.
The management of malignant mesothelioma is discussed in Chapters 66 and 67. Judgment in the
management of these patients is the keynote of appropriate care.
Chemical Pleurodesis
If the clinician has documented that therapeutic thoracentesis results in relief of dyspnea and lung
expansion and if the rate of recurrence and the return of symptoms is rapid, the conventional standard of
care has long been chest tube drainage with instillation of a sclerosing agent through the chest tube. This
has long been thought to be the most cost-effective and least morbid method for controlling a symptomatic
MPE. A cost-effectiveness analysis of possible interventions for treatment of MPE was conducted
combining outcome and utility data with Medicare allowable charges. In those patients expected to
survive for 12 months, the cost of repeat thoracenteses totaled $21,377 whereas the cost of bedside
pleurodesis and VATS pleurodesis amounted to $13,057 and $19,074, respectively. The incremental cost-
effectiveness ratio (ICER) for thoracoscopic pleurodesis over bedside pleurodesis was $250,000,
therefore favoring bedside pleurodesis as the most cost-effective treatment option for patients with
anticipated reasonable survival.59
In general, a patient is a sensible candidate for pleurodesis if the expected survival is several months,
the patient has a reasonable performance status, there is no severe comorbid disease, and the pleural fluid
pH is not extremely low. However, pleurodesis is not a viable option with an unexpandable lung; this
situation occurs most commonly with tumor involvement on the visceral pleural surface (lung entrapment)
and also with mainstem or lobar bronchial obstruction and is discussed later in this chapter. A low
pleural fluid pH not only suggests a limited survival as stated above, but also a decreased response to
both tetracycline pleurodesis and talc poudrage.55,60
The technique for chemical pleurodesis is critical for a successful result in the properly selected
patient (Table 68.2). Success need not be defined as complete pleural approximation with no recurrent
effusion but as diminishing the reaccumulation of pleural fluid so that dyspnea is relieved and repeat
therapeutic thoracentesis is not required. The pleural surfaces should reasonably be juxtaposed at the time
of the induced inflammation and remain in close contact over the ensuing 48 to 72 hours, which is best
accomplished by chest tube drainage. If the effusion is large to massive, the fluid should probably be
drained slowly, without suction, over the first several hours to decrease the risk of unilateral pulmonary
edema. Pulmonary edema is most likely to occur if the lung has been compressed for a long period of time
or there is an endobronchial obstruction or lung entrapment. To reiterate, pleurodesis should not be
attempted in the aforementioned situations because it will not be successful. Pleurodesis consideration
should be initiated when chest tube output is less than 150 mL/day.61 The sclerosing agent should be
instilled into the pleural space as soon as the lung is fully expanded radiographically.
TABLE 68.2 Procedure for Pleurodesis
1. Place chest tube in midaxillary line directed toward diaphragm.
2. Remove fluid in controlled manner under water seal.
3. Assess tube position on radiograph to position patient for optimal drainage.
4. Connect chest tube to suction (–20 cm H2O).
5. Demonstrate complete lung expansion on chest radiograph.
6. Give small doses of intravenous narcotic and midazolam as the patient’s condition tolerates. If possible, an epidural catheter should be
considered for pain control.
7. Instill 20 mL of 1% Xylocaine and 10 mL of 0.25% bupivacaine once through chest tube.a Flush tubing with 30 mL of sterile normal
saline. Wait 5 minutes.
8. Instill doxycycline, 500 mg in 30 mL of normal saline, or talc 5 g, in 150 mL of normal saline through chest tube. Flush tubing with 60 mL
of sterile saline.
9. If there is no air leak, clamp chest tube for 2 hours. If unable to clamp safely, raise and secure the Pleur-evac above the level of the
chest.
10. There is no need to rotate the patient periodically.
11. Connect chest tube to suction (–20 cm H2O).
12. Remove chest tube at discretion of attending surgeon.
a Dosing of local anesthetics may need to be adjusted based on body habitus to avoid toxicity.
It has long been the convention to rotate or roll a patient undergoing bedside chemical pleurodesis. On
the contrary, the results of several studies of radiolabeled tetracycline, as well as a meta-analysis, suggest
that the patient need not be rotated through various positions after intrapleural instillation to ensure
adequate distribution of the pleurodesis agent. Specifically, the agents were distributed completely
throughout the pleural space within seconds and neither the distribution nor the success rates were
enhanced by patient rotation.62–64 These recommendations have been corroborated for talc suspensions as
well.63–66 Thus, the recommendation is that patients receiving chemical pleurodesis need not be rotated,
thus avoiding extra discomfort for the patient and additional personnel time.
Another long-held belief is that sclerosing agents should be administered via a large-bore chest tube,
based on Poiseuille law. In the same meta-analysis, as it pertained to successful chemical pleurodesis, no
benefits were found for large-bore over small-bore chest tubes. Some of these studies even included
image-guided catheter placement and outpatient drain management protocols for pleuordesis. The
outcomes were similar across the wide range of chest tube calibers.63,67–71 In vitro studies of drainage of
a variety of fluids demonstrated that the maximum flow plateaued for simple fluids in a 9F catheter and
for viscous fluids in a 12F catheter. Therefore, the current recommendation for chemical pleurodesis is a
14F catheter.72
No studies have evaluated the optimal dwell time; a 1- to 2-hour dwell time for the pleurodesis agent
has been deemed adequate, as experimental studies have shown immediate mesothelial injury, and it is
ideal to have the two pleural surfaces in close contact as soon as possible.55 A trial of 41 patients
randomized to chest tube removal either 24 or 72 hours after talc pleurodesis demonstrate no difference in
effusion recurrence, but did note a statistically significant difference in length of hospitalization (4 vs. 8
days, respectively).61
Possible sclerosing agents include, but are not limited to, talc, tetracyclines, chemotherapy, betadine,
hydrogen peroxide, and hypertonic saline. Many patients treated with intrapleural doxycycline have
required more than one instillation compared with only a single dose of minocycline. The effectiveness of
the tetracyclines depends primarily on their fibrogenicity rather than antineoplastic activity and does so in
a dose-dependent manner.73,74 A large meta-analysis of 46 available randomized controlled trials
composed of 2,053 patients with MPE found no conclusive evidence to favor one agent over another.63
However, the trends favored talc as the superior sclerosing agent based on lack of effusion
reaccumulation. There was no significant difference between talc slurry or talc poudrage. There was no
significant difference when bleomycin was compared to tetracyclines.63,75 The average wholesale price
of talc is minimal when compared to doxycycline and miniscule when compared to bleomycin. Thus, cost
consideration may be kept in mind in the management of the malignant effusion. Of note, talc pleurodesis
has been shown to have equivalent success rates in both large- and small-bore chest tubes.76
The most common adverse effects of the sclerosing agents have been chest pain and fever, with
variability depending on the chemical agent used.73 The degree of pain associated with talc has been
reported from nonexistent to severe; however, in most patients, pain is not a major adverse effect with
talc. Fever after talc poudrage or slurry has been reported to occur in 16% to 69% of patients. It generally
occurs 4 to 12 hours after talc instillation and may last for 72 hours.77 It should be noted that both
tetracycline and lidocaine, the latter is used by some clinicians in an attempt to ameliorate chest pain, are
absorbed systemically and reach therapeutic levels by 30 to 60 minutes; a history of allergic reactions to
either drug is a contraindication to its use. The dose of lidocaine should not exceed 150 mg or 3 mg/kg,
whichever is less.77
Despite the efficacy of talc pleurodesis, historically, there have been concerns about its short-term
safety. There were several case reports of respiratory failure after either talc poudrage or talc slurry.78–80
Some of the patients did not survive the episode of respiratory failure. Talc crystals were found in the
bronchoalveolar lavage fluid of some of these patients and, at autopsy, talc crystals were detected in the
lungs and other organs. However, it is uncertain whether talc dissemination from the pleural space is
related to acute respiratory failure. Furthermore, it is unclear whether acute respiratory failure was
caused by talc or due to other causes, such as excess sedation, reexpansion pulmonary edema, severe
comorbid disease, or terminal malignancy. It is believed that variability in particle size conventionally
placed talc at greater risk and there have been no reported cases of respiratory failure or pneumonitis
when medicinal graded talc has been utilized.63,80–82 A prospective cohort analysis of 558 patients
undergoing pleurodesis with talc poudrage for MPE reported zero incidents of adult respiratory distress
syndrome, 2% 30-day mortality, and less than 2% perioperative complications. The most common
adverse events were fever lasting up to 4 days and development of a supplemental oxygen requirement
lasting up to 2 days.83 Three prospective trials in Europe and in the United States compared tube
thoracostomy with either talc poudrage or talc slurry. Although talc poudrage was significantly more
effective than talc slurry, both methods were safe, with no patients developing respiratory failure.54 The
existing evidence strongly suggests that talc is equally safe or safer than other sclerosing agents for
chemical pleurodesis.
Two prospective randomized control trials have shown that VATS administration of talc pleurodesis is
associated with fewer recurrences of effusions, which is thought to be, in part, due to the effect of
insufflation. However, based on the high success rate in clinical trials of bedside talc pleurodesis as well
as cost-effectiveness analyses, a strong recommendation has not been made to favor VATS talc
insufflation over bedside talc pleurodesis when completed within a regimented bedside protocol.63,75,84
However, a subgroup analysis of a multicenter randomized controlled trial did favor better outcomes with
talc insufflation in patients with primary breast and lung cancer.75 In this setting, the risks and resource
utilization associated with general anesthesia must always be considered.
Indwelling Catheter Placement

Malignant lung entrapment may be the result of a primary pleural malignancy or metastatic disease. It is
frequently diagnosed on chest radiography after initial thoracentesis and is marked by failure of the lung
to reexpand and by the appearance of an air–fluid level. It follows logically that malignant lung
entrapment makes chemical pleurodesis futile. Malignant lung entrapment, although not always
symptomatic, does not resolve spontaneously and rarely resolves after chemotherapy.
Symptomatic MPE complicated by lung entrapment are often palliated with a chronic indwelling
pleural drainage catheter.70,85–87 In this setting, long-term drainage catheters have been associated with
improvement in dyspnea, patient satisfaction, and quality of life88 as well as lower rates of mortality,
shorter hospital stays, and shorter intervals to systemic therapy when compared to propensity-matched
cohorts.89 Such catheters can be placed in the outpatient setting utilizing local anesthesia and with
minimal tissue trauma when compared to conventional chest tubes. They can be managed at home via
vacuum drainage bottles and do not require ongoing hospitalization. The advantages also include an initial
lower cost than chemical pleurodesis and achievement of spontaneous pleurodesis in up to 60% of
patients. Complete resolution of symptoms within 2 weeks of catheter placement is achieved in
approximately 40% of patients, while 50% report partial relief. Complications of indwelling catheters
occurred in 15% of the patients and included technical failures, infection, patient noncompliance, and
complications related to the nature of the disease process. Specifically, the failure rate for catheter
insertion is approximately 4% with experienced clinicians while 10% of patients require repeat pleural
procedures. Symptomatic loculations occur in approximately 8% of patients undergoing long-term
drainage catheter placement. Less than 4% of patients experience spontaneous pneumothoraxes, empyema,
or asymptomatic loculated effusions while less than 2% of patients suffer from cellulitis, catheter
dislodgement or blockage, bleeding, tumor seeding, or severe pain.87,90 One caveat, however, is in the
case of malignant mesothelioma where up to 40% of patients may develop malignant seeding, which is not
reduced by prophylactic drain-site radiotherapy.91 These complications are considered quite acceptable
when compared to those of more aggressive treatment modalities.75,92–94 Long-term catheters are
generally well tolerated with minimal impact on activities of daily living.70,87,95,96 It is our current
practice to use an indwelling catheter as palliative therapy in most of these symptomatic patients.
For the patient with very limited expected survival and MPE complicated by trapped lung, treatment
options include repeated thoracentesis, tunneled pleural catheter, bedside pleurodesis, or VATS
pleurodesis. We conducted a relative cost-effectiveness analysis of these possible interventions by
combining outcome and utility (quality-of-life) data for patients deemed fit to undergo any of the
procedures and with an expected survival of 3 months. Repeated thoracenteses were the least expensive
intervention ($4,946) but provided the fewest quality-adjusted life years (QALY). Tunneled pleural
catheter was less expensive than either bedside or VATS pleurodesis ($6,450, $11,224, and $18,604,
respectively). The tunneled pleural catheter was more cost-effective when compared to repeated
thoracentesis.59 A similar cost–utility analysis was conducted but also included a model for rapid
pleurodesis. Nevertheless, tunneled pleural catheters remained maximally cost-effective.97 In this
population, it is now recommended to place a long-term indwelling catheter as first-line therapy, although
this may be tailored to the patient’s functional status.59,96–100
Pleurectomy
Parietal pleurectomy with pleural abrasion is virtually always effective in obliterating the pleural space
and controlling recurrence of the effusion, although this requires either thoracoscopy or thoracotomy, the
latter being favored in the setting of trapped lung.43,101 The technique involved in pleurectomy is beyond
the scope of this chapter but has been previously well described.102 The procedure is applicable only to a
highly selected group of patients in good general condition with life expectancy of greater than 6 months,
whose MPE has failed to respond to chemical pleurodesis.103 Best results are obtained when the primary
lesion is a carcinoma of the breast or malignant mesothelioma.43,104,105 Results vary but are more often
poor in patients with carcinoma of the lung.43 Complications such as empyema, hemorrhage, or
cardiovascular failure are frequent, as high as 34%, and mortality rates are significant, with in-hospital
rates up to 9% and 3-month all-cause mortality of 17%.43 When decortication of the lung is necessary in
conjunction with the pleurectomy, the complication rate approaches 70% with a postoperative mortality
rate of 20%.43 There is insufficient evidence to support video-assisted thoracoscopic surgery over
thoracotomy in this setting. Therefore, due to high complications, poor survival, and prolonged length of
stay, pleurectomy is rarely indicated in the setting of MPE.
In patients undergoing surgical exploration for an undiagnosed pleural effusion who are found to have
malignancy, pleural abrasion with or without talc poudrage or pleurectomy should be carried out in most
patients. This prevents the subsequent development of a symptomatic pleural effusion. Pleurectomy,
however, even when indicated, is a major surgical procedure associated with substantial morbidity and
mortality.106 Thus, this procedure should be reserved for the small minority of patients with an expected
survival of at least 6 months with a relatively good performance status who have lung entrapment or who
have failed pleurodesis. Similar to diagnostic interventions in this population, VATS is preferable if
possible as thoracotomy should generally be avoided due to unacceptably high postoperative morbidity
and mortality.43
Chemotherapy or Radiation Therapy

With the notable exceptions of lymphoma, breast cancer, or small-cell carcinoma of the lung which may
respond well to systemic chemotherapy, chemotherapy yields disappointing results in the attempted
control of MPE.5,15,107–109 Specific to breast cancer, pleural fluid information about steroid receptors can
provide a source for determining potential response to hormonal manipulation.
In general, radiation therapy too is of limited value in controlling carcinomatous MPE. However, there
are a few exceptions in which irradiation may be valuable to the patient. Specifically, a therapeutic role
for radiation often exists for patients with MPE due to lymphoma or small-cell carcinoma of the lung who
are presenting with predominantly mediastinal lymph node involvement or a chylous effusion.110
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69
Malignant Pericardial Effusions
David Rice ■ Elie Mouhayar
Pericardial effusion is a relatively common feature in patients with advanced stage malignancy and has
been reported to occur in up to 21% of patients.1 It is generally associated with poor outcome although
survival may depend on the histologic type of the tumor of origin (Fig. 69.1). Acute symptoms including
dyspnea and hypotension related to tamponade warrant urgent palliative intervention, which is usually
successful. Traditionally, options for palliative treatment of pericardial effusion include surgical
pericardiotomy, however newer less-invasive percutaneous drainage techniques such as
pericardiocentesis with extended catheter drainage and balloon pericardiotomy are now often procedures
of first choice.2,3
ANATOMY AND PHYSIOLOGY OF THE PERICARDIUM

The pericardium comprises two separate layers including the outer fibrous parietal pericardium, which is
about 1 to 2 mm thick, an inner monolayer of mesothelial cells, the visceral pericardium, which is
contiguous with the epicardium. The pericardial space usually contains approximately 50 mL of serous
fluid. The role of the pericardium is to maintain the cardiac structures in a relatively fixed position and to
serve as a barrier to infection as well as providing lubrication between the beating heart and surrounding
tissue. The parietal pericardium is composed of wavelike bundles of collagen. With small volume
increases the pericardium is relatively elastic; however, once the collagen fibers have reached their
maximum stretch, the pericardium becomes resistant to further distension and intrapericardial pressure
rises abruptly (Fig. 69.2).
FIGURE 69.1 Survival by type of cancer. (Reprinted from Moores DW, Allen KB, Faber LP, et al. Subxiphoid pericardial
drainage for pericardial tamponade. J Thorac Cardiovasc Surg 1995;109(3):546–551; discussion 551–552. Copyright © 1995 The
American Association for Thoracic Surgery. With permission.)
PREVALENCE AND PATHOPHYSIOLOGY

Up to 18% of hemodynamically significant pericardial effusions are ultimately found to be the initial
presentation previously unrecognized malignancy.4,5 In a large retrospective series from Europe including
204 patients with pericardial effusion, neoplastic disease was confirmed to be the etiology in 15% of
cases.6 Conversely, in North America, a series of 117 patients who underwent treatment for pericardial
effusion, 75 (64%) of patients had underlying malignancy.7 Differences in incidence may reflect the fact
that patients with malignant infusions are more likely to require treatment and thus, series reporting
patients who underwent either surgical or percutaneous drainage are more likely to include a higher
proportion of malignant etiologies. A series of 1,029 autopsies revealed 28 patients with malignant
pericardial effusion resulting in a prevalence rate of 3%.8 Lung cancer is the most common malignancy
associated with pericardial effusion (29% to 36%), however, other solid organ tumors may also
metastasize to the pericardium or heart leading to pericardial effusion including breast, gastrointestinal
cancers, and melanoma.7,9,10 Malignant mesothelioma frequently invades the parietal pericardium may be
associated with pericardial effusion if transmural invasion occurs. Liquid tumors including acute
myeloblastic leukemia and lymphoma have been reported to occur in 11% to 16% of cases (Table 69.1).
Though exceedingly rare, primary tumors originating in the pericardium exist including malignant
mesothelioma and fibrosarcomas, and should be considered in the differential diagnosis in the absence of
other disease sites.
Malignant involvement of pericardium may occur by multiple mechanisms. Tumors may invade the
pericardium by direct extension as is often the case with lung cancer and mesothelioma or may see the
pericardium via lymphatic routes, often having first involved mediastinal nodes. Tumor involvement of
the epicardium is believed to be a prerequisite for the development of an effusion. Metastatic tumors also
may involve the cardiac muscle directly via hematogenous or lymphatic pathways and then secondarily
extend to the epicardium. The exact mechanism of fluid production is likely multifactorial involving direct
irritation of the mesothelial cells, obstruction of pericardial and epicardial lymphatics, and interference
with endothelial cell function. Malignant pericardial effusions may be either exudative or transudative in
nature. Transudates are associated with greater risk of bleeding leading to rapid decompensation. The
quality of the fluid may be serous, serosanguineous, hemorrhagic, or chylous (Fig. 69.3). Since the rate of
fluid accumulation within the pericardial space determines the risk of tamponade, etiologies such as
malignancy, which are associated with a more rapid effusive process, are at greater risk of causing
cardiac dysfunction.11 As noted above, relatively small increases in pericardial volume leads to
distention of the parietal pericardium to a point where maximum elasticity is reached. At this point
intrapericardial pressure rises rapidly. As fluid accumulates, left- and right-sided atrial and ventricular
diastolic pressures increase and eventually leads to near equalization with the intrapericardial pressure.
As cardiac diastolic filling declines, cardiac volumes diminish leading to reduced stroke volume. To
maintain cardiac output, compensatory tachycardia occurs. Cardiac tamponade physiology is reflected on
systemic venous and right atrial pressure tracings. This is manifested as loss of the y descent, which is
secondary to the fixed cardiac volume and severe tamponade. Blood can only enter the heart through the
tricuspid valve at the exact time it is trying to leave, thus negating the normal right atrial y descent, which
normally occurs when the valve opens.12 The clinical finding of pulsus paradoxus (a greater than 10 mm
Hg drop in systolic pressure during inspiration) is present in severe tamponade. The etiology is likely
multifactorial but is most likely related to an increase in right heart filling all because of increased venous
return occurring in the setting of a fixed cardiac volume. Transiently increased right-sided pressure causes
the intraventricular septum to bow into an already under-filled left ventricle, thereby further reducing
cardiac output. Several cardiac cycles are required for the resultant increased right ventricular stroke
volume to lead to an increased left ventricular stroke volume, which eventually counteracts the septal
shift.
FIGURE 69.2 The rate of pericardial fluid accumulation influences the risk of tamponade. (From Spodick DH. Acute cardiac
tamponade. N Engl J Med 2003;349(7):684–690. Copyright © 2003 Massachusetts Medical Society. Reprinted with permission
from Massachusetts Medical Society.)
TABLE 69.1 Etiology of Pericardial Tamponade in 117 Patients
Cause Percent (no.) of Patients
Underlying malignancy 64 (75/117)
Lung 36 (27/75)
Breast 34 (26/75)
Lymphoma 11 (8/75)
Miscellaneous 5 (4/75)
Unknown primary 3 (2/75)
Benign disease 36 (42/117)
Idiopathic 45 (19/42)
Uremic 21 (9/42)
Postcardiotomy syndrome 10 (4/42)
Collagen vascular disease 10 (4/42)
Human immunodeficiency disease 7 (3/42)
Purulent 5 (2/42)
Amyloidosis 2 (1/42)
Reprinted from Allen KB, Faber LP, Warren WH, et al. Pericardial effusion: subxiphoid pericardiostomy versus percutaneous catheter
drainage. Ann Thorac Surg 1999;67(2):437–440. Copyright © 1999 The Society of Thoracic Surgeons. With permission.
FIGURE 69.3 Gross appearance of malignant pericardial effusions. A: serous, B: serosanguinous, C: bloody, D: chylous.
(Photograph courtesy of Elie Mouhayar, MD.)
Unless hemodynamically significant, pericardial effusions generally do not cause symptoms by
themselves. Occasionally, effusions that arise with a component of pericarditis may present with
substernal pain without signs of hemodynamic compromise. The majority of patients with malignant
pericardial effusion have a preexisting diagnosis of cancer, however, in one series 18% of patients who
presented with a symptomatic effusion, it was the first sign of a previously unrecognized malignancy. In
patients with pericardial effusion causing tamponade, dyspnea and tachycardia are the most frequently
observed symptoms. Other associated features may include cough, tachypnea, hypertension, orthopnea,
and peripheral edema.13,14 Patients with tamponade are often more comfortable sitting forward. In patients
without cardiac tamponade, physical examination is usually unrevealing apart perhaps from difficulty in
discerning the cardiac impulse and indistinct heart sounds in patients with large effusions. In patients with
cardiac tamponade, the classic finding of Beck’s triad (elevated jugular venous pressure, muffled heart
sounds, and hypotension) may be present. Signs of cardiogenic shock are frequent including tachypnea,
peripheral cyanosis, hypotension, and diaphoresis.15 Pulsus paradoxus may be present. Malignant
pericardial effusions caused by intrathoracic malignancies are frequently associated with symptoms and
signs related to the thoracic extent of the cancer itself such as dyspnea, hemoptysis, pleural effusion, or
pain.
DIAGNOSIS
Several electrocardiographic (ECG) abnormalities may be seen. The most common but nonspecific
change is a reduction in voltage. This also may be seen in other conditions such as emphysema and
pneumothorax. Electrical alternans (beat-to-beat alternation of the QRS complex amplitude or axis) may
be seen in patients with significant pericardial effusions. This is thought to be related to changes in
electrical axis of the heart due to exaggeration in anterior to posterior cardiac movement with each
heartbeat. Chest radiography typically reveals a rounded cardiac silhouette on AP projection with
oligemic lung fields (Fig. 69.4). The epicardial fat pad sign may also be present. On lateral projection,
the pericardium can be seen as a thin line between the substernal pericardial fat and the epicardial fat. In
pericardial effusions or thickening, this thin stripe becomes wider, is considered abnormal if wider than 2
mm.16 Axial imaging including computed tomography (CT) and magnetic resonance imaging (MRI) are
frequently obtained in the cancer patient population and are excellent at showing the size and location of
pericardial effusions (Fig. 69.5). Axial imaging may be helpful in planning routes of access to effusions
for drainage purposes. Additionally, information may be obtained about the degree of pericardial
thickening and proximity to and extent of associated tumor. Coexistent pleural effusions may contribute
patient dyspnea and may be readily evaluated by CT imaging. M-mode and 2-D echocardiography are the
principal noninvasive methods of diagnosis and assessment of malignant pericardial effusions.
Pericardial effusions appear as hypoechoic regions separating the cardiac structures from the
pericardium. Both the location and extent of effusion may be easily assessed. Significant infusions are
defined as those with hypoechoic separation greater than 2 cm in width that is circumferential and
maintained throughout the entire cardiac cycle. Occasionally, hyperechoic signal densities may be
identified within the effusion, often appearing as shaggy fronds, which may indicate either clots or
loculations. Signs of tamponade on echocardiography include right atrial collapse in systole, right
ventricular collapse in early diastole, distention of the inferior vena cava, which does not decrease with
inspiration, decreased mitral valve inflow velocity with inspiration (threshold for significant finding is
20% change from peak to peak), increased tricuspid valve and flow velocity with inspiration (threshold
for significant finding is 40% change from peak to peak), and increased diastolic reversal of flow and the
hepatic veins after the onset of expiration (Figs. 69.6 to 69.8).12
FIGURE 69.4 Chest radiograph showing typical “flask”-like rounded appearance of the cardiac silhouette.
FIGURE 69.5 Computed tomogram showing large circumferential pericardial effusion.

FIGURE 69.6 Pericardial effusion by 2-D echocardiography. A: Subcostal views showing large circumferential effusion with
diastolic RV collapse (arrow). B: Apical views showing large effusion with systolic-RA collapse (arrow). (Photograph courtesy
of Elie Mouhayar, MD.)
TREATMENT
Therapeutic options for hemodynamically significant malignant pericardial effusions include
pericardiocentesis, pericardiocentesis with extended catheter drainage, pericardiocentesis with
intrapericardial sclerotherapy, percutaneous balloon pericardiomyotomy, surgical fenestration, and
pericardiectomy (Table 69.2). Choice of treatment must include consideration of the severity and acuity of
the patient’s symptoms, location and quality of the effusion, life expectancy, as well as institutional
resources and experience. Traditionally, surgical fenestration, most commonly via a subxiphoid approach,
has been the gold standard for relief of tamponade, however, newer catheter-based approaches appeared
to have near-equal efficacy, are simpler and are associated with less morbidity and probably less cost.
Long-term outcomes following treatment of malignant pericardial effusions is dependent to a large extent
on the histology of the underlying cancer. Patients with effusions secondary to lung cancer and
mesothelioma typically have a very poor prognosis (95 to 204 days) compared to those with effusions
related to breast cancer or hematologic malignancies (166 to 495 days).2,10,17 In large part, this is related
to the better responses seen with these tumors to systemic chemotherapy.
FIGURE 69.7 Parasternal M-mode echocardiography showing large circumferential effusion with diastolic RV collapse.
(Photograph courtesy of Elie Mouhayar, MD.)
FIGURE 69.8 Doppler pattern of tamponade with respiration. Upper panel: Mitral valve inflow velocity decreases after onset of
inspiration (blue) and increases after onset of expiration (red) (threshold for a significant finding is a 20% change from peak to
peak). Lower panel: Tricuspid valve inflow velocity is opposite with an increase during inspiration and a decrease after onset of
expiration (threshold for a significant finding is a 40% change from peak to peak). (Photograph courtesy of Elie Mouhayar, MD.)
TABLE 69.2 Treatment Modalities in the Management of Malignant Pericardial
Effusion
Drainage Modality Studies (n)/Patients (n) Complications (pooled %) Recurrence (pooled %)
Single pericardiocentesis 2/131 4 48
Extended catheter drainage 6/78 12 45
Pericardial sclerotherapy 12/474 21 12
Percutaneous balloon pericardiotomy 10/166 32 10
Surgical fenestration: 19/550 5 7
Subxiphoid
Anterior thoracotomy
VATS
Adapted from Jama GM, Scarci M, Bowden J, et al. Palliative treatment for symptomatic malignant pericardial effusion. Interact Cardiovasc
Thorac Surg 2014;19(6):1019–1026. Reproduced by permission of European Association for Cardiothoracic Surgery.
PERCUTANEOUS INTERVENTIONS
PERICARDIOCENTESIS AND CATHETER DRAINAGE

Originally developed in the 1970s, needle aspiration provides a rapid method for diagnosis and treatment
of pericardial effusions. The procedure may be performed blindly using anatomic landmarks and
preprocedural imaging, which may be required in the cutely decompensating patient, however real-time
image guidance using either 2D-echocardiography or fluoroscopy is the preferred approach as it lessens
the risk of injury to intrathoracic and upper abdominal organs.18 Original reports described outcomes of
patients who underwent single aspiration, and these have been associated with an unacceptably high rate
of recurrence. More recent literature suggests that use of an indwelling catheter that is left in place over
several days until the daily amount of drainage is less than 50 to 100 mL provides significantly lower
rates of recurrence.
Percutaneous pericardiocentesis is performed by accessing the pericardial cavity using the shortest
distance from the subxiphoid or intercostal space (Fig. 69.9). The subxiphoid approach has the lowest
risk of pneumothorax but a higher risk of injury to abdominal organs including the liver stomach and
colon.19 In obese patients the subxiphoid route may be difficult. The apical approach is associated with
the lowest risk of penetrating the intracardiac chambers but is not suitable for placement of indwelling
catheters. A left- or right-sided parasternal approach is useful under echocardiography guidance but may
be associated with a higher risk of pneumothorax and bleeding from the internal memory arteries. A small
access needle such as a 5-F micro puncture kit may be useful to avoid bleeding.10 Once the needle is
placed within the pericardial space, position can be confirmed by using saline contrast injection, if
echocardiography is used for guidance. A guidewire is then passed followed by serial dilatation, sheath
placement, and insertion of a multihole pigtail catheter.20 Catheters are typically left in place for at least
three days or until the volume of drainage is less than 50 mL with no residual effusion on follow-up
echocardiography.
In what remains one of the largest series reported to date, Tsang et al.21 reported outcomes of 257
patients with malignant pericardial effusion who underwent pericardiocentesis. Of 118 patients who
underwent simple pericardiocentesis, recurrence of effusion occurred in 36%, whereas only 12% of the
139 patients who underwent pericardiocentesis with extended catheter drainage recurred. In a recent
study from the M.D. Anderson Cancer Center in which 1,645 cancer patients with pericardial effusion
were evaluated, 212 underwent percutaneous pericardiocentesis.10 The recurrence rate was 23% in the
50 patients who had either simple pericardiocentesis without an indwelling catheter or who had drainage
for less than 3 days. Of the remaining 162 patients, in which extended catheter drainage lasted 3 days or
longer, the recurrence rate was only 12% (p = 0.013). Major complications associated with the procedure
occurred in only five cases (2%) and included liver laceration, intercostal artery laceration,
pneumothorax, and catheter-related infection into patients where the catheter remained longer than 7 days
in situ. In a retrospective evaluation of 88 patients presented with pericardial tamponade associated with
malignancy, Patel and colleagues22 found similar recurrence rates in 45 patients treated with subxiphoid
pericardiotomy and 43 patients treated with pericardiocentesis and extended catheter drainage (13% and
12%, respectively, p not significant). There were no serious complications in the percutaneous drainage
group compared to a 9% incidence in the patients who underwent surgical fenestration.
FIGURE 69.9 Technique of pericardiocentesis. A: Initial placement of 18-gauge needle. B: Passage of flexible guidewire. C:
Placement of 16-gauge fenestrated catheter over guidewire, which is then removed. (Reprinted from Stewart JR, Gott VL. The
use of a Seldinger wire technique for pericardiocentesis following cardiac surgery. Ann Thorac Surg 1983;35(4):467–468.
SCLEROTHERAPY
Because of the relatively high rates of recurrence following simple pericardiocentesis, installation of
sclerosing agents has been evaluated in several studies with the aim of inducing irritation and
inflammation with subsequent fibrosis and obliteration of the pericardial space. Several sclerosing agents
have been investigated including antibiotics such as tetracycline and doxycycline, as well as
chemotherapeutic agents including cisplatin, bleomycin, thiotepa, and mitomycin C.23–25 Rates of
recurrence following intrapericardial sclerotherapy are generally low (10% to 12%).26,27 However, given
the wide variety of sclerosants used, coupled with the fact that the majority of studies also have employed
use of an indwelling catheter to administer the sclerosing agent, it is difficult to assess the contribution of
sclerotherapy to the success of the drainage procedure. In a randomized trial comparing pericardial
drainage (percutaneous or surgical) with and without intrapericardial instillation of bleomycin
(JCOG9811), there was no statistically significant difference in effusion failure free survival (29% vs.
46%, p = 0.086).28 Nevertheless, in this small study that enrolled 79 patients, there appeared to be a trend
favoring the bleomycin arm. However, there were more patients with positive cytology in the drainage
alone arm (79% vs. 66%), which has been shown in other studies to be associated with worse survival.
Complications that are frequently reported include atrial and ventricular arrhythmias, chest pain, and
fever. Rarely constrictive pericarditis has been reported.
BALLOON PERICARDIOTOMY
Another method that has been employed to lessen the risk of recurrence following pericardiocentesis is
the use of percutaneous balloon pericardiotomy (PBP). PBP involves the use of the percutaneously placed
balloon catheter that is inflated under high pressure across the pericardial membrane thus creating a 1 to 2
cm defect in the pericardium that allows the effusion to drain.29 Typically the procedure is performed
using local anesthetic under fluoroscopic guidance in a cardiac catheterization laboratory. PBP is usually
performed using a subxiphoid approach. The pericardial space is accessed with the needle and a
guidewire placed intrapericardially, over which a dilator is passed. A 20-mm diameter 3-cm long
balloon-dilating catheter is then advanced over the guidewire and positioned so that the balloon traverses
the parietal pericardium. The balloon is then inflated manually two or three times using radiographic
contrast medium so that the balloon may be visualized using fluoroscopy. At the completion of the
procedure, a pericardial catheter is placed through the defect and removed when the daily drainage output
has declined (typically less than 50 mL per 24 hours). Despite the fact that the pericardium is accessed
via a subxiphoid route, PBP generally results in communication between the pericardium and the left
pleural space. Whether long-term patency of this communication is necessary for the success of PBP is
unclear. Studies reporting outcomes following PBP generally include small number of patients and the
two largest to date only contained 50 patients each. Recurrence rates of pericardial effusion are reported
to be between 9% and 12%.30,31 The most frequent complications following PBP are pleural effusion and
pain, although pneumothorax and right ventricular wall perforation have been reported.32
In a recent systematic review regarding the safety and efficacy of percutaneous interventions for
malignant pericardial effusion by Virk and colleagues,26 the recurrence rate for isolated
pericardiocentesis was 38%, significantly higher than the pooled recurrence rates for extended catheter
drainage, pericardial sclerotherapy, and PBP (12.1%, 10.8%, and 10.3%, respectively).
SURGICAL INTERVENTIONS
SURGICAL FENESTRATION
The traditional management of symptomatic pericardial effusion has relied on the creation of a surgical
window in the pericardium. Several approaches can be used including the subxiphoid route, left anterior
minithoracotomy and thoracoscopy through either the right or left chest.33–35 The goal of the procedure is
to remove a small section of the pericardium to allow free drainage into either the subcutaneous tissues in
the case of the subxiphoid approach, or the pleural space. As previously mentioned, it is questionable
whether long-term patency of the window is important or whether efficacy is related to symphysis
between the epicardial and pericardium due to inflammatory fibrosis. The subxiphoid approach is most
frequently performed. The procedure may be performed under general anesthetic or with local anesthesia
and sedation. Small upper midline incision is made without dividing the abdominal fascia (Fig. 69.10).
The xiphoid process usually resected to allow better visualization of the pericardium, which is incised
sharply and partially excised. Careful exploration of the pericardial space is performed with a blunt
suction catheter to break down any loculations. A small-bore drainage catheter is then placed in the
pericardial space and removed postoperatively when drainage is minimal. The left phrenic nerve is
identified and a 4 × 4 cm portion of pericardium anterior to the phrenic nerve is excised. Occasionally,
the effusion will be located predominantly posterior to the heart, in which case the pericardium posterior
course of the phrenic nerve is excised instead. A pleural drainage catheter is then placed.36
Thoracoscopic pericardial window is performed in a similar fashion, however, requires only three 5-mm
ports and is arguably less painful than a minithoracotomy. A 5-mm thoracoscope may be used along with
5-mm graspers, scissors, or a variety of energy devices. In patients with cardiac tamponade who are
hemodynamically unstable the subxiphoid approach is the quickest and safest approach. Patients should
be prepared and draped prior to the induction of anesthesia in case of sudden cardiovascular collapse that
would require urgent surgical intercession. In a hypotensive patient one-lung ventilation (required for
VATS) is inappropriate.
FIGURE 69.10 Technique of subxiphoid pericardial window. A: incision, B: exposure of xyphoid C: digital exploration, D:
incision of pericardium between clamps. (Reproduced with permission from Brewster SA, Thirlby RC, Snyder WH III.
Subxiphoid pericardial window and penetrating cardiac trauma. Arch Surg 1988;123(8):937–941. Copyright ©1988 American
Medical Association. All rights reserved.)
In a pooled analysis of 15 studies of pericardial fenestration, the overall success rate was 93.3% with
recurrence 5.7% of patients’ complications occurring in 4.5%.27 Ten studies involved the subxiphoid
approach, which was associated with an overall success rate of 93.2% (range 80.5% to 100%). Three
studies involved VATS pericardial window with a pool success rate of 90.9% (range 88.7% to 100%). A
single study used a left anterior minithoracotomy approach in 26 patients and reported a 96.2% success
rate.34 Complication rates are generally low following surgical fenestration (pooled rate 4.5%), but
include cardiac arrest, myocardial injury, atrial and ventricular arrhythmias, atelectasis, and pneumonia.
Reported rates of 30-day mortality are generally between 0% and 10% but rates as high as 16% have
been reported and are related more to the underlying condition of the patient rather than the procedure
itself.7,37,38
Several studies have compared the efficacy of surgical fenestration with percutaneous drainage. All
have been based on retrospective data and are therefore subject to selection bias. Nevertheless, the data
seem to suggest better efficacy of surgical fenestration in terms of control of effusion. Allen and
colleagues compared 94 patients who underwent subxiphoid pericardiostomy with 23 patients who
underwent percutaneous catheter drainage. Effusions recurred in 1% of the surgical group and in 30% of
patients treated by percutaneous drainage. Additionally, percutaneous drainage was associated with
higher mortality and complication rates (4% and 17%, respectively).7 McDonald and colleagues
evaluated 246 patients with symptomatic pericardial effusions, of which 150 retreated by surgical
fenestration and 96 with percutaneous drainage. Symptomatic effusions recurred in 4.6% of the surgically
treated patients compared to 16.5% in the nonsurgical group (p = 0.002) and in-hospital mortality was
also significantly higher in the group that underwent percutaneous drainage (22% vs. 10.7%).37 Similar
findings were observed by Petcu and Droc who reported higher rates of cardiac complications (42.6%
vs. 18.8%, p = 0.001) and mortality (20.4% vs. 13.0%, p = NS) in patients undergoing percutaneous
drainage versus subxiphoid fenestration.39 Freedom from occurrence of effusion at 1 year was 92.8% in
patients treated surgically compared to 79.6% in those treated with percutaneous catheter drainage.
Finally, a systematic review of surgical and nonsurgical treatment of malignant pericardial effusion by
Jama et al.27 concluded that surgical drainage of the pericardium was superior to nonsurgical approaches
for symptom relief, effusion recurrence, and morbidity. It is worth noting however, that this analysis did
not include the two largest studies of percutaneous extended catheter drainage, both of which reported
recurrence rates of only 12%, in a recent comparison of patients who underwent surgical or percutaneous
drainage by Patel et al. (referenced above), there were no differences in recurrence rates and fewer
complications in the percutaneously drained group.10,21,22
FIGURE 69.11 Suggested algorithm for management of malignant pleural effusion.
PERICARDIECTOMY
Pericardiectomy implies the subtotal resection of the pericardium and is usually performed through a
median sternotomy for constrictive pericarditis rather than for effusive pericardial disease. Given the
extensive nature of the procedure and the ready availability of simpler, efficacious, and less-invasive
options, it cannot be recommended for palliation for patients with malignant pericardial effusions. A
retrospective analysis from the Mayo Clinic including 145 patients of which complete pericardial
resection was performed in 50%, partial resection in 25%, and pericardial window in the remainder
reveals a 30-day mortality of 19.4% in patients with malignant effusions and 1-year survival was only
23.4% in these patients (mean 4 months).40 There have been several published reports of VATS
pericardiectomy, which mainly describe partial resection of the pericardium rather than complete
pericardiectomy.41–43 In one report, the mean area of resected pericardium was only 16 cm², which is
only slightly larger than the extent of resection typically carried out with VATS pericardial window.44 The
procedure appears to be associated with a low rate of recurrence (0% to 6%).
CONCLUSION
Malignant pericardial effusion is generally associated with a poor overall prognosis but is highly
dependent on the type of underlying malignancy. Symptomatic effusions warrant palliative therapy.
Traditionally this has required surgical intervention; however, several effective, less-invasive catheter-
based therapies now exist. In the absence of randomized prospective data, the optimal therapeutic
approach for malignant pericardial effusion remains unclear. Choice of drainage procedure should take
into account procedural risk, local resources and expertise, the severity of symptoms the life expectancy
of the patient. A suggested algorithm for management of malignant pericardial effusions is presented in
Figure 69.11.
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13. Okamoto H, Shinkai T, Yamakido M, et al. Cardiac tamponade caused by primary lung cancer and the management of pericardial
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14. Swanepoel E, Apffelstaedt JP. Malignant pericardial effusion in breast cancer: terminal event or treatable complication? J Surg Oncol
1997;64(4):308–311.
15. Spodick DH. The pericardium in the cancer patient. In: Ewer MS, Yeh E, eds. Cancer and the Heart. Shelton, CT: The Peoples
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16. Demos TC, Cardella RG, Moncada R, et al. Epicardial fat sign due to extrapericardial disease. AJR Am J Roentgenol 1983;141(2):289–
291.
17. Kim SH, Kwak MH, Park S, et al. Clinical characteristics of malignant pericardial effusion associated with recurrence and survival.
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18. Tsang TS, Freeman WK, Sinak LJ, et al. Echocardiographically guided pericardiocentesis: evolution and state-of-the-art technique.
Mayo Clin Proc 1998;73.
19. Lestuzzi C, Berretta M, Tomkowski W. 2015 update on the diagnosis and management of neoplastic pericardial disease. Expert Rev
Cardiovasc Ther 2015;13(4):377–389.
20. Stewart JR, Gott VL. The use of a Seldinger wire technique for pericardiocentesis following cardiac surgery. Ann Thorac Surg
1983;35(4):467–468.
21. Tsang TS, Enriquez-Sarano M, Freeman WK, et al. Consecutive 1127 therapeutic echocardiographically guided pericardiocenteses:
clinical profile, practice patterns, and outcomes spanning 21 years. Mayo Clin Proc 2002;77(5):429–436.
22. Patel N, Rafique AM, Eshaghian S, et al. Retrospective comparison of outcomes, diagnostic value, and complications of percutaneous
prolonged drainage versus surgical pericardiotomy of pericardial effusion associated with malignancy. Am J Cardiol 2013;112(8):1235–
1239.
23. Maher EA, Shepherd FA, Todd TJ. Pericardial sclerosis as the primary management of malignant pericardial effusion and cardiac
tamponade. J Thorac Cardiovasc Surg 1996;112(3):637–643.
24. Girardi LN, Ginsberg RJ, Burt ME. Pericardiocentesis and intrapericardial sclerosis: effective therapy for malignant pericardial
effusions. Ann Thorac Surg 1997;64(5):1422–1427; discussion 1427–1428.
25. Maruyama R, Yokoyama H, Seto T, et al. Catheter drainage followed by the instillation of bleomycin to manage malignant pericardial
effusion in non–small cell lung cancer: a multi-institutional phase II trial. J Thorac Oncol 2007;2(1):65–68.
26. Virk SA, Chandrakumar D, Villanueva C, et al. Systematic review of percutaneous interventions for malignant pericardial effusion.
Heart 2015;101(20):1619–1626.
27. Jama GM, Scarci M, Bowden J, et al. Palliative treatment for symptomatic malignant pericardial effusion. Interact Cardiovasc Thorac
Surg 2014;19(6):1019–1026.
28. Kunitoh H, Tamura T, Shibata T, et al.; JCOG Lung Cancer Study Group, Tokyo, Japan. A randomised trial of intrapericardial bleomycin
for malignant pericardial effusion with lung cancer (JCOG9811). Br J Cancer 2009;100(3):464–469.
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tamponade. Cathet Cardiovasc Diagn 1991;22(4):244–249.
30. Ziskind AA, Pearce AC, Lemmon CC, et al. Percutaneous balloon pericardiotomy for the treatment of cardiac tamponade and large
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31. Wang HJ1, Hsu KL, Chiang FT, et al. Technical and prognostic outcomes of double-balloon pericardiotomy for large malignancy-related
pericardial effusions. Chest 2002;122(3):893–899.
32. del Barrio LG, Morales JH, Delgado C, et al. Percutaneous balloon pericardial window for patients with symptomatic pericardial
effusion. Cardiovasc Intervent Radiol 2002;25(5):360–364.
33. Brewster SA, Thirlby RC, Snyder WH III. Subxiphoid pericardial window and penetrating cardiac trauma. Arch Surg 1988;123(8):937–
941.
34. Celik S, Celik M, Aydemir B, et al. Surgical properties and survival of a pericardial window via left minithoracotomy for benign and
malignant pericardial tamponade in cancer patients. World J Surg Oncol 2012;10:123.
35. Georghiou GP, Stamler A, Sharoni E, et al. Video-assisted thoracoscopic pericardial window for diagnosis and management of
pericardial effusions. Ann Thorac Surg 2005;80(2):607–610.
36. Sugimoto JT, Little AG, Ferguson MK, et al. Pericardial window: mechanisms of efficacy. Ann Thorac Surg 1990;50(3):442–445.
37. McDonald JM, Meyers BF, Guthrie TJ, et al. Comparison of open subxiphoid pericardial drainage with percutaneous catheter drainage
for symptomatic pericardial effusion. Ann Thorac Surg 2003;76(3):811–815; discussion 816.
38. Sarigul A, Farsak B, Sanser Ates M, et al. Subxiphoid approach for treatment of pericardial effusion. Asian Cardiovasc Thorac Ann
1999;7:297–230.
39. Petcu CP, Droc I. The efficiency of surgical subxiphoid pericardial drainage and percutaneous pericardial drainage in pericardial
effusions associated with cardiac tamponade. Chirurgia (Bucur) 2013;108(2):226–233.
40. Piehler JM, Pluth JR, Schaff HV, et al. Surgical management of effusive pericardial disease. Influence of extent of pericardial resection
on clinical course. J Thorac Cardiovasc Surg 1985;90(4):506–516.
41. Mack MJ, Landreneau RJ, Hazelrigg SR, et al. Video thoracoscopic management of benign and malignant pericardial effusions. Chest
1993;103(4 Suppl):390S–393S.
42. Hazelrigg SR, Mack MJ, Landreneau RJ, et al. Thoracoscopic pericardiectomy for effusive pericardial disease. Ann Thorac Surg
1993;56(3):792–795.
43. Neragi-Miandoab S, Linden PA, Ducko CT, et al. VATS pericardiotomy for patients with known malignancy and pericardial effusion:
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2008;6(2):110–114.
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2010;30(11):4691–4694.
Section
XIII
THE TRACHEA AND BRONCHI

70
Tracheostomy
Shamus R. Carr ■ Joseph S. Friedberg
INTRODUCTION
References to tracheostomy can be found from ancient times to popular culture. It is one of the earliest
recorded operations and references to it are found on artifacts from ancient Egypt1 to the popular 1970s to
1980s TV show M*A*S*H, when the character of Father Mulcahy performed one as he was guided over
the radio by the surgeon Hawkeye Pierce.2
Despite tracheostomy being performed for thousands of years, it was not until 1909 that Dr. Chevalier
Jackson standardized the open procedure.3 While the open technique has remained largely unchanged,
advances to include a percutaneous approach4 and improved tracheostomy tubes have been developed
and widely adopted.
INDICATIONS AND CONTRAINDICATIONS FOR TRACHEOSTOMY

Tracheostomy can be used in a variety of settings, but the indications are always the same, to secure the
airway to bypass an airway obstruction, allow for positive pressure ventilation in the setting of
pulmonary failure, access the airway for control of secretions, and/or protect the airway in the setting of
neurologic compromise. In the emergent setting, however, transglottic endotracheal tube intubation, rather
than subglottic placement of a tracheostomy tube, is currently the method of choice to establish an
emergent airway. If an endotracheal tube cannot be placed, other options including a ventilating rigid
bronchoscope or laryngeal mask can be used. Once an airway is established in the emergent setting,
tracheostomy can then be performed in a nonemergent setting. Yet, in the acute setting it can be used for
airway obstruction in pediatric patients with severe upper respiratory illnesses such as epiglottitis or
adults resulting from blunt trauma to the anterior neck. In the subacute setting, it is most commonly
indicated for prolonged ventilatory support. It is also utilized as part of the treatment strategy for
laryngeal cancer, tracheal stenosis, or excessive secretions requiring frequent suctioning. In the chronic
setting, tracheostomy is superior to prolonged endotracheal intubation for patients with primary
respiratory failure or severe brain injury that will be on ventilatory support for extended periods of time.
There are almost no absolute contraindications to performing elective tracheostomy except
hemodynamic instability or inability to tolerate a short period of apnea during the performance of the
procedure. There are certain situations that while not absolute contraindications, care must be exercised.
These include substernal goiter, severe kyphosis, anatomic defects, soft tissue infections, bleeding
diathesis, and certain modes of ventilation that require spontaneous ventilation (i.e., APRV).5
ADVANTAGES AND DISADVANTAGES FOR TRACHEOSTOMY
There are numerous advantages of tracheostomy. Foremost it provides a safe and secure way to provide
ventilatory access for long-term airway management. It also provides excellent access for pulmonary
toilet, airway protection from various forms of aspiration, improved oral hygiene by increasing access
after removal of an endotracheal tube, decreased risk of ventilator-associated pneumonia (VAP),
increased options for weaning from mechanical ventilation, and the ability for the patient to mouth words
and communicate with both family members and the care team. As the tracheostomy is also a much shorter
tube that an endotracheal tube, it has both a decreased resistance to airflow and eliminates about 25 cm3
of dead space. Elimination of this dead space may facilitate weaning from the ventilator in patients with
marginal pulmonary function.
Despite the numerous advantages, there are disadvantages that need to be considered and discussed
with a patient’s family as part of informed consent. Depending on the manner in which the tracheostomy is
performed, open versus percutaneous, these are different. Generally speaking, an open tracheostomy is a
safe procedure but tracheal stricture can result, although this is also true for prolonged endotracheal
intubation or following percutaneous tracheostomy (PCT). In addition, the risk of bleeding and injury to
the membranous trachea are well-described complications of both open tracheostomy and PCT.
There is also a psychological impact of this procedure. In patients who are suffering respiratory
failure, one needs to be cognizant that a tracheostomy may trigger a sense of hopelessness in family
members. The family, therefore, needs to be educated that a tracheostomy is part of a plan for eventual
recovery and, in most cases, temporary.
The safe conduct of a tracheostomy begins with an appropriate surgical evaluation and should be
conducted within the context of relevant anatomic considerations. As the trachea enters the chest,
posterior to the sternal notch, it lies at about a 45-degree angle to the long axis of the patient. This angle
can be even more severe and can approach 90 degrees in elderly patients, especially in those with severe
kyphosis (Fig. 70.1). This underappreciated fact can lead to difficulty in placing the tracheostomy due to
orientation of the trachea as it enters the neck and can result in mediastinal intubation. Another issue in
both elderly and morbidly obese patients is that the second and third tracheal rings, the standard insertion
point for the tracheostomy, may be beneath the sternal notch. This challenge can be exacerbated when
these patients have limited neck extension. As the neck is extended, the trachea rises from the
mediastinum, allowing greater access to the appropriate insertion site. The limited neck extension can
also increase the likelihood of encountering the thyroid isthmus, which may need to be divided to
correctly perform a tracheostomy.
FIGURE 70.1 Severe kyphosis of the cervical spine distorting the anatomy of the trachea.
Another issue to keep in mind is location of blood vessels that may be encountered when performing a
tracheostomy. The two most commonly encountered vessels are the thyroid ima artery and the
brachiocephalic trunk. The thyroid ima ascends in the neck anterior to the trachea to supply the inferior
pole of the thyroid gland. It has a reported incidence of less than 0.5%, but can be a source of significant
hemorrhage if unexpectedly encountered. The brachiocephalic trunk crosses beneath the posterior table of
the sternum and generally is too caudal to be encountered. However, with neck extension in a younger
patient, it can elevate to nearly the level of the sternal notch.
After considering anatomic issues, attention should turn to variables over which a surgeon does have
control. If a patient is coagulopathic, this should be corrected. A patient should have a platelet count of
greater than 50,000 platelets/mL, not be on antiplatelet agents (e.g., clopidogrel, warfarin, apixaban), and
have an international normalized ratio (INR) of less than 1.6. Administration of appropriate blood
products can help to correct these variables.
Next a patient needs to be assessed to see if they can tolerate a brief period of apnea from a
cardiopulmonary standpoint. In ideal settings the period of apnea lasts a few seconds, but can be
considerably longer. If a patient is on an inspired oxygen level of greater than 60%, care should be
exercised on timing of the tracheostomy.
In addition to the anatomic considerations mentioned above, one must evaluate the neck to make sure it
is free from infection. While concerns for performing a tracheostomy in a patient with a sternotomy are
routinely brought up, the literature does not support an increase in complications in patients with a
sternotomy.6 Burn victims, when the neck is involved, are another area where there are concerns. If the
burn does not involve the neck then these patients can be treated as any patient that is intubated. Studies in
patients with burns that do involve the neck show that tracheostomy does not increase mortality, but may
be associated with an increase in respiratory infections, and both percutaneous and open tracheostomy
can be safely performed. It is recommended that the tracheostomy be performed either through an autograft
or greater than 10 days after skin grafting to decrease infectious complications.7,8
Some have advocated for an ultrasound evaluation of the neck and airway to evaluate for vascular
structures or the thyroid in the area of the planned tracheostomy to decrease bleeding complications.9
While ultrasound is now widely available in hospitals, and is safe, reproducible, and does not cause
patient distress, the experience with ultrasound for performing a tracheostomy is limited.
A special consideration needs to be mentioned for patients who are on extracorporeal membrane
oxygenation (ECMO). In addition to correcting the INR and assuring that the platelets count is greater than
50,000 platelets/mL, it is sometimes prudent to administer both platelets and fresh frozen plasma during
the procedure. At our institution a unit of fresh frozen plasma and a pack of platelets will be infused
during the procedure, regardless of the laboratory values for a patient on ECMO.
OPERATIVE TECHNIQUES
STANDARD OPEN TRACHEOSTOMY

While there are various approaches to the standard open tracheostomy, what follows is a technical
summary as described in detail by Dr. Grillo.10
The incision is planned based upon the cricoid cartilage, not the sternal notch. Prior to incision have
anesthesia limit the inspired oxygen concentration to 30%, if possible, in order to decrease the risk of an
airway fire. The incision is carried directly down to the trachea, retracting the strap muscles laterally
from the midline. The thyroid isthmus is normally found at the level of the second cartilaginous ring. It is
dissected off the trachea and divided and suture ligated with 0 silk ties. This should provide full exposure
of the trachea from the cricoid membrane to the fourth cartilaginous ring. A vertical incision is made
through the second and third rings with a no. 11 scalpel. Bleeding is controlled and the incision is slightly
dilated by lateral retraction.
The balloon on the endotracheal tube is then deflated and the tube is pulled back, by anesthesia, under
direct vision until the end is seen in the newly created tracheotomy. An appropriate sized tracheostomy
tube, coated in water-soluble lubricant, is then inserted into the airway. Sometimes retractors are required
to remain in the airway to allow the tracheostomy tube to be easily inserted into the trachea. The cuff,
which was previously tested to ensure there is no leak, is inflated and cross-table ventilation is
established. Once end-tidal CO2 is confirmed by anesthesia, the endotracheal tube can be removed. The
flange of the trachea of the tracheostomy is then sutured to the skin in all four quadrants using 2-0 Prolene
sutures. Any excess skin incision should also be closed to provide a snug fit around the tube. Finally a
tracheostomy tape is placed around the neck and secured.
It should be noted that some surgeons place traction sutures, perform a horizontal tracheal incision, or
remove a portion of a tracheal ring to create a “trap door.” These all are unnecessary and may actually
lead to increased risk of tracheal stenosis.10
CRICOTHYROIDOTOMY
There are two indications for a cricothyroidotomy. One is reserved for emergent situations when an oral
airway cannot be established in a patient with acute upper airway obstruction. The other is for the
performance of the mini-tracheostomy (Fig. 70.2) to aid in removal of airway secretions. Since the
widespread adoption of the PCT as described by Ciaglia, there has been a sharp decline in the use of the
mini-tracheostomy. The main use of the mini-tracheostomy is for the patient that needs constant suctioning
without the need for mechanical ventilation.
Both of these procedures can be performed in essentially the same manner. First, after the skin is
prepped, the cricoid membrane is palpated, as it is a constant and easily identifiable landmark. The
easiest way to palpate this is to palpate the larynx and while staying midline feel for the space between
the larynx and the first tracheal ring. Using a scalpel an incision is made directly over the cricoid
membrane. Using cautery, the dissection can then be continued down through the platysma to the strap
muscles. These are separated along the median raphe and the trachea is exposed. Using a no. 11 blade
scalpel a horizontal incision in made in the cricothyroid membrane. This is dilated with a hemostat to
allow insertion of a tube into the airway. If a percutaneous method is to be used, a modified Seldinger
technique aids in the insertion. The membrane is palpated as described above; a 16-gauge angiocatheter
connected to a syringe with 5 mL of saline is placed directly into the airway. Return of bubbles confirms
that the airway has been entered. A guide wire, included with the kit, is inserted through the angiocatheter
after the needle has been removed. The tract is dilated over the wire. Leaving the wire in place in the
airway, the tracheostomy appliance is then inserted into the airway over the wire. The wire is removed
and the appliance is sutured to the skin.
FIGURE 70.2 Mini-tracheostomy kit (Portex® Mini-Trach®, Smiths Medical).
PERCUTANEOUS TRACHEOSTOMY
While there have been various designs over the decades for a PCT, the most commonly employed
technique today was reported by Ciaglia in 1985.4 This system now comes as a pre-packaged kit (Fig.
70.3) known as the Ciaglia Blue Rhino (Cook Medical, Inc., Bloomington, IN). This technique has gained
widespread acceptance and has been demonstrated both in primary papers and a meta-analysis that PCT
has the same complication rate and profile as an open tracheostomy.11–14 While previously there was
controversy about performing a tracheostomy outside of an operating room, the fact that a PCT can be
performed safely has allowed this procedure to be done at bedside in the intensive care unit.
This technique should always be performed under bronchoscopic guidance. In addition to identifying
that the airway has been accessed at an optimal insertion site, use of the bronchoscopy allows directing
the wire and, consequently the dilators, to the right or the left lung, perhaps to avoid potential injury of a
fresh bronchial stump after a pulmonary injury. Furthermore, performing the procedure under
bronchoscopic guidance essentially eliminates the risk of injury to the membranous airway and/or
esophageal injury that can occur with blind passage.
After appropriately positioning the patient as one would for a standard open tracheostomy with a
shoulder roll in place, the bronchoscope is utilized to visualize retraction of the endotracheal tube to just
below the level of the vocal cords. A 22-gauge needle is then inserted and visualized to identify the
proper tracheal ring level. Care must be exercised as intubation through the cricoid membrane is
associated with a higher incidence of subglottic complications and thus should be avoided.15 Having a
syringe partially filled with saline is helpful with this step, by drawing back and seeing bubbles in the
saline, to identify being in the airway in case the needle is not immediately visualized with the
bronchoscope. Once the appropriate site is determined, a 15-gauge angiocatheter is placed into the
airway. With the catheter in the intercartilagenous space between the second and third rings, the J-wire is
then inserted. With the wire in place, a horizontal 1-cm skin incision is made centered on the wire. A
short 14-Fr dilator is passed over the wire and then removed. The Ciaglia Blue Rhino dilator is then
loaded onto an 8-Fr sheath and inserted along the wire to dilate the tract to the prescribed mark on the
dilator. The appropriate size tracheostomy is already loaded on the corresponding lubricated insertion
dilator. The Blue Rhino dilator is removed and the insertion dilator and tracheostomy are placed over the
8-Fr sheath and inserted into the airway. Once the tracheostomy tube is confirmed to be in the airway via
bronchoscopy, the wire and dilator are removed. The bronchoscope can be immediately inserted into the
tracheostomy tube to reconfirm appropriate positioning and confirm that the field is hemostatic. Cross-
table ventilation is then established and once end-tidal CO2 is confirmed, the endotracheal tube can be
finally removed. Bronchoscopy should be performed to clear the airway of debris. The flange is sutured
to the skin as described above and a tracheal tie is then placed.
FIGURE 70.3 Ciaglia Blue Rhino Percutaneous Tracheostomy kit. (Permission for use granted by Cook Medical, Bloomington,
Indiana.)
PEARLS AND PITFALLS OF TRACHEOSTOMY

When a tracheostomy goes as planned it is a relatively straightforward case. However, there are multiple
“unexpected” events that can occur and when they do, in the words of the senior author, “No shambles
like an airway shambles” (origins of this quote are unknown). The authors would like to share a few
points for those hopefully rare times when things do not go quite as planned.
Keeping the inspired oxygen percent as low as possible is key. One can always find a senior surgeon
that can tell a story about an airway fire. In the case that one cannot safely lower the oxygen concentration,
do not place electrocautery on the field.
The most common sources of bleeding are anterior jugular veins. These are easily and readily ligated
with 2-0 silk ties and divided. It is imperative that prior to incising the trachea to perform the tracheotomy
the surgical field is hemostatic. Failure to do this can lead to misery for the surgeon as visualization into
the wound to try and control bleeding with a tracheostomy in place can be near impossible.
In patients that have a large neck or are obese, initial consideration to a tracheostomy with a longer
tube can be very helpful. In these cases place a Shiley XLT-P tracheostomy at the time of initial surgery.
If the balloon does not hold or there is an airleak with ventilation, the use of a self-inflating Bivona
tracheostomy tube should be considered or again a tracheostomy with a longer cannula.
COMPLICATIONS
Complications may occur intraoperatively or in the early or late postoperative periods (Table 70.1).
INTRAOPERATIVE
For an elective tracheostomy, bleeding as the result of uncorrected coagulopathy should be avoidable. As
stated above, venous bleeding is most common and is reported to occur in about 1% to 2% of patients
undergoing open tracheostomy and up to 5% of patients undergoing percutaneous approaches.16,17 Arterial
bleeding is most commonly from the thyroid ima artery and has been reported to occur with an incidence
of less than 0.5%.
TABLE 70.1 Immediate, Early, and Late Complications of Tracheostomy

Immediate Early Late
Apnea Bleeding Bleeding
Adjacent structure injury Cellulitis Stenosis
Bleeding Displacement/dislodgement Tracheocutaneous fistula
Mediastinal intubation Mucous plugging Tracheoesophageal fistula
Pneumothorax Subcutaneous emphysema Tracheoinnominate fistula
Postobstructive pulmonary edema Tracheitis Tracheomalacia
Wound infection Wound infection
Laceration of the membranous trachea is typically the result of excessive force during insertion of the
tracheostomy.18–20 It is a potentially devastating injury that requires immediate identification and
management. It is more commonly reported during the percutaneous approach with blind passage of the
dilators, which is why performing this procedure under direct bronchoscopic visualization greatly
enhances the safety of this approach. If injury occurs, treatment options depend on the extent and location
of the injury. If it is limited, the endotracheal tube can be reinserted with the cuff placed below the distal
extent of the injury to prevent air from dissecting into the mediastinum, which will be contaminated with
airway secretions. Between 7 and 10 days later the patient can return to the operating room to evaluate the
injury and determine how well it is healing. However, if the patient has increasing subcutaneous air or
develops sepsis, conservative management must be aborted and immediate evaluation and operative
exploration is imperative. Sometimes the injury extends all the way to the carina, and in these cases
operative repair or placement of a Y-stent are both options that have been used successfully.
Injury to adjacent structures (i.e., great vessels, esophagus, and the recurrent laryngeal nerves) can
largely be eliminated with adequate exposure and identification of crucial landmarks. During PCT, there
is no direct visualization of adjacent structures, but meticulous attention to accessing the airway centrally
and performing the procedure under bronchoscopic guidance can help avoid these complications. Using
ultrasound as an adjunct to PCT has been reported as potentially helpful, particularly in obese patients.21
Unrecognized mediastinal intubation can be a catastrophic problem due to the failure to ventilate the
patient. In addition to the resultant hypoxia and hypercarbia that can occur, a malpositioned tube can also
result in pneumomediastinum. This can be further complicated by aggressive bagging prior to recognition
of the misplaced tracheostomy, which may result in a pneumothorax. While the exact incidence of
mediastinal intubation is difficult to discern, it has been reported to occur in up to 5% of patients.22 The
key point in management is immediate recognition. Immediate confirmation of end-tidal CO2 and/or the
immediate introduction of a bronchoscope are critical in confirming that the newly placed tracheostomy
tube is in the airway. Hypercarbia, and complications from it, can result from a relatively uneventful
procedure and this needs to be kept in mind when difficulty ventilating a patient after tracheostomy is
encountered.23,24 Hypercarbia may also be due to multiple reasons: hypoventilation, prolonged apnea,
residual effects of anesthetic drugs, or comorbid conditions such as COPD or obesity but tracheostomy
tube placement within the airway is critical to confirm.25
Aspiration can also occur during this procedure. Again, the use of bronchoscopy at the completion of
the case can identify if this complication occurred and can also be used for pulmonary toilet to mitigate
the damage caused by the aspiration. Other minor complications such as transient hypotension most
commonly due to sedation, oxygen desaturation from either poor pulmonary reserve or excess apneic time
during tracheostomy tube placement, or nonsurgical bleeding from the edges of the tracheotomy or skin,
can occur in 6% to 10% of patients.9,26
Early
Previously, it was felt that early complications of open standard tracheostomy and PCT were different and
occurred at different rates. Comparison of a 10-year experience with both techniques, however, has
shown that the incidence of early complications are essentially the same.27 The two most common early
postoperative complications are bleeding and tube dislodgement.
Bleeding occurs most commonly as the result of either ongoing coagulopathy or resumption of
anticoagulation therapy. These can typically be corrected with appropriate blood products. Otherwise,
bleeding is “surgical” and speaks to the need for meticulous hemostasis at the time of surgery, especially
as the tracheostomy tube will be moving in the surgical field postoperative and can provoke bleeding if
the field is not secure.
Inadvertent dislodgement of a new tracheostomy can be fatal if not immediately corrected. The safest
option, the default option, is reintubation of the patient. Then, with a secure airway, the patient can be
evaluated for replacement of the tracheostomy. If, in the judgment of a skilled and experienced operator,
the patient is stable and the situation is favorable for replacement of the tube then this can be attempted.
Ideally this is done via some sort of Seldinger technique, optimally over a bronchoscope that is placed
into the airway. Regardless of how it is done, the tube must be confirmed to be in the airway at the
conclusion of the replacement to avoid insufflation of the mediastinum and a potential fatal cascade of
events. Again, it cannot be overstressed that the default option for dislodgement of a freshly placed
tracheostomy tube is transoral reintubation with an endotracheal tube.
Mucous impaction in the tracheostomy can occur and usually is easily remedied with either suctioning
or in some cases removal and replacement of the inner cannula. There are some tracheostomy appliances
that do not have an inner cannula. In these cases, saline lavage and suctioning should suffice.
Subcutaneous crepitus can be a sign of either a tracheostomy in the mediastinum or an air leak around
the tube. Evaluation should begin with first confirming that the tracheostomy is indeed in the airway. Once
this is confirmed, the cuff on the tracheostomy should be tested. Most respiratory therapists now carry a
manometer to allow for the pressure in the cuff to be precisely measured. If inflation of the cuff does not
solve the problem, then a repeat bronchoscopy is indicated. One should be suspicious of a tracheal injury
and the bronchoscopy should be performed in a way to allow for a thorough evaluation of the entire upper
airway. Management of an airway injury was discussed previously under immediate complications.
Infection is a well-recognized complication of tracheostomy. Despite attempts to perform this case in a
sterile fashion, as soon as the airway is opened it is a contaminated case. The reason for this is the airway
is colonized with bacteria, most commonly staphylococci or gram-negative organisms.28 If a patient does
develop a cellulitis or wound infection around a tracheostomy site, one needs to be cognizant of the
possibility of developing a devastating necrotizing infection. If this occurs, the first step is removal of the
tracheostomy appliance and oral reintubation. Then the wound is managed as any other infections with
wide surgical debridement. Once granulation tissue begins to appear, the tracheostomy appliance can be
replaced.
Another area of concern is placing a tracheostomy near a recent operative space, the most common
being a sternotomy. The concern is if the tissue planes connect between the tracheostomy and the
sternotomy, the respiratory secretions could track into, and infect, the fresh sternotomy incision. While
this concern is appropriately raised, published studies are unable to predict a safe time interval between
the two procedures.29 Others have not shown a relationship between tracheostomy and sternotomy in the
development of mediastinitis or a mediastinal wound infection.6,30
LATE
Compared to the immediate and early complications, late complications can occur at almost any time
point. In general, late complications are significantly more challenging and have a significantly higher
morbidity and mortality associated with them.
Bleeding can still occur during the late period. While it is most commonly due to granulation tissue
around the stoma due to chronic irritation from the appliance, it can also herald a more significant and
life-threatening issue, tracheoinnominate fistula (TIF). Therefore, in a patient that has had a tracheostomy
in for over a week, the algorithm that should be followed is one that first rules out the life-threatening
complications (see later). Once this is done, silver nitrate or electrocautery can be applied to the
granulation tissue at the stoma.
FISTULAE
These occur due to necrosis of surrounding tissue and erosion into adjacent structures. These can occur
not only in as short as a few days, but also years later. While none of the fistulae (cutaneous, esophageal,
or innominate) are desirable, TIF is the most dreaded.
TIF
As one approaches a patient that has a possible TIF it is important to realize that this can occur from
either direct erosion of the tracheostomy tube into the vessel or by the cuff eroding through the airway into
the vessel. This is important as it changes the operative plan and what can be done to temporize the
bleeding en route to definitive treatment.
Historically, bleeding from a TIF occurs most commonly due to erosion of the balloon through the
anterior trachea into the brachiocephalic (innominate) artery. This has a reported incidence of around
2%,22 but seems to be much less common in the current era, likely due to high-volume, low-pressure
cuffs.31 More common now is direct erosion into the vessel at the angle of the tracheostomy tube due to a
tracheostomy that is placed initially too low on the trachea.
Anytime a patient with a tracheostomy that has been in for more than a week develops bright red
blood, an immediate inspection of the trachea needs to be performed. This recommendation applies for
blood emanating through or around the tube. This can be a sentinel bleed, heralding impending massive
hemorrhage by hours to days. If there is reasonable suspicion that a TIF exists, then it is most prudent to
perform the interrogation in the operating room with the team and equipment immediately available to
perform the repair.
If the bleeding has subsided, careful airway inspection with flexible bronchoscopy is paramount with
the tracheostomy tube removed. The bronchoscopy should be done via the nose or mouth to allow for a
more thorough inspection of the area of concern for a TIF. If there is high suspicion on this exam, plans
need to be made for immediate surgical intervention (see later).
If the bleeding is persistent, the first move is to overinflate the cuff of the tracheostomy to provide time
to get the patient to the operating room. If the cuff was deflated and the bleeding is coming from above,
then inflation can also prevent internal hematemic drowning. Pulling up on the tracheostomy tube, such
that it compresses the artery against the sternum, may also be helpful and should be attempted if inflation
does not help. If this does not work, the next step is to provide direct manual compression of the vessel
against the posterior table of the sternum with a finger inserted into the trachea. Sliding a finger alongside
the trach is the first maneuver, but if this does not work then the patient will need to be intubated from
above and the tracheostomy appliance will need to be removed after the endotracheal tube has been
passed into the distal trachea and inflated. This may require removal of the tracheostomy appliance and
reinsertion of an endotracheal tube via the tracheostomy or via a transoral intubation to allow digital
pressure to be appropriately applied.
A bronchoscope is very helpful for this maneuver as it can be placed through the endotracheal tube and
the tracheostomy tube is visible. This allows, essentially, instantaneous exchange of the tubes, appropriate
placement of the endotracheal tube in the distal trachea, the ability to aspirate blood and secretions from
the airway, and the potential to get a view of the pathology in the trachea and make the diagnosis. The cuff
of the endotracheal tube should be overinflated at this point to protect the more distal airway and
minimize blood running into it. It is important to mention that if the TIF is due to erosion by the cuff
through the anterior trachea and into the vessel, manual palpation may not be possible as it may not be
able to be reached by a finger. In these cases, overinflating the endotracheal tube balloon is the correct
management decision. No matter the etiology, the patient should be immediately brought to the operating
room while maintaining pressure the entire time, including during prepping and draping the patient for
sternotomy.
The key point in management is that minimal intervention should be done at the bedside to achieve
control of the bleeding. Once that is done, the patient must be taken emergently to the operating room for
the remainder of the evaluation and treatment. At any step along the way, it is possible that control of the
bleeding can be lost placing the patient at risk for internal hematemic drowning before the resources are
available to effectively intervene.
At this point, a bronchoscopy is performed in the operating room to assess for TIF and the cause. This
is best seen by examining with a bronchoscope through the tracheostomy stoma, now that the tracheostomy
tube has been removed and an endotracheal tube is in place. Most commonly, the bleeding is from either
the thyroid or the subcutaneous tissue. If TIF is seen, a median sternotomy provides excellent exposure,
but some advocate for a partial sternotomy angled into the third interspace to the right due to concerns of
sternal infection.32 More recently, others have started to advocate for the placement of vascular stents,
with varying levels of success.33,34 Placing a vascular stent does pose the concern, however, of
potentially placing a stent into an infected field.
Operative management begins with a median sternotomy. At this point it is critical to evaluate if the
TIF is due to direct erosion into the vessel or erosion through the anterior wall of the trachea into the
vessel, as the operative plan differs. A TIF occurs when the angle of the tracheostomy appliance is in
direct contact with the vessel. This can produce a defect in the vessel at the sternal notch while causing no
injury to the trachea. Therefore, in patients with direct erosion, a tracheal resection is unnecessary. In
these cases, proximal and distal control of the brachiocephalic artery is obtained and the branches off of
the aorta are evaluated to ensure that both carotid arteries do not arise from a common trunk. The
damaged artery is then resected and oversewn. Either a new stoma is constructed at the appropriate level
and proximal to the old stoma or the patient can be left intubated from above. If a new tracheostomy tube
is inserted, the cannula must be of sufficient length to be placed distal to the old stoma site. The prior
stoma site is then debrided and closed. Finally, a tissue flap (e.g., thymus, omentum, strap muscles) should
be advanced into the area as it is an infected area and this may help to protect against late erosion of the
ligated ends of the vessels and proper healing of the old stoma site.
In the event that the TIF is due to erosion of the anterior tracheal wall into the overlying
brachiocephalic artery, it is important to realize that the area of concern is in the mediastinum and not at
the stoma site. Again, after sternotomy the first step is to gain both proximal and distal control of the
artery with either vascular clamps or vessel loops with a tourniquet. The damaged portion of the vessel is
resected and oversewn with a Prolene suture. This will provide excellent exposure to the diseased area
of the trachea. Dissection of the damaged area of the trachea is next. All of the surgical tenets of trachea
surgery must be adhered to. The dissection should only be anterior and posterior to the airway with
minimal disruption of tissue lateral to the trachea so as to not compromise blood supply to other areas of
the trachea that are uninjured. At the site of injury dissection must remain immediately on the tracheal
wall circumferentially so as to not cause nerve injury. The injury usually involves only a single tracheal
ring or two. Resection of the ring above the site of injury to the ring below the site of injury should
provide the appropriate resection of the diseased and injured airway and still allow primary anastomosis
without tension. At this point, a sterile cross-table ventilation circuit is required. The trachea is then
dissected off the esophagus to the planned proximal resection margin. Once the diseased segment of
trachea is resected, reconstruction begins.
First, anesthesia places the patient in a position with the neck flexed. Traction sutures on the proximal
and distal edges of the trachea are then used to confirm that the airway comes together without tension.
Starting in the midline of the membranous trachea, interrupted 4-0 PDS or 4-0 Vicryl stitches are placed.
These are not tied until all stitches are placed. The suturing continues circumferentially with the anterior
stitches placed around the tracheal rings that will form the anastomosis. Once all stiches are placed, the
oral endotracheal tube is advanced by anesthesia and guided into the distal airway and the traction
stitches are tightened to allow the airway to come together without tension. Stiches are then tied in the
reverse order in which they were placed. The anastomosis is tested for pneumostasis by having anesthesia
performed by a valsalva manuever, with the endotracheal cuff deflated, to 30 cm of water pressure.
Finally, a pedicled tissue flap is brought up to the area of the anastomosis. While many different flaps
can be used, the authors prefer omentum. An upper midline abdominal incision is made via an extension
from the sternotomy incision. A pedicled flap of omentum is mobilized off of the greater curve of the
stomach and brought into the chest via the foramen of Morgagni (also known as the triangle of Larrey). It
is then tacked into place with interrupted Vicryl stitches to cover the anastomosis and separate it from the
ligated vessel. Incisions are closed in the usual fashion.
TEF
Erosion can also occur posteriorly into the esophagus, thus creating a tracheoesophageal fistula. This
usually only occurs when there is some type of foreign body in the esophagus such as a nasogastric tube or
esophageal stent. The presence of bile-tinged secretions from tracheal suctioning should raise the clinical
suspicion of a TEF. Diagnosis can be difficult, but bronchoscopy and esophagoscopy are the mainstays to
securing the diagnosis. While diagnosis may be a challenge, the operative repair is an even greater
challenge.
With stents becoming more commonly used, “kissing stents” are sometimes placed with a stent in the
airway and another in the trachea. Care needs to be taken and this should not be the sole method of
management, unless the patient is on comfort measures or has absolutely no other options, as the two
stents pressing against each other are likely to actually increase the size of the fistula. Placing stents in
both the airway and the esophagus does not address the problem, but it can be used to allow time to
discuss with the patient and their family a more definitive care plan.
Surgical repair is no different than for any other fistula. The two structures need to be separated and a
vascularized tissue flap needs to be inserted between the two stents along with repair of both the trachea
and the esophagus. Depending on the site of the TEF, this can be either approached via a neck incision or
right thoracotomy. At the conclusion of the case, an appropriate length tracheostomy needs to be inserted
so that the cuff is distal to the site of repair.
Persistent Tracheal Stoma

If after 6 months a tracheal stoma has not closed, it is due to epithelialization of the tracheostomy tract.
This is addressed by resection of the skin growth along the tract thereby allowing healing and primary
closure of the stoma.
Tracheal Stenosis/Malacia
Prior to the invention of the high-volume, low-pressure cuff,35 tracheal stenosis was much more common.
Despite these advances and recognition of the etiology being chronic pressure on the trachea, tracheal
stenosis still occurs.31 This pressure can come about from a myriad of reasons. An overinflated
endotracheal tube cuff and an improper angle of the tracheostomy tube, especially in patients with severe
kyphosis, have both been implicated.36–38 The initial damage to the trachea occurs within a few hours and,
without prompt recognition, eventually sets up a cycle of injury that can result in tracheal stenosis. It is
important for everyone involved in the care of a mechanically ventilated patient with a tracheostomy tube
to be attentive to the system being used to support the ventilator tubing leading to the tracheostomy tube. If
the tubing is not supported in the appropriate position it can cause torque on the tracheostomy tube and
will result in pressure at the insertion site and, because the tube is a rigid right angle, potentially at the tip
within the trachea as well.
There are also reported cases of tracheomalacia occurring with long-term tracheostomy use.39
Management options include stenting, tracheoplasty, tracheal resection, or placement of a longer
tracheostomy tube.
CURRENT CONTROVERSIES
IS THERE A BENEFIT TO EARLY TRACHEOSTOMY?

Since the initial reports of the benefit of early tracheostomy,40–42 there have been multiple similar studies
that have questioned this concept. Some of these studies have shown possible benefits to early
tracheostomy in various settings and it has been proposed that early tracheostomy may decrease VAP, time
in ICU, mortality, sedation, and days on the ventilator. This has led to different guidelines from various
groups about the role of early tracheostomy.43,44
One of the problems with making broad statements about benefits of early tracheostomy is that most
studies focus on select groups of patients (e.g., burn, cardiothoracic, stroke, trauma).45–48 While early
tracheostomy may benefit some select groups of patients, its widespread adoption in all critically ill
patients is not supported by the currently available literature.49 A meta-analysis in 2014 of 14 randomized
controlled trials with 2,406 patients demonstrated that the only variable that benefited in those who
received early tracheostomy (<10 days) was shorter duration of sedation.50 As predicted, the other
finding was that patients in the early tracheostomy arms underwent more procedures. While this meta-
analysis includes trials from 1976 to the present, they found no difference in the result when they grouped
the studies by year. This is in contrast to a meta-analysis from 2005 which found early tracheostomy
significantly reduced duration of artificial ventilation and length of stay in the ICU.51 The most recent
Cochrane Review reported divergent results for time spent on the ventilator and pneumonia rates and was
only suggestive of a decrease in mortality with early tracheostomy.52 However, this may have been due to
a selection bias in trials of early tracheostomy since patients with expected high mortality were not
enrolled. However, if there is a benefit to early tracheostomy it does not seem to translate to patients with
head injuries, as this group actually experience higher mortality with early tracheostomy.53
SHOULD A TRACHEOSTOMY BE PERFORMED OUTSIDE THE OPERATING

ROOM?
Numerous studies17,54,55 have shown that tracheostomies can be safely performed outside of the operating
room, especially PCT.56 This requires additional training of the staff, but limited investment in additional
hospital resources.57 While it is possible to perform tracheostomies in the ICU, each patient should be
evaluated on a case-by-case basis to determine the ideal and safest location for the patient. While there
are limited studies58 that delineate variables that help a clinician determine for which patients
tracheostomy should be done in the ICU versus the operating room, there are a number of variables that
help in the decision process. Despite a few case reports to the contrary, the authors believe that for
patients59,60 who are morbidly obese, have thrombocytopenia or other coagulopathies, or currently are on
ECMO, tracheostomy should be done in the operating room. However, a redo tracheostomy, in our
opinion, is an ideal case to be done as a PCT at the bedside in the ICU.
CONCLUSIONS
A tracheostomy is a commonly performed procedure that has been around for thousands of years. It allows
for creation of an airway and removal of an endotracheal tube. While the procedure can be
straightforward, careful evaluation of patients to limit complications is necessary. When complications do
occur, they can range from minor to life-threatening that require immediate intervention. Both open and
percutaneous methods are well established and can be performed safely. Early tracheostomy in certain
subsets of patients may be beneficial, but this has not been shown to be a universal benefit in all
ventilator-dependent patients.
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71
Therapeutic Bronchoscopic Procedures
Daniel P. McCarthy ■ Douglas E. Wood
INTRODUCTION
In 1898 Gustav Killian reported his early experience with “direct bronchoscopy” and described removing
a pork bone from the right mainstem bronchus.1 At the time of publication, foreign body aspiration was
associated with chronic airway complications and a considerable mortality rate. Bronchoscopic removal
of foreign bodies provided an effective solution many years before thoracic surgeons were able to safely
perform pulmonary resections. Killian techniques were further refined by Chevalier Jackson, a prolific
and innovative clinician who accelerated the growth of bronchoscopy by conducting hands-on education
courses and writing the first textbook on the subject.
Therapeutic bronchoscopy remains an important component of the thoracic surgeon’s armamentarium
for the same reasons it was revolutionary in Gustav Killian’s time. Bronchoscopy provides expeditious,
minimally invasive treatment for airway pathologies that are otherwise difficult to access through
traditional surgical approaches. There are now a wide variety of bronchoscopic interventions available
to achieve several therapeutic objectives. This chapter will review the basic principles of therapeutic
bronchoscopy, and the technical conduct of the most common therapeutic interventions.
FLEXIBLE VERSUS RIGID BRONCHOSCOPY FOR THERAPEUTIC

INTERVENTIONS
Although certain interventions can only be conducted with one approach, many treatment objectives can
be accomplished with either a flexible or rigid bronchoscope. The endoscopic approach should be
tailored to a patient’s anatomy, pathology, and therapeutic goals. It is essential for the operator to
understand the advantages and limitations of both rigid and flexible bronchoscopy.
The rigidity of a bronchoscope affects both functionality and navigation. A rigid bronchoscope can be
used to shear off an endobronchial tumor, dilate a stenotic area, and achieve hemostasis by directed
pressure. Although stiffness enhances functionality, it limits navigability. The flexible bronchoscope is
better suited to evaluating airways distal to an obstruction and can be navigated into segmental bronchi.
The size of the working channel influences the versatility and efficiency of the bronchoscope. Rigid
bronchoscopes can be used with instruments and devices (e.g., suction catheters, large biopsy forceps,
silicone stents) that are larger than those that can be used with flexible endoscopes. Versatility is further
increased by introducing a flexible bronchoscope directly through the barrel of a rigid bronchoscope. In
addition, rigid bronchoscopes enhance efficiency by allowing the use of multiple instruments at once. For
example, a coagulation device and a suction catheter can be simultaneously deployed through the rigid
scope when dealing with airway bleeding. In contrast, the coagulation device must be removed from the
working channel of a flexible bronchoscope before in-line suctioning can be performed.
Finally, the rigid bronchoscope provides efficient establishment of a secure airway for anesthesia
management. Several ventilation strategies can be employed using the rigid scope itself as an artificial
airway. Flexible bronchoscopes are frequently used in combination with endotracheal or laryngeal mask
airways. Yet the flexible bronchoscope partially occludes the lumen of the artificial airway and the scope
and may need to be withdrawn frequently to allow ventilation.
Multiple considerations must be weighed when selecting between a flexible or rigid bronchoscope for
airway interventions. There are limited data directly comparing the risk profile of rigid versus flexible
bronchoscopy, and it is difficult to isolate the technical complications from the influence of the underlying
disease, anesthetic strategy, and therapeutic intervention. Rates of pulmonary complications
(pneumothorax, respiratory failure, bronchospasm) and bleeding appear to be less than 1% for both
methods.2,3 The risk of mechanical trauma to the teeth, oropharynx, and airway is presumably higher with
rigid bronchoscopy but remains low with proper technique. Given the low complication rates in
experienced hands, the performance characteristics of bronchoscopes are particularly important when
selecting a treatment plan. Flexible scopes are suitable for therapeutic procedures in low-risk patients
and can be conducted with minimal or no sedation. In patients at high risk for bleeding or airway
compromise, a rigid scope should be used because of more versatile instrumentation and the ability to
maintain secure access for ventilation and oxygenation. Many therapeutic interventions fall between these
two extremes. In the event of a major airway complication the rigid scope is the best option for salvage
therapy, assuming the operator is well skilled in its insertion and use.
The rigid bronchoscope is versatile, efficient, provides direct airway control, and can be used to
deploy a flexible bronchoscope if necessary. For these reasons, the rigid bronchoscope is the primary
approach for therapeutic airway intervention. Therefore, the thoracic surgeon must be thoroughly familiar
with the equipment, anesthetic implications, and technical conduct of rigid bronchoscopy.
PRINCIPLES OF RIGID BRONCHOSCOPY
EQUIPMENT
The rigid bronchoscope has three essential components: the barrel, proximal head, and visualization
elements (Fig. 71.1).
FIGURE 71.1 Rigid bronchoscopes, headpieces, and attachments. A: Rigid scopes are available in multiple diameters and
lengths. B: Assembled rigid bronchoscope. C: Close-up of proximal headpiece with a pneumostatic rubber cap, fiberoptic cable,
and anesthesia circuit connector. (Images from Dr. Daniel P. McCarthy.)
Adult and pediatric bronchoscope barrels vary in length (18.5 to 43 mm) and outer diameter (2 to 14
mm). Short barrels (e.g., 33 mm) can be used for tracheal interventions. Longer barrels (e.g., 43 mm)
provide access to the mainstem bronchi, bronchus intermedius, and the orifice of segmental bronchi. Long
barrels typically have side holes along their distal end to provide cross-ventilation to the contralateral
lung when the bronchoscope is advanced beyond the carina. Inner diameters are typically 1 to 3 mm less
than the outer diameter. Narrow barrels (e.g., <6.5 mm) are useful in pediatric interventions or in adults
with benign or malignant stenoses. The distal end of the barrel is beveled to allow the bronchoscope to
engage or navigate between structures (e.g., epiglottis, vocal cords, tumor).
The head of the modern bronchoscope provides multifunctional access to the central channel. The
proximal end of the main working channel is open, providing a direct line-of-sight through the barrel as
well as coaxial access for instruments. Side ports interface with the main channel without impairing
visualization, and are used for ventilation, illumination, and instrumentation. These ports are either
integrated directly into the barrel, or are located on a headpiece that attaches to the barrel. Fenestrated
adapters are available to pneumatically seal ports and/or instruments when necessary.
Finally, the bronchoscope has lighting and optical elements to enable visualization. Modern
bronchoscopes provide field illumination with either a fiber optic light guide along the working channel
or a proximal prismatic light deflector. Bronchoscopes that use a prismatic light deflector do not require
an integrated light guide, and therefore have a smooth, unobstructed central channel. Both options connect
externally to a high-intensity cold light source. Visualization of an illuminated airway can be achieved
directly through the open proximal end of the bronchoscope barrel. Better magnification and clarity can be
obtained with telescope systems introduced into the working channel or integrated into the barrel.
Telescopes are available with either a proximal viewing lens or more commonly a digital camera system,
and can be viewed at 0-, 30-, 45-, and 90-degree angles to visualize different airways.
ANESTHETIC CONSIDERATIONS
Therapeutic rigid bronchoscopy poses several challenges for anesthetic management. First, airway
pathology influences the likelihood of an airway emergency. A symptomatic central airway lesion can be
transformed into a critical airway obstruction by bronchospasm, secretions, clot, or muscle relaxation.
Standard salvage measures such as endotracheal intubation or emergent cricothyroidotomy may not be
useful. The location of the obstructing lesion will dictate the emergency airway plan, which may include
establishment of a surgical airway or initiation of extracorporeal life support. Second, the shared airway
creates several limitations. Certain interventions temporarily occlude the airway (e.g., balloon dilation)
or necessitate low fractions of inspired oxygen (e.g., laser therapy). The rigid bronchoscope has no cuff,
and substantial air leak can occur around the scope or out the proximal ports. Adequate tidal volumes may
not be achieved without converting to a closed ventilation system, which may not be feasible during
certain parts of the intervention. End-tidal carbon dioxide may be impossible to accurately measure. The
anesthesiologist and bronchoscopist must be in close communication to maintain safe and efficient control
of the shared airway.
Four general ventilation strategies are commonly used during rigid bronchoscopy: spontaneous,
intermittent, continuous, and jet ventilation. Spontaneous ventilation is favored for very high risk airways.
The patient is maintained under light anesthesia with either inhalational or intravenous agents. Respiratory
depression is minimized. Neuromuscular blockade is not used in an effort to avoid muscular relaxation
with resultant catastrophic collapse of a narrowed central airway. However, bronchoscope insertion can
be difficult without paralysis, and the light level of anesthesia increases the possibility of patient
awareness and physiologic response to noxious stimuli. Therefore, spontaneous ventilation is typically
converted to one of the remaining anesthetic strategies once a definitive airway is established.
Intermittent and continuous ventilation strategies involve delivering positive-pressure breaths through
the bronchoscope. The anesthesia circuit is connected directly to the bronchoscope. Although rarely
needed, the mouth may be packed with saline-soaked gauze to minimize leak around the bronchoscope.
Intermittent ventilation alternates between periods of apnea and ventilation. Oxygen may be supplied
passively through the bronchoscope or through a separate catheter placed through the vocal cords. The
partial pressure of arterial carbon dioxide gradually increases, typically at a rate of 4 to 6 mm Hg for the
first minute of apnea and 2 to 4 mm Hg for each subsequent minute. When significant hypercarbia or
hypoxia develops, the operation is paused, the central channel is capped, and ventilation is commenced.
This approach allows the surgeon periods of unrestricted activity, interrupted by pauses for ventilation. In
contrast, continuous ventilation delivers breaths throughout the procedure. Visualization and active
intervention are largely uninterrupted. Fenestrated caps are used to create a seal around the telescope and
any instruments introduced through the side ports. Continuous ventilation limits the development of
respiratory acidosis and hypoxemia; thus, brief periods of apnea required for certain parts of the
intervention are well tolerated. Total intravenous anesthesia may be preferable with continuous
ventilation due to the inevitable leak of anesthetic gas through the imperfectly closed circuit.
Jet ventilation allows continuous gas exchange without requiring a closed system. High pressure
oxygen is delivered via the side port of the bronchoscope through a small-bore catheter, creating a high-
velocity jet at the open proximal end of the bronchoscope. High-velocity flow generates a negative
pressure by the Venturi effect, which entrains room air and ultimately creates a positive-pressure head at
the tip of the bronchoscope. Expiration occurs with passive recoil between breaths. With low-frequency
or manual jet ventilation, the jet pressure is titrated to effect based on physiologic end points and visible
chest rise. A Sanders jet ventilator or similar device is used to adjust pressure and rate. The jet pressure
is maintained below 50 psi; pressure values of 25 to 30 psi at a respiratory rate of 10 to 20 breaths per
minute are typical. Alternatively, high-frequency jet ventilation uses rates of 10 to 15 Hz. This technique
delivers oxygen and entrained air at volumes less than dead space, resulting in minimal chest movement.
Gas exchange occurs by influencing airflow characteristics in small airways.
The choice of anesthetic strategy is ultimately dependent on institution, practitioner, and the nature of
the procedure. There are no data directly comparing the various ventilation strategies during rigid
bronchoscopy. Spontaneous ventilation is ideal for central airway obstruction but it is not suited for long,
stimulating procedures. Positive-pressure ventilation is familiar and easy to monitor, but requires a
semiclosed system and increased coordination between the anesthetist and bronchoscopist. Jet ventilation
works well for procedures that require an open system due to frequent instrument exchanges or specimen
retrieval. However, jet ventilation techniques are unfamiliar to many surgeons and anesthesiologists,
create noise and aerosolization of blood and secretions into the field and onto the operator, and there is a
risk of causing barotrauma in narrowed airways without adequate pressure monitoring.
PREPARATION
Procedural preparation begins at the initial patient encounter and continues through the preoperative time-
out. A complete history and physical is obtained. Attention is paid to symptoms of obstruction, aspiration,
risk factors for bleeding, and need for supplemental oxygen. Physical examination is used to predict
difficulty with mask ventilation and intubation (Table 71.1).4,5 Current and historical imaging studies are
evaluated to anatomically localize the pathology, identify nearby structures at risk (e.g., blood vessels
near a planned ablation site), and estimate the duration of obstruction. Relative contraindications to
therapeutic bronchoscopy include high risk for difficult intubation, severe coagulopathy, and extreme
problems with ventilation or oxygenation. Flexible bronchoscopy via laryngeal mask airway may be
considered as an alternative when patient anatomy makes rigid bronchoscopy hazardous or impossible.
Because many patients with airway pathology have limited life expectancy, it is important to discuss
quality of life and define the objectives of treatment.
The intervention plan is discussed in detail among the surgical, anesthesia, and nursing staff during the
preprocedure time-out. This discussion should include the planned procedure, anesthetic strategy,
adjunctive interventions, emergency airway plan, and potential for airway fire. Equipment for all planned
or potential interventions must be readily available.
TABLE 71.1 Predictors Useful for Preoperative Assessment of a Difficult Airway
Difficulty with mask ventilation Age >55
BMI >26
Edentulous
Bearded
History of snoring
Active airway obstruction
Difficulty with tracheal intubation Mallampati class >2
Interincisor distance <3 cm
Thyromental distance <3 fingerbreadths
Short, thick neck
Limited cervical spine extension/flexion
Overbite or inability to bring lower incisors anterior to upper incisors
POSITIONING AND TECHNIQUE

The patient is positioned supine on the operating room table, as close to the head of the bed as possible. A
transverse shoulder roll facilitates neck extension; alternatively, the head of the table can be dropped.
Although an extended position is optimal after the rigid scope has been inserted, the head up “sniffing
position” optimizes initial intubation by alignment of the axes of the oropharynx, larynx, and trachea for
visualization of the vocal cords. This position is achieved by placing a pillow or ramp of blankets to flex
the lower cervical spine, and extending the head at the atlanto-occipital joint. The oropharynx is
thoroughly evacuated using a Yankauer suction. A rubber mouthguard or saline-soaked gauze can be used
for dental protection. Induction agents and paralytics are given depending on the anesthetic strategy.
Equipment for urgent insertion of the rigid scope is made available prior to induction. At a minimum, this
equipment includes several bronchoscopes of different diameter, a video telescope, and large-bore
suction catheters. If necessary, diagnostic flexible bronchoscopy can be performed through a temporary
supraglottic airway to define anatomy prior to insertion of the rigid bronchoscope.
Direct intubation with the rigid bronchoscope proceeds with the surgeon standing at the head of the
bed. Intubation is performed by either looking down the working channel or with the video telescope
inserted into the bronchoscope and the video monitor directly in front of the surgeon. The thumb of the
nondominant hand is used to protect the teeth throughout intubation, and acts as both a fulcrum for rotation
and to help direct the scope. The bronchoscope is held in the dominant hand with the beveled tip
positioned anteriorly. The scope is inserted into the mouth at 90-degree angle to the floor. It is directed
along the posterior median groove of the tongue into the space behind the base of the tongue. Adequate
depth of insertion may be confirmed by identifying the uvula at the bottom aspect of the visualized field.
The scope is then translated anteriorly with the nondominant thumb to displace the base of the tongue and
bring the epiglottis into view. The tip of the scope is advanced under the epiglottis, and the epiglottis is
displaced anteriorly to expose the glottis. The vocal cords should be well visualized and open. The scope
is then rotated 90 degrees clockwise along the axis of the barrel, to align the tip of the bronchoscope with
the gap between the cords. The bronchoscope is advanced through the vocal cords in this rotated position
to minimize trauma. Once the scope is in the proximal trachea it is rotated counterclockwise to position
the beveled tip anteriorly. Ventilation can be initiated and the patient can now be taken out of the “sniffing
position” to enable better extension for the remainder of the case.
There are several alternatives to direct intubation with the rigid bronchoscope. Direct laryngoscopy
with a Miller blade can be used to rehearse bronchoscopic intubation in patients with difficult anatomy,
or with a Macintosh blade to enhance exposure while the bronchoscope is inserted across the cords,
analogous to endotracheal tube intubation. In patients who are already intubated, the bronchoscope can be
advanced next to the endotracheal tube until the vocal cords are visualized. The endotracheal tube is
withdrawn slowly until the tip emerges from the vocal cords, then the bronchoscope is inserted across the
cords under direct vision. This technique is also useful in patients who do not tolerate prolonged
separation from the ventilator circuit.
After successful intubation the airways are examined. The rigid bronchoscope can be used for
diagnostic evaluation of the trachea, mainstem bronchi, bronchus intermedius, and orifices of segmental
bronchi. A gentle corkscrew motion may be helpful to decrease friction when advancing the
bronchoscope. If significant resistance is met, patient positioning should be evaluated or the
bronchoscope should be downsized. In general, the surgeon should select the largest bronchoscope that
does not cause airway trauma. To navigate down the mainstem bronchi, the patient’s head is rotated in the
contralateral direction and the proximal end of the scope is moved to the contralateral side of the patient’s
mouth. Airway lesions are closely scrutinized. Their proximal, distal, and circumferential extents are
carefully measured and recorded. The scope is advanced beyond a lesion to a reliable anatomic landmark
such as the carina or the takeoff of a segmental bronchus. A ruler is used to measure the distance between
two fixed external positions (e.g., from the incisors to the side port of the bronchoscope). The scope is
then slowly withdrawn and repeat measurements are taken in a similar manner at the carina, distal lesion
margin, proximal lesion margin, and cricoid cartilage. Involvement of the membranous or cartilaginous
portions of the airway is noted. The operative dictation should include clear, objective, and reproducible
language describing the extent of disease in order to facilitate planning for a surgical resection and to
provide a baseline for comparison with future examinations. The flexible bronchoscope can be introduced
via the rigid scope to evaluate the segmental and subsegemental bronchi, or to evaluate and clear the
airways distal to a partial obstruction.
THERAPEUTIC TECHNIQUES FOR INTRALUMINAL DISEASE

Many pathologic processes obstruct airflow by affecting luminal diameter. The etiology of an airway
obstruction may be characterized as intraluminal, extrinsic, or mixed based on whether the pathologic
process is mucosal, within the wall, or external to the airway (Fig. 71.2). Several bronchoscopic
techniques are available to manage obstructed airways. The data supporting these techniques come almost
exclusively from case series; there are no randomized, head-to-head comparisons available to guide
treatment selection. In the absence of definitive evidence, it is important to understand the strengths and
limitations of the available bronchoscopic treatments for central airway obstruction to rationally select
therapy based on individual patient characteristics.
MECHANICAL DEBRIDEMENT
Mechanical debridement, or “core-out,” is a fundamental technique in the treatment of endobronchial
tumors. Several methods can be employed. First, the rigid bronchoscope itself can be used for
debridement. The tip of the scope is used to engage the base of a central airway tumor. The scope is then
advanced through the lesion, using a back-and-forth rotation if necessary. The translational motion is
directed parallel to the airway to avoid injury to the wall. This technique can rapidly recanalize the
airway and provides a large biopsy specimen for pathologic analysis. Second, airway tumors can be
debrided piecemeal using biopsy forceps. A variety of biopsy forceps are available for both rigid and
flexible bronchoscopy. Small tumor fragments may be removed through the working channel of a flexible
bronchoscope, but larger fragments require the scope to be withdrawn. With rigid bronchoscopy the tumor
fragments are pulled out through the working channel or aspirated with a large suction catheter after
sufficient biopsy material has been obtained. Third, a microdebrider can be used through a rigid
bronchoscope. This device is a rigid suction catheter with a small opening on the side of its distal end.
This opening exposes a rotating blade that is controlled by a foot pedal. Suction draws small amounts of
tissue into the catheter channel where the tissue is excised and evacuated. The microdebrider device
provides simultaneous suction and irrigation to maintain an unobstructed field.
FIGURE 71.2 Classification of airway pathology. Extrinsic disease affects airway patency by mechanical compression without
directly involving the tracheobronchial wall. Intraluminal disease causes obstruction but is largely confined to the mucosal layer.
Mixed lesions involve the entire airway wall, in addition to an extrinsic or intraluminal component. (From Cheng AM, Wood DE.
Chapter 2: Airway stenting. In: Mathiesen DJ, Morse C, eds. Master Techniques in Surgery: Thoracic Surgery: Lung
Resections, Bronchoplasty. Philadelphia, PA: Wolters Kluwer; 2014.)
Mechanical debridement has several advantages over other modalities. It is low cost and does not
require sophisticated instrumentation. The tissue effect is immediate and directly visible. In contrast, the
tissue effect of energy delivery therapies evolves over several days and penetrates to a variable depth
beyond the visible surface. The main drawback of mechanical debridement is the potential for bleeding.
Minor bleeding will often stop with directed pressure from the barrel of a rigid bronchoscope. Dilute
epinephrine may also be used. More serious bleeding can be treated with energy devices (e.g., laser,
electrocautery). Because of the potential for bleeding and the challenges of specimen retrieval, large
tumor debridement is best done with rigid bronchoscopy.
Electrocautery and Argon Plasma Coagulation

Electrocautery and argon plasma coagulation (APC) are methods of using electrical current to generate
thermal tissue effects. Modern electrosurgical generators offer different modes of current output, and by
modulating the voltage and duty cycle of current delivery these modes create either vaporization (cutting)
or desiccation (coagulation) of tissue.
A variety of electrocautery devices can be used during both flexible and rigid bronchoscopy.
Instruments include direct contact probes, knives, forceps, and snares. Electrocautery contact probes are
brought into direct contact with the tissue to achieve cauterization. Depending on power setting and mode,
contact probes create a sequence of tissue blanching, desiccation, and eventually carbonization with
increasing amount of energy delivery. Electrocautery probes with integrated suction capabilities are
available for rigid bronchoscopy. Because the depth of effect is limited and carbonized tissue does not
conduct electricity, superficially treated layers may need to be mechanically excised prior to treating
deeper tissue in large lesions. Electrocautery snares are useful in excising polypoid lesions. The snare
can be deployed around the stalk and tightened until there is circumferential contact. A combination of
sequential cautery activation and mechanical snare tightening will result in hemostatic transection of the
lesion. The cut mode of the electrosurgical generator is useful during snare polypectomy. Finally, the
electrosurgical knife can be used to incise stenoses or airway lesions. In contrast to the broad contact
probe, the electrosurgical knife is designed for a narrow point of tissue contact and maximum current
density. Using the knife in cut mode will result in limited thermal spread and thus precise tissue
vaporization, but is less effective in providing hemostasis.
APC is a noncontact electrosurgical modality best suited to coagulation and combined procedures, but
can be used for destruction of small, superficial lesions. Both flexible and rigid APC probes are
available. These probes contain an internal tungsten electrode and a channel for the delivery of ionized
argon gas. The argon gas acts as an electrical bridge that completes the circuit between the active
electrode, the patient, and the grounding pad. The argon plasma beam generates a large contact surface
area. The tissue effect is primarily coagulation to a depth of approximately 2 mm. APC is ideal for
achieving rapid hemostasis of broad areas, such as the resection bed that remains after a mechanical core-
out, for example. In order to treat thick lesions with APC, surface tissue layers must be mechanically
debrided to expose and coagulate deeper tissue.
Electrocautery and APC have both been shown to be safe and effective for use in the airway. In a
retrospective series of 94 patients undergoing 117 procedures for malignant and benign endobronchial
disease, electrocautery was successful in achieving endoscopic improvement in 94% of patients and
symptomatic improvement in 71% of patients, with a less than 1% rate of serious complications.6
However, the majority of these cases involved concomitant use of tissue excision (60%), stents (31%), or
balloon dilation (25%).
Endobronchial electrosurgery is attractive for several reasons; the system is low cost when compared
to alternatives, electrosurgical generators are already available at most hospitals, the instrumentation is
often reusable, and the modality is very familiar to surgeons. Finally, the breadth of instrumentation
available allows versatility in treating lesions in different locations.
Several limitations affect the utility of endobronchial electrosurgery. As with all thermal energy
systems, there is the potential for airway fire and thermal spread causing damage to nearby structures.
Direct contact probes have a tendency to generate carbonization on the superficial tissue and on the probe
itself. Theoretically, direct contact with the lesion may cause inadvertent bleeding. Although new
generator modes can be used to increase depth of penetration, these devices usually require at least some
degree of mechanical debridement to treat all but the smallest lesions.
Laser Therapy
The use of laser therapy for palliation of airway pathology was first described in 1972 by Strong and
Jako. Since that time, laser therapy has become a popular method for hemostatic debridement of benign or
malignant endobronchial tissue. Safe utilization of this modality requires the operator to be familiar with
the generation, tissue effect, and delivery of laser energy.
The biologic effect of laser energy is dependent on the characteristics of both the laser and the tissue.
Bronchoscopic laser therapy is dependent on basic physical principles.7 Laser light is monochromatic
(single wavelength), coherent (single phase), and collimated (single direction of travel). These properties
allow energy to be delivered with high power and precision. When laser light reaches tissue it is either
scattered, reflected, or absorbed. Although several biologic changes occur with light absorption, the
principal effect is the generation of thermal energy. At the microscopic level, thermal energy results in
protein denaturation, water vaporization, and cell wall rupture. These changes are responsible for the
macroscopic effects of coagulation and vaporization. Thermal effect varies based on the laser
wavelength, application time, pulsed versus continuous application, optical characteristics of the tissue,
and changes in these characteristics over time.
Bronchoscopic laser therapy uses thermal energy from lasers to coagulate or ablate endobronchial
tissue. Several types of lasers have been used for airway interventions. The carbon dioxide (CO2) laser
was used in the early series but is now largely of historical significance for airway interventions, due to
its limited depth of penetration and bulky delivery apparatus. The CO2 laser provides a shallow, precise
tissue effect. Neodymium:yttrium–aluminum–garnet (Nd:YAG) lasers are currently the most commonly
used and have relatively deeper tissue penetration. The Nd:YAG laser generates an infrared wavelength
outside the visible spectrum, so the system typically includes a visible laser to help with sighting. The
laser light is transmitted through a flexible quartz fiber to the tip of the instrument, and can be used with
either flexible or rigid bronchoscopy. Large central airway tumors can be photocoagulated by the laser
and then debrided mechanically. This approach is best performed with rigid bronchoscopy for efficient
specimen removal. Flexible bronchoscopy may be used to vaporize small, distal airway tumors or to
remove small amounts of endobronchial tissue prior to balloon dilation or metal stenting of tracheal
stenosis.
Attention to technique will enhance the safety and efficacy of endobronchial laser therapy. First, the tip
of the laser fiber is maintained at a variable distance from the tissue based on the desired effect.
Coagulation is favored with greater tip distance (5 to 10 mm) whereas vaporization and carbonization
occurs with shorter distances (3 to 4 mm). The tip should not be activated in direct contact with tissue
unless using a direct contact fiber, because carbonaceous material on the tip can be ignited. Second, the
fiber tip direction must be controlled to minimize collateral tissue damage. The laser is fired in pulses
starting from the circumference and working toward the center of the lesion. The laser should only be
activated when it is directed parallel to the airway. The thermal effect of the Nd:YAG laser can penetrate
to a depth of 10 mm. Thus, if the tip is directed toward the airway wall, there is increased risk of damage
to the airway itself, major vascular structures, the esophagus, and other nearby structures. Clear discharge
instructions should be given to the patient, as the thermal tissue effect continues to evolve over the next 48
to 96 hours and has the potential to cause delayed complication.
Third, device-appropriate adjustment of control functions alters energy delivery and thus tissue effect.
Coagulation is best achieved with longer applications at low power, while tissue vaporization requires
short, high-power volleys. It is important to respect the manufacturer recommendations unique to each
device. Finally, the technique should be modified to minimize the risk of airway fire. High temperatures
can cause ignition of combustible material in the airway such as plastic suction catheters, silicone stents,
and even the flexible bronchoscope itself. Therefore, the oxygen fraction should be maintained as close to
30% as possible, and should never exceed 50%. The laser fiber must not be activated closer than 5 mm to
the tip of the flexible bronchoscope, and ablation should be performed well away from the endotracheal
tube or other combustible items including silicone and covered metal stents.
Multiple retrospective series document the safety and efficacy of endobronchial laser therapy in the
treatment of benign and malignant disease. The best studied indication for laser therapy is in the palliation
of malignant central airway obstruction, where large retrospective series have documented >90% rates of
increased luminal patency following laser treatment.8
Cryotherapy
Cryotechniques use probes with extremely cold temperatures to generate clinical effects. The cryotherapy
systems consists of a cryogen tank (e.g., liquid nitrogen or nitrous oxide), a control console, and a
cryoprobe. The coolant is stored at room temperature under very high pressure. As the cryogen reaches
atmospheric pressure at the probe tip, it expands and through the Joule–Thomson effect results in cooling
of the cryoprobe to a temperature of −40°C or less. When the cryoprobe is placed into contact with tissue,
it results in rapid freezing causing extracellular and intracellular ice formation. These ice crystals cause
damage to intracellular organelles, cellular dehydration, and downstream effects resulting in protein
damage. The direct effect is cell death. There is also an indirect effect through changes in
microcirculation such as vasoconstriction, endothelial cell injury, and formation of microthrombi. The
vascular effect can extend to tissue beyond the region of freezing. After passive or active rewarming, an
additional cooling cycle can be applied. The tissue effect varies based on the temperature, rate of cooling,
and intrinsic tissue characteristics. Hypervascular, well-hydrated tumor tissue is cryosensitive. The
connective tissue and cartilaginous components of the airway are relatively insensitive to cryodestruction
due to lower water content. It is important to note that the tissue effect of cryoablation is not immediate
with tissue necrosis developing over several days.
Cryotherapy can be used for destruction of endobronchial tissue. Probes are available for both flexible
and rigid bronchoscopy. The probe is extended far enough that the tip of the bronchoscope will not be
frozen. The side or tip of the probe can be applied to the surface of a lesion, or the tip of the probe can be
embedded inside the lesion, to create different geometries of tissue effect. The target tissue is traditionally
treated with a series of three freeze–thaw cycles. The probe is activated for approximately 30 to 60
seconds during the initial cycle. Shorter activation times are used with nitrous oxide and with subsequent
cycles. Some probes have impedance monitors that signal when to transition between freezing and
thawing. In the absence of impedance monitoring, freezing is continued until the tissue ice halo stops
growing, and thawing is continued until just before the probe releases from the tissue. Some rigid
cryoprobes are designed for active rewarming, and thus reduce the treatment time. Greater tissue
destruction is obtained by increasing the number of freeze–thaw cycles; prolonging the freezing length
does not increase destruction. Cryoablation has been described to induce tissue necrosis to a depth of
approximately 3 mm. Multiple applications at distances of 5 to 6 mm away from each other are necessary
for complete ablation of larger lesions.
The unique attributes of cryotherapy account for its relative strengths and weaknesses. Cryotherapy
poses no risk of airway fire and is therefore useful in patients who will not tolerate a reduction in
inspired oxygen below 50%. Because tissue sticks to the active cryoprobe, a phenomenon known as
cryoadhesion, the cryoprobe can be used to remove tissue, blood clot, and even foreign bodies from the
airway. Finally cryotherapy offers the theoretical advantage of minimizing destruction to the cryoresistant
tissue elements of the tracheobronchial tree. Nevertheless, cryotherapy has several major limitations
related to the delayed tissue effect. Traditional cryotherapy does not result in immediate relief of airway
obstruction and is not suitable for patients requiring immediate symptomatic relief. Repeat bronchoscopy
is required 5 to 10 days after cryoablation to remove necrotic tissue that has not been expectorated.
Finally, the gradual development of tissue necrosis may result in delayed hemoptysis.
Cryorecanalization techniques have been described as a way to minimize these limitations.9 The
cryoprobe is inserted directly into the tumor tissue and activated. Using the effect of cryoadhesion, the
probe is then forcefully pulled to dislodge the ablated tissue and the probe is withdrawn from the airway
while the tissue is still adherent. Reports of cryorecanalization have suggested successful restoration of
luminal patency in 91% of patients, with a 12% rate of mild or moderate bleeding.10
Photodynamic Therapy
Photodynamic therapy (PDT) uses a combination of light and a photosensitizing agent to treat airway
tumors. Treatment begins with systemic administration of a photosensitizer such as Photofrin (Pinnacle
Biologics, Chicago, IL), a commercially available porfimer sodium. This agent is a derivative of
hematoporphyrin with two key properties: it preferentially accumulates in tumor tissue, and can produce
singlet oxygen radicals when excited by light. Activated Photofrin begins a cascade of events that
ultimately result in tumor destruction. Singlet oxygen, either directly or through the creation of other
reactive oxygen species, triggers apoptosis and cell death. Activated Photofrin also causes small vessel
thrombosis and subsequent ischemic necrosis. The effects of PDT also may induce tumor-specific
cytotoxic immunity.
The process of bronchoscopic PDT occurs over several days. First, Photofrin is injected systemically
at a dose of 2 mg/kg over 3 to 5 minutes. Peak uptake in tumor cells occurs at approximately 48 hours, and
therapeutic bronchoscopy is scheduled for optimum effect. PDT is performed with the bronchoscope
using a diffuser fiber to deliver light at a wavelength of 630 nm, optimized for interaction with Photofrin.
The fiber is positioned adjacent to or imbedded within the airway tumor. Long tumors may require
several cycles of activation. The diffuser fiber can be adjusted to deliver a specific dose of light over a
specific time interval (usually no more than 500 seconds) depending on the location of the tumor. While
200 J/cm is the FDA recommended dose for bronchoscopic PDT, lower doses (100 to 200 J/cm) have
been used in lobar and higher doses (300 J/cm) in tracheal disease. The tumor undergoes necrosis over
the next 48 hours, and therefore a repeat bronchoscopy is typically performed to debride devitalized
tissue. A second light application can be performed at that time without redosing the photosensitizer.
PDT is safe and effective in carefully selected patients, but several limitations prevent wider adoption.
Efficacy has been demonstrated in the treatment of superficial endoluminal tumor and selected cases of
malignant obstruction. PDT may also offer more durable symptom relief compared to other ablative
modalities. However, PDT is not appropriate in patients who require immediate relief of airway
symptoms as induced tissue swelling may actually worsen symptoms or lead to critical airway obstruction
in the first 48 hours after therapy. Furthermore, PDT is inappropriate for patients who are unable or
unwilling to avoid sun exposure. Because Photofrin also builds up in the skin, patients are at risk of
significant skin damage from exposure to sunlight for up to 6 weeks after treatment. For some patients
with limited life-expectancy, this restriction is not aligned with their goals of care. Finally, PDT is
expensive. The photosensitizer alone costs several thousand dollars per dose.
THERAPEUTIC TECHNIQUES FOR MIXED AND EXTRINSIC DISEASE
Ablative therapies alone are not appropriate for disease processes involving the airway wall or located
outside the airway entirely. These processes may affect the tracheobronchial wall through tumor
extension, fibrosis, fistulization, extrinsic compression, and loss of mechanical integrity resulting in
perforation or dynamic airway collapse. The goal of bronchoscopic therapy is re-establishment of airway
patency through mechanical expansion and structural support.
AIRWAY DILATION
Bronchoscopic dilation is indicated for the treatment of benign central airway stenoses that are not
amenable to surgical reconstruction, or to temporize symptoms from a stenotic lesion until more definitive
management can be employed. Stenosis is the end result of a deranged cycle of airway damage,
inflammation, and generation of fibrotic scar. This process involves the airway wall itself, thus removal
of intraluminal scar alone is ineffective. Repeat dilations are often needed until the airway stabilizes at a
greater caliber or the inciting pathology resolves. Stenoses can be characterized in various ways to
predict the likelihood of successful dilation. Concentric stenoses of the proximal airway may be
pretreated by creating precise cuts in the anterior portion of the scar using either a laser or electrocautery
knife.11 Asymmetric stenosis from prior tracheostomies are often relatively resistant to dilation, as the
force of dilation is transferred preferentially to the more compliant membranous airway rather than the
fibrotic segment anteriorly. Risk factors for failure of simple dilation include stenosis length greater than
1 cm, short symptom-free interval after prior dilation, active inflammation, cartilaginous destruction, or
associated malignancy.
Dilation can be accomplished through a variety of rigid and flexible techniques. Rigid bronchoscopes
can be used to directly dilate a stenosis by passing sequentially larger scopes through the stenosis using a
corkscrew motion. Bougie dilators can be passed through the rigid bronchoscope and advanced across the
stenosis in a similar fashion.
Flexible or rigid bronchoscopy can also be used to deploy balloon dilators. Commercially available
dilation balloons come in a variety of diameters and lengths. Balloons should be long enough to extend
beyond the stenosis and prevent slippage with inflation, while minimizing the risk of damage to a smaller
caliber distal airway. Balloon diameter should not significantly exceed the diameter of the airway.
Application of progressively larger balloons may be necessary when dilating a tight stenosis. Although
balloon dilation can be performed without general anesthesia, a laryngeal mask airway with deep
sedation is often useful due to procedural length and discomfort. Most balloon catheters can be advanced
directly through a 2 mm or larger working channel. Prior to inserting the balloon, saline and air are
aspirated through the flexible bronchoscope to clear the working channel, so visualization is not impaired
by secretions when the balloon is advanced through the channel. When dealing with a tight stenosis, or if
anticipating the need for large balloons, a guidewire can be directed across the stenosis. The
bronchoscope is then withdrawn and replaced alongside the guidewire, which is used as a rail for
positioning of the balloon. The center of the balloon is positioned across the stenosis under direct
visualization or fluoroscopic guidance, then inflated to a predetermined pressure based on manufacturer
recommendations. Inflation is repeated as necessary with the same or larger balloons. After dilation the
airway is inspected for lacerations or bleeding, and the distal airway is cleared of retained secretions.
There are theoretical differences between dilation techniques. Dilation with the rigid bronchoscope
allows for continuous ventilation of distal airways. In contrast, bougie and balloon dilation involve a
period of total airway obstruction. There may be less mucosal trauma and inflammation with gradual,
sequential dilation when compared to balloon dilation. However, there are no direct comparisons of
different techniques, and thus procedure selection is based on institutional preference and individual
patient considerations.
Airway dilation results in safe, immediate palliation for select patients, but has limited long-term
efficacy. The most common complication is airway laceration, which is typically superficial and only
rarely associated with full thickness airway disruption. While nearly all patients experience immediate
symptom relief, a minority of patients achieve a durable response from a single dilation session.12,13
Patients requiring multiple dilations are more likely to require additional therapies, such as stenting or
endobronchial tissue ablation. The duration of symptom palliation, and the type of adjunctive intervention
needed, varies based on underlying pathology. Improved patient selection may facilitate better long-term
outcomes through early identification of patients needing multimodal treatment.
Airway Stenting
Stenting is an important primary or adjunctive therapy in pathologies affecting the mechanical integrity of
the airways. Dynamic collapse from malacic conditions and pure extrinsic airway compression are both
readily treated with stenting. Stents are a particularly important element in the management of malignancy
with mixed intraluminal and extraluminal components, or intraluminal tumor with a significant likelihood
of early recurrence. Benign stenoses associated with cartilaginous destruction can be managed with a
combination of dilation and stenting, although only when more definitive surgical correction is
contraindicated. Finally, covered stents may be used for palliation of tracheoesophageal or
bronchopleural fistulae.
Stents may be broadly categorized as either silicone stents, expandable metal stents, or hybrids (Figs.
71.3 and 71.4). Silicone stents are solid cylinders, with various features (studs, flanges, etc.) that help
prevent migration. They are available in multiple configurations which reflects the diversity of uses.
Straight stents are used in the trachea and mainstem bronchi. Carinal disease can be managed with Y-
stents, while subglottic stenosis may be treated with T-tubes that include an external limb extending out a
tracheal stoma. Silicone stents are resistant to ingrowth of malignant or granulation tissue. They can be
repositioned or removed with relative ease, but are also more susceptible to migration. They also impair
mucociliary clearance and can cause significant secretion build-up. Silicone stents require rigid
bronchoscopy for deployment. In contrast, expandable metal stents can be placed with a combination of
flexible bronchoscopy and fluoroscopy. These stents are either self-expanding or balloon deployed, and
conform to irregular tracheobronchial anatomy. Uncovered metal stents are incorporated into nearby
tissue, rarely migrate, maintain mucociliary clearance, and do not obstruct segmental bronchi. Yet, they
are generally unremovable and frequently complicated by tissue ingrowth that leads to secondary stent
obstruction. Uncovered expandable metal stents have been largely abandoned, are contraindicated in
benign disease, and have only limited application in terminally ill patients with malignant stenosis.
Partially covered metal stents prevent tumor from invading through the stent interstices but, are fixed in
place by tissue ingrowth at their proximal and distal ends. Finally, hybrid stents feature elements from
both categories. The Polyflex airway stent (Boston Scientific, Marlborough, MA) is a self-expanding
plastic stent. The Aero stent (Merit Medical Endotek, South Jordan, UT) is composed of a nitinol metal
skeleton with complete polyurethane covering. The Dynamic (Y) stent (Boston Scientific, Marlborough,
MA) is a silicone Y-stent with metal strut reinforcement that mimics the cartilaginous trachea and a soft
silicone posterior wall. These third- and fourth-generation stents are now used almost exclusively when
stenting is indicated, as they combine the ease of delivery of the expandable metal stents with the ability
to adjust, remove, and avoid tissue/tumor ingrowth noted with solid silicon stents.
Stent selection depends on anatomic factors including the diameter and contour of the airway lumen, as
well as location of disease along the tracheobronchial tree. Metal and expandable hybrid stents will
conform to a complex, irregular malignant obstruction, whereas silicone stents may remain partially
folded if they cannot achieve their natural shape. Hybrid stents may also be preferable when stenting
small diameter airways, since their lower profile causes minimal reduction in lumen size compared to
solid silicone stents. Anatomic location in the airway dictates the need for straight, Y or T stents. These
complex geometries reduce the rate of silicone stent migration. In general, stenting is only feasible for
central airways (trachea, mainstem bronchi, bronchus intermedius) as lobar orifices are too short to allow
adequate stent seating, and segments are too small to achieve reliable and durable patency. The one
occasional exception is the middle lobe bronchus which is longer and potentially suitable for stenting, if
no surgical option is available for more definitive management.
FIGURE 71.3 Silicone stents. Molded silicone rubber stents are available in a variety of shapes and sizes. A: Hood stents. B:
DUMON stents. (From Cheng, Wood DE. Chapter 2: Airway stenting. In: Mathiesen DJ, Morse C, eds. Master Techniques in
Surgery: Thoracic Surgery: Lung Resections, Bronchoplasty. Philadelphia, PA: Wolters Kluwer; 2014.)
FIGURE 71.4 Expandable stents. Expandable stents may be uncovered (A), partially covered (B), or fully covered (C and D).
The degree of coverage affects the rate of tissue ingrowth, which in turn influences migration rates and the ease of repositioning
or removal. (From Cheng, Wood DE. Chapter 2: Airway stenting. In: Mathiesen DJ, Morse C, eds. Master Techniques in
Surgery: Thoracic Surgery: Lung Resections, Bronchoplasty. Philadelphia, PA: Wolters Kluwer; 2014.)
The most important determinant of stent selection is underlying pathology. Benign conditions are
treated with tube stents whenever possible to allow for stent removal or repositioning. Similarly, tube
stents are preferable when endoscopic therapy is used to stabilize an obstructed airway prior to definitive
surgery. Covered stents or tube stents are also used when treating airway fistulas. Central airway
obstruction from extrinsic malignancy is often managed with metal stents due to their increased radial
force. Uncovered metal stents are classically reserved for palliation of advanced malignancy, since
removal of these stents can be hazardous due to stent fracture.
The stent procedure begins with a thorough airway suctioning and assessment. The location and
characteristics of the lesion are noted. Adjunctive procedures, such as dilation or debridement of
intraluminal tissue, are performed first. Assessments are then made to guide stent sizing. Tracheal lesions
can often be stented to allow for 1 cm of proximal and distal length beyond the lesion to improve stent
fixation. Bronchial stents are typically sized to the length of the lesion to avoid obstructing branch
segments. The diameter can be estimated using the diameter of the bronchoscope as a reference, or with
commercially available stent sizers. If necessary, radiopaque fiducials are precisely positioned on the
chest to mark the lesion for fluoroscopic stent deployment, and a 0.035- or 0.038-in guidewire is
advanced well beyond the distal extent of the lesion.
Metal stents can be placed using either rigid or flexible bronchoscopy in accordance to the
manufacturer’s unique instructions for use. A variety of proprietary delivery systems are incorporated into
the stent system. In general, these delivery systems involve either a sheath that is withdrawn over a self-
expanding stent, or a balloon inflation mechanism. Because these systems can be delivered over a wire,
rigid bronchoscopy is not absolutely necessary. The stents may be molded postdeployment by additional
balloon dilations to address uneven stent deployment around an irregular lesion.
Silicone stent deployment is more challenging due to their bulk and inability to fully collapse. Three
general techniques are often described. First, a DUMON-stent specific system is commercially available.
This system features the ability to dilate, size, and deploy stents using a mechanism of telescoping tubes
and a plunger. Second, the rigid bronchoscope can be used to directly deploy the stent. One option
involves mounting both the stent and either an endotracheal tube or chest tube on the outside of a rigid
scope. The entire assembly is inserted through the vocal cords and across the lesion. The bronchoscope is
slowly withdrawn while holding the endotracheal tube in a fixed position, thus keeping the stent from
migrating as the bronchoscope is removed. Once the bronchoscope has been separated from the stent, the
endotracheal tube and scope are removed, the bronchoscope is reinserted, and the final position of the
stent is adjusted with grasping forceps. Alternatively, the stent can be lubricated, folded, and placed
inside the lumen of the bronchoscope after positioning the tip of the scope at the distal end of the stenosis.
Grasping forceps or a small chest tube can be used to advance the stent through the scope and into
position while the bronchoscope is withdrawn. This technique is useful for stents smaller than 14 mm.
The third and final technique uses a grasper to place a folded stent directly into the proximal trachea.
Direct laryngoscopy is used to visualize the glottis and allow careful placement of the stent beyond the
vocal cords. The rigid bronchoscope is subsequently inserted and grasping forceps are used to unfold and
position the stent. This technique is particularly important for placing silicone stents with diameter >14
mm or complex geometry that makes the stent too bulky for insertion through the bronchoscope. The direct
insertion technique may minimize vocal cord trauma compared to the over-the-scope technique due to the
reduced profile of the folded stent.
Airway stenting is a safe and effective method of palliating central airway obstruction. A prospective
single-institution database review demonstrated a 94% rate of symptomatic palliation in the setting of
benign or malignant central airway obstruction.14 Multiple endoscopic interventions were required to
maintain palliation in 41% of patients.
Brachytherapy
Endobronchial brachytherapy uses localized ionizing radiation for airway palliation. Transnasal flexible
bronchoscopy is used to place polyethylene afterloading catheters at the site of disease. The catheters are
advanced either through the working channel or alongside the bronchoscope. To ensure accurate
placement, the airway tumor must be clearly visible and the distal airway must be sufficiently patent to
advance the catheter 2 cm beyond the lesion. Positioning is confirmed bronchoscopically and
fluoroscopically before the catheter is secured to the nares. The afterloading catheters are loaded with
radio-opaque dummy seeds for radiation treatment planning. The treatment plan specifies the total dose,
fractionation, and radiation field. At each treatment session, radioactive seeds (typically iridium-192) are
loaded into the catheters for a predetermined duration. Endobronchial brachytherapy typically utilizes
high-dose rate (HDR) protocols at 10 to 12 Gy/hr, fractions of 3 to 10 Gy, and a total dose of 5 to 40 Gy.
At the end of each treatment session, the catheter is removed and the patient can be discharged home.
Contemporary HDR regimens usually require 2 to 4 fractions given at 1- to 2-week intervals.
Tissues within the treatment field are exposed to ionizing radiation, inducing DNA damage that leads
to apoptosis of tumor cells. Healthy cells are generally more effective at repairing the DNA damage and
are thus relatively spared. While the depth of the treatment field is dependent on multiple factors, it is
often on the range of a 1 cm radius around the catheter. This depth of penetration, combined with the
differential effect on normal tissue, makes brachytherapy a reasonable treatment for extraluminal tumors
extending through the tracheobronchial wall.
Endobronchial brachytherapy can be a useful method of palliating advanced, surgically unresectable
cancers involving the airway. Brachytherapy can be very effective in managing hemoptysis, and to a
lesser extent can mitigate obstructive symptoms including dyspnea and pneumonia.15 Case reports have
also described the successful use of brachytherapy to decrease recurrent granulation tissue in benign
airways stenoses.16
The conceptual benefits of endobronchial brachytherapy are eclipsed by logistical and therapeutic
limitations. First, the therapy is labor intensive. It requires multiple sessions, each time involving
bronchoscopic catheter placement, treatment planning, and radiation delivery. Second, the delayed
treatment effect means that brachytherapy for obstructing airway tumors is best combined with other
methods for rapid symptom improvement. Third, brachytherapy is associated with infrequent but serious
complications including massive hemoptysis and fistulization. Finally, the effective radiation is only
achieved in a 1 to 2 cm diameter radius from the catheter and radiation beads, so brachytherapy is not
effective for bulky tumors with significant extraluminal disease. In the absence of comparative advantages
over other methods of airway palliation, it is unlikely that endobronchial brachytherapy will become a
first-line treatment of endobronchial malignancy.
REFERENCES
1. Panchabhai TS, Mehta AC. Historical perspectives of bronchoscopy. Connecting the dots. Ann Am Thorac Soc 2015;12(5):631–641.
2. Lukomsky GI, Ovchinnikov AA, Bilal A. Complications of bronchoscopy: comparison of rigid bronchoscopy under general anesthesia
and flexible fiberoptic bronchoscopy under topical anesthesia. Chest 1981;79(3):316–321.
3. Stahl DL, Richard KM, Papadimos TJ. Complications of bronchoscopy: a concise synopsis. Int J Crit Illn Inj Sci 2015;5(3):189–195.
4. American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Practice guidelines for management of the
difficult airway: an updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway.
Anesthesiology 2003;98(5):1269–1277.
5. Langeron O, Masso E, Huraux C, et al. Prediction of difficult mask ventilation. Anesthesiology 2000;92(5):1229–1236.
6. Wahidi MM, Unroe MA, Adlakha N, et al. The use of electrocautery as the primary ablation modality for malignant and benign airway
obstruction. J Thorac Oncol 2011;6(9):1516–1520.
7. van de Berg NJ, van den Dobbelsteen JJ, Jansen FW, et al. Energetic soft-tissue treatment technologies: an overview of procedural
fundamentals and safety factors. Surg Endosc 2013;27(9):3085–3099.
8. Cavaliere S, Foccoli P, Farina PL. Nd:YAG laser bronchoscopy. A five-year experience with 1,396 applications in 1,000 patients. Chest
1988;94(1):15–21.
9. Hetzel M, Hetzel J, Schumann C, et al. Cryorecanalization: a new approach for the immediate management of acute airway obstruction.
J Thorac Cardiovasc Surg 2004;127(5):1427–1431.
10. Schumann C, Hetzel M, Babiak AJ, et al. Endobronchial tumor debulking with a flexible cryoprobe for immediate treatment of malignant
stenosis. J Thorac Cardiovasc Surg 2010;139(4):997–1000.
11. Mehta AC, Lee FY, Cordasco EM, et al. Concentric tracheal and subglottic stenosis. Management using the Nd-YAG laser for mucosal
sparing followed by gentle dilatation. Chest 1993;104(3):673–677.
12. Sheski FD, Mathur PN. Long-term results of fiberoptic bronchoscopic balloon dilation in the management of benign tracheobronchial
stenosis. Chest 1998;114(3):796–800.
13. Shitrit D, Kuchuk M, Zismanov V, et al. Bronchoscopic balloon dilatation of tracheobronchial stenosis: long-term follow-up. Eur J
14. Wood DE, Liu YH, Vallières E, et al. Airway stenting for malignant and benign tracheobronchial stenosis. Ann Thorac Surg
2003;76(1):167–172; discussion 173–174.
15. de Aquino Gorayeb MM, Gregório MG, de Oliveira EQ, et al. High-dose-rate brachytherapy in symptom palliation due to malignant
endobronchial obstruction: a quantitative assessment. Brachytherapy 2013;12(5):471–478.
16. Halkos ME, Godette KD, Lawrence EC, et al. High dose rate brachytherapy in the management of lung transplant airway stenosis. Ann
Thorac Surg 2003;76(2):381–384.
72
Surgical Anatomy of the Trachea and
Techniques of Resection and
Reconstruction
Pierre Delaere ■ Paul De Leyn
This chapter is a revision, adaptation, and update on the original chapter written by Hermes C. Grillo,
Douglas J. Mathisen, and Moishe Liberman.
Nonmalignant and malignant obstruction of the tracheal airway causes significant morbidity and mortality.
A common cause of tracheal stenosis includes damage from endotracheal and tracheostomy tubes. With
increased use of artificial airways, benign and iatrogenic complications are increasing. Minor tracheal
lesions may be treated endoscopically, whereas more extensive lesions usually require more invasive
procedures to maintain the airway lumen. A tracheal stenosis that is less than 5 cm in length can be
resected with end-to-end anastomosis.1 Longer tracheal lesions can be treated in a palliative way by
placement of a stent to secure airway lumen patency.2 The management of tracheal defects is an evolving
field. Tracheal transplantation and tracheal regeneration may bring major treatment advances to cases
with restenosis after segmental resection and in long-segment tracheal involvement.
ANATOMY
The adult human trachea averages 11.8 cm in length (range, 10 to 13 cm) from the infracricoid level to the
top of the carinal spur. Typically, 18 to 22 cartilaginous rings occur within this length, approximately two
rings per centimeter. In an adult male, the internal diameter of the trachea measures about 2.3 cm laterally
and 1.8 cm anteroposteriorly. These measurements vary roughly in proportion to the size of the individual
and are smaller in women.
The surgeon usually visualizes the trachea as he or she learned to see it in the thyroidectomy position,
with the neck extended, as a structure that is one-half cervical and one-half thoracic. However, the trachea
becomes almost entirely mediastinal when the neck is flexed because the cricoid cartilage drops to the
level of the thoracic inlet. This may be the permanent position in aged people secondary to cervical
kyphosis. When viewed laterally in the upright individual, the trachea courses backward and downward
at an angle from a nearly subcutaneous position at the infracricoid level to rest against the esophagus and
vertebral column at the carina. Anteriorly, the thyroid isthmus passes over the trachea in the region of the
second tracheal ring. The lateral lobes of the thyroid are closely applied to the trachea, and a common
blood supply is obtained from the branches of the inferior thyroid artery. Lying in the groove between
trachea and esophagus are the recurrent laryngeal nerves, coursing from beneath the arch of the aorta on
the left side and therefore having a longer course in proximity to the trachea than on the right side, where
the nerve loops around the subclavian artery and then approaches the groove. These nerves enter the
larynx between the cricoid and thyroid cartilages just anterior to the inferior cornu of the thyroid cartilage
(Fig. 72.1).
The anterior pretracheal plane may be easily developed through a cervical approach. The innominate
vein lies anteriorly, away from the trachea. The innominate artery, however, crosses over the midtrachea
obliquely from its point of origin from the aortic arch to the right side of the neck. In children, the
innominate artery is higher and is encountered in the lower part of the neck. In some adults, the artery is
unusually high and crosses the trachea at the base of the neck when slight cervical extension is present. At
the level of the carina, the left main bronchus passes beneath the aortic arch and the right beneath the
azygos vein. The pulmonary artery lies just in front of the carina. On either side of the trachea lies
fibrofatty tissue containing lymph node chains and a large packet of nodes lies just beneath the carina.
The course of the trachea from the anterior cervical position to the posterior mediastinal position with
close relationships to major vascular structures makes access to the entire trachea through a single
incision difficult. Grillo3 emphasized that these anatomic relationships demand precise definition of the
extent and nature of tracheal lesions when surgical procedures are being planned.
The cartilaginous rings give the human trachea its lateral rigidity. They extend about two-thirds of the
circumference. The posterior wall is membranous. The trachea is lined with respiratory mucosa, which is
tightly applied to the inner surface of the cartilages. The normal epithelium is columnar and ciliated. Cilia
on the tracheal epithelium sweep particles trapped by mucus upward in a synchronized wave-like fashion.
In habitual smokers and others with chronic throat irritation, the cilia may be damaged or destroyed and
squamous metaplasia may occur. Secretions may be cleared successfully by coughing, despite the
presence of metaplasias. This observation, plus the demonstrated feasibility of cutaneous reconstructions
and intraluminal stents, makes it clear that ciliated epithelium, although highly desirable, is not essential
for tracheal reconstruction.
FIGURE 72.1 Topographical anatomy of the trachea. A: Frontal view. B: Sagittal view. The adult trachea averages between
10 and 13 cm in length from the lower border of the cricoid cartilage to the tip of the carinal spur.
Considerable contraction of the muscular membranous wall can occur with coughing and spasm, the
tips of the cartilages being drawn inward. Calcification of the rings is seen most often with advancing
age. Local trauma or operation may also lead to calcification. The normal trachea slides easily in its layer
of fibrofatty areolar tissue from neck to mediastinum.
The blood supply of the human trachea is segmental, largely shared with the esophagus and derived
principally from multiple branches of the inferior thyroid artery above and the bronchial arteries below.
The arteries approach laterally, and fine branches pass anteriorly to the trachea and posteriorly to the
esophagus (Fig. 72.2). Miura and Grillo4 demonstrated that the inferior thyroid artery nourishes the upper
trachea, usually through a pattern of three principal branches with fine subdivisions and extremely fine
collateral vessels but with many variations, as noted by Salassa and colleagues.5 The bronchial vessels
nourish the lower trachea, carina, and mainstem bronchi. Sometimes the internal mammary artery
contributes. Excessive circumferential dissection with division of the lateral pedicles during an operative
procedure can easily devascularize the trachea.
WOUND HEALING OF THE MUCOSAL LINING
REGENERATION VERSUS SECONDARY HEALING

The relative contribution of tissue regeneration versus scarring in the healing of the airway mucosal lining
depends on the extent of injury inflicted. A superficial epithelial wound can heal by way of regeneration
of the surface epithelium (Fig. 72.3).6 Indeed tissues with a high proliferative capacity, such as airway
tract epithelia, renew themselves continuously and, after injury, can regenerate above the basal membrane
as long as the stem cells in these tissues have not been destroyed. The repair and regeneration process
occurs through several mechanisms, including basal cell spreading and migration, followed by
proliferation and differentiation of epithelial cells.
SECONDARY HEALING
If a tissue injury is severe and involves damage of both epithelial cells and the submucosal layer, healing
cannot be accomplished by regeneration alone. Under these conditions, the main healing process is repair
by deposition of collagen, causing the formation of a scar. The healing pattern of circumferential full-
thickness mucosal defects is illustrated in Figure 72.4.
Future therapies should aim to promote regeneration and reduce scar tissue formation when dealing
with full-thickness mucosal tracheal defects. Exploration of the potential use of stem cells for true
regenerative healing is ongoing. The present challenge for regenerative medicine is to overcome the
barriers to regeneration of the mucosal and epithelial lining in full-thickness epithelial defects. However,
regeneration of full-thickness mucosal defects is not yet possible.
METHODS OF RECONSTRUCTION OF THE TRACHEA

Functionally, the trachea serves principally as a conduit for ventilation. Viewed in this way, it would
seem to be an ideal structure for replacement or reconstruction when involved by surgical disease.
Anatomically, however, it presents several unique features that partially account for the difficulty in its
surgical management. These features are its unpaired nature, unique structural rigidity, short length,
relative lack of longitudinal elasticity, proximity to major cardiovascular structures, and segmental blood
supply.
FIGURE 72.2 Schematic view of the tracheal blood supply. The rich vascular network beneath the endotracheal mucosa
originates from the transverse intercartilaginous arteries derived from the lateral longitudinal anastomosis.
FIGURE 72.3 Regeneration of the respiratory epithelium. The basement membrane of the mucosal layer supports a
pseudostratified epithelium, the surface layer of which is columnar and ciliated, with deeper layers of oval or rounded basal cells.
Goblet cells interspersed in the epithelium secrete mucus, which lubricates the tracheal surface and traps foreign particulate
matter such as dust and bacteria. Goblet cells constitute about 20% to 30% of cells in the more proximal trachea and decrease in
number distally. The submucosal layer is composed of a loose mesh of connective tissue containing large blood vessels, nerves,
and mucous glands. The ducts of the glands pierce the overlying layers and open at the surface. A superficial epithelial wound
can heal through regeneration of the surface epithelium. Tissues with high proliferative capacity renew themselves continuously
and can regenerate after injury above the basal membrane through proliferation and differentiation of basal cells.
FIGURE 72.4 Wound healing of a circumferential tracheal mucosal defect. The healing pattern of a circumferential full-
thickness mucosal defect is shown. Healing of full-thickness mucosal wounds combines granulation tissue formation, wound
contraction, and re-epithelialization from the wound edges (arrows). Airway stenosis in the middle part of the denuded segment
can develop from circumferential wounds. Healing of anastomotic sites can enable several millimeters of respiratory epithelium
to grow into the wound margins, while the remaining tissue between those margins is left as uncovered. Granulation tissue will
develop over the uncovered areas. Regeneration of the mucosal lining by applying epithelial stem cells (yellow-colored) to a
trachea segment with a preserved blood supply and cartilaginous support is not yet possible.
Segmental Resection
Tracheal Resection
Introduction
For tracheal stenosis, tracheal resection and anastomosis is now accepted as the procedure of choice,
with excellent results reported in many large series.7,8 The length of trachea that may be resected safely in
an individual varies widely with age, posture, body habitus, extent of disease, and prior tracheal surgery.
Planned resections of less than 4 cm of trachea will almost always be tolerated, unless incomplete
mobilization or fixed cervical kyphosis raises anastomotic tension. There is no universally applicable
limit for the maximum resectable length, although resection of more than half of the trachea rarely
succeeds.
Preoperative Work-up
Pre-operative assessment is the first step to success in tracheal surgery, because the best opportunity to
correct the tracheal lesion is at the initial operation. Clinical preoperative evaluation includes a detailed
patient history and physical examination. Previous treatment (previous surgery, tracheostomy, stents) may
have transformed the initial problem into a different entity, most often becoming increasingly difficult to
correct. Pulmonary function tests may be useful to assess obstruction. Computer tomography scans with
sagittal and coronal reconstructions reveal essential information about the stenosis, including length,
location, and vocal cords involvement. Flexible bronchoscopy is probably the most important component
of the preoperative work-up. Essential information about tracheal mucosa, the vocal cords (paralysis,
cords fixation, glottic stenosis) and their distance from the stenosis, and location, length, and assessment
of the stomas is considered a key aspect of surgical planning.
Anesthesia and Airway Management

The airway must be under full control at all times during reconstructive surgery of the trachea, so that
hypoxia does not occur. The patient should preferably breathe spontaneously during the operation and
always at its conclusion so that ventilatory support is not necessary postoperatively. Cardiopulmonary
bypass has been used for tracheal surgery, but it is not necessary for relatively simple resection.
Induction is carried out slowly and gently, especially in a patient with a highly obstructed trachea. If a
benign stenosis presents an airway diameter of <5 mm, dilatation is performed, and an endotracheal tube
is passed beyond the lesion to prevent arrhythmia caused by CO2 buildup during the early stages of
operation. If tracheostomy is already present, induction is simplified.
In patients with critical airway stenoses, an inhalational induction technique should be employed in
order to preserve spontaneous ventilation. A slow inhalational induction may be required if there is a high
degree of obstruction. This technique is preferable to paralysis of respiration, which may necessitate the
urgent establishment of an airway. In patients with less critical airway stenoses, total intravenous
anesthesia (TIVA) techniques (the use of an IV agent or agents exclusively to provide a complete
anesthetic) can be used. This allows for prompt reversal and spontaneous breathing following resection
and reconstruction. The goal should be extubation of all patients undergoing tracheal resection at the end
of the procedure.
In very critical stenosis, with a very small passage for the tube, it is very sensible to start with rigid
bronchoscopy to dilate the lumen, allowing placement of a tube with the appropriate diameter to prevent
ventilation problems during the surgery. Other methods are also feasible, such as high-frequency jet
ventilation administered through small catheter(s). Patients with tracheostomy are increasingly common in
the specialized units, frequently with previous surgical or conservative treatments. In these patients, the
airway can be secured with little effort by placing the tracheal tube distal to the lesion. Basically,
successful airway surgery requires skilled coordination between the anesthesiologist and the surgeon.
Surgical Technique
A horizontal collar incision is made 2 cm above the sternal notch (Fig. 72.5). For thoracic tracheal
stenosis, the cervical incision approach can be insufficient and an upper partial or total median
sternotomy may be necessary.
FIGURE 72.5 Tracheal resection.
The strap muscles are divided at the midline; likewise, the thyroid isthmus and both sides are sutured
and kept away from the trachea. At times, the exact location of the stenosis is easily recognizable by the
bottleneck deformity of the trachea. Should this not be the case, the exact location of the stenosis is
identified using a bronchoscope inserted through the intubation tube, which is temporarily withdrawn to
the subglottic level. Visualization on a monitor enables the surgeon to insert a needle into the stenotic
segment with precision, and to mark the site with a thread on the anterior tracheal wall.
Dense scar is often present in association with benign stenosis, and dissection is done close to the
trachea to avoid damage to the recurrent nerves, especially near the cricoid. Isolation and visualization of
the nerves is avoided because this increases the danger of injury. Freeing the trachea below the lesion
early allows easy establishment of airway control and expedites dissection of a cicatrized segment from
the esophagus.
Mobilization is undertaken anterior and posterior to the trachea both proximally and distally. Tentative
approximation with traction sutures, while the neck is flexed by the anesthetist, demonstrates whether
approximation may be accomplished or whether further dissection is needed.
The blood supply to the trachea is almost entirely from the lateral blood supply. Thus, lateral
dissection must be limited to the injured segment and 2 to 4 rings beyond in order to avoid postoperative
ischemia and subsequent healing problems.
The trachea is opened transversally at the midpoint of the stenosis. At the time of tracheal division, the
orotracheal tube is pulled back or removed and a sterile, cuffed, flexible, armored endotracheal tube is
inserted into the distal airway across the operative field. Sterile connecting tubing is passed to the
anesthesiologist to allow ventilation of the patient. The trachea is then progressively sliced cranially and
caudally until steady tracheal rings are reached. If tracheal mobilization shows excessive tension when
attempting to approximate the two tracheal stumps, then stepwise tracheal mobilization with laryngeal
release or, less commonly, hilar release should enable a safe resection and anastomosis.
The posterior anastomosis is carried out first. The membranous trachea is freed from the esophagus
over several millimeters in order to place inverted interrupted 3-0 vicryl stitches with the knots tied on
the outside. Some surgeons favor a running suture, thus obtaining an improved mucosal approximation.9
The lateral and anterior anastomosis is then performed with interrupted 3-0 vicryl stitches. Toward the
completion of the operation, the original endotracheal tube is advanced into the distal airway and the
anastomotic sutures are tied.
Upon completion of the anastomosis, fibrin glue (Tisseel) is applied to the suture line, and a Penrose
drain is placed. Cervical flexion decreases tension on the suture line approximating the anastomosed
tracheal ends. The patient’s cervical flexion may be maintained by a “sentinel” chin stitch.
Results
Surgical treatment for tracheal stenosis has been shown to be reliable and usually successful in
experienced hands. Wright et al.10 reported the longest series to date, with a low rate of anastomotic
complication (9%) and success in 95% of the cases.
Other experienced groups have reported a similar success rate with mortality rates of less than 3%.8,9
These series have identified a few risk factors for complications: resection longer than 4 cm, diabetes,
previous radiotherapy, and associated laryngotracheal reconstruction. Restenosis is a challenging
complication and may occur with an anastomosis performed under too much tension.
Cricotracheal Resection
When benign stenosis of the upper trachea also involves the subglottic larynx, one-stage reconstruction is
possible.11 Cricotracheal resection with anastomosis of the trachea to the thyroid cartilage is the treatment
of choice for the cure of (idiopathic) subglottic stenosis with normal vocal fold mobility. The anterior
subglottic larynx is resected and the posterior cricoid lamina is bared but preserved in order to protect
the recurrent laryngeal nerves (Fig. 72.6). The distal tailored trachea is advanced to replace the anterior
subglottic laryngeal wall and to resurface the posterior cricoid plate with the membranous tracheal wall.
Results are generally favorable.12,13 Stenting of the anastomosis is not necessary if the repair is precise.
Slide Tracheoplasty
Short-segment congenital tracheal stenosis is effectively managed by resection and reconstruction, bearing
in mind that length of resection must be limited in the juvenile trachea.14 Vicryl sutures 5-0 are employed
for anastomosis.
Long congenital stenosis, usually caused by complete tracheal rings may be managed by slide
tracheoplasty.15,16 The long stenotic segment is transected at its midpoint; the upper half of stenosis is
divided vertically posteriorly and the lower half anteriorly. Corners are trimmed, the two segments slid
together, and anastomosis performed (Fig. 72.7). The tracheal circumference is thus doubled, the cross-
sectional area is quadrupled, tension is acceptable, and blood supply remains adequate. Advantages of
this direct method over prior use of patches of cartilage or pericardium are (a) trachea reconstructed with
trachea, minimizing granulation tissue or necrosis; (b) immediate epithelialized lumen; (c) generally
prompt extubation postoperatively; and (d) elimination of the need for cardiopulmonary bypass except
when pulmonary artery sling or other cardiac anomalies are present. Wright and colleagues14 have
demonstrated long-term growth of the trachea repaired in this way. Slide tracheoplasty is not useful for
acquired, long-segment stenoses.
TISSUE RECONSTRUCTION OF THE TRACHEA

Ideally, a tissue for tracheal reconstruction would consist of viable cartilage and respiratory mucosal
lining similar to that of the original trachea. Unfortunately, there is no such composite tissue elsewhere in
the body that meets these requirements. Most of the reconstructive tissues applied clinically lack one or
both components leading to a large variation in results.
Tracheal Autotransplantation
Orthotopic revascularization of a tracheal segment can be used to reconstruct extended hemilaryngectomy
defects during tracheal autotransplantation. Tracheal autotransplantation is not useful for tracheal stenosis
treatment. Nevertheless, it is useful to mention it in when describing options for tracheal reconstruction.
A 4-cm segment of healthy trachea can be autotransplanted to a hemilaryngeal defect after in situ
revascularization. Before autotransplantation, the tracheal segment has to become revascularized by a
new vascular pedicle that allows for transfer of the revascularized segment (Fig. 72.8).17,18 The preferred
tissue for revascularization of tracheal autografts is the forearm fascia and subcutaneous tissue, which can
be brought to the neck area by attaching the associated radial artery and vein to the neck vessels.
Orthotopic revascularization is not possible for completely avascular tracheal grafts since shearing stress
from breathing, swallowing, and coughing prevents capillary connection, resulting in eventual necrosis of
the tracheal segment. As shown in Figure 72.9, in situ revascularization is only possible for tracheal
segments that have an interruption of the extrinsic blood supply but preservation of the intrinsic blood
supply. The intrinsic, mucosal blood supply will be sufficient to provide a blood supply to a tracheal
segment for which the extrinsic, segmental blood supply has been interrupted. For example, during a total
thyroidectomy, the cervical trachea can maintain its viability through the preserved intrinsic, mucosal
blood supply while both inferior thyroid arteries are disrupted.
FIGURE 72.6 Cricotracheal resection.
FIGURE 72.7 Slide tracheoplasty.
FIGURE 72.8 Principle of tracheal autotransplantation. After revascularization, the upper 4 cm of cervical trachea will be used
to reconstruct an extended hemilaryngectomy defect. A: Coronal CT scan of larynx and trachea to indicate the repair of an
extended hemilaryngectomy defect with the upper 4 cm of cervical trachea. B: Cervical trachea after total thyroidectomy with
interruption of the extrinsic blood supply and preservation of the intrinsic blood supply. C: Radial forearm fascia flap is wrapped
around a 4 cm segment of cervical trachea for revascularization.
FIGURE 72.9 Orthotopic revascularization and tracheal autotransplantation. A: An overview of the extent of a laryngeal defect
that can be reconstructed with autotransplantation is shown. Outline of an extended hemilaryngectomy defect (A1). A defect
involving half of the cricoid cartilage can be reconstructed with the top 4 cm of cervical trachea (A2). B: This upper 4 cm of
trachea is wrapped with a vascularized soft tissue flap and the radial vascular pedicle is sutured to the neck vessels (B1). The
preserved intrinsic blood supply of the tracheal graft prevents tissue necrosis (B2). After several weeks, sufficient vascular
connections have formed between the soft tissue flap and trachea (red arrows) to allow interruption of the intrinsic blood supply
of the enveloped segment (B3, white line), thereby enabling the isolated segment to be autotransplanted to the larynx (A2, black
arrow) after creation of a hemilaryngeal defect. Only the cartilaginous trachea is included in the autotransplant. The blood supply
from the fascia to the autotransplant is established through the intercartilaginous ligaments (red arrows).
FIGURE 72.10 Visualization after tracheal autotransplantation. Coronal (A) and axial (B,C) sections of a reconstructed larynx
after autotransplantation. The tracheal autotransplant provides more (at the subglottic level, C) or less (at the glottic level, B)
convexity, depending on the width of the defect. This panel illustrates how “optimal airway support” provided by repair tissue can
be defined. A: double arrow: a 1.5 cm segment of cervical trachea near the recurrent laryngeal nerve remains intact. Arrow:
entrance of the recurrent laryngeal nerve into the larynx.
After several weeks of orthotopic revascularization, the fascia-enveloped tracheal segment can be
transplanted to a hemilaryngeal defect site on its new vascular pedicle. The remaining trachea can be then
sutured to the reconstructed larynx, restoring tracheal continuity. It has been shown that tracheal
autotransplantation can prevent a total laryngectomy in selected lateralized tumor cases.19–21 The same
tracheal transplant will provide more or less convexity, depending on the width of the defect (Fig. 72.10).
For us, tracheal autotransplantation also served as a guide for directing research in tracheal
allotransplantation.
Epithelial-Lined Reconstruction
A linear repair, comparable to the composition of the membranous trachea is the best result that can be
obtained with a mucosal-lined radial fascial flap (Fig. 72.11). The advantages are the intrinsic blood
supply of the repair tissue and its lining with buccal mucosa. The disadvantage is the lack of cartilage
support.
Some long-segment stenoses and restenoses after segmental resection may be suitable for a
longitudinal incision, expansion, and placement of a mucosal-lined fascial flap.22,23 This reconstruction
can be used to restore the anterior airway defect with sufficient remaining native airway concavity (Figs.
72.12 and 72.13). The safest way is to apply the mucosal graft(s) 10 days before harvesting of the flap.
Cartilage
Alternatively, costal cartilage grafts may be used to augment the tracheal airway for treatment of a short-
segment stenosis that is not suitable for a segmental resection. The primary advantage is the support
provided by the graft. The disadvantage is the absence of both a mucosal lining and an intrinsic blood
supply.24 Healing of an avascular cartilage graft is unpredictable and a well vascularized environment is
required to prevent necrosis. A costal cartilage graft is harvested at the sixth, seventh, or eighth rib (Fig.
72.14). A vertical midline incision is placed over the stenotic segment. A silicone stent is inserted and
carefully fixed using Vicryl 2-0 sutures. The properly sized stent expands the airway to its normal size,
leaving an anterior defect in the exact size of the graft needed. The costal cartilage is trimmed to a boat-
shaped graft. The perichondrial side of the graft should face the lumen and 3-0 vicryl stitches are used to
suture the graft into position. A precise approximation of the graft should facilitate the reepithelialisation
process over the perichondrium of the cartilage (Fig. 72.15). Well-vascularized tissue has to be placed
over the cartilage graft. If available, the thyroid lobes may be slightly mobilized, and the thyroid isthmus
can be resutured over the cartilage graft in order to maintain an optimal vascular supply to the
reconstruction. The silicone stent can be removed after 5 to 6 weeks during direct laryngoscopy.
FIGURE 72.11 Epithelial-lined reconstruction. A: The tissue used for reconstruction can be compared with the membranous
trachea with a nonkeratinized stratified squamous epithelial lining replacing the respiratory epithelium. B: A silicone stent is
placed in the expanded airway. The anterior airway defect is reconstructed with the mucosal-lined fascia. The stent can be
removed after 5 weeks via rigid bronchoscopy.
FIGURE 72.12 Mucosal grafting of radial forearm fascia flap. One or two buccal mucosal grafts are applied 10 days before
harvest of the flap. A Gore-Tex sheet is placed between the mucosal grafts and the overlying skin to prevent adhesions.
FIGURE 72.13 Airway repair with a radial forearm flap lined with buccal mucosa. A restenosis (preoperative CT scan) at the
anastomosis after segmental resection is incised anteriorly (double arrow) and expanded (arrows). A mucosal-lined radial
forearm fascial flap is sutured into the airway defect. A silicone stent is placed to support the reconstructed airway during 4 to 5
weeks. The stent is secured with one or two Vicryl sutures (3.0 or 2.0) to prevent migration. It can be removed by rigid
bronchoscopy.
FIGURE 72.14 Tracheal reconstruction with cartilage graft. A costal cartilage graft is used for anterior airway repair.
FIGURE 72.15 Cartilage graft used to resolve a restenosis after segmental resection. A rib cartilage graft was used to augment
the airway.
IMMEDIATE REPAIR OF LONG-SEGMENTAL DEFECTS
Prosthetic Tracheal Repair
In recent years, most synthetic materials used for tracheal replacement have been tested in experimental
animal research. From these studies, it became clear that definitive prosthetic replacement of the airway
wall was not possible.25 To date, nearly all surgical prostheses that have been successful were observed
in potentially sterile mesenchymal tissues. Successful prosthetic repair has not been possible in the
respiratory, gastrointestinal, or genitourinary tract. The internal surface of the airway tract belongs to the
outside world, and bacterial contamination at the interface between the airway and prosthesis prevents its
ingrowth (Fig. 72.16). The complications of wound breakdown at the anastomoses can be temporarily
delayed by wrapping the prosthesis in vascularized tissue, mostly transposed omentum.
Palliative Treatment of Long-Segment Tracheal Defects

Long-segmental tracheal defects, which result after removal of malignant tumors are extremely rare.
Currently, the only possibility for immediate reconstruction of these defects is to reduce the length of the
defect by inserting a silicone stent, which is sutured to the upper and lower margins of the defect. A free
fasciocutaneous skin tube (lateral thigh flap, radial forearm flap) can be used to wrap the silicone stent as
a temporary closure (Fig. 72.17).26 Tracheal allotransplantation may bring a definitive solution in such
cases.
FUTURE DEVELOPMENTS
ATTEMPTS AT TRACHEAL REGENERATION

Since 2008 the trachea has been termed the first human organ that can be man-made with stem cells and an
“engineered” trachea has been implanted in several patients.27 The engineered trachea was originally
represented as a regenerated trachea after applying bone marrow cells to a de-cellularized28 or synthetic
scaffold.29 There is no blood supply. However, the optimism surrounding tracheal regeneration has been
disappointing as it is clear that a devascularized windpipe cannot survive, even if transplanted into the
airway straightaway. The removed part of the windpipe can only survive if its blood vessels are repaired.
However, contrary to other organs and tissues, repairing the blood supply of the trachea is a very difficult
process.
To date, mucosal grafts have not been produced by tissue-engineering techniques and regeneration of
the internal mucosal layer of a completely intact trachea is still not possible (Fig. 72.18). Only the most
superficial epithelial cells can be multiplied and produced in the form of a very thin layer. The clinical
application in mucosal regeneration has thus remained very limited.
FIGURE 72.16 Prosthetic replacement: airway versus vascular conduits. A: Blood vessel prosthesis. Endothelialization of the
luminal surface of vascular grafts occurs only 1 to 2 cm into the graft from the anastomotic site. These endothelial cells are
derived from adjacent, native endothelium and they enable the anastomosis to heal. B: Airway prosthesis. In the respiratory
tract, the flow of inspired air will lead to bacterial contamination and wound breakdown at the anastomosis. The respiratory
epithelium will not grow over the prosthesis-airway anastomosis. C: Airway prosthesis wrapped in vascularized tissue. A
prosthesis may act as a temporary airway stent when it is wrapped by well-vascularized tissue (e.g., omentum). The vascularized
tissue around the prosthesis may temporarily avoid the complications of wound breakdown at the anastomotic sites.
FIGURE 72.17 A circumferential defect can be shortened (from 9 to 10 cm to 5 to 6 cm) by placing of a silicone stent. The
stent is wrapped with a soft tissue free flap (e.g., the anterolateral thigh flap) to delay complications.
FIGURE 72.18 Importance of both an intact blood supply and mucosal lining in tracheal transplantation.
Attempts to use “engineered” tracheas in patients have placed the tracheal implant between a stent and
vascularized tissue wrapped around the stent. However, this has not been successful. Most patients with a
synthetic or biological scaffold have died in the short term and the survivors for more than a couple of
months are functioning with a stent inside the scaffold. It is well known that a synthetic tube or stent can
repair the airway temporarily and that to avoid immediate complications, the stent has to be wrapped in
well-perfused tissue, usually omentum. It is also known that the stent will eventually cause serious
complications at the edges of the defect in the short or midterm but that this technique can ensure a
temporary airway for patients in a palliative situation. Any tissue such as an “engineered” trachea,
inserted between the stent and the vascularized tissue wrap has very little impact on the repair or outcome
(Fig. 72.19).
A nonvascularized “engineered” trachea is not a clinically viable solution and thus new approaches
will be needed for the future.30
TRACHEAL ALLOTRANSPLANTATION
A tracheal transplant may be necessary to repair surgical defects of the laryngotracheal airway tract that
are unsuitable for segmental resection and autologous tissue repair. With the exception of some anecdotal,
poorly documented cases performed without blood supply restoration31 or immunosuppressive
medication,32 no clinical tracheal allotransplants have been transplanted orthotopically as an isolated
composite tissue graft. In tracheal allotransplantation, it is important to deal with both immunosuppression
and indirect revascularization in a heterotopic position. The first documented preserved viability of a
heterotopically revascularized allotransplant was published by Klepetko et al.33 in 2004. The graft was
revascularized in the omentum of a patient who underwent lung transplantation from the same donor.
Ultimately, the trachea transplant was not used, but its viability was documented for at least 60 days.
The first documented revascularized tracheal allotransplant to be reported was published in 2010.34
Our approach to tracheal heterotopic revascularization, orthotopic transplantation, and withdrawal of
immunosuppressive medication is based on a series of seven transplant cases.35 For tracheal
allotransplantation, we consider a “good match” to mean that the donor is of the blood group as the patient
(Fig. 72.20).
Revascularization of the trachea is the first step toward successful tracheal transplantation. The typical
arterial and venous blood supply, consisting of several small tracheoesophageal branches, does not
enable direct tracheal transplantation. Currently, the only reliable way to achieve tracheal
revascularization is to wrap the isolated trachea with a well-vascularized soft tissue flap perfused by a
vascular pedicle, which then allows for transfer of the revascularized trachea to an airway defect. The
forearm fascia flap pedicled on the radial artery and vein has proven to be reliable for tracheal
revascularization.35 It is important to have complete immobility between the donor trachea and the
surrounding recipient’s vascular bed to obtain a fast revascularization of the blood vessels of the tracheal
adventitia (Fig. 72.21).
FIGURE 72.19 The “engineered” trachea.

FIGURE 72.20 Overview of tracheal allotransplantation. Orthotopic transplantation of a tracheal transplant to resolve a long-
segment airway stenosis is illustrated. The long-segment tracheal stenosis is incised longitudinally (double arrow). After full
revascularization and mucosal regeneration have been achieved, the tracheal allotransplant is transplanted from the forearm to
the airway defect on a radial vascular pedicle. The radial blood vessels are sutured to the neck vessels to facilitate
revascularization. The cartilaginous trachea is sutured into the airway defect to restore the concavity of the airway lumen. After
revascularization, a buccal mucosa graft from the recipient can be applied to the midportion of the transplant to allow for a safer
withdrawal of immunosuppressive drugs.
FIGURE 72.21 Orthotopic tracheal revascularization. The optimal approach to heterotopic revascularization is shown. The
forearm skin is incised and dissected away from the underlying fascia and subcutaneous tissue. After removal of the
membranous part, the trachea is wrapped with the radial forearm fascia and the forearm skin flaps are sutured to the incised
trachea. Revascularization can be achieved by the outgrowth of capillary buds from the native vascularized tissue to unite with
capillaries in the adventitia of the trachea. This connection should be well developed by the third day.
Revascularization has to be achieved by the outgrowth of capillary buds from the fascia flap (recipient
blood vessels) uniting with those on the adventitia (donor blood vessels) of the tracheal segment.
Inosculation is the establishment of direct vascular anastomoses between the vascularized soft tissue flap
and the adventitia of the trachea (Fig. 72.21). Compared to a free skin graft, there are three additional
barriers to revascularization for a tracheal mucosa graft: (a) Cartilage rings and intercartilaginous
ligaments may interfere with the revascularization of the mucosal lining of the cartilaginous trachea; (b)
Cartilaginous tissue does not allow for the ingrowth of blood vessels; and (c) Revascularization of the
mucosal layer of an avascular tracheal segment occurs through the intercartilaginous ligaments (Fig.
72.21). Full revascularization and mucosal regeneration of the cartilaginous trachea can be achieved
within 3 months of the trachea being implanted in the forearm.
A tracheal allotransplant is a composite tissue transplant that may be used to restore the airway, with
the goal of improving quality of life. The benefits garnered by tracheal allotransplantation have to be
balanced against the morbidity of long-term immunosuppression therapy. Immunosuppressive medication
should be withdrawn before immunosuppressant-related complications occur. The cartilage tissue seems
to escape immunologic rejection owing to the absence of blood vessels, and because the chondrocytes are
protected within a matrix.34,36,37 In our initial patient series of tracheal transplantations, it became clear
that the intercartilaginous ligaments formed an obstruction for the ingrowth of native blood vessels (Fig.
72.22). The placement of intercartilaginous incisions at the time of forearm implantation was an important
adaptation. The incisions of the intercartilaginous ligaments facilitated revascularization, enabling the
ingrowth of recipient vessels into the submucosal space of the transplant. When incisions through the
intercartilaginous ligaments were made at regular intervals, full revascularization and mucosal
regeneration of the cartilaginous allotransplant could be obtained in a shorter time period. Regularly
spaced intercartilaginous incisions provide avenues for angiogenic recipient vessels to breach the
ligamentous barrier and thus grow into the submucosal space of the transplant tissue after withdrawal of
immunosuppressants.
FIGURE 72.22 Withdrawal of immunosuppressive drugs and importance of intercartilaginous incisions. Immunologically induced
lymphocytes attack the microcirculation. Inflammatory vascular infiltrates lead to thrombosis of donor-derived blood vessels
(blue-colored capillaries) and necrosis of the mucosal layer. The intercartilaginous ligaments were observed to be acting as a
barrier to the ingrowth of recipient blood vessels (purple-colored capillaries), resulting in necrosis of the mucosal lining. Full-
thickness mucosal grafts can be applied in the midportion of the transplant. These newly formed blood vessels will allow the
recipient mucosal lining in the midportion of the transplant to survive immunosuppressant withdrawal.
FIGURE 72.23 The full length of the trachea and main bronchi can be used for allotransplantation. Two cartilaginous tracheal
segments with a length of 9 cm may be implanted at two forearm sites. These segments allow for replacement of nearly the
complete tracheal length. Circumferential tracheal repair with a bilateral cartilaginous tracheal allotransplant. By suturing the two
allotransplants together, a tube with a length of 9 cm may be created for circumferential airway repair.
A circumferential airway repair may be necessary after resection of malignant tumors or in cases of
tracheal agenesis. Tracheal allotransplantation at the time of tumor resection will be possible only for
low-grade malignancies and not for other malignant tumors, because of the risk of tumor progression in
the 3-month period of pretransplant immunosuppression. A circumferential defect left by tumor resection
can be reconstructed temporarily with a stent wrapped in vascularized tissue. This type of reconstruction
must be considered temporary due to inevitable stent-related complications. Tracheal allotransplantation
may be considered in those patients with a temporary repair who remain tumor-free.
The best protocol for circumferential allotransplantation may lie in bilateral transplantation of the
cartilaginous trachea (Figs. 72.23 and 72.24). In adults, a circumferential allotransplant as long as 9 cm
can be built when using the full-length of the trachea and the two main bronchi.
FIGURE 72.24 The first transplant is used to restore the posterior and lateral walls of the airway. A part of the forearm skin
can be included as a reconstruction of the anterior wall. In a second operation, the second transplant can be used to replace the
forearm skin and to further augment the airway lumen.
REFERENCES
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2003;109:467–472.
2. Dumon JF. A dedicated tracheobronchial stent. Chest 1990;97:328–332.
3. Grillo HC. Surgical approaches to the trachea. Surg Gynecol Obstet 1969;129:347.
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109: 486–492.
8. Couraud L, Jougon JB, Velly JF. Surgical treatment of nontumoral stenoses of the upper airway. Ann Thorac Surg 1995;60:250–259.
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stenosis. J Thorac Cardiovasc Surg 2001;121:68–76.
10. Wright CD, Grillo HC, Wain JC, et al. Anastomotic complications after tracheal resection: prognostic factors and management. J
11. Grillo HC. Primary reconstruction of airway resection of subglottic laryngeal and upper tracheal stenosis. Ann Thorac Surg 1982;33:3.
12. Grillo HC, Mathisen DJ, Wain JC. Laryngotracheal resection and reconstruction for subglottic stenosis. Ann Thorac Surg 1992;53:54.
13. Monnier P, Lang F, Savary M. Partial cricotracheal resection for severe pediatric subglottic stenosis: update of the Lausanne
experience. Ann Otol Rhinol Laryngol 1998;107:961–968.
14. Wright CD, Graham BB, Grillo HC, et al. Pediatric tracheal surgery. Ann Thorac Surg 2002;74:308.
15. Grillo HC. Slide tracheoplasty for long-segment congenital tracheal stenosis. Ann Thorac Surg 1994;58:613.
16. Elliott M, Hartley BE, Wallis C, et al. Slide tracheoplasty. Curr Opin Otolaryngol Head Neck Surg 2008;16:75–82.
17. Delaere P, Liu ZY. Tracheal autograft revascularization and transplantation. Arch Otolaryngol Head Neck Surg 1994;120:1130–1136.
18. Delaere P, Goeleven A, Poorten VV, et al. Progress in larynx-sparing surgery for glottic cancer through tracheal transplantation. Plast
Reconstr Surg 1999;104:1635–1641.
19. Delaere P, Goeleven A, Vander Poorten V, et al. Organ preservation surgery for advanced unilateral glottis and subglottic cancer.
Laryngoscope 2007;117:1764–1769.
20. Delaere P, Vranckx J, Dooms C, et al. Tracheal autotransplantation: guidelines for optimal functional outcome. Laryngoscope
2011;121:1708–1714.
21. Loos E, Meulemans J, Vranckx J, et al. Tracheal autotransplantation for functional reconstruction of extended hemilaryngectomy
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22. Delaere P, Hierner R, Vranckx J, et al. Tracheal stenosis treated with vascularized mucosa and short-term stenting. Laryngoscope
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Ann Thorac Surg 2007;83:1213–1215.
24. Zhi L, Wenli W, Pengfei G, et al. Laryngotrachea reconstruction with autogenous rib cartilage graft for complex laryngotracheal stenosis
and/or anterior neck defect. Eur Arch Otorhinolaryngol 2014;271:317–322.
25. Grillo HC. Tracheal replacement, a critical review. Ann Thorac Surg 2002;73:1995–2004.
26. Beldholm BR, Wilson MK, Gallagher RM, et al. Reconstruction of the trachea with a tubes radial forearm free flap. J Thorac
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36. Sykes M. Immune evasion by chimeric trachea. N Engl J Med 2010;362:172–174.
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1570.
73
Management of Nonneoplastic Diseases of
the Trachea
Jennifer L. Wilson ■ Sidhu P. Gangadharan
Benign diseases of the trachea are caused by infection, trauma including iatrogenic injury, extrinsic
lesions, and many inflammatory conditions that are yet not fully understood.
INFECTION
TUBERCULOSIS
Tuberculosis of the airway is a rare cause of symptomatic airway stenosis. Over 50% of patients with
active pulmonary tuberculosis may have evidence of endotracheobronchial tubercular disease.1 In these
patients, the majority of the central airway tuberculosis will be localized to the bronchi; however, 16%
will have disease of the trachea.
While most endotracheobronchial disease will respond to antituberculosis therapy with no chronic
sequelae, significant airway stenosis may result in up to 20% of patients. These occasionally will require
surgical or bronchoscopic intervention.2 Bronchoscopic interventions remain the mainstay tuberculosis-
related airway stenoses, with surgery reserved for recalcitrant lesions. Unfortunately, the multifocality or
length of these stenosis can make surgical options highly challenging. Bronchoscopic interventions often
entail multiple staged dilations and stent placements.3 Caution is necessary when considering the use of
covered or uncovered self-expanding metal stents4 due to the propensity to promote granulation which can
lead to airway obstruction and further stricture formation if left in place for extended periods of time.5
HISTOPLASMOSIS
Histoplasmosis is a fungal infection that results from inhalation of infected bird feces most commonly in
the Ohio and Mississippi River Valley areas in immunocompromised hosts. It can mimic several other
benign causes of airway stenosis including tuberculosis, Wegener granulomatosis, leprosy, tertiary
syphilis, actinomycosis, sarcoidosis, and other fungal diseases such as blastomycosis.6 Thus, tissue
culture with Grocott silver staining is often required to distinguish between these different etiologies. The
organism Histoplasma capsulatum is more often identified by special stains on surgical specimens rather
than on cultures. Organisms have been identified in fewer than 50% of patients who are presumed to have
diseases originating from this source. It has been theorized that the continuing fibrotic process is a
reaction to products of the infection rather than to viable organisms. Thus, diagnosis is often presumptive,
based on pathologic and radiologic findings as well as on a history of exposure and clinical evolution of
the disease.
Infection can present with a multitude of symptoms including dyspnea, hemoptysis, postobstructive
pneumonia, and superior vena cava obstruction. Histoplasmosis may produce massive mediastinal
fibrosis with involvement of the distal trachea, carina, and main bronchi, or it may principally involve the
right bronchial tree with masses of lymph nodes in the right paratracheal and pretracheal area or in the
middle-lobe sump nodes. The fibrosing process may extend centrally to involve the right pulmonary artery
up to its point of origin even within the pericardium. The lesions may be a composite of airway
compression plus intrinsic fibrotic involvement. Massive histoplasmoma at the carina may compress the
airway. In such lesions there may be central caseation with a fibrotic capsule that actually involves one or
both main bronchial walls intimately. Another presentation is with densely fibrotic and calcified
subcarinal and precarinal lymph nodes, which may invade and erode through the wall of the trachea,
carina, or bronchi. Broncholiths also occur peripherally in the lobar bronchi. Secondary infection and
hemorrhage may follow. More recently, broncholithiasis in general has been associated with
histoplasmosis rather than with tuberculosis, as it was in an earlier era. These clinical manifestations
have been described by Mathisen and Grillo.7
OTHER INFECTIOUS DISEASE PROCESSES

In recent years, only a small number of patients who have suffered from diphtheria in childhood presented
many years later with tracheal stenosis or laryngotracheal stenosis. Because most of these patients had
tracheostomies in infancy or early childhood for treatment of the acute disease, it is difficult to
differentiate whether the late stenoses were caused by the disease or the treatment. Reconstruction is
possible with careful surgical planning.
Rhinoscleroma is a rare disease from infection with Klebsiella rhinoscleromatis that may involve the
airways as well as the nasopharynx. It is found most often in patients from the Middle East, Mexico, and
Central America and has been reported in immigrants from these areas to other countries. It can present as
acute airway obstruction and thus, emergent tracheostomy is required in these rare situations.8
Mucormycosis is a rare and deadly opportunistic infection that can affect the respiratory tract most
often in patients in an immunocompromised state (i.e., leukemia, lymphoma, solid malignancy, prior organ
transplant, diabetes). The in-hospital mortality of isolated pulmonary mucormycosis has been reported at
65%. There have been three case reports of tracheal involvement by mucor treated by aggressive surgical
resection.9–11
While Aspergillus is a ubiquitous organism, an immunocompromised patient may be susceptible to
infection. Infection may manifest in saprophytic, allergic, or invasive forms, and the airway involvement
is evidenced by obstructing bronchial aspergillosis, bronchocentric granulomatosis, and
tracheobronchitis, respectively.12
POSTTRAUMATIC LESIONS
BLUNT TRAUMA
Diagnosis and treatment of blunt force airway injury are often delayed. In the acute phase blunt force
airway injury almost always presents with a unilateral or bilateral (tracheal rupture) pneumothorax and/or
massive subcutaneous emphysema. If the injury is large, tube thoracostomy may initially compromise
oxygenation paradoxically. In addition, the injury may manifest as a persistent air leak, which should
prompt bronchoscopic evaluation for an airway injury while the patient is in the hospital. For patients in
which the injury seals, postinjury scarring may occur and a refractory course may ensue. Chronically,
patients can present with recurrent pneumothoraces, postobstructive parenchymal collapse, recurrent
postobstructive pneumonia, wheezing, and/or dyspnea.
Bronchoscopy is the mainstay of diagnosis for patients that present in both the acute and delayed
phases. Most airway injuries occur on the right side within 2 cm of the carina perhaps because the right
mainstem bronchus is less protected than the left by other mediastinal structures.13 If the diagnosis is
delayed, the trachea or bronchus may be reduced to only a tiny opening by the time a diagnosis is made.
Surgical intervention is indicated for most patients if the defect is visualized and the patient remains
symptomatic. Intervention may be avoided acutely if the air leak resolves and only a very small defect is
seen. However, these patients should be followed closely for postinjury stricture formation and resection
is indicated if symptoms develop.
When only the bronchus is injured, every effort is made to salvage the distal lung. This is usually
possible unless severe infection has developed in the airway. Deslauriers and colleagues14 have
demonstrated adequate function of reimplanted lungs. Functional return appears to be roughly inversely
proportional to the length of time that the lung was compromised.
In complex injuries, delayed surgical intervention may be the best option if the patient is stable. This
allows for acute inflammation and/or infection to subside. For example, in the case of complete tracheal
separation treated by tracheostomy only, one may wait months after injury to intervene. Laryngeal
reconstruction, when necessary, with stabilization of the glottic aperture, is generally accomplished first.
The larynx is then reconnected to the trachea, as described by Mathisen and Grillo.15 An effective
although unmodulated voice is obtained. Associated pharyngoesophageal separation that was not repaired
initially is reconstructed at the same time.
Blunt cervical tracheal injury may present as complete or partial transection. As with thoracic airway
injury from blunt trauma, vigilance must be maintained for associated injury. In one series of 51 patients,
recurrent nerve, esophagus, larynx, and cervical spine injuries were seen in high frequency when cervical
tracheal injury was diagnosed.16
INHALATION BURNS
Inhalation injury may be caused by heat, smoke, or chemical toxins. It is a major contributor to death
following burns.17 Patients often show little damage to the pharynx or supraglottic larynx once the acute
inflammatory reaction has subsided. Persistent damage often commences in the subglottis just below the
vocal cords and extends down the airway in a gradually diminishing intensity of injury. The depth of
injury and the length of airway injured probably relate to the dose received as well as to the actual injury
potential of the agent. Gaissert, Lofgren and Grillo65 found that in 18 patients treated for tracheal stenosis
caused by inhalation injury, 14 had subglottic strictures and 2 had main bronchial stenosis.
In most cases, the tracheal rings are not destroyed and the injury is confined to various depths of
mucosal and submucosal damage. Attempts at resection of injuries should not be made, especially in the
early phase. First, involvement often commences immediately below the cords and involves the entire
subglottic larynx, making repair almost impossible. Second, the burned airway responds poorly to early
surgery, even where the lesion appears to be limited, much in the way that burned skin elsewhere in the
body does (i.e., by the reformation of massive scarring). With appropriately placed splinting, silicone T-
tubes, and a great deal of patience, a stable and open airway can usually be obtained in most of these
patients over time. If resection is required, it should be deferred until the acute inflammatory response to
airway injury has subsided completely.
COMPLICATIONS OF TRACHEAL RESECTION

The largest series of tracheal resection reported an overall complication rate of 18% and an anastomotic
complication rate of 9%.18 The anastomotic complications were split evenly between dehiscence and
restenosis, with technical considerations of excessive resection length and excessive devascularization
thought to be causative. Excessive anastomotic tension following tracheal resection can occur,
particularly when more than 50% of the length of the trachea is resected in an adult and more than 30% in
a child. Carinal resections are particularly at risk because of their complex nature.
Restenosis at the anastomosis may be addressed with endoscopic dilation. Small anastomotic
dehiscence may be treated expectantly with antibiotics, voice rest, and neck flexion.19 However,
reoperation and reresection for stenosis or dehiscence, or patching with a muscle flap of an anastomotic
separation may be required. Placement of a prosthesis, either tracheostomy tube or T-tube, may be the best
option for salvage in some cases as well. More recently, reports have described salvage of small
anastomotic dehiscences utilizing hyperbaric oxygen therapy.20
Patients chronically on high steroid doses are especially at risk if extensive tracheal resection is
performed. Patients with a history of radiation to the airway (>4,000 cGy given previously by a year or
more) also have a high incidence of anastomotic complications due to fibrosis and microvascular
compromise. An omental buttress may hasten healing of an anastomosis in these cases.21
There is some debate about the impact of suture material on the formation of granulation tissue after
tracheal resection and reconstruction. Intractable obstructive endobronchial granulation secondary to
surgical materials have been reported after sleeve resection for tracheal carcinoma.22 While the author’s
personal preference is to use an absorbable suture, either 4-0 braided (polyglycolic acid) or
monofilament (polydioxanone), other groups have had success using nonabsorbable sutures such as
polypropylene.
Stenosis of the airway also may result from radiation therapy and laser injury. Brachytherapy has
contributed to a number of main bronchial stenoses. The contribution of laser therapy to tracheal damage
is more difficult to assess because the laser is often applied for attempted treatment of pre-existing
lesions and may be performed in conjunction with a tracheostomy performed to safeguard the airway.
Whereas laser injury may often be dealt with by subsequent resection and reconstruction, irradiation
injuries may either be surgically uncorrectable or correctable only with considerable risk.
POSTINTUBATION AND POSTTRACHEOSTOMY AIRWAY INJURY

Even with modern day low-pressure high-volume endotracheal tube cuffs, intubation can cause a spectrum
of tracheal lesions (Fig. 73.1) as described by Grillo23,24 as well as Andrews and Pearson.25 Lindholm26
showed that endotracheal tubes may cause injury at the laryngeal level even after only 48 hours of
intubation: glottic edema, vocal cord granulomas; erosions (particularly over the arytenoids), granulation
tissue, polypoid obstructions, and actual stenosis, particularly at the subglottic intralaryngeal level. The
most common lesions and those most amenable to definitive treatment are those responsible for airway
obstruction. Because a single patient may have more than one lesion and because the treatment of these
lesions differs, precise definition of the pathologic state is essential for treatment planning.
The airway can be injured by improper placement of the tracheostomy site, posterior membrane
laceration during tracheostomy insertion, overinflation of the cuff or a combination of multiple factors that
can ultimately lead to airway stricture. Subglottic injury can also be produced by cricothyroidotomy and
by cricoid erosion caused by high tracheostomy in the presence of kyphosis. Strictures can develop and
be partial, as in an A-frame deformity, or fully circumferential, as with a cuff injury (Fig. 73.2).
FIGURE 73.1 Diagram of inflammatory lesions related to cuffed tracheostomy tubes. A: Location of the stoma and the
distorting effect of a conventional cuff. B: Lesions developing at corresponding sites of injury. At the stoma, an anterior stricture
(a), a granuloma (b), or a combination may occur. At the cuff site (c), circumferential stricture occurs. Between the stoma and
such a stricture, varying degrees of tracheomalacia may result, with functional occlusion (d). At the site of erosion by the tip of
the tube (e), a granuloma may occur. Innominate erosion and a tracheoesophageal fistula are seen at both cuff level and tip level.
FIGURE 73.2 Circumferential stenosis at cuff level. This surgical specimen shows the narrow size to which the lumen may be
reduced before recognition of symptoms.
Even with proper placement of a tracheostomy, obstructing granulomas may form at the tracheostomy
site or at the tip of an uncuffed endotracheal tube and require serial debridement. The stoma site may
contract after decannulation, leading to an A-frame deformity which is not amenable to simple dilation.
Bronchoscopic appearance before and after tracheal resection for an A-frame deformity is depicted in
Figure 73.3. Symptomatic tracheal malacia may result from thinning of the tracheal cartilage from
presumed infection or irritation from the tracheostomy.
The etiologic basis of the cuff stenosis has been variously attributed to pressure necrosis by the cuff,
the irritating quality of materials in rubber and plastic cuffs and tubes, irritant materials produced by gas
sterilization, hypotension, and bacterial infection. Studies by Cooper and Grillo,27 and earlier by
Florange and colleagues,28 of autopsy specimens of patients who had been on ventilators with inflated
cuffs (Fig. 73.4), prospective studies of similar patients by Andrews and Pearson,25 and analysis of
surgically removed lesions caused by cuffs and experimental reproduction of these lesions under
controlled conditions by Cooper and Grillo,27,29 point to pressure necrosis as the principal etiologic
agent. As Grillo and colleagues30 showed, if standard cuffs are inflated to just provide a seal at
ventilatory pressures of approximately 25 cm H2O, intracuff pressures increase to 180 to 250 mm Hg. The
trachea has an elliptic form, so it becomes deformed at the point where a seal is obtained. If perfusion
pressures in the patient are lower than normal, necrosis can occur even more easily. The mucosa
overlying the cartilage is initially destroyed. The bared cartilages become necrotic and ultimately slough.
Attempts at repair after full-thickness damage to the tracheal wall lead only to scar formation. Because
the erosion is circumferential, the resultant strictures are also. Even further erosive damage can lead to
tracheoesophageal fistula posteriorly or to perforation of the innominate artery anteriorly.
Patients with stenosis and malacia develop symptoms and signs of airway obstruction consisting of
dyspnea on exertion, stridor, cough, and obstructive episodes. On occasion, a patient, while still
intubated, begins to develop obstruction from formation of granulations around the tip of the tube. In most
instances, the obstruction appears only after extubation, because the tube splints a cuff stenosis or
potential stomal stenosis as long as it remains in place. Any patient developing symptoms of airway
obstruction who has been intubated for over 24 hours within the previous 2 years must be considered to
have organic obstruction until proven otherwise. Many such patients have been treated for varying lengths
of time with the incorrect diagnosis of asthma. In the opinion of several surgeons (by oral communication)
who have treated these lesions, such errors result from lack of awareness of these lesions and the fact that
in most patients routine radiography of the chest shows normal lung fields. If a patient remains sedentary
while recovering from the original disease, the airway may shrink to a critical diameter of 4 to 5 mm
before symptoms become obvious. At this aperture, fatal obstruction may occur acutely.
FIGURE 73.3 Bronchoscopic appearance before (A) and after (B) tracheal resection for an A-frame deformity.
FIGURE 73.4 Autopsy specimen of larynx and trachea reveals tracheal injury caused by cuffed tracheostomy tube. A: Portex
tracheostomy tube had been in place for 19 days. Note the dilatation of the trachea where the cuff had been inflated. B:
Inflammatory erosive changes have bared multiple cartilages. Note also a distal erosion caused by the tip of the tube. Similar
injuries occur with metal or rubber tubes. (Reprinted from Grillo HC. Surgery of the trachea. Curr Probl Surg 1970;7:3–59.
Copyright © 1970 Elsevier. With permission.)
Although the design of large-volume low-pressure cuffs has improved, most cuffs can still produce
tracheal injury if slightly overinflated, because of their relatively inextensible materials.
Cricothyroidotomy may lead to severe or irreparable subglottic injury.
Three additional and particularly severe injuries to the airway may also occur as a result of intubation.
These are tracheoesophageal fistula, tracheoinnominate artery fistula, and subglottic laryngeal or
laryngotracheal stenosis.
Tracheoesophageal fistula occurs most commonly in patients that have an endotracheal tube in the
trachea for a long period of time as well as a feeding tube in the esophagus. The two foreign bodies
compress the common wall between trachea and esophagus, leading first to inflammation, which seals one
against the other, and then perforation, which may enlarge to include the entire membranous wall of the
trachea. Concomitant circumferential injury to the trachea is usually present as well, as pointed out by
Grillo and colleagues,31 because this is basically a cuff lesion. Tracheoesophageal fistula can manifest
with severe sepsis from mediastinitis, pneumonia, a sudden increase in “gastric” secretions in the trachea,
and acute gastric distention in a ventilated patient.
Anterior erosion of the trachea may lead to a tracheoinnominate fistula as described by Deslauriers et
32
al. A small number of anterior erosions seen in the past were caused by angulation of a tube tip or a
high-pressure cuff that directly eroded through the tracheal wall and into the artery. More common,
although still rare, are erosions into the artery that occur at the inferior border of a low-placed
tracheostomy stoma that is in direct contact with the artery. It occurs most often in children and young
adults when the tracheostomy is placed too low, because on hyperextension more than one-half of the
trachea rises up into the neck. If the stoma is placed in relation to the sternal notch rather than to the
cricoid cartilage, the tracheostomy will reside just above the elevated innominate artery.
Tracheoinnominate arterial fistulae are fortunately rare but may present as a “herald bleed” or by massive
initial hemorrhage. In treating bleeding from a tracheostomy, it is important to differentiate between
erosion of tracheal granulations or mucosa versus an arterial fistula. Sometimes angiography demonstrates
a false aneurysm that soon bleeds massively. A review of the literature by Wright33 demonstrated that of
the 70 survivors of operations performed for tracheoinnominate artery fistulae, only 40 survived for more
than 2 months. About 25% of the patients with tracheoinnominate arterial fistulae who reach the operating
room survive. Most patients die as a result of the underlying disease or other complications. More
recently, endovascular stent grafting and coiling have been described in small case series with promising
results as a bridge to definitive repair or palliation in patients that may not be operative candidates.34,35
Stenosis of the upper trachea may be associated with a severe subglottic stenosis as well. Stenosis of
the subglottic larynx arises from three causes. The principal one is erosion, which is caused by an
endotracheal tube that has been left in place for some time. The principal factor at fault may be use of a
tube that has a bore too large for the patient. One of the narrowest parts of the upper airway is at the level
of the cricoid cartilage. The second-most common cause is erosion by a tracheostomy tube upward
through the cricoid cartilage to affect the lower anterior larynx. It occurs most commonly in older patients
who are kyphotic and in whom the cricoid cartilage is close to the sternal notch. A third cause of
subglottic stenosis is the deliberate use of cricothyroidotomy for ventilation. If damage occurs at the
stomal level, it is by surgical selection within the larynx. Lesions that involve the subglottic larynx as
well as the upper trachea are much more difficult to repair surgically, although single-staged techniques
have been devised by Grillo36 as well as by Pearson37 and Couraud38 and their colleagues. Currently, it is
unknown if the increase in endoscopic-guided percutaneously placed tracheostomies will modify the
incidence of tracheal problems.
EXTRINSIC LESIONS
GOITER
Large goiters, either cervical or mediastinal, may gradually compress the airway sufficiently to cause
symptoms. The slow growth of the goiter may deform cartilaginous rings without destroying them. When
the goiter is removed, the trachea may remain distorted in shape and narrowed, but clinically significant
airway obstruction is rarely present. Quite frequently, removal of the goiter leads to immediate
improvement in respiratory symptoms. If, however, sufficient softening of the cartilages has occurred that
was caused by the prolonged compression, removing the mass of thyroid tissue actually allows the
trachea to collapse with respiratory effort. This is determined by intraoperative bronchoscopy, local
examination and palpation in the operative field, and, finally, by observation of the patient in the operating
room after extubation. Several methods of managing this problem have evolved, including intubation with
an uncuffed tube followed by tracheostomy, preferably with insertion of a silicone T-tube several days
later when the wound is sealed, immediate buttressing of the trachea with specially made polypropylene
plastic rings, or in the past, by using traction sutures from the tracheal wall tied over either internal or
external buttons.
An anterior substernal goiter usually does not exert pressure on the trachea because of its position in
front of the great vessels. Katlic and colleagues39 reported that the trachea was more likely to be
compressed by posterior descending goiters that enter the thoracic strait lateral to the esophagus and
trachea.
VASCULAR COMPRESSION
Congenital tracheal compression caused by vascular compression is rare and treated at specialized
centers. Symptoms of tracheal compression caused by vascular compression include wheezing, dyspnea,
cough, stridor, and dysphagia. Tracheal compression or malacia may be caused by congenital vascular
rings or by aneurysms of the innominate artery or an anomalous retroesophageal subclavian artery.
Tracheomalacia in children is most often treated with aortopexy if it is due to simple vascular
compression or division of the vascular ring if present.40
Patients with a right aortic arch that rises high, turns down sharply in a hairpin configuration, and
descends on the right (accompanied by a left anomalous subclavian artery, often a diverticulum of
Kommerell, ligamentum arteriosum, and also with a narrow anteroposterior chest with or without a
degree of pectus excavatum) may suffer tracheal compression and develop severe symptoms. Excision of
the diverticulum and transplantation of the anomalous left subclavian artery to the left common carotid
artery has been described.41 In some cases, aortopexy of the arch or even arch division after aortic bypass
may be required.
MEDIASTINAL MASSES
Most mediastinal masses that compress the trachea are malignant neoplasms. On rare occasions a large
bronchogenic cyst located at the carina actually compresses the airway. Infant tracheal compression may
be caused by a large thymic cyst.
POSTPNEUMONECTOMY SYNDROME
This rare syndrome occurs if excessive and exaggerated mediastinal shift occurs toward the ipsilateral
thorax (Fig. 73.5). The resulting angulation of mediastinal structures can cause symptomatic compression
of the airway and esophagus. It was formerly thought that this was principally a syndrome seen in
children, but Grillo and colleagues42 described a number of patients in whom the problem appeared after
pneumonectomy in adulthood. Patients most commonly present with stridor or wheezing (56%) but can
also present with infection, cough, gastroesophageal reflux disease, hemoptysis, chest pain, and/or
dysphagia.43 The bronchus is actually compressed between the pulmonary artery, which is stretched in
front of it, and either the aorta or the vertebral bodies posteriorly. It cannot be predicted which patient
will suffer this distortion after pneumonectomy; however, it does occur more frequently after right
pneumonectomy. It can occur after left pneumonectomy with a left- or right-sided aortic arch. The
patient’s symptoms may be rapidly progressive and lead to total disability. Shen et al.43 have described
the surgical treatment of this problem in 18 patients by performing an extensive lysis of adhesions,
medializing the mediastinum and filling the remaining chest cavity with saline-filled breast implants with
promising results.
MISCELLANEOUS LESIONS
RELAPSING POLYCHONDRITIS
Relapsing polychondritis is a very rare progressive disease of unknown origin with no curative treatment
options. Most often, the nasal and ear cartilages and those of the tracheobronchial tree are affected. The
airway changes may precede the more diagnostic changes in the nose and ears, sometimes by years. When
the lower trachea and bronchi are affected first, the disease manifests itself by progressive airway
obstruction with difficulty in clearing secretions and ultimately pulmonary infections. In the largest series
of 145 patients with relapsing polychondritis published by Ernst et al.,44 airway involvement was
observed in 21% of patients. In this series a variety of airway pathology was described including
subglottic stenosis (26%), focal or diffuse malacia (48%), and focal stenosis.44 Bronchoscopic
interventions including dilation and stenting are often required while surgical tracheoplasty or resection
are usually not applicable and best avoided given the progressive nature of the disease and often diffuse
airway involvement. It can often become necessary to place a tracheostomy or place a silicone T-tube or
T-Y tube to secure the airway and provide palliation for a time.
FIGURE 73.5 Postpneumonectomy syndrome. A: Diagram shows extreme lateral displacement and rotation of heart and aortic
arch after right pneumonectomy with left aortic arch. The midline is indicated by a dashed line. The trachea and carina are
displaced to the right and posteriorly. The origin of the left main bronchus at the carina is compressed between the pulmonary
artery and aorta or vertebral column. The opposite occurs after left pneumonectomy with right aortic arch. (Reprinted from Grillo
HC, Shepard JA, Mathisen DJ, et al. Postpneumonectomy syndrome: diagnosis, management and results. Ann Thorac Surg
1992;54(4):638–650. Copyright © 1992 The Society of Thoracic Surgeons. With permission.) B: Posteroanterior chest
roentgenogram of a 19-year-old woman 11 months following right pneumonectomy for congenital cystic lung with hemorrhage.
Note marked mediastinal shift. Lateral radiograph confirmed posterior displacement of heart and arch. The left lung is herniated
and overexpanded. C: CT scan of the same patient showing the displacement described. The carina is also markedly shifted, and
the left main bronchus is compressed over the spine. (From Grillo HC, Shepard JA, Mathisen DJ, et al. Postpneumonectomy
syndrome: diagnosis, management and results. Ann Thorac Surg 1992;54:638–650. With permission.)
GRANULOMATOSIS WITH POLYANGIITIS

Granulomatosis with polyangiitis (GPA; previously referred to as Wegener granulomatosis) may affect the
larynx and trachea with inflammatory lesions that lead to airway obstruction from severe laryngotracheal
stenosis. The rate and extent of involvement are highly unpredictable. With response to medical treatment,
an apparently stable stenosis may result. Patients with presumed idiopathic subglottic stenosis should be
screened by serum ANCA to rule out GPA. GPA isolated to the subglottic area is best managed with
bronchoscopic interventions such as dilation and steroid therapy in most cases and this has been proven
effective for most patients achieving long-term airway patency in almost all patients.45 Complete
laryngotracheal reconstruction has been described but patients with GPA often require future
bronchoscopic interventions.46
SARCOIDOSIS
Sarcoidosis is an inflammatory disease that can affect many organ systems including the lungs and airway
both intraluminally or through external airway compression secondary to massive enlargement of
mediastinal lymph nodes. Intraluminal findings can include cobble-stoning, mucosal erythema, plaques,
nodules, bronchial stenosis, airway distortion, and bronchiolitis.47 The primary treatment for sarcoidosis
is medical, of course, and airway surgery is rare, if ever indicated. If a circumferential stenosis results
that involves a long segment of trachea and main bronchi, and sometimes, bronchi more distally. These
lesions are not amenable to surgical treatment because of their diffuseness and extent, but periodic
dilation is effective for some time.
TRACHEOBRONCHIAL AMYLOIDOSIS
Amyloid disease on rare occasions involves the trachea and main bronchi in an extensive process leading
to narrowing of the tracheobronchial tree causing dyspnea and wheezing. Due to its rarity, there is no
standard treatment. Therapies that have been described include medications, bronchoscopic interventions,
external beam radiation, and rarely airway resection for short segment disease.
TRACHEOPATHIA OSTEOPLASTICA
Tracheopathia osteoplastica or tracheobronchopathia osteoplastica is a rare disease with an unknown
cause and no known curative treatment option. It manifests itself pathologically by the formation of
calcified nodules beneath the mucosa, adjacent to but not actually originating from the cartilages, as
described by Young and colleagues.48 The involvement may commence in the subglottic larynx and extend
throughout the trachea and more distally into the bronchial tree. The trachea often is of saber-sheath
configuration. It appears in adults, progressing insidiously. Patients have difficulty in raising their
tenacious secretions as the disease progresses and recurrent infections can occur. Ultimately, severe
obstructive symptoms may ensue. In some patients, however, the disease remains a curiosity and does not
seriously impair them. Medical support is indicated and bronchoscopic interventions may be required if
airway obstruction occurs.
TRACHEOBRONCHOMEGALY
Tracheobronchomegaly (Mounier-Kuhn syndrome) is probably of congenital origin, although it usually
becomes clinically manifest in adulthood. The trachea appears markedly widened on radiographic
examination, with both unusually elongated and deformed cartilages, and a redundant membranous wall.
The cartilages gradually tend to assume a reverse curve, which brings the redundant membranous wall up
against the cartilages, causing severe malacia. The significant expiratory collapse manifests as symptoms
of disabling cough, dyspnea, and secretion retention. Central airway stabilization via a posterior mesh
tracheobronchoplasty may offer symptomatic relief in select patients with Mounier-Kuhn syndrome and
tracheobronchomalacia.49
SABER-SHEATH TRACHEA
Saber-sheath trachea is a deformity seen usually as an incidental finding in patients with varying degrees
of chronic obstructive pulmonary disease later in their life. The original radiologic presentation was
detailed by Greene and Lechner50 in 1975. The lower two-thirds of the trachea, the intrathoracic trachea,
gradually assume a configuration in which the side-to-side diameter diminishes progressively and the AP
diameter increases, thereby changing the configuration of the airway. In early stages the deformity causes
no difficulty, but as it becomes more and more marked, the posterior part of the cartilages approximate
one another with attempts to cough and breathe deeply, and the patient finds that he or she cannot clear
secretions. The proximal cervical portion of the trachea usually appears quite normal. Currently, surgical
intervention is not indicated and treatment is medical.
IDIOPATHIC TRACHEAL STENOSIS

Idiopathic tracheal stenosis presents over a wide spectrum of age, almost exclusively in women, with
progressive dyspnea on exertion and wheezing.51–53 Patients with idiopathic tracheal stenosis are usually
found to have a short stenosis (approximately 2 to 3 cm) involving the uppermost trachea and, in many
cases, the subglottic larynx as well. Distally, the trachea appears quite normal. The patients have no
history of trauma, infection, inhalation injury, intubation for ventilation, or any other tracheal or airway
disease. In a clinical series by Grillo and colleagues,52 only three patients had any systemic symptoms.
Two had mild arthralgias, and one had poorly defined arteritis. Many who had been followed for as long
as 15 years had never developed any other systemic symptoms. There is some thought that
gastroesophageal reflux disease may be a contributing factor to the development of stenosis in these
patients.54
The stricture itself is roughly circumferential and pathologically shows only chronic inflammation with
marked submucosal fibrosis. The cartilages are uninvolved. The pathology is distinct from polychondritis,
GPA, or any of the aforementioned conditions. The patients do not have mediastinal fibrosis or pathologic
processes involving mediastinal lymph nodes. An antinuclear cytoplasmic antibody (ANCA) test is
essential to exclude isolated upper-airway stenosis due to GPA. Idiopathic laryngotracheal stenosis
characteristically is not progressive, nor does it recur after successful resection, as shown by Ashiku and
Mathisen.51
In addition to this quite well-defined lesion, some patients present with stenosis involving a large part
of the trachea, or with an undefined inflammatory fibrotic process involving the carina or main bronchi, or
both. In this small group of patients, no other incriminating signs, symptoms, or laboratory findings occur
to implicate any known disease or syndrome. The process progresses in some of these patients,
sometimes fatally.
TRACHEOBRONCHOMALACIA
Tracheomalacia is classically defined as expiratory collapse of the posterior membrane with a reduced
anterior–posterior caliber of at least 50% of the airway diameter; however, this definition undoubtedly
overlaps with physiologically normal levels of dynamic airway collapse.55 More significant levels of
obstruction—80% to 100% of the luminal cross-sectional area—are generally thought to be associated
with significant symptoms, including dyspnea, a barking seal-like cough, and recurrent infections. It can
be idiopathic but is associated with gastroesophageal reflux disease, COPD, obesity and can also be
iatrogenic due to postintubation injury of the airway.
Dynamic CT and dynamic bronchoscopy are the best objective tests to assess for this disease.56
Surgical management of this disease is performed at specialized centers and patient selection for
tracheobronchoplasty is extremely important. If a patient with tracheobronchomalacia is a potential
operative candidate, further workup is obtained to assess whether or not central airway stabilization using
a permanent Marlex mesh (tracheobronchoplasty) is likely to benefit the individual. Therefore, the next
step to determine operative candidacy is to perform a stent trial whereby a temporary silicone Y stent is
placed in the airway to mimic posterior membrane stabilization. PFTs, including the 6-minute walk test,
are repeated with the stent in place and the patient is evaluated for subjective improvement of their
symptoms using validated scales. If the patient clinically responds to the stent, a tracheobronchoplasty is
offered. This procedure is performed via a right thoracotomy and involves plicating the posterior
membrane to Marlex mesh.57,58 In a review of 63 patients that underwent tracheobronchoplasty, both
subjective and objective measures of improvement were statistically significant including the Karnofsky
performance scale, ATS dyspnea score, SGRQ quality of life measure, and a 6-minute walk test.58
DIAGNOSTIC STUDIES
Tracheal lesions often are recognized late despite a prolonged period of respiratory symptoms including
cough, stridor, wheeze, recurrent infections, and dyspnea lasting months or even years. Physicians should
be suspicious of a diagnosis of adult-onset asthma and this should prompt further workup to rule out a
tracheal lesion. Computed tomography (CT) is used to rule out the possibility of a tracheal lesion in any
patient who has obstructive airway symptoms but radiographic demonstration of normal lung fields.
However, bronchoscopy remains the gold standard and should be used if symptoms are progressive or
suspicious and CT does not reveal any other causes for the patient’s symptoms.
RADIOGRAPHIC EXAMINATION OF THE TRACHEA

Radiographic studies of the trachea are used not only to rule in or out the presence of a tracheal lesion but
also to define the location, extent, and sometimes the character of the lesion (Fig. 73.6).
Older techniques such as tracheal laminography largely have been supplanted by CT scans. CT scans
are valuable in showing the mediastinal extent of a tumor, goiter, vascular lesions, or histoplasmosis. CT
images may also imply inflammatory conditions of the airway such as relapsing polychondritis with
abnormally thickened walls. Dynamic (inspiratory and expiratory) CT is especially useful when
evaluating patients for tracheobronchomalacia.59
FIGURE 73.6 Radiographs showing various injuries from tracheostomy tubes. A: Lateral view of the neck. The circular opaque
marker is on the skin at the tracheostomy site. The black arrow points to a large inflammatory granuloma occluding the tracheal
lumen. Some narrowing of the trachea is seen at this level. Endoscopic removal alone was required. B: Similar view showing an
anterior stomal stricture. A deep indentation of the anterior trachea is seen at the level marked by the arrow. Resection and
reconstruction were necessary. C: Detail of left anterior oblique view of the chest, showing a lengthy midtracheal stenosis
marked by the two black arrows. D: Laminogram showing the stenosis in (C). The upper narrowing is at the laryngeal level and
is normal. E: Lateral neck view with hyperextension to demonstrate granuloma in a child’s trachea at the level of the tube’s tip.
Ventilatory support without a cuff had been given after a cardiac operation in this child. (B, C: Reprinted from Grillo HC. Surgery
of the trachea. Curr Probl Surg 1970;7:3–59. Copyright © 1970 Elsevier. With permission.)
If a patient with tracheal stenosis still has a tracheostomy tube in place, it should be removed during
radiographic examination to obtain useful information with caution and only if possible. Even if a tube has
been in place for many months, it should be removed with provision made for immediate reinsertion.
Emergency equipment including suctioning devices and a range of replacement tubes should be available.
Weber and Grillo60 described the radiographic findings in the tracheal tumors and stenosis in 1971.
Magnetic resonance imaging (MRI) is another imaging modality that can be used to evaluate tracheal
pathology. Normal anatomic structures can be differentiated on the basis of different signal intensities on
T-1 weighted sequences. A bright signal is elicited by fat, hyaline cartilage, submucosal fascial planes,
and false cords. Intermediate signal intensities are given off by the aryepiglottic folds, the true cords, and
the intrinsic laryngeal muscles. Low signals are given off by calcified cartilage, the airway, and blood
vessels.
Virtual bronchoscopy using 3D reconstructions from CT images is a noninvasive modality useful for
evaluating tracheal and bronchial pathology.61 This new imaging modality can be used for initial
evaluation of the trachea, but does not replace the precise and direct evaluation of the trachea by
traditional bronchoscopy. Finkelstein and colleagues62 demonstrated that virtual bronchoscopy had a
sensitivity of 100% for diagnosing obstructive lesions of the trachea in 32 consecutive patients.
BRONCHOSCOPY
Bronchoscopic examination is required in nearly all patients. When a lesion is known to be present,
whether it is neoplastic or inflammatory, and when all else points to a surgical correctable lesion,
bronchoscopy is best deferred until preparations have been made for definitive treatment of the lesion.
The trauma of bronchoscopy in a patient who is subtotally obstructed may precipitate complete
obstruction. Little is lost by delaying the bronchoscopy until the time of the definitive operation. Frozen
sections may be obtained for histologic diagnosis. In the presence of most obstructive lesions, the
requirements for resection are clear at the outset. The bronchoscopy is done with the patient under general
anesthesia, permitting unhurried, atraumatic examination, and manipulation.
Bronchoscopic examination and removal are all that is required in patients with polypoid granulomas
at the stomal site or at the site of the tube tip. Esophagoscopy is also performed when neoplasms are
examined. Rigid bronchoscopy, under general inhalational anesthesia, using ascending serial pediatric
bronchoscopes, is used to dilate severe stenosis for emergency relief. Urgent operation is almost never
required. Obstructing tumors may similarly be relieved in an emergency situation, or if time is needed to
assess a patient, by coring out tumor tissue with the tip of the bronchoscope assisted with biopsy forceps.
Bleeding or obstruction has rarely been encountered using this technique.
OTHER DIAGNOSTIC STUDIES

Pulmonary function studies in patients with obstructing lesions of the trachea confirm a high degree of
airway obstruction. Measurements are sometimes useful in clarifying the presence of parenchymal disease
and may alter the extent of the operative approach. Obstructing lesions generally require surgical relief.
Function studies provide a useful basis for measurement of results, especially FEV1, peak expiratory flow
rate, and flow–volume loops. Bacteriologic cultures are made from tracheal secretions and tracheostomy
wounds. Antibiotic sensitivities guide prophylactic perioperative antibiotic choice.
OPERATIVE VERSUS NONOPERATIVE TREATMENT

In the case of central airway obstruction, emergent bronchoscopic mechanical, ablative (electrocautery,
argon plasma coagulation, laser), and cryoprobe recanalization are indicated and usually very successful,
without the need for emergency surgical resection.63 The preferred treatment of long segment benign
obstruction of the trachea is resection and reconstruction. With careful evaluation, planning, and
execution, most patients with lesions such as postintubation tracheal stenosis can be successfully treated
operatively when they have recovered from the primary disease that led to the stenosis. A properly
conducted anesthesia and operative repair from the anterior approach do not have great physiologic
impact on the patient. Rarely, the medical condition may preclude even the relatively benign procedure
required for correction. If the patient has serious neurologic or psychiatric deficits that prevent
cooperation in the postoperative phase, reconstruction is best deferred. Anesthesia should be selected to
avoid the need for ventilatory support postoperatively. If ventilatory support is needed postoperatively in
a shortened trachea, the cuff might rest against the anastomosis and lead to dehiscence.
Temporizing methods available are repetitive bronchoscopic dilation of a stenosis or reinstitution of a
tracheostomy, dilation of the stricture, and passage of a tracheostomy tube or a silicone tube through the
lesion to splint the airway. Lesions in the immediate supracarinal position are not easily managed in this
way. A tube long enough to remain seated often causes episodes of obstruction when it is near the carina,
and a T-Y tube or a silicone dynamic stent may lead to bronchial granulations. Generally, however, it is
wiser to use a tube for a permanent airway than to undertake a hazardous reconstruction that has a high
risk for failure. Cooper and colleagues64 and Gaissert and colleagues65 have detailed the uses and results
of T-tube management of complex airway problems.
Repeated dilation and splinting have been proposed as definitive methods for treating tracheal
stenosis. In most severe lesions in which the whole thickness of the tracheal wall has been converted to
scar tissue, even prolonged stenting for many years may not lead to permanent recovery. When lesser
degrees of damage have occurred, either in the completeness of a stricture of the circumference of the
trachea or in the depth of the tracheal wall, a period of prolonged splinting may, on occasion, result in an
adequate airway after removal of the splint. Such a result has been reported in children. Self-expanding
metal stents should be used for short durations with caution because they have been shown to incite
granulation tissue formation in the trachea and potentially cause tracheoesophageal fistula.5
Expandable stents, even when coated, may cause severe complications over time, such as acute
obstruction, migration, granulation, and stenosis. Although acceptable for palliation in fatal neoplasms
that are not otherwise manageable, stents in benign disease may convert a surgically curable lesion to an
incurable one and should be used with caution at experienced centers. Most patients with postintubation
tracheal stenosis can be repaired successfully when first identified. Successive failed or inappropriate
therapies such as repeated dilation or stenting for long segment strictures can make such patients’ stenoses
unreconstructable. A recent series has looked at endoscopic treatment of A-frame tracheal stenosis and
found that longer-term (12 to 18 months) indwelling stents (silicone and self-expanding metal) in patients
not suitable for tracheal resection yielded a success rate of just 63%.66
Newer endoscopic techniques such as cryospray to establish and maintain airway patency deserve
further study but the early results are promising.67
PREVENTION OF POSTINTUBATION TRACHEAL STENOSIS

The incidence of stenosis at the stomal level can be reduced by careful placement of the stoma, avoidance
of large apertures, elimination of heavy and prying ventilatory connecting equipment, and meticulous care
of the tracheostomy. Many proposals have been made to reduce the formerly inevitable occurrence of
some stenoses at the cuff level. These methods included use of double-cuff tubes, changes in materials and
sterilization techniques, attempts to avoid cuffs altogether, use of disk and sponge seals instead of cuffs,
use of spacers to relocate the cuff level periodically, and prestretching of plastic cuffs. The development
of large-volume, low-pressure cuffs that conform to the shape of the trachea rather than deforming it,
described by Cooper and Grillo29 and by Grillo et al.30 (Fig. 73.7) has been a major breakthrough in
mitigating the risk of tracheal injury during intubation. Such a cuff provides a seal at intracuff pressures of
33 mm Hg compared with 270 mm Hg in a comparative Rusch standard cuff. Thus, in a series of 45
randomized patients in whom such a low-pressure cuff was compared with standard cuffs, 25 patients
with the low-pressure cuff showed half as much damage as the 20 patients with standard cuffs when
viewed endoscopically at the time of cuff deflation. All severe damage was in the standard group. The
incidence of cuff stenosis has markedly decreased as equipment has improved, but low-pressure cuffs
must be inflated carefully to avoid converting them to high-pressure cuffs. Failure to do so has continued
to produce a steady flow of stenoses requiring reconstruction. Although laryngeal injury is rare,
cricothyroidotomy should be avoided because injury may not be correctable when it does occur. Tracheal
injuries are usually reparable when they first occur. Inappropriate treatment serves to make some
uncorrectable.
RESULTS OF TREATMENT
Grillo and colleagues68 have had a large experience with postintubation injury. Between 1965 and early
1992, a total of 104 of the referred patients had undergone prior reconstructive attempts or other major
tracheal procedures; 251 had postintubation stenoses at the site of an inflatable cuff; 178 stomal stenoses;
and 38 stomal and cuff stenoses. In 36 patients the origin was uncertain, while 62 had involvement of the
subglottic larynx, and one presented with a tracheoinnominate arterial cuff fistula. Corrective
reconstructive surgery was effected via a cervical incision alone in 350 of these patients, with the
addition of an upper sternotomy required in 145 patients. Six required surgery through the transthoracic
route. A skin tube replacement was constructed in one patient, for a total of 521 operations in 503
patients.
In 440 patients, the results were good or excellent. An excellent result denotes an anatomically and
functionally normal airway. The patient suffers no limitation because of the airway, and essentially no
narrowing is demonstrated at the anastomotic site on either radiographic or bronchoscopic examination.
Patients classified as having a good result have no functional difficulty but may have a minimal anatomic
narrowing that is definable on either radiographic study or bronchoscopic examination. The results in 31
patients were classified as satisfactory. These patients are able to carry out all of their normal daily
activities but have enough narrowing of the airway to limit major physical effort.
FIGURE 73.7 A: Diagram of the mechanism of pressure necrosis by a tracheostomy cuff and its avoidance. (a) Normal elliptic
shape of the trachea. When a conventional cuff is inflated, it may expand in circular fashion in its widest diameter but at this
point fails to occlude the basically irregularly elliptic shape of the trachea. (b) Further distention has been required to effect a
seal. At this point the trachea is deformed by the cuff, and much of the considerable intracuff tension is transmitted to the
tracheal wall. (c) A large-volume, low-pressure cuff has been inflated with a minimal amount of air. The cuff conforms to the
irregular shape of the lumen and provides a seal at low intracuff pressures. Correspondingly low pressures are transmitted to the
tracheal wall. B: Comparison of a standard cuff and a large-volume, low-pressure cuff. On the left, the large-volume cuff is
shown spontaneously filled with air. No stretch has been placed on the rubber of the cuff wall at this point. The volume is
sufficient to occlude most adult tracheas. On the right, a Rusch cuff has been distended with 8 mL of air. It is tense and
eccentric. The stretching of the rubber has created a hard structure that exerts considerable pressure on the trachea, which it
must deform to provide a seal. (Reprinted from Grillo HC, Cooper JD, Geffin B, et al. A low pressure cuff for tracheostomy
tubes to minimize tracheal injury: a comparative clinical trial. J Thorac Cardiovasc Surg 1971;62:898. Copyright © 1971 The
American Association for Thoracic Surgery. With permission.)
Twenty patients had treatments listed as failures. Causes of failure included inadequate appreciation of
existing neurologic dysphagia, cardiac decompensation requiring postoperative ventilation, unappreciated
severe laryngeal dysfunction, and restenosis. Five deaths occurred. In four of the patients that died, the
patients were intubated prior to transfer, and hence reconstruction was contraindicated but undertaken
because no therapeutic alternative existed. The fifth patient developed bilateral pneumonia and could not
be weaned from postoperative ventilator support.
The management of acquired benign tracheoesophageal fistula depends on whether the adjacent
segment of trachea is circumferentially damaged, as it almost always is in postintubation lesions, or
whether the posterior wall fistula is the sole tracheal pathology, as is common in fistulae resulting from a
foreign body. In the first case, concomitant tracheal resection is done with lateral excision of the fistula in
the esophageal wall. In the latter, tracheal resection is unnecessary, and both membranous tracheal wall
and esophageal wall are precisely repaired after division of the fistula. Healthy tissue, such as strap
muscles anteriorly or intercostal muscles from the transthoracic approach, is always interposed between
the two suture lines to prevent recurrence. Mathisen and colleagues69 noted excellent results after repair
of 27 postintubation fistulae, with one death after anastomotic separation consequent to an extensive
tracheal resection. Three deaths also occurred after transthoracic repair of distal posttraumatic fistula in
the presence of established mediastinal sepsis. All three required postoperative ventilation. Prompt
recognition and repair following the initial injury would likely have been successful.
Grillo and colleagues70 reported on single-stage laryngotracheal resection and repair of postintubation
subglottic stenosis involving the larynx and upper trachea in 50 patients. An additional 30 patients had
stenoses in the same location from other causes: trauma (7); idiopathic (19); and miscellaneous (4). Long-
term results were excellent in 18 patients, good in 51, satisfactory in 8, and failed in 2. One died of acute
myocardial infarction. Maddaus71 and Couraud72 and their colleagues have produced similar encouraging
results.
Mathisen and Grillo15 found that 16 of 17 patients treated for laryngotracheal stenosis resulting from
trauma had good airways and voices, despite the initial presence of vocal cord paralysis in 14. Four also
had esophageal injury requiring repair. Eight needed intralaryngeal procedures before laryngotracheal
repair.
Gaissert and colleagues65 found that complex laryngotracheal strictures caused by burns responded
well in many cases to prolonged stenting (mean 28 months), with recovery of a functional airway and
voice in most patients. In a few, resection of subglottic stenosis was necessary. Early tracheal resection
was best avoided. Of 16 patients treated, 9 required no airway support, 4 have permanent tracheal tubes,
2 died (1 from respiratory failure and 1 from an unrelated cause), and 1 was lost to follow-up.
After a failed attempt at tracheal reconstruction with postoperative stenosis, it is best to wait for a
prolonged period to permit resolution of the scar and inflammation in the operative field. A minimum of 4
months and preferably 6 months should be allowed. In the interim, it may be necessary to insert a tracheal
T-tube or tracheostomy tube to maintain the airway.73 Reoperation is often extremely difficult. It is
surprising, however, to find that in some situations where the original anastomosis appeared to be under
tension, the reresection of a limited stricture may be done with no apparent tension at the time of the
second repair. This, however, is not universally true. The greatest enemy of secondary resection is the
possibility of anastomotic tension, which may have led to the first failure. Much, therefore, depends on the
individual history of the patient.
Histoplasmosis can present nearly insurmountable problems in airway management. In a description of
the manifestations of mediastinal fibrosis and histoplasmosis, Mathisen and Grillo7 listed nine patients
who had undergone tracheobronchoplastic procedures: right carinal pneumonectomy in four, carinal
reconstruction in one, sleeve lobectomy in three, and main bronchial sleeve resection in one. Of these
nine patients, three died postoperatively, one from anastomotic separation after extended resection and
two from postpneumonectomy respiratory distress syndrome. Mitchell and colleagues74 reported 143
carinal resections with reconstruction, 16 of which were for benign or inflammatory strictures from a
variety of etiologies.
Grillo and colleagues42 presented the results of surgical attempts to treat severe postpneumonectomy
syndrome in 11 adults; 10 underwent mediastinal repositioning (Fig. 73.8).
Among these, five who did not also develop tracheobronchomalacia did well. Another died from
presumed pulmonary embolism and four suffered malacic obstruction unrelieved by repositioning. Aortic
division with bypass to relieve compression and resection of the malacic airway in these desperately ill
patients produced only one success. Clearly, correction must be done early, before malacia develops.
Since then an additional 11 patients have undergone mediastinal repositioning with insertion of saline-
filled prostheses to prevent recurrence. All have survived with improvement; none displayed malacia.
Extrinsic compression caused by substernal or intrathoracic goiter is generally relieved by
thyroidectomy, without the need for tracheal procedures, as shown by Katlic and colleagues39 in a series
of 80 patients. Dyspnea was present preoperatively in 28% and stridor in 16%; 79% had tracheal
deviation. Flow–volume loops showed tracheal obstruction. No deaths occurred. The procedure is well
tolerated even by frail and aged patients: only a few required tracheal splinting. No effective medical
treatment exists.
Ashiku and Mathisen51 treated 73 patients with idiopathic laryngotracheal stenosis by one-stage
resection and reconstruction: 19 (26%) of 72 achieved normal airway and voice while 47 (64%) had
some expected diminution of voice projection or quality of singing voice because of laryngeal reshaping.
Median follow-up of 8 years revealed no progression of disease or recurrence, the latter casting doubt on
suspicion of pharyngolaryngeal reflux as a possible cause.
For severe obstructive tracheopathia osteoplastica, a tracheal fissure from the cricoid to the carina
may be performed with insertion of a T-tube or T-Y tube for splinting. Once the trachea has been divided
anteriorly, because the membranous wall is not involved by the disease process, it is possible to hinge the
two anterolateral walls on either side outward so that a wide lumen is created by the T-tube. The tracheal
wall can then be sutured together again. The T-tube is allowed to remain in place for 4 to 6 months to
allow healing of the trachea in an open position. The tube is then removed, having established an adequate
airway. Prior attempts to use the laser have failed.
An attempt at splinting and shortening the posterior membranous wall combined with an attempt to
reshape the reverse curve of the cartilages failed in one patient with Mounier-Kuhn disease in whom it
was attempted. It was necessary to insert an inlying permanent tracheal T-tube. Two other patients were
treated in similar fashion since that time, and all achieved satisfactory palliative results.
In patients with tracheobronchomalacia affecting the lower two-thirds of the trachea and main bronchi
with softened, splayed out cartilages in an archer’s bow configuration and a redundant membranous
tracheal wall, stabilizing the trachea by plicating the posterior membrane using Marlex mesh has been
well described.57,58 A strip of splinting material is placed along the membranous wall of the trachea (Fig.
73.9) in a width corresponding to the estimated normal dimension. The corners of the cartilages on either
side are sutured to the splint, and the membranous wall is quilted to the splint as well. Pulling the two
ends of the cartilages together posteriorly causes the cartilages to arch forward, recreating a more normal
cross-sectional configuration. The redundant membranous wall is fixed to the splint posteriorly so that it
cannot pout forward to obstruct the lumen.
FIGURE 73.8 Correction of postpneumonectomy syndrome. Same patient as seen in Figure 73.5, postoperatively. A:
Posteroanterior chest roentgenogram. The trachea and mediastinum are restored to midline, and the left lung volume is reduced
to normal. B: CT scan shows normalized mediastinal anatomy with widely open left main bronchus. The prosthesis necessary to
maintain correction is clearly visible in the right hemithorax.
FIGURE 73.9 Posterior airway plication and stabilization using Marlex mesh performed via a right thoracotomy for
tracheobronchomalacia.
Gore-Tex (W.L. Gore & Associates, Flagstaff, AZ) gives an excellent initial result. After some months,
fluid may accumulate between the Gore-Tex and the membranous wall where sutures pull through,
because Gore-Tex does not become enmeshed in scar tissue. Strips of pericardium have been used but
tend to attenuate with time.
Marlex mesh has pores large enough to permit ingrowth of connective tissue that fuses it to the
membranous wall, providing permanent correction, but has been known to cause erosion into surrounding
structures. The procedure does not correct underlying obstructive pulmonary disease, from which most of
these patients suffer, but it improves the patients’ ability to raise secretions with a more effective cough.
The intrathoracic lower two-thirds of the trachea, right main bronchus, bronchus intermedius, and left
main bronchus are splinted using this method via a right thoracotomy. Despite the arduous nature of this
surgery, nearly 80% of patients report improvement in their symptoms of dyspnea, cough, or recurrent
infection.
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74
Benign and Malignant Tumors of the
Trachea
Henning A. Gaissert
Located between larynx and lung, two common sites of respiratory neoplastic disease, the trachea enjoys
relative protection from exposure to carcinogens due to the laminar flow characteristics of respiration.
Tracheal tumors are rare. The patient presenting with a tracheal tumor faces the problems arising from
rare disease. Unless far advanced or accompanied by bleeding, symptomatic airway obstruction is most
often attributed to the more common benign structural lung diseases. Uncertainty about evaluation and
management contributes to treatment delay. Treatment options available at centers of experience may not
be common knowledge; surgical resection is often not considered; nonsurgical management may substitute
for missing surgical expertise. Therefore, optimal management and subsequent outcome usually depend on
a sequence of fortuitous events beginning with attention to symptom characteristics and the referral to one
of now more numerous centers of experience.
Given these limitations, the tumor least likely to receive adequate management is squamous cell
carcinoma, which is the most common of all. This is due to its rapid progression over weeks and months
within the airway and to distant sites. In contrast, benign and slowly progressive malignant tumors
constitute those tumors most accessible to complete resection. In this chapter, the clinical experience with
benign and malignant tracheal tumors is reviewed.
EPIDEMIOLOGY
National disease statistics rely on a certain clinical diagnosis for all suspected cases and a certainty of
disease absence in the unsuspected population. Neither may be assumed for tracheal tumors since
radiologic and pathologic confirmation are missing for most epidemiological studies. The majority of
tumors listed as tumors in the trachea are, in fact, metastatic lesions. A comparison between
epidemiological and clinical studies points to differences in tumor histology that are best explained by the
reporting physicians and pathologists mistaking lymphatic metastasis growing into the trachea as primary
tumors. Table 74.1 shows the histologic variations between population and clinical studies. This
comparison has appeared elsewhere, but is essential to an understanding of tracheal tumors. A greater
proportion of squamous carcinoma in epidemiological surveys could be explained by rapid tumor growth
so that more patients with unresectable disease present to clinicians. Conversely, so few adeno- and small
cell carcinomas are seen in surgical series that one should doubt that the percentages listed in these
epidemiological reports; these histologic types in the trachea are most often metastatic. One
epidemiological survey, shown in Figure 74.1, included reviews of radiographs and a part of the medical
record. A third of all tracheal tumors in this report, originally thought to be primary were subsequently
labeled metastatic.
Manninen and his colleagues1 determined the annual incidence of tracheal tumors for Finland as 1 per
million. A study of the Dutch cancer registry that includes a radiographic review2 confirms this estimate,
counting 1 to 2 cases per million persons per year. Data from the American National Cancer Institute’s
Surveillance, Epidemiology and End Results (SEER) project3 estimated the incidence at 2.6 per million
per year. Licht and colleagues4 in Denmark found over an 18-year period that tracheal tumor made up
0.02% of all tumors. Resection rates in such studies are low. Rates of 6.3% in Finland and 8.2% in
Denmark led Licht and colleagues4 to lament a nihilistic attitude about surgical therapy. A disappointing
overall 5-year survival of 13% for all cases is not a surprise. Honings and colleagues2 estimated by
radiographic review from Dutch cancer cases that the resection rate of 24% could be potentially doubled
to 56% with more determined use of tracheal resection. The authors demonstrated that expert review as
part of the audit reverses the proportions of tumors treated with resection and primary radiation.
CLINICAL FEATURES, DIAGNOSIS, AND SURGICAL TREATMENT
SYMPTOMS AND FINDINGS

Except when airway bleeding or near-asphyxiation forces a reconsideration of the diagnosis, primary
treating clinicians often mistake dyspnea, wheezing, or cough caused by neoplastic tracheal obstruction
for symptoms of chronic obstructive lung disease. However, close observation and follow-up may point
to symptoms inconsistent with asthma or emphysema such as the rapid progression or unilateral wheezing
in adult-onset neoplastic asthma, the invariable lack of response to medical therapy and obstruction on
inspiration. It must be recognized that such symptoms are frequently missed by very astute clinicians, even
those who treat airway disease.
Table 74.2 lists the symptoms of the two most common tracheal carcinomas. Groups of tracheal tumors
progress at different rates. Mean symptom duration as shown in Figure 74.2 reveals characteristic
differences between squamous carcinoma, other bronchogenic carcinomas, or high-grade sarcomas on one
side and benign, low-grade malignant, or adenoid cystic carcinomas on the other. While the clinical
course of individual tumors may deviate substantially from the mean, these symptom ranges should serve
to suggest a tumor type when obtaining a patient’s history. More than half of all squamous cell carcinomas
and less than a third of adenoid cystic carcinomas presented with hemoptysis,5 a difference likely
reflecting a mix of tumor necrosis and vascularization. In clinical scenarios, hemoptysis may lead to
earlier investigation and thus can abbreviate the time to diagnosis.
TABLE 74.1 Comparison of Tumor Types Observed in Population Surveys and in
Retrospective Clinical Studies
Author Year Period Cases Squamous Adenoid Adenocarcinoma Small Cell Large Cell Mucoepid
Cell Cystic Carcinoma Carcinoma
Carcinoma Carcinoma
Population-Based Studies
Kurien31 1981 1957– 97 46 3 6 5

1974
Manninen1 1991 1967– 95 72 6 13 7

1985
Gelder32 1993 20 years 321 52 11 4 5 6
Yang33 1997 1979– 67 52 8 15 6 5

1994
Licht4 2001 1978– 109 63 7 10 7 2 1

1994
Honings2 2007 1989– 308 54 7 6 11 8

2002
Clinical Radiotherapeutic Studies
Chao34 1998 1962– 42 67 7 5 5

1995
Clinical Surgical Studies
Pearson35 1984 1963– 44 20 64

1983
Grillo36 1990 1963– 198 35 40 1 1 2

1989
Regnard10 1995 1970– 208 45 31 2 2

1993
Perelman12 1996 1996– 120 17 55 1 3 1

1995
Zhengjaiang37 2008 1981– 69 30 51 3 3 7

2002
Numbers under tumor type indicate percentages.

With permission from Honings J, Gaissert HA. Tumors of the trachea. In: Kużdżał J, Praktyczna M, eds. ESTS Textbook of Thoracic
Surgery. Cracow, Poland; 2014.
FIGURE 74.1 A consort diagram demonstrating the effect of individual radiographic review on epidemiological data from the
Netherlands Cancer Registry for tracheal tumor. Note the high proportion of metastatic lesions registered as primary tumor and
the reversal of the proportion of cases treated with radiation and resection when epidemiological records are judged after
radiographic and chart review. (From Honings J, Gaissert HA, Verhagen AF, et al. Undertreatment of tracheal carcinoma:
multidisciplinary audit of epidemiologic data. Ann Surg Oncol 2009;16(2):246–253. Reproduced with permission of Springer
New York LLC in the format Book via Copyright Clearance Center.)
The opportunity to diagnose a curable squamous carcinoma of the trachea is remarkably short. As
suggested in Figure 74.2, a few months spent following up an unclear symptom may mean the difference
between curative and palliative therapy. More than one-fourth of patients with tracheal squamous cell
carcinomas had prior lung resections for cancer. This emphasizes the importance of large airway
surveillance in patients with bronchogenic carcinoma.5
Tumors growing close to the recurrent laryngeal nerve may cause vocal cord paresis. Yet, hoarseness
is not the typical symptom of cord paresis. In fact, hoarseness fails to predict vocal cord dysfunction in
subglottic tumors. Among 25 patients undergoing laryngotracheal resection, seven patients without
hoarseness were found to have invasion of the recurrent laryngeal nerve while four patients with
hoarseness had no invasion.6 A diminished projection of the voice and the patient’s own sense of a change
in voice quality are more subtle signs of nerve dysfunction.
TABLE 74.2 Symptoms Among 270 Patients With Primary Tracheal Adenoid Cystic or
Squamous Cell Carcinoma. The Cases Were Evenly Divided Between Both Tumor
Types; Note the Predominance of Nonspecific Obstructive Symptoms and a
Presentation with Hemoptysis in a Majority of Squamous Carcinoma. ACC—Adenoid
Cystic Carcinoma, SCC—Squamous Cell Carcinoma
ACC SCC x2 p Value
Symptoms (%)
Dyspnea 65 50 0.014
Cough 55 52 0.626
Hemoptysis 29 60 <0.001
Wheeze 44 27 0.003
Stridor 21 27 0.200
Hoarseness 10 13 0.495
Dysphagia 7 7 0.812
Fever 7 4 0.184
Other 12 14 0.495
Reprinted from Gaissert HA, Grillo HC, Shadmehr MB, et al. Long-term survival after resection of primary adenoid cystic and squamous cell
carcinoma of the trachea and carina. Ann Thorac Surg 2004;78(6):1889–1896; discussion 1896–1897. Copyright © 2004 The Society of
Thoracic Surgeons. With permission.
Physical examination is rarely specific. Auscultation of the trachea may or may not indicate stridor
unless tumor size or degree of obstruction or both are advanced. The final extent of airway obstruction
tolerated by individual patients when tumors are slowly evolving is surprising, as patient awareness of
even the use of the accessory muscles of respiration may be lost. Careful observation of chest wall
excursion informs the examiner about the degree of obstruction in these cases.
DIAGNOSIS
Various tests may lead to the discovery of a tracheal tumor, such as a characteristic flow-volume loop
with flattened and prolonged inspiration or a localized opacity along the tracheal air shadow on the chest
radiograph. Incidental discovery most often suggests a benign or low-grade malignant tumor. Figure 74.3
shows the computed tomogram of an incidentally discovered chondroma. Conversely, though more
common in malignancy, symptoms do not exclude a benign or low-grade tumor. Additional information
sought in malignant tumors are the dimensions of the tumor in longitudinal and radial extent, any vascular
invasion, and more subtle signs of invasion such as the thickness of the tracheal wall. Figure 74.4 shows
images of an adenoid cystic carcinoma of the trachea and carina at different levels. Figure 74.5
demonstrates new tracheal thickening in a patient followed after lung resection for squamous cell
carcinoma. This subtle finding was missed on first reading of the CT but discovered on surveillance
bronchoscopy.
FIGURE 74.2 Mean symptom duration recorded as months from onset of symptoms to diagnosis in patients with primary
tracheal tumors. The two most common primary tumors, adenoid cystic and squamous carcinoma, are separated into resectable
(R) and unresectable (U). Note the short symptomatic interval for resectable bronchogenic carcinomas. (Reprinted from
Gaissert HA, Burns J. The compromised airway: tumors, strictures, and tracheomalacia. Surg Clin North Am 2010:90;1065–
1089. Copyright © 2010 Elsevier. With permission.)
FIGURE 74.3 Incidentally discovered midtracheal chondroma in a 58-year-old man with unrelated rib pain. A: Cross-sectional
view. B: Coronal view.
FIGURE 74.4 Adenoid cystic carcinoma of the lower trachea and carina with occlusion of the proximal left main bronchus. A:
Normal trachea above the tumor. B: Thickened tracheal wall and luminal tumor at the level of the carina. C: Normal right and
abnormal left main bronchial walls below the carina.
FIGURE 74.5 Squamous cell carcinoma of the midtrachea abutting, but not invading, the aortic arch in Panel B discovered
during surveillance bronchoscopy after prior lung resection for squamous cell carcinoma. Subtle thickening of the left tracheal
wall also seen on Panel A was missed on first reading of the CT.
FIGURE 74.6 Comparison of three-dimensional reconstruction (Panel A, oblique view) with coronal views (Panel B) of a long
adenoid cystic carcinoma with substantial extramural component. Because this three-dimensional reconstruction offers luminal
views, the clinical usefulness for treatment planning is limited.
Imaging for evaluation should begin with computed tomography (CT) using a multidetector CT, if
available, and intravenous contrast. A multidetector CT acquires volumetric data in a single breath-hold,
reducing respiratory and cardiac motion artifacts. Three-dimensional reconstruction of the tracheal axis
allows an assessment of luminal and extrinsic extent of the tumor.7 An example of luminal views from
three-dimensional reconstruction is shown in Figure 74.6. Although informative and increasingly
available, bronchoscopic evaluation remains indispensable at present.
During interpretation of the CT, the clinical observer is expected to separate tracheal obstruction by
metastatic tumor from primary lesions. Several criteria serve to accomplish this goal. Primary tumors are
rarely associated with separate lung masses. Metastases of locally advanced adenoid cystic carcinoma
are the uncommon exception. Paratracheal adenopathy does not give rise to, and is rarely observed in,
primary tracheal tumors. Other distant metastases are either absent or proven not to originate from the
tracheal tumor (with the above-noted exception for adenoid cystic carcinoma). CT can be helpful in
identifying invasion into the vascular structures surrounding the trachea, although involvement of the
esophagus is difficult to prove and even harder to rule out with CT.
BRONCHOSCOPY
By the time a patient undergoes bronchoscopy, axial CT imaging has informed the surgeon of the nature of
the tracheal disease. The goals of endoscopic evaluation are to assess vocal cord function, localize the
tumor in relation to the cricoid and carina, determine the length of the luminal disease, and biopsy the
tumor.
Some tumors, among them adenoid cystic and squamous carcinoma, are known to infiltrate the tracheal
wall well beyond the gross disease. Malignant infiltration at the border between tumor and “normal”
trachea may produce cobblestoned or edematous mucosa or abnormal mucosal vessels. In the absence of
critical airway obstruction, this examination is conducted under general anesthesia with a laryngeal mask
airway using a fiberoptic bronchoscope. Video 74.1 shows the endoscopy of a patient with slowly
progressive shortness of breath over 3 years. The marked abnormality associated with this adenoid cystic
carcinoma evolved over many months.
Browser issues
Video 74.1 Preoperative bronchoscopy of an adenoid cystic carcinoma of the lower trachea and carina.
Use of a rigid bronchoscope is helpful in the presence of obstruction or bleeding, allowing control of
bleeding and core-out of tumor as a form of resection to enlarge the tracheal lumen.8 Concomitant
esophagoscopy is performed in the presence of dysphagia or if the tumor cannot be separated from the
esophagus, although invasion of the esophageal lumen is rare.
Biopsy of the tumor is not obligatory prior to resection. In the symptomatic patient, any localized tumor
requires resection unless life expectancy due to unrelated disease is extremely short. In the absence of
symptoms, resection is also advised in good surgical candidates. The purpose of a biopsy is to determine
the diagnosis prior to a complex resection or when the option of resection is doubtful.
PATHOLOGY
The vast majority of tumors reported in epidemiological or clinical studies are malignant. Nonspecific
tumor designations like bronchial adenoma used to suggest benign or low-grade malignant behavior are
obsolete today. Tumors may be categorized according to their origin: bronchial glands (adenoid cystic
carcinoma, mucoepidermoid carcinoma, pleomorphic adenoma); squamous epithelium (squamous cell
carcinoma, squamous papilloma); neuroendocrine cells (typical carcinoid, atypical carcinoid, large cell
carcinoma, small cell carcinoma); and various mesenchymal tissues (chondroma, chondroblastoma,
chondrosarcoma; leiomyoma, leiomyosarcoma among others). In all categories, even among bronchial
gland tumors,9 malignancy is most common. Most malignant tumors belong to one of two epithelial
origins, squamous and adenoid cystic carcinoma. The latter refers to salivary gland origin. In
epidemiological studies, squamous carcinoma is by far the most common tumor type, while in clinical
series these two types are either balanced5,10 or skewed toward adenoid cystic carcinoma.11–13 Except for
squamous papillomas that are limited to the tracheal epithelium, most of these tumors derive from
structures of the wall and therefore require full-thickness removal of the wall for complete resection. The
tumor types encountered at a single institution over 4 decades are shown in Table 74.3.
TABLE 74.3 Tumor Histology Encountered in 360 Specimens of 357 Patients Over 4
Decades
Malignant Lesions
Adenoid cystic carcinoma 135
Squamous cell carcinoma 135
Carcinoids 11
Typical 10
Atypical 1
Lymphoma 2
Melanoma 1
Mucoepidermoid carcinoma 14
Non-squamous carcinoma 15
Small cell carcinoma 5
Adenocarcinoma 4
Large cell carcinoma 4
Adenosquamous carcinoma 2
Sarcoma 13
Spindle cell sarcoma 6
Chondrosarcoma 3
Leiomyosarcoma 1
Carcinosarcoma (pseudosarcoma) 1
Invasive fibrous tumor 1
Malignant fibrous histiocytoma 1
Total malignant tumors 326
Benign Lesions
Capillary hemangioma 1
Chondroblastoma 1
Chondroma 2
Fibrous histiocytoma 1
Glomus tumor 1
Granular cell tumor 2
Hamartoma 2
Hemangiomatous malformation of the mediastinum 1
Inflammatory pseudotumor (plasma cell granuloma) 1
Leiomyoma 3
Neurogenic tumor 4
Schwannoma 1
Plexiform neurofibroma 1
Peripheral nerve sheath tumor 1
Atypical schwannoma 1
Paraganglioma 1
Pleomorphic adenoma 3
Pyogenic granuloma 1
Squamous papillomas 9
Multiple 5
Solitary 4
Vascular tumor of borderline malignancy 1
Total benign tumors 34
All tumors 360
Note the predominance of malignant tumors. Three patients had two tumors with different histology.
Adapted from Gaissert HA, Grillo HC, Shadmehr MB, et al. Long-term survival after resection of primary adenoid cystic and squamous cell
carcinoma of the trachea and carina. Ann Thorac Surg 2004;78(6):1889–1896; discussion 1896–1897; and Gaissert HA, Grillo HC, Shadmehr
MB, et al. Uncommon primary tracheal tumors. Ann Thorac Surg 2006;82(1):268–272; discussion 272–273.
BENIGN TUMORS
Less than 10% of all tracheal tumors (34 of 360 or 9.4%) in a retrospective single-institution study were
benign.14 Among these 34 tumors were nine squamous papillomas, four neurogenic tumors, and three
leiomyomas, while the rest defy categorization due to their varied histology.
MALIGNANT PRIMARY TUMORS

The two most common malignant tumors are squamous cell carcinoma and adenoid cystic carcinoma. Due
to marked differences in disease progression, the former is more common in population studies, the latter
more common in series of surgical resection.
Squamous cell carcinoma is a rapidly invasive and progressive tumor that extends commonly beyond
the tracheal wall with metastasis early to regional lymph nodes and distant sites. Smoking is the most
common carcinogen, although the risk factor for some patients in our institutional experience is
occupational exposure to organic solvents. In a pathologic review of 59 resected cases, Honings and
colleagues15 identified depth of invasion and lymphatic invasion as predictors of poor overall survival,
while tumor differentiation, dyskeratosis, acantholysis, and necrosis did not predict death. No patient
whose cancer extended into the thyroid gland survived 5 years after resection. Figure 74.7 illustrates the
levels of tumor invasion into the tracheal wall and Table 74.4 lists the effect of pathologic characteristics
on survival. In the Massachusetts General Hospital (MGH) series, a small group of tumors, 15 among
360, were nonsquamous carcinoma and mirrored the clinical behavior of squamous carcinoma.14
Adenocarcinoma is extremely uncommon in surgical series but ranks third in incidence in population-
based studies. Lacking an alternative explanation, most adenocarcinomas in the trachea should be
attributed to metastatic nodal disease.
Adenoid cystic carcinoma is a slowly advancing salivary gland tumor that often demonstrates
extensive infiltration of adjacent tissue planes by the time of diagnosis. Disease progresses along nerves
and can spread to regional lymph nodes. Distant sites of metastasis include lung, liver, brain, and bone.
However, prolonged survival has been observed even in the presence of distant disease. In 108
consecutive operative survivors, Honings and colleagues16 observed longer disease-free survival after
resection if negative airway margins were achieved and extramural disease, perineural growth, or lymph
node metastasis was not present (Figure 74.8 and Table 74.5). Figure 74.9 shows the relation of length of
resection as measured by the pathologist to margin status. Resection of longer tracheal segments, imposed
by longer and larger tumors, reduces the likelihood of complete resection with negative tracheal and
radial margins because the surgeon tries to conserve tracheal length to avoid excessive anastomotic
tension.
FIGURE 74.7 Depth of invasion in squamous cell carcinoma of the trachea; the corresponding Table 74.4 shows the survival
for each level. Level definitions: 0, carcinoma in situ; 1, infiltrating lamina propria; 2a, abutting or extending between cartilage; 2b,
invading through cartilage; 3a, invading peritracheal fibroadipose tissue; 3b, abutting soft tissue resection margin; 4, invading into
thyroid gland. (From Honings J, Gaissert HA, Ruangchira-Urai R, et al. Pathologic characteristics of resected squamous cell
carcinoma of the trachea: prognostic factors based on an analysis of 59 cases. Virchows Arch 2009;455(5):423–429.
Reproduced with permission of Springer-Verlag Berlin/Heidelberg in the format Book via Copyright Clearance Center.)
TABLE 74.4 Pathologic Characteristics and their Impact on Survival in Squamous Cell
Carcinoma. Note the Close Relationship of Depth of Primary Tumor Invasion and
Lymphatic Invasion to Survival
Pathologic Subgroup Number Percent Mean Survival (Years) P Value Survival (%)
5-Year 10-Year
Tumor differentiation
Well differentiated 14 23.7 8.8 0.164 73 55
Moderately differentiated 29 49.2 6.3 44 25
Poorly differentiated 16 27.1 4.5 29 10
Keratinization
Yes 39 66.1 6.5 0.719 50 28
No 20 33.9 6.6 39 26
Necrosis
Extensive 12 20.3 7.2 0.726 46 27
Focal 28 47.5 6.1 45 26
No 19 32.2 6.2 47 30
Dyskeratosis
Yes 35 59.3 6.7 0.942 51 34
No 24 40.7 6.3 39 20
Acantholysis
Yes 16 27.1 5.6 0.307 47 31
No 43 72.9 6.9 46 26
Lymphatic invasion
Yes 22 37.3 4.6 0.049 24 24
No 37 62.7 7.6 60 31
Depth of invasion
Level 0 2 3.4 n.a. 0.001 100 100
Level 1 5 8.5 7.6 75 25
Level 2a 14 23.7 6.0 50 25
Level 2b 11 18.6 7.1 50 38
Level 3a 16 27.1 7.7 53 31
Level 3b 6 10.2 2.1
Level 4 5 8.5 1.4 0
Tumor thickness
0.1–1.0 cm 29 49.2 6.8 0.650 48 32
1.1–2.0 cm 21 35.6 6.8 56 26
>2.0 cm 9 15.3 4.1 13 13
Overall 59 100.0 6.5 46 27
From Honings J, Gaissert HA, Ruangchira-Urai R, et al. Pathologic characteristics of resected squamous cell carcinoma of the trachea:
prognostic factors based on an analysis of 59 cases. Virchows Arch 2009;455(5):423–429. Virchows Archiv by European Society of
Pathology. Reproduced with permission of Springer-Verlag Berlin/Heidelberg in the format Book via Copyright Clearance Center.
Mucoepidermoid carcinoma represents a tumor encountered mainly in the trachea and large bronchi.
In the trachea, this tumor is most often localized and small, with long-term survival after complete
resection. One-third of the 14 tumors encountered at MGH14 had metastasized at presentation, and their
survival was short.
A group of sarcomas including spindle cell, chondro-, leiomyo- and carcinosarcoma were treated at
MGH by resection. In a few patients, regional or distant recurrence was observed.14
Both typical and atypical carcinoid tumors were observed in the trachea. These neoplasms
responded well to complete resection.14
SECONDARY MALIGNANT TUMORS

Thyroid carcinoma is associated with laryngeal or tracheal invasion in about 6% of patients presenting
for resection and represents an independent predictor of death.17,18 Invasion of the subglottic larynx or
trachea by thyroid carcinoma is accompanied by a dedifferentiation of the tumor.19 Transmural invasion
and preoperative vocal cord palsy are common. Also, many patients have had prior attempts at resection,
but recurred. For this reason, curative resection is not always possible. The purpose of salvage resection
with palliative intent in patients with advanced disease is the prevention of airway hemorrhage and
asphyxiation.
FIGURE 74.8 Disease-free survival in resected adenoid cystic carcinoma by (A) airway margins; (B) radial margins; and (C)
lymph node invasion. Long-term survival is possible, though less likely, when airway or radial margins are microscopically
involved or close. (From Honings J, Gaissert HA, Weinberg AC, et al. Prognostic value of pathologic characteristics and
resection margins in tracheal adenoid cystic carcinoma. Eur J Cardiothorac Surg 2010;37(6):1438–1444. Reproduced by
permission of European Association for Cardiothoracic Surgery.)
PRINCIPLES AND RESULTS OF SURGICAL THERAPY

The treatment of a localized tracheal tumor is segmental tracheal resection. Most tumors grow into or
through the tracheal wall. Luminal endoscopic resection does not achieve or confirm complete resection.
Alternatives to tracheal resection are of interest in patients of advanced age, limited life expectancy,
severe comorbidity, and those to whom complete resection cannot be offered. These alternatives consist
of endoscopic resection with local destruction of tumor by core-out, laser vaporization or cryotherapy
and primary radiotherapy by external beam or luminal application of radiation. Indwelling tracheal stents
may be inserted to enlarge the airway lumen, with certain important caveats. In candidates for resection,
self-expanding stents should be avoided as these injure the remaining normal tracheal wall. In palliative
situations, the lumen of trachea or main bronchi may be restored by stents. However, the palliation of
slow-growing tumors, for example, adenoid cystic carcinoma, must take into account prolonged survival
and thus protect the patient from the occasionally catastrophic complications caused by stent erosion into
mediastinal structures.
PATIENT PREPARATION
The systemic effects of drugs or comorbid disease should be controlled. Oral or intravenous steroids must
be weaned off since the tracheal anastomosis is sensitive to any delay in healing. Glucose control in
diabetics should be optimized. Smoking is a contraindication to resection. Postobstructive pneumonia and
purulence discovered on bronchoscopy must be treated with specific antibiotic therapy. The operation
should be delayed until optimal conditions exist, and urgent resection is rarely justified.
SURGICAL APPROACH
Tumors occupying the subglottic larynx and upper trachea are best exposed with a cervical collar
incision, adding upper sternotomy to improve access to the lower trachea as needed. Two approaches
exist for tumors of the lower trachea with carinal proximity: complete sternotomy or right thoracotomy.
Bilateral hilar release maneuvers are accomplished by pericardial semilunar incision or circumferential
hilar incisions. Left hilar release is more easily performed through a sternotomy. Bilateral
thoracosternotomy does not provide adequate exposure to the trachea proper. Details of tracheal resection
are provided in Chapter 72.
TABLE 74.5 Characteristics Predictive of Survival in 108 Operative Survivors After

Resection of Adenoid Cystic Carcinoma. Disease-Free Survival is Predicted by a
Combination of Micro- and Macroscopic Factors
Overall and Disease-free Survival According to Pathologic Subgroups
Median Survival (%) Median DFS Disease-free Survival
Survival
Pathologic N Years 95% Cl P 5- 10- 15- 20- Years 95% Cl P 5- 10- 15- 20
Subgroup Year Year Year Year Year Year Year Ye
Airway Resection Margins
Grossly positive 9 6.1 2.1– a 56 28 28 28 2.6 1.2–4.0 b 31 31 31 31
10.1
Microscopically 59 13.3 6.7– 75 65 46 33 9.7 7.8– 66 48 24 7
positive 20.0 11.5
Negative 40 20.4 15.4– 86 71 64 57 16.6 6.7– 76 63 56 50
25.4 26.5
Radial Resection Margins
Grossly positive 3 2.5 na 0.050 50 2.3 na 0.090 50
Microscopically 95 13.3 7.5– 77 62 47 36 9.7 7.3– 64 50 33 25
positive 19.2 12.1
Negative 10 21.7 20.1– 100 100 100 100 17.9 15.2– 100 86 86 43
23.2 20.7
Extramural Extent
Yes 92 13.3 8.9– 0.007 74 60 44 35 9.3 7.1– 0.008 61 47 29 22
17.6 11.4
No 16 21.7 na 100 93 93 80 17.9 11.1– 100 93 85 49
24.7
Invading Adjacent Organ(s)
Yes 22 10.3 4.1– 0.257 69 52 31 31 3.0 0.0–6.4 0.167 44 44 33 16
16.5
No 86 19.0 13.4– 81 68 57 46 11.2 7.2– 73 55 39 29
24.8 15.2
Perineural Growth
Yes 37 7.5 4.6– 0.011 62 40 23 23 6.6 2.3– 0.033 51 33 27 13
10.4 10.9
No 12 22.8 na 91 91 91 78 17.9 16.1– 92 80 80 32
19.8
Not noted in 59 19.0 12.6– 86 73 58 46 11.9 8.0– 72 58 35 31
report 25.4 15.8
Lymph Node Invasion
Yes 16 6.1 1.4– 0.017 54 32 16 16 3.0 2.1–3.9 0.005 34 7
10.8
No 45 16.8 10.7– 76 66 54 38 10.2 6.7– 63 56 33 20
22.8 13.7
No lymph nodes 47 21.6 10.2– 91 80 71 71 18.4 10.8– 86 71 62 47
sampled 33.0 26.0
Overall 108 17.7 12.0– 78 65 53 43 10.2 7.4– 67 53 38 26
23.3 12.9
a Negative versus positive (n = 68) P = 0.028. Gross positive versus gross negative (n = 99), P = 0.026. Microscopic positive versus negative,
P = 0.069. All three compared (Fig. 74.1A), P = 0.017.
b Negative versus positive (n = 68), P = 0.005. Gross positive versus gross negative (n = 99), P = 0 074. Microscopic positive versus negative.
P = 0.012. All three compared (Fig. 74.2A), P = 0.010.
DFS, disease-free survival; CI, confidence interval; na, not able to calculate 95% confidence interval.
From Honings J, Gaissert HA, Weinberg AC, et al. Prognostic value of pathologic characteristics and resection margins in tracheal adenoid
cystic carcinoma. Eur J Cardiothorac Surg 2010;37(6):1438–1444. Reproduced by permission of European Association for Cardiothoracic
Surgery.
FIGURE 74.9 The status of airway or tracheal length resection (panel A) and radial resection (panel B) margins relative to the
extent of resection in adenoid cystic carcinoma. With increasing length of resected trachea, forced of course by tumor extent, the
likelihood of achieving tumor-free tracheal and radial resection margins diminishes. (From Honings J, Gaissert HA, Weinberg
AC, et al. Prognostic value of pathologic characteristics and resection margins in tracheal adenoid cystic carcinoma. Eur J
Cardiothorac Surg 2010;37(6):1438–1444. Reproduced by permission of European Association for Cardiothoracic Surgery.)
SEGMENTAL TRACHEAL RESECTION

The region of the tumor is explored with complete mobilization of the anterior trachea over its entire
length. Extraluminal tumor and any invasion into adjacent structures are noted. Normal trachea is
encircled above and below the lesion. At this point, all available information about the patient and the
tumor is again reviewed before committing the patient to resection. Reconstruction must be possible with
all gross disease excised. In a single-institution report of the two most common tracheal cancers, 25% of
adenoid cystic carcinoma and 33% of squamous carcinomas proved unresectable, but only 21% of
unresectable tumors required either exploratory thoracotomy or neck exploration, to establish that
resection was not an option.5
Complete resection of the tracheal tumor with tumor-free margins at the anastomosis is almost always
achieved in benign tumors. Many, if not most tracheal carcinomas rarely are diagnosed when the length of
the tumor has reached 3 cm or more. In this instance, the surgeon must judge resectability while
considering the patient’s anatomy, the extent of luminal and extrinsic tumor and the ability to mobilize
tracheal ends, all to avoid excessive tension and failure of the anastomosis. This limit of resectability is
specific to each patient. In tracheal cancers, the submucosal tumor extension may involve a tracheal
segment previously thought to be normal. A safe anastomosis in this case should always take precedence
over a possibly unachievable notion of complete resection.
The value of surgical resection with microscopically positive airway margins (R1 resection) has been
called into question in malignant tracheal tumors. Given the space constraints within the mediastinum and
the limitations of tracheal mobilization, tumors often are close to the peripheral radial and airway
margins. In adenoid cystic carcinoma, less than 10% of all resections leave more than 1 mm of normal
tissue between a clear margin and tumor, while in squamous cell carcinoma this proportion reaches 60%.5
In that study, evidence of tumor at any tracheal margin was present in 59% of patients with adenoid cystic
carcinoma, but only in 18% with squamous carcinoma.
Poor long-term survival of R1 resection in bronchogenic carcinoma of the lung is also applicable to
the trachea; overall 5-year survival of airway-positive squamous carcinoma approaches 25%.5 In
contrast, adenoid cystic carcinoma is slowly progressive and considered sensitive to radiation. Honings
and colleagues observed a median disease-free survival of 16.6 years in patients with adenoid cystic
carcinoma when airway margins were negative, 9.7 years when airway margins were microscopically
positive, and 2.6 years when gross disease was left at the tracheal anastomosis.16 Similar relationships
are assumed, even if not demonstrated due to small number of patients, in the rare high-grade sarcomas or
uncommon bronchogenic carcinomas of the trachea. Surgical compromises should be considered in
tumors of lower grades that are close to critical laryngeal structures in order to preserve the voice.
TABLE 74.6 An Institutional Experience with Tracheal Resection for Primary Tracheal
Carcinoma, Expanded From One Surgeon to Multiple Surgeons at Massachusetts
General Hospital Over 4 Decades
Decade Total Patients ACC Patients Sec Patients Resections Resection Rate Hospital Mortality
(n) (n) (n) Performed (n) (n) (%)
1962– 19 7 12 13 68 21
1971
1972– 54 29 25 33 61 11
1981
1982– 107 54 53 71 66 5
1991
1992– 88 43 45 72 82 3
2001
Total 268 133 135 189 75 7
Two patients operated in 2002 were excluded from the Table.

ACC, adenoid cystic carcinoma; MGH, Massachusetts General Hospital; SCC, squamous cell carcinoma.
Reprinted from Gaissert HA, Grillo HC, Shadmehr MB, et al. Long-term survival after resection of primary adenoid cystic and squamous cell
carcinoma of the trachea and carina. Ann Thorac Surg 2004;78(6):1889–1896; discussion 1896–1897. Copyright © 2004 The Society of
Thoracic Surgeons. With permission.
The oncologic value of systematic lymph node dissection for staging purposes is widely recognized.
The central obstacle to nodal dissection during tracheal resection is their location along the lateral
vascular arcades supplying the segmental tracheal arteries.20 Lymph node retrieval along the remaining
airway wall thus reliably devascularizes the trachea and leads to anastomotic failure. Only lymph nodes
along the tumor-bearing section of the trachea may be safely resected. A description of the impact of
lymph node involvement on survival is therefore incomplete.
During resection, the lower trachea is usually divided close to the tumor first and cross-table
ventilation is re-established. The tumor is resected including the lateral soft tissues and the upper trachea
is divided. Esophageal muscle, if invaded, is resected en bloc, but invasion of adjacent vascular
structures is considered unresectable. Once the tumor is removed, tension on the anastomosis is judged by
approximating the tracheal ends with the neck flexed. If at this point frozen sections suggest residual tumor
and further resection seems feasible, additional trachea is resected one tracheal ring at a time.
OPERATIVE COMPLICATIONS
Major complications after segmental tracheal resection and reconstruction are respiratory failure, adult
respiratory distress syndrome, anastomotic dehiscence, and late stricture. The risk of complications rises
with resection of the carina. Reflecting the increase in complexity, the operative mortality of tracheal
resection for carcinoma at MGH was 3.9% and that of carinal resection was 16%.5 As shown in Table
74.6, for each consecutive decade, as operative experience at a referral center increased, mortality
decreased and resection rate increased. The operative lessons learned by one individual surgeon
improved outcome for the entire institution. Wright and colleagues studied tracheal anastomotic failure in
a retrospective analysis of 901 patients undergoing resection for inflammatory and neoplastic disease.
Negative predictors of good outcome were reoperation, diabetes, resection length longer than 4 cm,
laryngotracheal resection, patient age less than 17 years, and preoperative tracheostomy.21
MEDIASTINAL RADIATION AS ADJUVANT THERAPY
The described limitations of surgical resection imposed by close proximity of vital organs and a short
disposable length of trachea, the lymphatic permeation associated with primary carcinoma, and the
observation of local recurrence at the anastomosis have led to the practice of postoperative radiation as
guided by experience and judgment. The approach has changed with two-dimensional external beam
therapy being used until 1995 when three-dimensional conformal therapy was introduced. Since 2000,
MGH has utilized intensity modulated therapy (IMRT) administered at a dose of 63 Gy covering the
anastomosis, 3 to 4 cm of trachea above and below and the peritracheal soft tissues as shown in Figure
74.10 (Noah Choi, Department of Radiation Oncology, MGH, personal communication). When gross
disease is present at the anastomosis, the dose may be increased to between 66 and 70 Gy.
FIGURE 74.10 Treatment fields as outlined on CT before adjuvant intensity modulated radiation therapy in a 61-year-old patient
after midtracheal resection of a lymph node-positive squamous cell carcinoma. The patient is free of disease 4 years after
resection. Panel A axial view, panel B coronal view. Courtesy Dr. Henning Willers, Department of Radiation Therapy, MGH.
Patients with all but the earliest malignant tumors are selected for postoperative radiotherapy. Because
tracheal anastomotic tension is always present, treatment is not initiated until 6 to 8 weeks after operation
and a bronchoscopy must confirm adequate healing before treatment begins.
Since preoperative radiation raises the risk of resection and chemotherapy might increase the
inflammatory response of the tracheal tumor, there is no role for neoadjuvant therapy. In selected patients
who received preoperative radiation, a tracheal tumor may still be resected. However, additional
measures, including the use of protective flaps, are required to provide vascularity and enable healing. As
expected, the risk of stricture and dehiscence of the anastomosis is increased.
PRIMARY MEDIASTINAL RADIOTHERAPY

Patients whose disease is too extensive or in whom important contraindications to tracheal resection exist
are candidates for primary radiation. External beam radiotherapy may be applied with doses from 66 to
70 Gy if the entire tumor can be encompassed within the field and distant metastatic disease is absent. As
an exception, adenoid cystic carcinoma with limited metastatic disease should be considered for full-dose
radiation due to the slowly progressive nature of this cancer.
Concomitant or sequential chemotherapy is often administered for bronchogenic carcinoma. There is
no evidence to suggest its benefit in adenoid cystic carcinoma. Cheung22 observed a mean survival of 5
months in 20 patients with squamous and 4 with adenoid cystic carcinoma, while Fields and colleagues23
reported a 5-year survival of 25% in a similarly composed patient cohort. Maziak and colleagues11 found
a mean survival of 74 months in six patients with adenoid cystic carcinoma. Bittner and his colleagues24
applied neutron radiation to 20 patients with adenoid cystic carcinoma and observed a mean survival of
97 months (a little over 8 years) and a 5-year survival of 89 months. Observation periods of less than 10
years after diagnosis of adenoid cystic carcinoma provide limited information because the natural history
is prolonged and the average patient age for this tumor is between 40 and 45 years.
ENDOSCOPIC MANAGEMENT
Endoscopic management using locally destructive techniques including laser, microwave ablation, cautery
snare, cryotherapy, with or without concomitant stenting may be applied in properly selected patients who
are not candidates for complete resection or in whom complete resection may not be required for long-
term control. Kajiwara and colleagues25 elected to treat four patients with benign tracheal and bronchial
tumors with a variety of endoscopic techniques including YAG laser, microwave and high frequency
snare. During a follow-up reaching from 51 to 112 months, no local recurrence was observed. Figure
74.11 shows a specimen photograph of a benign tracheal chondroma treated with surgical resection. Of
note, the extramural extent of this tumor that would be left behind after any therapy limited to the lumen is
clearly visible. Two other reports involving the use of self-expanding tracheobronchial stents26 or
endoscopic argon plasma coagulation27 did not report long-term outcome.
FIGURE 74.11 Resection specimen of a benign chondroma of the trachea showing luminal and extraluminal extent of tumor.
(Courtesy Department of Pathology, Massachusetts General Hospital.)
SURGICAL RESULTS
Benign and low-grade malignant tracheal tumors respond well to complete resection. The overall
survival after resection of benign tumors was 100% at 5 years and 94% at 10 years; no locoregional
recurrence was observed in benign tumors, carcinoid tumors,14 or invasive fibroid tumors.28
In 18 mucoepidermoid tumors occurring mostly in the trachea and bronchi, none of the 12 resected
low-grade tumors recurred and no patient died, while all three high-grade tumors were unresectable and
proved fatal.29 The overall survival at 5 years was 100% and at 10 years, 83%.14 The lack of recurrence
during long-term follow-up supports resection in suitable surgical candidates. Endoscopic destruction is a
second option in these tumors when the operative risk is high or patient age is advanced.
Reports from multiple institutions around the world have demonstrated long-term survival after
surgical resection of tracheal carcinoma, sarcoma, and other malignant tumors. In one of the earliest
reports, Perelman and colleagues12 noted a 5-year overall survival of 35.9% in 66 adenoid cystic
carcinomas and 27.1% in 21 squamous cell carcinomas. More recently, Maziak and colleagues11 found an
actuarial survival of 79% at 5 years and 51% at 10 years in 32 adenoid cystic carcinomas treated with
resection and postoperative adjuvant radiotherapy. In a collective series of several French thoracic
centers, Regnard and his colleagues10 reported the 5- and 10-year survival of 73% and 57% in adenoid
cystic carcinoma and 47% and 36% in squamous cell carcinoma. They also noted a longer survival after
complete, compared to incomplete, resection. In 82 consecutive patients with adenoid cystic carcinomas
of the trachea and bronchi operated between 2001 and 2012, Zhao and colleagues30 observed a 5- and 10-
year disease-free survival of 66.9% and 11.2%.
Prognosis of bronchial adenoid cystic tumors was worse, presumably due to fewer complete
resections and a greater lymph node burden. In analyzing a consecutive series of 108 operative survivors
with adenoid cystic carcinoma by Honings and colleagues,16 82% received adjuvant radiotherapy
resulting in a median overall survival of 17.7 years and median disease-free survival of 10.2 years.
Survival was shortened in the presence of positive resection margins, extramural disease, perineural
growth, and lymph node metastasis. Honings and colleagues15 reviewed 59 consecutive squamous
carcinomas in which 24% involved the carina and 14% the subglottic larynx. Mean survival was 6.5
years, overall 5-year survival 46% and 10-year survival 27%. The survival of squamous carcinoma
correlated with the depth of invasion as shown in Table 74.4.
Among the less common tracheal malignancies, a single-institution study14 found that 5- and 10-year
overall survival in 11 resected nonsquamous bronchogenic carcinomas was 60% and 33%. No one
survived to 5 years in unresected cases. For sarcoma, the overall survival among 12 resected patients
was 78% and 62%, respectively.
CONCLUSION
Most tracheal tumors are found to be resectable. The challenge, therefore, is to raise awareness to
recognize presenting symptoms and to decrease the barriers to referral. Resection in patients with or
without symptoms is followed by long-term survival, even when performed for locally progressive,
malignant tumors. Resection with adjuvant postoperative radiotherapy in selected patients with localized
disease remains the preferred treatment.
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5. Gaissert HA, Grillo HC, Shadmehr MB, et al. Long-term survival after resection of primary adenoid cystic and squamous cell
carcinoma of the trachea and carina. Ann Thorac Surg 2004;78(6):1889–1896; discussion 1896–1897.
6. Gaissert HA, Grillo HC, Shadmehr BM, et al. Laryngotracheoplastic resection for primary tumors of the proximal airway. J Thorac
Cardiovasc Surg 2005;129(5):1006–1009.
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814.
11. Maziak DE, Todd TR, Keshavjee SH, et al. Adenoid cystic carcinoma of the airway: thirty-two-year experience. J Thorac Cardiovasc
Surg 1996;112(6):1522–1531; discussion 1531–1532.
12. Perelman MI, Koroleva N, Birjukov J, et al. Primary tracheal tumors. Semin Thorac Cardiovasc Surg 1996;8(4):400–402.
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15. Honings J, Gaissert HA, Ruangchira-Urai R, et al. Pathologic characteristics of resected squamous cell carcinoma of the trachea:
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16. Honings J, Gaissert HA, Weinberg AC, et al. Prognostic value of pathologic characteristics and resection margins in tracheal adenoid
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18. Czaja JM, McCaffrey TV. The surgical management of laryngotracheal invasion by well-differentiated papillary thyroid carcinoma.
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19. Shin DH, Mark EJ, Suen HC, et al. Pathologic staging of papillary carcinoma of the thyroid with airway invasion based on the anatomic
manner of extension to the trachea: a clinicopathologic study based on 22 patients who underwent thyroidectomy and airway resection.
Hum Pathol 1993;24(8):866–870.
20. Salassa JR, Pearson BW, Payne WS. Gross and microscopical blood supply of the trachea. Ann Thorac Surg 1977;24(2):100–107.
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23. Fields JN, Rigaud G, Emami BN. Primary tumors of the trachea. Results of radiation therapy. Cancer 1989;63(12):2429–2433.
24. Bittner N, Koh WJ, Laramore GE, et al. Treatment of locally advanced adenoid cystic carcinoma of the trachea with neutron
radiotherapy. Int J Radiat Oncol Biol Phys 2008;72(2):410–414.
25. Kajiwara N, Kakihana M, Usuda J, et al. Interventional management for benign airway tumors in relation to location, size, character and
morphology. J Thorac Dis 2011;3(4):221–230.
26. Shah R, Sabanathan S, Mearns AJ, et al. Self-expanding tracheobronchial stents in the management of major airway problems. J
Cardiovasc Surg (Torino) 1995;36(4):343–348.
27. Okada S, Yamauchi H, Ishimori S, et al. Endoscopic surgery with a flexible bronchoscope and argon plasma coagulation for
tracheobronchial tumors. J Thorac Cardiovasc Surg 2001;121(1):180–182.
28. Tan-Liu NS, Matsubara O, Grillo HC, et al. Invasive fibrous tumor of the tracheobronchial tree: clinical and pathologic study of seven
cases. Hum Pathol 1989;20(2):180–184.
29. Heitmiller RF, Mathisen DJ, Ferry JA, et al. Mucoepidermoid lung tumors. Ann Thorac Surg 1989;47(3):394–399.
30. Zhao Y, Zhao H, Fan L, et al. Adenoid cystic carcinoma in the bronchus behaves more aggressively than its tracheal counterpart. Ann
Thorac Surg 2013;96(6):1998–2004.
31. Kurien G, Cole I. Primary carcinoma of the trachea. Clin Otolaryngol Allied Sci 1981;6(3):197–204.
32. Gelder CM, Hetzel MR. Primary tracheal tumours: a national survey. Thorax 1993;48(7):688–692.
33. Yang KY, Chen YM, Huang MH, et al. Revisit of primary malignant neoplasms of the trachea: clinical characteristics and survival
analysis. Jpn J Clin Oncol 1997;27(5):305–309.
34. Chao MW, Smith JG, Laidlaw C, et al. Results of treating primary tumors of the trachea with radiotherapy. Int J Radiat Oncol Biol
Phys 1998;41(4):779–785.
35. Pearson FG, Todd TR, Cooper JD. Experience with primary neoplasms of the trachea and carina. J Thorac Cardiovasc Surg
1984;88(4):511–518.
36. Grillo HC, Mathisen DJ. Primary tracheal tumors: treatment and results. Ann Thorac Surg 1990;49(1):69–77.
37. Zhengjaiang L, Pingzhang T, Dechao Z, et al. Primary tracheal tumours: 21 years of experience at Peking Union Medical College,
Beijing, China. J Laryngol Otol 2008;122(11):1235–1240.
75
Compression of the Trachea by Vascular
Rings
Carl L. Backer
The phrase vascular ring refers to a group of congenital vascular anomalies of the aortic arch complex
that form an anatomic “ring” that constricts and compresses the trachea or esophagus or both. Hommel,
cited by Turner,1 first described a vascular ring, a double aortic arch, in 1737. Almost all clinically
significant vascular rings become symptomatic in infants or young children and initially present with
airway obstruction from tracheal compression. Esophageal compression and obstruction usually become
apparent later when solid foods are started.
The classification of vascular rings that is used today is based on specific anatomic features,
particularly the location of the aortic arch. This classification scheme was endorsed by the Congenital
Heart Surgery International Nomenclature and Database Project, as reported by the author and
Mavroudis.2 Table 75.1 represents the experience at Ann & Robert H. Lurie Children’s Hospital of
Chicago and indicates the relative frequency of the different anomalies evaluated for surgical intervention
over the past 65 years. Some of these anomalies are anatomically complete rings, or true vascular rings;
others are anatomically incomplete, or partial vascular rings, but are grouped with the true vascular rings
because they present with similar pathophysiology and hence clinical symptoms. Complete tracheal rings
are included because of their close association with pulmonary artery sling, and the similar respiratory
symptoms.
Gross3 reported the first successful operation for a vascular ring when he divided a double aortic arch
that had caused tracheal obstruction in a 1-year-old infant. Gross and Neuhauser4 also reported the first
successful suspension of the innominate artery to the sternum for innominate artery compression syndrome
in a 4-month-old infant with wheezing and respiratory distress.
TABLE 75.1 Classification and Relative Frequency of Vascular Rings—Ann & Robert
H. Lurie Children’s Hospital of Chicago Experience, 1947 to 2015
Vascular Rings No. of Patients
Complete
Double aortic arch 155
Right aortic arch left ligamentum 172
Incomplete
Innominate artery compression 89
Pulmonary artery sling 46
Complete tracheal rings 84
Total 546
Potts and colleagues5 coined the term “pulmonary artery sling” in their report of successful repair of
that anomaly in a 5-month-old with intermittent attacks of dyspnea and cyanosis. Idriss and colleagues6
first reported the successful use of pericardium as a tracheoplasty technique in a 7-month-old with
complete tracheal rings. This report included the first successful use of cardiopulmonary bypass for
tracheal stenosis. These historical milestones are summarized in Table 75.2.
EMBRYOLOGY
Congdon7 reported an extensive experience with the embryonic development of the human aortic arch
system, showing that six pairs of aortic arches connect the two primitive ventral and dorsal aortae (Fig.
75.1). Most portions of the first, second, and fifth arches regress. The third arches become the carotid
arteries. A branch from the ventral bud of the sixth arch meets the lung bud to form the pulmonary artery.
On the right side, the dorsal contribution to the sixth arch disappears; on the left, it persists as the ductus
arteriosus.
The formation of a vascular ring depends on preservation or deletion of specific segments of the
embryonic aortic arch complex. To help visualize this, Edwards8 proposed a schematic model with a
double aortic arch system and bilateral ductus arteriosus. By convention, the “location” of the aortic arch
is determined by its relationship to the trachea. In the normal arch formation, the right fourth arch
regresses, leaving a left aortic arch system (i.e., apex of aortic arch to the left of the trachea). If both
fourth arches persist, a double aortic arch is formed. If the left fourth arch regresses, a right aortic arch
system is created (apex of aortic arch to the right of the trachea). This is schematically demonstrated in
Figure 75.2.
TABLE 75.2 Historical Milestones in Vascular Ring Surgery

Year Anomaly Surgeon
1945 Double aortic arch Robert E. Gross
1948 Innominate artery compression Robert E. Gross
1954 Pulmonary artery sling Willis J. Potts
1984 Complete tracheal rings Farouk S. Idriss
FIGURE 75.1 The embryonic aortic arches. Six pairs of aortic arches develop between the dorsal and ventral aortae. Areas
that are shaded regress. The seventh intersegmental arteries migrate cephalad to form the subclavian arteries. (Reproduced with
permission from Lowe GM, Donaldson JS, Backer CL: Vascular rings: 10-year review of imaging. RadioGraphics 11:637,
1991.)
FIGURE 75.2 Aortic arch development. Beginning with the embryonic aortic arch, the first, second, and fifth arches involute to
form Edwards’ classic double aortic arch. If the development stops at this point, the child has a double aortic arch. If the right
fourth arch involutes, a normal left arch is formed. If the left fourth arch involutes, a right aortic arch is formed. (From Backer
CL, Mavroudis C. Surgical approach to vascular rings. In: Karp R, Laks H, Wechsler AS, eds. Advances in Cardiac Surgery.
Vol. 9. St. Louis, MO: Mosby-Year Book; 1997:31. With permission.)
CLINICAL FEATURES, DIAGNOSES, AND SURGICAL TREATMENT
DOUBLE AORTIC ARCH

A double aortic arch is a complete vascular ring that causes tracheoesophageal compression. Potts and
colleagues9 noted that patients typically present in the first months of life with symptoms of stridor,
respiratory distress, and a cough that sounds like a seal’s bark. A simple cold may precipitate severe
respiratory difficulty. The ascending aorta divides into two arches that pass around the trachea and
esophagus and join posteriorly to form the descending aorta (Fig. 75.3). Backer and colleagues10 showed
that in two-thirds of these infants, the right-sided (posterior) arch is dominant, and in one-third, the left-
sided (anterior) arch is dominant. Rarely, the arches are of equal size (balanced arches). The carotid and
subclavian arteries originate symmetrically and separately from each arch. The tight, constricting ring thus
formed compresses the trachea and esophagus.
The diagnosis can be suspected on examination of the chest radiograph because the location of the
aortic arch in relation to the trachea is indeterminate. In addition, the tracheal air column often shows
compression that is more prominent on the side of the dominant arch. Although for many years a barium
esophagram was the next diagnostic procedure of choice, currently a computed tomography (CT) scan
with contrast is recommended.11,12 The double aortic arch on an anteroposterior esophagram appears as
bilateral indentations of unequal size that persist in location. However, the barium esophagram does not
define the precise anatomy of the vascular ring. The review by Backer11 and that of Lambert13 have shown
that CT scanning is very accurate in the identification of vascular anomalies of the aortic arch and great
vessels. A double aortic arch is diagnosed with certainty when both limbs are patent and enhanced with
the administration of contrast material (Fig. 75.4).12
FIGURE 75.3 Autopsy photograph of a child who died from airway obstruction who had a double aortic arch. Desc Ao,
descending aorta; E, esophagus; LAA, left aortic arch; LCC, left common carotid; LSC, left subclavian; PT, pulmonary trunk;
RAA, right aortic arch; RSA, right subclavian artery; RCC, right common carotid; T, trachea. (From Backer CL, Popescu AR,
Rastatter JC, Russell M. Vascular rings and slings. In: Da Cruz EM, Ivy D, Jaggers J, eds. Pediatric and Congenital
Cardiology, Cardiac Surgery and Intensive Care. Vol. 4. London: Springer-Verlag: 2219–2238. Copyright © 2014 Springer-
Verlag London Ltd. With permission of Springer.)
As described by Lowe and associates,14 one clue to an arch anomaly, specifically a double aortic arch
or a right aortic arch with retroesophageal subclavian artery and a ligamentum arteriosum, is the “four
artery sign.” This is seen on sections cephalad to the aortic arch and consists of two dorsal subclavian
arteries and two ventral carotid arteries spaced evenly around the trachea. The sign is present when the
two dorsal subclavian arteries arise directly from the aorta and not from a brachiocephalic artery. Three
dimensional (3D) reconstruction of the CT scan provides superb anatomic detail which allows clear
planning of the surgical approach, reducing the chance of error in selecting the site and approach for ring
division (Fig. 75.4).
Magnetic resonance (MR) imaging, as described by Van Son and associates,15 also demonstrates the
arch and vessel anatomy. MR images provide the same information as CT without ionizing radiation or
the need for intravenously administered contrast material. However, if the child moves during the scan
there will be motion artifact, making the analysis difficult. Another disadvantage of MR imaging is the
length of time required for the study and thus necessitating sedation. Therefore, the author11 feels that the
ultrafast CT scan with contrast is the test of choice. Acquisition of the images requires less than 1 second.
The scan can easily be done without sedation or intubation. Cardiac catheterization is recommended now
only for infants with associated complex congenital cardiac anomalies.
Bronchoscopy is obtained sometimes as the initial study because of the presentation with stridor and
shows typical external compression of the trachea. All vascular ring patients should have bronchoscopy
as part of their evaluation, either prior to surgical intervention or more commonly at the time of their
operation. They should also have an echocardiogram as 12.4% have associated intracardiac lesions.11
All infants with double aortic arch should be operated on; a narrowed trachea, when further
compromised by mucosal edema from even a mild upper respiratory infection, can cause hypoxic or
apneic episodes. As Midulla and colleagues16 reported, these children are also at risk for aortic
dissection. In addition, as Heck,17 Othersen,18 and Angelini,19 and their colleagues have reported,
improper management of respiratory obstruction with prolonged intubation and nasogastric tube drainage
may lead to catastrophic erosion of an arch into the esophagus. During an operation on a 5-month-old
child hospitalized for 2 weeks with an endotracheal tube and a nasogastric tube, it was noted that the
esophagus had a 6-mm perforation caused by erosion of the nasogastric tube into the left arch (Figs. 75.5
and 75.6).
Surgical approach is determined by which arch is dominant. When the right arch is dominant (75%),
the approach is through a left thoracotomy. When the left arch is dominant (18%), the approach is through
a right thoracotomy. When the arches are balanced (7%), a left thoracotomy is preferred. If the patient has
a significant intracardiac lesion, the ring can be divided through a median sternotomy. The left
thoracotomy can be performed with a muscle-sparing technique, elevating the serratus anterior and the
latissimus dorsi and entering the thorax through the fourth intercostal space. The vascular ring caused by
the double aortic arch is released by dividing the lesser of the two arches, usually where it inserts into the
descending aorta (Fig. 75.7A–C). The definition of which arch is “smaller” is best made on the
preoperative CT or MR imaging. In 30% to 40% of these patients, the site where the smaller arch inserts
into the descending aorta will be atretic. After applying the vascular clamps, the anesthesiologist
carefully checks the carotid and radial pulses on both sides to ensure blood flow is not interrupted. The
arch is then divided between the vascular clamps, and the stumps are oversewn with Prolene sutures;
simple ligation should not be done. The ligamentum arteriosum is also divided. Careful dissection is then
performed around the trachea and esophagus to lyse any residual adhesive bands. The recurrent laryngeal
and phrenic nerves are identified and protected throughout the procedure. The mediastinal pleura is not
sutured closed because this could contribute to scar formation that might recreate the problems caused by
the original vascular ring. The pleural space is drained for 24 to 48 hours with a soft, silastic Blake drain
(Ethicon Inc., Somerville, NJ). One technical factor that the surgeon should be aware of is that when the
clamps are placed on the vascular ring before ring division, the ring is temporarily tightened by inserting
the clamps into the area between the ring and the trachea and esophagus. Patients at times will have a
drop in their oxygen saturation and may require increased ventilatory pressures to provide adequate
ventilation during the time that the clamps are on the vascular ring.
FIGURE 75.4 Computed tomogram (3D reconstruction) of a child with a double aortic arch, Same view as in Figure. 75.3. This
child has balanced right and left arches. A, ascending aorta; D, descending aorta; L, left arch; R, right arch. (From Backer CL,
Popescu AR, Rastatter JC, Russell M. Vascular rings and slings. In: Da Cruz EM, Ivy D, Jaggers J, eds. Pediatric and
Congenital Cardiology, Cardiac Surgery and Intensive Care. Vol. 4. London: Springer-Verlag: 2219–2238. Copyright © 2014
Springer-Verlag London Ltd. With permission of Springer.)
FIGURE 75.5 3D Reconstruction of CT scan. A 5-month-old child with a double aortic arch, right arch dominant. The distal left
arch can be clearly seen projecting like a thumb from the descending aorta. The vertical structure inside the “ring” is the
nasogastric tube. The anterior portion of this left arch is atretic just distal to the left subclavian artery. The left arch had eroded
into the esophagus. (From Backer CL. Compression of the trachea by vascular rings. In: Shields TW, LoCicero J III, Reed CE,
et al., eds. General Thoracic Surgery. 7th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2009:999–
1016.)
FIGURE 75.6 This is the same patient after partial resection of the left arch, primary repair of the esophagus, and division of
the ligamentum. The “ring” is gone. The appearance of the arch is now that of a right aortic arch with mirror image branching.
(From Backer CL. Compression of the trachea by vascular rings. In: Shields TW, LoCicero J III, Reed CE, et al., eds. General
Thoracic Surgery. 7th ed. Philadelphia, PA, Wolters Kluwer/Lippincott Williams & Wilkins; 2009:999–1016.)
The postoperative care includes high humidity to loosen secretions, oxygen therapy when needed as
monitored by pulse oximetry, chest physiotherapy, and nasopharyngeal suctioning. Vigorous attempts
should be made to achieve early extubation. Other helpful postoperative modalities include inhaled
corticosteroids, albuterol treatments, and Heliox. Results of surgical intervention are excellent (n = 155),
and no surgical mortality has resulted at Lurie Children’s from a double aortic arch procedure since 1952.
Median age at surgery was 1.2 years. Patients are discharged at a median of 3 days postoperatively. As
Nikaidoh and colleagues20 reported, some children have residual noisy breathing for 6 months to 2 years,
but in nearly all instances, this gradually resolves.
RIGHT AORTIC ARCH

Right aortic arch with a left ligamentum arteriosum completing the vascular ring is slightly more common
than double aortic arch. The ring, however, is usually not as tight, and children typically present
somewhat later in life (6 to 12 months of age). Symptoms are similar to those in infants with double aortic
arch, with stridor, barky cough, and respiratory distress. In older children, dysphagia may be present.
Some of these children eat very slowly and tend to be the last to leave the table because they have to
carefully chew their food as a learned procedure to prevent choking. Embryologically, depending on the
exact site or sites of interruption of the left fourth arch and the branching pattern to the left subclavian
artery, left carotid artery, and ductus arteriosus, different configurations of right aortic arch are possible.
Felson and Palayew21 showed that the two common variations are retroesophageal left subclavian artery
(65%) and mirror-image branching (35%) (Fig. 75.8A,B). In either case it is the left ligamentum
arteriosum between the descending aorta and the left pulmonary artery that completes the ring. Although
Da Cruz and colleagues22 have reported that one-third of patients with tetralogy of Fallot and truncus
arteriosus have a right aortic arch, our group did not find a reverse association with a specific cardiac
defect when a vascular ring is formed by a right arch. In most infants with a cardiac defect and a right
aortic arch, there is mirror-image branching with the ligamentum from the innominate artery to the
pulmonary artery, so a vascular ring is not formed (Fig. 75.8C).
FIGURE 75.7 A: Double aortic arch with right arch dominant. The vascular ring is divided at the sites shown by the arrows.
LCA, left carotid artery; RCA, right carotid artery. B: Division of double aortic arch via left thoracotomy. A patent left aortic
arch is being divided. There is a Potts ductus clamp on the proximal portion of the arch and a Castaneda clamp on the distal arch
adjacent to the descending thoracic aorta. The vascular ring has been partially transected and a single polypropylene suture
placed on the distal portion of the divided arch. The ligamentum has already been divided and oversewn. C: Completed repair
with clamps removed. The stumps of the vascular rings have now separated nicely and the esophagus is clearly visible. (From
Backer CL, Mavroudis C. Surgical approach to vascular rings. In: Karp R, Laks H, Wechsler AS, et al., eds. Advances in
Cardiac Surgery. Vol. 9. St. Louis, MO: Mosby-Year Book; 1997:41. With permission.)
The diagnosis is suggested by the chest radiograph, which shows an aortic arch to the right of the
tracheal air column. Barium esophagram used to be the diagnostic procedure of choice (Fig. 75.9A,B).
However, using the same analysis as for a double aortic arch, CT imaging is now considered the best
diagnostic procedure of choice. This reveals the precise anatomy of the ring, including the identification
of a Kommerell diverticulum as part of the pathology. Chun and colleagues23 have emphasized the
importance of an associated Kommerell24 diverticulum. This diverticulum is embryologically a remnant
of the left fourth aortic arch that did not undergo complete involution. The diverticulum may independently
compress the esophagus or trachea. Fisher and colleagues25 have noted the possible complications of
ruptured diverticulum and aortic dissection from the diverticulum. This aneurysmal dilatation should be
resected if present and usually necessitates transfer of the left subclavian artery to the left carotid artery.
An example of an MRI image in a patient with a Kommerell diverticulum, right aortic arch, left
ligamentum, and retroesophageal left subclavian artery is shown in Figure 75.10.
FIGURE 75.8 A: With a right aortic arch and retroesophageal left subclavian artery, the ring is divided by dividing the
ligamentum arteriosum, which extends from the aorta opposite the origin of the left subclavian artery to the left pulmonary artery
(PA). B: With a right aortic arch and mirror-image branching of the great vessels, it is the ligamentum between the descending
aorta and pulmonary artery that is divided to release the ring. C: With a right aortic arch and mirror-image branching, if the
ligamentum connects the innominate artery to the pulmonary artery, a vascular ring is not formed, and the child would have no
symptoms.
The surgical approach is through a left thoracotomy. After careful dissection and identification of the
configuration of the aortic arch, the ligamentum arteriosum is identified as compressing the esophagus.
The ring is released by dividing the ligamentum between vascular clamps and oversewing the stumps with
Prolene suture. Any adhesive bands around the esophagus are lysed.
In the initial experience at our institution that was published by the author and colleagues,26 10
children required additional surgery because their vascular ring (ligamentum) was divided without
addressing the associated Kommerell diverticulum. All were symptomatic, with recurrent respiratory
symptoms or recurrent dysphagia. All patients responded to reoperation with resection of the diverticulum
and transfer of the left subclavian artery to the left carotid artery with resolution of airway symptoms (Fig.
75.11A–C). Because of the success with these reoperations, the author now recommends division of the
ligamentum, resection of Kommerell diverticulum, and left subclavian artery transfer as the primary
approach for patients with a right aortic arch, left ligamentum, and Kommerell diverticulum. The author
and his colleagues have done this as a primary procedure in 20 patients as reported in 2012.27 The
preoperative versus postoperative CT images of a patient with a Kommerell diverticulum that was
resected are shown in Figure 75.12A,B. Several other groups have also reported a successful experience
with primary resection of Kommerell diverticulum, including Shinkawa,28 Kim,29 and Luciano,30 and their
colleagues.
FIGURE 75.9 Anteroposterior (A) and lateral (B) views of simultaneous esophagram and aortogram in a patient with right
aortic arch and left ligamentum. The origin of the left subclavian artery is aneurysmal, forming a Kommerell diverticulum. The
combination of the tight ligamentum and the diverticulum (arrow) severely compresses the esophagus. In particular, the lateral
film shows a classic deep posterior indentation from the large right arch. (From Backer CL. Compression of the trachea by
vascular rings. In: Shields TW, LoCicero J III, Reed CE, et al., eds. General Thoracic Surgery. 7th ed. Philadelphia, PA;
Lippincott Williams & Wilkins/ Wolters Kluwer Health; 2009:999–1016.)
FIGURE 75.10 A 17-year-old patient with dysphagia. Magnetic resonance imaging shows a right aortic arch (small arrow) and
a Kommerell diverticulum (large arrow) at the origin of the left subclavian artery. (Reprinted from Backer CL, Ilbawi MN,
Idriss FS, et al. Vascular anomalies causing tracheoesophageal compression. Review of experience in children. J Thorac
Cardiovasc Surg 1989;97:725. Copyright © 1989 The American Association for Thoracic Surgery. With permission.)
A very rare group of children with right aortic arch and left ligamentum have a left-sided descending
thoracic aorta, the so-called “circumflex aorta” (Fig. 75.13A). Robotin and colleagues31 described an
aortic “uncrossing” operation for these rare patients (3 of 468 patients in their series of patients with
vascular rings). This procedure is performed through a median sternotomy with cardiopulmonary bypass
and hypothermic circulatory arrest. The aortic arch is mobilized, divided, and brought in front of the
tracheobronchial tree, then reanastomosed end-to-side to the lateral aspect of the ascending aorta (Fig.
75.13B). All three patients described by Robotin had prior ligamentum division via left thoracotomy. The
author and his colleagues have done an aortic “uncrossing” in six patients. Our experience with this
operation is reviewed in Russell’s article from 2013.32
The results of surgical intervention for right aortic arch with left ligamentum are very good. No
mortality occurred in the Lurie Children’s series (n = 172) since 1959. The median postoperative length
of stay is 2 days for simple ligation and division and 4 days with Kommerell diverticulum resection and
left subclavian artery transfer. Like patients with a double aortic arch, it may take 6 to 12 months for
resolution of airway symptoms.
INNOMINATE ARTERY COMPRESSION SYNDROME

Innominate artery compression syndrome results from anterior compression of the trachea by the
innominate artery. There is a “normal” left aortic arch, but the innominate artery appears to originate
somewhat more posteriorly and leftward on the aortic arch than usual. Ardito and colleagues33 have
described how, as the artery then courses to the right, upward, and posterior to reach the thoracic outlet, it
compresses the trachea anteriorly. These infants present with stridor, respiratory distress, cyanosis, and
apnea with feeding. The infant may hold the head hyperextended to splint the trachea and improve
breathing. Apnea or cyanosis may be precipitated by swallowing a bolus of food that presses on the soft
posterior trachea with the innominate artery compressing the anterior trachea.
FIGURE 75.11 A: The typical anatomy of a patient with a right aortic arch, retroesophageal left subclavian artery, and large
Kommerell diverticulum. The Kommerell diverticulum is an embryologic remnant of the left fourth aortic arch. LCA/RCA,
left/right carotid artery; LSA/RSA, left/right subclavian artery. B: A schematic illustration of the resection of a Kommerell
diverticulum through a left thoracotomy. There is a vascular clamp partially occluding the descending thoracic aorta at the origin
of the Kommerell diverticulum. The Kommerell diverticulum has been completely resected. The clamp on the distal left
subclavian artery is not illustrated. C: The completed repair. The orifice where the Kommerell diverticulum was resected is
usually closed primarily, or, as shown in the inset, the orifice can be patched with polytetrafluoroethylene if necessary. The left
subclavian artery has been implanted into the side of the left common carotid artery with fine running polypropylene suture.
(From Backer CL, Hillman N, Mavroudis C, et al. Resection of Kommerell’s diverticulum and left subclavian artery: transfer for
recurrent symptoms after vascular ring division. Eur J Cardiothorac Surg 2002;22:64. Reproduced by permission of European
Association for Cardiothoracic Surgery. With permission.)
FIGURE 75.12 A: Computed tomographic axial image of a 7-year-old patient with a right aortic arch (R) and a significant
Kommerell diverticulum (KD), which is the origin of the left subclavian artery. The diverticulum is shown occupying the space
immediately posterior to the trachea. The esophagus is not visible because it is severely compressed by the diverticulum. B:
Post-repair image of patient in Fig. 75.12A. Computed tomographic axial image demonstrates that there is now no posterior
occupation of space by the Kommerell diverticulum or the subclavian artery. The trachea is completely free posteriorly. The right
aortic arch has been released to move slightly to the right. The esophagus (E) is now visible as a small second opening below the
trachea. (Reprinted from Backer CL, Russell HM, Wurlitzer KC, et al. Primary resection of Kommerell diverticulum and left
subclavian artery transfer. Ann Thorac Surg 2012;94:1612–1617. Copyright © 2012 The Society of Thoracic Surgeons. With
permission.)
FIGURE 75.13 A: The vascular anatomy present in a circumflex aorta. The right-sided aortic arch (Ao) passes over the right
main bronchus, then takes a retroesophageal course posterior to the trachea and joins the left-sided descending aorta superior to
the carina. B: The aortic uncrossing procedure. This operation is performed through a median sternotomy with the use of
cardiopulmonary bypass and circulatory arrest. The aortic arch is transected just distal to the origin of the right subclavian artery.
The distal aorta is brought anterior to the trachea where it is mobilized and reanastomosed to the left side of the ascending aorta
in front of the trachea. Ao, aorta; Pa, pulmonary artery. (Reprinted from Russell HM, Rastatter JC, Backer CL. The aortic
uncrossing procedure for circumflex aorta. Oper Tech Thorac Cardiovasc Surg 2013;18:15–31. Copyright © 2013 Elsevier.
With permission.)
Enthusiasm for this diagnosis increased in the late 1970s with the switch from local to general
anesthesia for bronchoscopy. However, as experience with these patients was gained, the selection
criteria for surgery became more stringent. The diagnosis is made with rigid bronchoscopy, which should
demonstrate a pulsatile anterior compression of the trachea extending from left to right, with at least 80%
obstruction of the tracheal lumen. Anterior compression of the tracheal wall by the bronchoscope may
compress the innominate artery and temporarily obliterate the right radial pulse. The diagnosis can be
confirmed by CT scan, which will demonstrate flattening and obliteration of the tracheal lumen by the
contrast-filled innominate artery (Fig. 75.14A,B). Radionuclide studies for gastroesophageal reflux, sleep
studies, and neurologic evaluation, including CT of the brain and electroencephalograms, should all be
performed to rule out other causes of apnea. Barium esophagogram is normal in these infants.
When indicated, the management of compression of the trachea by the innominate artery classically has
been with suspension of the innominate artery to the posterior aspect of the sternum, as originally
described by Gross and Neuhauser.4 Access via a small right submammary thoracotomy is our current
standard approach. The right lobe of the thymus is excised, taking care not to injure the right phrenic
nerve. The innominate artery is secured with pledget-supported sutures to the posterior periosteum of the
sternum to lift the innominate artery away from the trachea, simultaneously pulling the anterior tracheal
wall open (Fig. 75.15). Hawkins and colleagues34 have described using a median sternotomy with
division of the innominate artery and reimplantation into the ascending aorta at a site more to the right and
anterior to the original site. This technique seems to sacrifice the active suspending mechanism on the
tracheal wall provided by the classic technique and to have some risk of cerebrovascular accident.
At Lurie Children’s, the author and colleagues35 reported suspension for 76 (now 89) children, with 2
(3%) undergoing reoperation,36 71 (93%) relieved of symptoms, and no deaths related to the actual
procedure. Innominate artery compression of the trachea historically has been well managed by
innominate artery suspension through a right anterolateral thoracotomy, and I continue to recommend this
approach. Jones and colleagues37 have also reported good results with standard innominate artery
suspension.
FIGURE 75.14 Computed tomographic scan with contrast of an infant with innominate artery compression syndrome. The
superior cut (top) shows a normal-size trachea (arrow). The inferior cut (bottom) shows the trachea (arrow) compressed by the
innominate artery.
FIGURE 75.15 Innominate artery suspension. Exposure is through a right submammary thoracotomy. Fixing the adventitia of
the innominate artery to the posterior table of the sternum with pledgetted sutures pulls the innominate artery anteriorly and
actively pulls the tracheal wall forward and opens it. Asc. Ao, ascending aorta. (From Backer CL, Mavroudis C. Surgical
approach to vascular rings. In: Karp R, Laks H, Wechsler AS, et al. eds. Advances in Cardiac Surgery. Vol. 9. St. Louis, MO:
Mosby-Year Book; 1997:49. With permission.)
PULMONARY ARTERY SLING

A pulmonary artery sling is a rare vascular anomaly in which the left pulmonary artery originates from the
right pulmonary artery and encircles the right main-stem bronchus and distal trachea before coursing
anterior to the esophagus and descending aorta to enter the hilum of the left lung (Fig. 75.16). This
anomaly was first reported by Glaevecke and Doehle38,45 as a postmortem finding in a 7-month-old infant
with severe respiratory distress. Sade and associates39 reported that embryologically, a pulmonary artery
sling occurs during development of the lung bud when the left lung captures its arterial supply from
derivatives of the right (instead of the left) sixth aortic arch through capillaries caudad rather than
cephalad to the developing tracheobronchial tree. The “sling” compresses and compromises the distal
trachea and right main-stem bronchus. In addition, Cosentino and colleagues40 have shown that many of
these infants will also have complete tracheal rings, a combination that Berdon and colleagues41 have
appropriately referred to as the “ring-sling” complex.
Nearly all infants with pulmonary artery sling present within the first months of life with respiratory
distress, particularly if there are associated complete tracheal rings. A chest radiograph may show
unilateral hyperaeration of the right lung field. A barium esophagogram shows anterior compression of the
esophagus on the lateral views. The barium swallow has a high false-negative rate. Diagnosis can be
confirmed by cardiac echocardiogram, CT scan, or MR imaging. Angiography is no longer recommended,
unless an associated congenital cardiac anomaly is suspected. Both CT and MR imaging will show the
left pulmonary artery originating from the right pulmonary artery, encircling the trachea, and coursing to
the hilum of the left lung (Fig. 75.17). Three-dimensional reconstruction shows the precise anatomic
detail (Fig. 75.18). Currently, however, echocardiography is our diagnostic procedure of choice for
pulmonary artery sling for the patient with an unstable airway. Alboliras and colleagues42 reviewed two-
dimensional and color flow Doppler to make this diagnosis, and noted the correct diagnosis was made in
seven of seven patients. Many of these infants have a tenuous respiratory status, and it is much safer to do
an echocardiogram at the bedside than to move the patient to the scanner. Bronchoscopy should be
performed in all these infants to check for associated complete tracheal rings. In our experience, complete
tracheal rings were found in 79% of patients with pulmonary artery sling. Tracheograms are indicated
only in select cases and must be done with extreme caution to avoid further ventilatory compromise.
FIGURE 75.16 Pulmonary artery sling. The left pulmonary artery (LPA) originates from the right pulmonary artery (RPA) and
courses between the esophagus and trachea to reach the left lung. Inset shows lateral relationship of LPA to esophagus. MPA,
main pulmonary artery. (From Backer CL, Mavroudis CM. Surgical approach to vascular rings. In: Karp R, Laks H, Wechsler
AS, et al. eds. Advances in Cardiac Surgery. Vol. 9. St. Louis, MO: Mosby-Year Book; 1997:52. With permission.)
FIGURE 75.17 Computed tomographic scan with contrast material from a 14-month-old girl with pulmonary artery sling and
complete tracheal rings from the fourth tracheal ring to the carina. Curved arrow points to the main pulmonary artery. Small
arrow points to the left pulmonary artery, which is wrapping around the trachea from right to left. Note that the tracheal lumen is
small from complete tracheal rings.
FIGURE 75.18 Three-dimensional (3D) reconstruction (pulmonary artery sling). A: This is a 3D reconstruction of a 2-month
old boy that had several apneic episodes requiring CPR. The child had a pulmonary artery sling causing significant tracheal
compression. This posterior view shows the left pulmonary artery wrapping around and compressing the distal trachea and right
bronchus. B: More cranial view of the same patient with the trachea removed to show the origin of the left pulmonary artery
from the right pulmonary artery. The child had no further apneic spells after sling repair.
Surgical intervention should be undertaken as soon as the diagnosis is made because of the usual
tenuous respiratory status. The first successful operation for pulmonary artery sling was performed by
Potts and colleagues5 at Children’s Memorial Hospital, through a right thoracotomy. Potts operated upon a
5-month-old infant who did not have an exact preoperative diagnosis but was felt to have vascular
compression of the lower trachea and right bronchus by a vascular structure of some sort. He made the
correct intraoperative diagnosis and considered several surgical alternatives, including right
pneumonectomy, before deciding to transect the left pulmonary artery and reanastomose it to the main
pulmonary artery anterior to the trachea. That particular child survived the surgery and is still alive;
however, as Campbell and colleagues43 reported, the left pulmonary artery is occluded. Koopot and
colleagues44 reported on several patients using the approach through a left thoracotomy and the technique
described by Potts.
The author and associates45–47 advocate for a median sternotomy approach with the use of
extracorporeal circulation. This allows accurate division of the left pulmonary artery with implantation
into the main pulmonary artery anterior to the trachea (Fig. 75.19). The operation can be performed
without respiratory compromise, and enough time and care can be taken to ensure patency of the left
pulmonary artery. Because over two-thirds of patients with pulmonary artery sling will have associated
complete tracheal rings (the “ring-sling” complex), the median sternotomy approach allows simultaneous
tracheoplasty. Since 1954, 46 patients with pulmonary artery sling have been operated upon at Lurie
Children’s. From 1985 to 2015, 38 infants had repair using a median sternotomy approach and
cardiopulmonary bypass. Seventy-five percent of these children had associated complete tracheal rings.
There has been no operative mortality, and there have been three late deaths, all in patients having
tracheoplasty for complete tracheal rings, with deaths occurring at 2.5 months, 7 months, and 2.5 years
postoperatively. All left pulmonary arteries repaired on cardiopulmonary bypass are patent, and the mean
percentage blood flow to the left lung by nuclear scan is 41%.47
FIGURE 75.19 Operative technique. Repair is performed by transecting the left pulmonary artery (LPA) at its origin from the
right pulmonary artery (RPA) and anastomosing the LPA to the main pulmonary artery (MPA) anterior to the trachea at a site that
approximates the usual anatomic configuration. (From Backer CL, Mavroudis CM. Surgical approach to vascular rings. In: Karp
R, Laks H, Wechsler AS, et al. eds. Advances in Cardiac Surgery. Vol. 9. St. Louis, MO: Mosby-Year Book; 1997:54. With
permission.)
COMPLETE TRACHEAL RINGS

As illustrated in Figure 75.20, when the child has complete tracheal rings, there is congenital absence of
the membranous trachea, causing the cartilage to be circumferential. This causes tracheal stenosis, which
often leads to severe respiratory distress in infancy. Benjamin and associates48 reported that medical
management of this lesion is associated with a 43% mortality rate. Cantrell and Guild49 classified these
patients into three categories: segmental stenosis, funnellike stenosis, and generalized hypoplasia.
Although the number of rings and extent of the stenosis can be variable, most of our patients have had
complete tracheal rings from one or two rings below the cricoid extending nearly to the carina. This
diagnosis and the extent of involvement are established by rigid bronchoscopy. Often the bronchoscope
itself will not pass through the stenosis, only the fine telescope.
Surgical options for the management of children with long-segment congenital tracheal stenosis from
complete tracheal rings include pericardial patch tracheoplasty, cartilage tracheoplasty, slide
tracheoplasty, tracheal homograft, and tracheal autograft. The author published a History of Pediatric
Tracheal Surgery in 2010.50 From 1982 to 2015, 28 patients have had pericardial tracheoplasty, 22 have
undergone slide tracheoplasty, 13 have had resection of short segments of complete rings, and 20 have
had repair using a free tracheal autograft at Lurie Children’s. Twenty-seven of these 83 patients (33%)
had simultaneous pulmonary artery sling repair. Fourteen patients (17%) had simultaneous intracardiac
repair of ventricular septal defect in four, tetralogy of Fallot in three, atrial septal defect in three,
complete atrioventricular canal in two, correction of a double-outlet right ventricle in one, and pulmonary
atresia in one. The current approach favored by our group is to use the slide tracheoplasty as the
procedure of choice.51
FIGURE 75.20 Complete tracheal rings causing long-segment congenital tracheal stenosis from the third tracheal ring to the
carina. The membranous portion of the trachea is absent and the cartilages are circumferential. This patient has an associated
tracheal right upper lobe bronchus. (From Backer CL, Mavroudis CM. Surgical approach to vascular rings. In: Karp R, Laks H,
Wechsler AS, et al. eds. Advances in Cardiac Surgery. Vol. 9. St. Louis, MO: Mosby-Year Book; 1997:56. With permission.)
FIGURE 75.21 Completed pericardial patch tracheoplasty augments the trachea anteriorly, opening the tracheal lumen
significantly, as shown in the inset. (From Backer CL, Mavroudis C. Surgical approach to vascular rings. In: Karp R, Laks H,
Wechsler AS, et al. eds. Advances in Cardiac Surgery. Vol. 9. St. Louis, MO: Mosby-Year Book; 1997:57. With permission.)
The technique of pericardial tracheoplasty was first described by Idriss and colleagues.6 The approach
is through a median sternotomy, and cardiopulmonary bypass is used for respiratory support.
Bronchoscopy is used to guide an anterior incision in the trachea, which is extended proximal and distal
to the complete tracheal rings. The trachea is patched open with an autologous pericardial patch anchored
with interrupted 6-0 Vicryl sutures (Fig. 75.21). The patch is usually 1.5 to 2.0 cm wide and extends the
length of the stenosis. The patch is stented open with an endotracheal tube for 7 to 10 days. Cosentino and
colleagues40 reported intermediate results, and Dunham and colleagues,52 updated recently by the author
and colleagues,53 discussed the role of postoperative bronchoscopy to remove secretions and granulation
tissue and perform dilation as needed. Cheng and associates54 reported complete re-epithelization of the
graft site with ciliated pseudostratified columnar epithelium, suggesting the likelihood of normal
mucociliary flow.
Our group has used the pericardial patch technique in 28 patients, with two early and four late deaths.
One early death was from patch dehiscence and mediastinitis. The other was related to complications of
postoperative extracorporeal membrane oxygenation. Three late deaths were related to residual or
recurrent airway stenosis, and one to pulmonary hypertension. I and my colleagues55 reported that six of
these patients required surgical revision, four with cartilage grafts and two with pericardium. As Furman
and colleagues56 reported, three of these patients have required seven Palmaz stents. These balloon-
expandable metallic stents were placed in the distal trachea or proximal bronchi with a bronchoscope
under fluoroscopic guidance as originally described by Filler and colleagues.57
FIGURE 75.22 Slide Tracheoplasty. A: The trachea is transected at the midpoint of the complete tracheal rings. The upper
trachea is opened posteriorly; the lower trachea is opened anteriorly. The corners of the two tracheal ends are trimmed. B:
Anastomosis between upper and lower trachea is performed with interrupted (or running) polydioxanone surgical (PDS)
(Ethicon, Somerville, NJ). The length of the trachea has been reduced by almost half; the luminal diameter has been increased by
a factor of four. (From Dayan SH, Dunham ME, Backer CL, et al. Slide tracheoplasty in the management of congenital tracheal
stenosis. Ann Otol Rhinol Laryngol 1997;106:914–919.)
The slide tracheoplasty was first described by Tsang and colleagues,58 and was modified by Grillo.59
A median sternotomy approach with the use of cardiopulmonary bypass is very useful in children. The
mid-portion of the trachea is identified bronchoscopically, and then the trachea is transected at this site.
The lower trachea is opened anteriorly, and the upper trachea is opened posteriorly (Fig. 75.22A). The
two tracheal openings then “slide,” one on top of the other, after trimming the corners of the transected
trachea. The two are anastomosed with running PDS suture (Fig. 75.22B). This creates a trachea that is
one-half as long as the original but has four times the diameter. Of course, the patient still has complete
circumferential tracheal rings. Dayan and colleagues60 reported our initial results using this technique in
two infants. The author and his colleagues have now done 22 slide tracheoplasties with two deaths
(10%). Grillo and associates61 reported eight consecutive patients undergoing successful slide
tracheoplasty. Manning62,63 reported 80 patients having a slide tracheoplasty with four deaths (5%
mortality). Kocyildirim64 and Butler65 from Great Ormond Street also reported excellent results with the
slide tracheoplasty in 101 patients with 12 deaths (12%). As mentioned, this is our current procedure of
choice.
Because of the high reoperation rate after pericardial tracheoplasty our group developed a new
operation that the author and colleagues66,67 labeled the tracheal autograft technique. Our group had noted
that in children with complete tracheal rings the trachea is frequently longer than normal. Because of this,
a pericardial tracheoplasty may result in an excessively long patch that does not have intrinsic support.
The autograft procedure shortens the trachea and then uses the resected trachea as an anterior patch,
similar to the tracheal homograft repair reported by Jacobs and colleagues.68
The technique again employs a median sternotomy approach with the use of cardiopulmonary bypass
for respiratory support during the tracheal repair. The trachea is incised anteriorly through the extent of
the stenosis (Fig. 75.23A). A segment of trachea (1.0 to 2.0 cm) is excised, generally in the midportion of
the trachea. The trachea is then reapproximated posteriorly (Fig. 75.23B) with interrupted PDS sutures.
The portion of trachea that was resected is brought in anteriorly as a free autograft. The corners of the
autograft are trimmed, and it is sutured in place with interrupted PDS sutures. In a patient like the one
illustrated, this completes the repair. In a child with longer stenosis, the autograft is used as a distal patch
at the critical junction of the carina and left and right main-stem bronchus. The remaining opening in the
upper trachea is augmented with a pericardial patch (1.5 cm to 3.0 cm in length).
FIGURE 75.23 Tracheal autograft technique. A: The lower trachea is incised anteriorly through 12 tracheal rings (8 complete
rings). A 1.5-cm segment of trachea is excised, essentially the extent of the complete tracheal rings. B: The two cut ends of the
trachea are anastomosed posteriorly with interrupted sutures. The corners of the autograft are trimmed so that autograft fits in
the remaining anterior tracheal opening, where it is sutured in place. (From Backer CL, Mavroudis C, Dunham ME, et al. Repair
of congenital tracheal stenosis with a free tracheal autograft. J Thorac Cardiovasc Surg 1998;115:869–874.)
Since January 1996, as reported by the author and colleagues69,67 we have used this technique in 20
infants (mean age 6 months). Fourteen were completed with the autograft alone; six required pericardial
augmentation. There were two early deaths (10% early mortality) and two late deaths (10% late
mortality). Four patients required temporary tracheostomies.
Tracheal resection was performed through a median sternotomy with the use of cardiopulmonary
bypass in 13 patients. Median age was 4 months, and the mean number of tracheal rings excised was five
rings (range two to eight rings). There was one late death secondary to liver failure while awaiting liver
transplantation. Mean hospital stay was 14 days. Wright and colleagues70 have demonstrated in a large
series that resection of more than 30% of the trachea is more likely to result in anastomotic failure. In
such a case, the procedure should be converted to the slide tracheoplasty technique if more than six to
eight rings (30% of a trachea that normally has 18 to 22 total rings) require resection.
As mentioned earlier, European surgeons have reported using cadaveric treated homograft for
congenital tracheal stenosis. Jacobs and colleagues71 reported the use of cadaveric trachea that was
harvested fresh, fixed in formalin, washed in thimerosal, and stored in acetone.71 The stenosed trachea
was patched open with the tracheal homograft, placed over a temporary silicone rubber intraluminal stent.
Jacobs and colleagues71 reported on 24 children (mean age 8 years), with 20 survivors, of whom 16 are
free of airway symptoms. Six of these patients had long-segment congenital tracheal stenosis, had prior
tracheal operation, and were approached with a median sternotomy. The technique was successful in three
of these children. Jacobs and colleagues72 updated this experience in 1999.
ABERRANT RIGHT SUBCLAVIAN ARTERY

A left aortic arch with aberrant origin of the right subclavian artery from the descending thoracic aorta
may cause posterior indentation of the esophagus (Fig. 75.24). Gross73 described this as the cause of
“dysphagia lusoria.” Abbott74 reported that this is the most common vascular anomaly of the aortic arch
system, occurring in 0.5% of humans. As Beabout and colleagues75 confirmed, however, it is usually not a
source of symptoms severe enough to cause surgical intervention, unless there is aneurysmal dilatation of
the subclavian origin. In adults, however, the base of the aberrant right subclavian artery may become
dilated and aneurysmal, compressing the esophagus and causing symptoms of dysphagia. In that case, the
right subclavian artery should be divided, the aneurysm resected, and the right subclavian artery
implanted into the aorta or carotid artery.
Pifarre and colleagues76 described this operation as a one-stage procedure with a left thoracotomy
approach. More recently, Van Son and colleagues77 have recommended a surgical approach through a
right thoracotomy. Esposito and colleagues78 found only 26 cases of aneurysm of an aberrant subclavian
artery in the world literature, and only 16 patients had been operated on. They recommended an initial
approach through a right cervical incision to divide the right subclavian distal to the aneurysmal dilatation
and anastomosis of the distal end to the right carotid artery to preserve blood flow to the distal
distribution of the artery. The patient is then placed in a right lateral decubitus position, and the aneurysm
is excised through a left thoracotomy approach. These authors believe this approach obviates the possible
complications of upper limb ischemia, cerebral embolization, and intraoperative hemorrhage. I have
never divided an aberrant right subclavian artery.
FIGURE 75.24 Aberrant right subclavian artery originating as the last branch from the aortic arch. The artery courses posterior
to the esophagus up to the right arm.
RARE VASCULAR RINGS
A cervical aortic arch may ascend into the neck and compress the trachea and esophagus. An anomalous
left carotid artery may compress the trachea as it courses from right to left across the trachea. Whitman
and associates79 reported that a left aortic arch with right-sided ligamentum and right-sided descending
aorta is another unusual cause of tracheoesophageal compression. Watanabe and colleagues80 noted that
this has been reported approximately 19 times in the world literature. This is one of the very rare vascular
rings that, as McFaul and colleagues81 reported, may necessitate a right thoracotomy for successful
correction. These infants often have associated cardiac anomalies, such as absent left pulmonary artery,
ventricular septal defect, tetralogy of Fallot, and transposition of the great arteries, as noted by Park and
colleagues,82 and the diagnosis is made by cardiac catheterization. The esophagogram also has a very
distinctive appearance, with extrinsic indentation in the upper left posterior aspect of the esophagus at the
level of the second thoracic vertebra.
Our group, as reported by Dodge-Khatami and colleagues,83 encountered one patient (5 months old)
with a right aortic arch and right ligamentum compressing the right main bronchus. This child also had
absence of the left pulmonary artery, requiring division of the ligamentum through a median sternotomy
approach because of severe hyperinflation and blebs of the right lung.
Binet and colleagues84 described a single case report of a ductus arteriosus traversing from the right
pulmonary artery to the descending aorta between the trachea and esophagus with an aberrant right
subclavian artery. The ductus was compressing the trachea and right bronchus in a manner analogous to
pulmonary artery sling.
Ben-Shachar and colleagues85 reported a hemitruncal sling creating a vascular ring. The right
pulmonary artery originated from the ascending aorta and coursed in a dorsocranial direction, wrapping
around the trachea.

There have been reports of using video-assisted thoracoscopic surgery (VATS) for the division of
vascular rings. This has occurred as an extension of the use of VATS for patent ductus arteriosus ligation
as reported by Laborde and colleagues.86 Burke and associates87 reported the use of VATS for eight
patients with vascular rings. Anatomy of the rings included double aortic arch with an atretic left arch
(three patients) and right aortic arch, left ligamentum arteriosum (five patients). Three patients (37.5%)
required a thoracotomy to complete the procedure. The median operating time was 4 hours, and the
median hospital stay was 3 days. The mean hospital stay of our vascular ring patients has also been 3
days, so I do not believe that the VATS technique is a sufficient improvement to recommend its routine use
at this time. It is interesting to note there were no patients in Burke’s series with a patent arch. A real
concern for the patient with a patent arch is that once the clips are applied and the ring divided, the two
stumps retract because of the tension on the ring. The posterior stump often retracts into the mediastinum,
and if the clip should slip off, the risk of hemorrhage is great. It is not always possible to tell externally
whether a segment of the ring is atretic or patent. The author has heard anecdotal reports of this
complication occurring with resultant substantial brain injury from bleeding and hypotension, providing
additional evidence against the use of a VATS approach in these patients.
CONCLUSION
Infants and children with vascular rings typically present with noisy breathing and varying degrees of
respiratory distress. The diagnosis of a vascular ring requires a high index of suspicion. Our current
diagnostic procedure of choice is the computed tomographic scan (CT) with contrast. The patients with a
true vascular ring (double aortic arch, right aortic arch, left ligamentum) are usually approached through a
left thoracotomy incision. The vascular ring is divided at a site predetermined by CT scan using vascular
clamps and fine vascular suture. Innominate artery compression syndrome is very infrequently diagnosed
in the current era and is treated with suspension of the innominate artery to the posterior sternum. Patients
with a pulmonary artery sling should be evaluated for tracheal stenosis and are repaired through a median
sternotomy incision with the use of cardiopulmonary bypass. If there is associated tracheal stenosis our
repair of choice is the slide tracheoplasty. The successful treatment of these patients depends on a close
collaboration between the thoracic surgery, otolaryngology, anesthesia, and cardiac intensive care unit
teams.
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Section
XIV
CONGENITAL, STRUCTURAL, AND

INFLAMMATORY DISEASES OF THE
LUNG
76
Congenital Parenchymal Lesions of the
Lungs
Antonio Bobbio ■ Laureline Berteloot ■ Claude Guinet ■ Marco Alifano
Congenital anomalies, also known as birth defects, congenital disorders, or congenital malformations,
affect 1 out of 33 infants and result worldwide in approximately 3.2 million birth defect–related
disabilities every year, as reported in 2014 by World Health Organization
(http://www.who.int/mediacentre/factsheets/fs370/en/).1 They are the most common causes of death
during the first year of life (Fig. 76.1) and they are even most prominent as cause of death in those
countries where overall neonatal mortality is low.2 In this setting, national and transnational health
institutions such as the International Clearinghouse for Birth Defects Surveillance and Research
(http://www.icbdsr.org), the US National Centres for Disease and Control Prevention
(http://www.cdc.gov/ncbddd/birthdefects/index.html), and the European Surveillance of Congenital
Anomalies (http://www.eurocat-network.eu) are currently financing and coordinating epidemiologic
surveillance, primary and secondary prevention, projects treatment and care of congenital diseases.
Congenital anomalies involving the trachea, the bronchial three, and the lung which refer to anomalies
in the development of the primitive lung bud are rare, and no specific database for this subgroup of
diseases has ever been set up. Some of these anomalies, however, are included in institutional registries.
For example, the incidence of congenital adenomatoid cyst malformations, the most common congenital
lung anomaly, is reported as 1.05 cases every 10,000 births in the European Community registry for the
surveillance of birth defects.3
In last decades prenatal, good quality, and radiation-free imaging has transformed our knowledge on
development and course of primitive lung bud congenital anomalies (Figs. 76.2 and 76.3). Public health
policies of systematic ultrasound surveillance of foetus development have merged to our attention a new
spectrum of diseases which are often referred as foetal echogenic lung lesions, as described by Achiron
et al.4 It should be noted that at this clinical stage, the histopathologic diagnosis is in almost all the cases
lacking, and the natural history of the lesions is dynamic. As reported by Laberge et al.,5 up to half cases
of congenital cystic malformation of the lung diagnosed by echography could disappear spontaneously
during the last gestational trimester, and, as reported by Cavoretto et al.,6 most of the extralobar
pulmonary sequestration lesions shrink dramatically before birth. On the other hand, in utero therapeutic
procedures have become available; in case of foetal malformations with features of unfavourable
outcome, pleuroamniotic shunting or intrafetal vascular laser ablation have been demonstrated to be safe
and useful.7,8 On the other hand, open foetal surgery, which has been implemented in 1990s, is now
scantly performed.9 Ultimately, a set up of prognostic scores based on clinical and radiological features,
and the possible association with other congenital anomalies may help counselling the parental decision
on the risks and benefits in the prosecution of pregnancy.10
FIGURE 76.1 Infant mortality rates for the five leading causes of infant death in 2009, United States. (Adapted from Mathews
TJ, MacDorman MF. Infant mortality statistics from the 2009 period linked birth/infant death data set. Natl Vital Stat Rep.
2013;61(8):1–27.)
FIGURE 76.2 Antenatal diagnosis of pulmonary CCAM with MRI shows hypersignal of the right lower lobe containing a fluid
cystic lesion.
FIGURE 76.3 Antenatal diagnosis of pulmonary sequestration with MRI shows hypersignal of the left lower lobe containing an
aberrant systemic artery.
Surgery has been hugely influenced by the possibility of early diagnosis and better knowledge on the
natural history of the congenital lung anomalies. Before the advent of prenatal ultrasound, only
symptomatic anomalies merged to medical attention and surgical correction was the rule. Nowadays, both
in paediatric and adult population congenital anomalies are often incidentally discovered and the type and
timing of management is less consensual. There is no doubt that, in asymptomatic cases, the risk of
congenital anomalies to lately become complicated with infection, malignancy, pneumothorax,
haemoptysis, hemothorax, and infarction should be taken into account, although it is difficult to be
estimated for each individual patient, as extensively exposed by Laberge et al.11 Nevertheless, in last two
decades, thoracic surgeons have largely adopted an endoscopic armamentarium which includes
mechanical endoscopic stapler and vessel sealing instruments aimed at reducing surgical trauma in the
treatment of this particular population of patients characterized by a young age.12
TRACHEAL AGENESIS AND ATRESIA

Tracheal agenesis or atresia is referred as to the complete or partial absence of the trachea below the
larynx. This anomaly could be associated to a tracheoesophageal fistula. Floyd et al. categorized the
anomalies into three subtypes (Fig. 76.4).13 Type I (10%) includes partial atresia of the trachea with a
normal short segment of distal trachea arising from the anterior esophageal wall. Type II (59%) is
complete tracheal agenesis with normal bronchi, bifurcation, and carina, with the carina connecting to the
esophagus. Type III (31%) is complete agenesis of the trachea, with the bronchi arising from the
esophagus. It should be noted that Floyd’s classification, as well as the one proposed by Faro et al.14 are
not exhaustive of all the possible anomalies of tracheal agenesis with or without tracheoesophageal
fistula. According to de Groot-van der Mooren et al., in up to 80% of cases, associated cardiopulmonary,
gastrointestinal, or vertebral anomalies are also observed.15 In those cases without tracheobronchial
fistula, prenatal ultrasound shows an abnormal accumulation of fluid in the lungs and in the
tracheobronchial remnant configuring the radiologic features of a congenital high airway obstruction
syndrome (CHAOS).16 However, if tracheal agenesis is associated with a tracheoesophageal fistula, the
fluid could pass from the lungs in the stomach or in the amniotic sac and a polyhydramnion is much
commonly observed. Prenatal MRI may help provide a definitive diagnosis.17
FIGURE 76.4 Tracheal agenesis as described by Floyd. Type I, a distal trachea communicating with the esophagus via a
tracheoesophageal fistula. Type II, the trachea is completely absent with the carina communicating with the esophagus. Type III,
the trachea and carina are absent with the bronchi separately arising directly from the esophagus.
If not diagnosed prenatally, tracheal agenesis leads to an emergency partum characterized by an acute
respiratory distress. At birth, the babies turn blue and do not have an audible cry. An endotracheal tube
cannot be positioned beyond the vocal cords or, if positioned in the tracheal pouch, it cannot generate
effective lung ventilation. However, in the presence of a tracheoesophageal fistula, an esophageal
intubation may temporarily improve ventilation. A tracheotomy is sometime attempted but often
impossible, whereas pulmonary ventilation is ameliorated by esophageal ligature distal to the
tracheoesophageal fistula. Most neonates do not survive and very few cases are alive at 1 year or more.
In those case with antenatal diagnosis of tracheal agenesis, as for those presenting with other CHAOS, a
procedure called ex utero intrapartum treatment (EXIT) to avoid acute respiratory distress syndrome
could be planned.16–18 The procedure is based on maintenance of uteroplacental blood flow during the
diagnostic and therapeutic manoeuvres necessary to manage the airway obstruction. Those patients
surviving after delivery undergo multiple surgical procedures and, in favorable cases, the esophageal
reconstruction is finally performed with a gastric, colic, or jejunal pedicle graft.19
BRONCHIAL ANOMALIES
TRACHEAL DIVERTICULUM AND BRONCHUS

A tracheal diverticulum may arise from the cervical or thoracic portion of the trachea and may end in a
blind pouch. A true diverticulum, also referred as congenital, is diagnosed when all layers of the tracheal
wall, including smooth muscle and cartilage, are involved. A tracheal bronchus not connected to lung
tissue which has either resorbed or not developed presents as a tracheal diverticulum. Dilatation and
distortion of tracheal wall in Mounier-Kuhn disease could lead to the formation of true secondary tracheal
diverticula. On the other hand, a false diverticulum is the result of mucosal and submucosal layers
herniation through a defect of tracheal wall and it is also referred as acquired diverticulum because it is
thought to occur secondary to an increased intratracheal pressure. Surgical resection of true or false
diverticula is performed when it causes compression of adjacent structures or become a source of
continued pulmonary infection.
When a tracheal diverticulum connects to a normal segment or lobe of the lung, it is referred as a
tracheal bronchus (Fig. 76.5).20 The tracheal bronchus is usually located at the junction of the mid and
distal thirds of the trachea on the right lateral wall and it is also termed “bronchus suis,” or “pig
bronchus,” because it is normally seen in swine as well as in certain others Ungulates. A tracheal
bronchus is termed as “supernumerary” when it coexists with a normal branching of the upper lobe
bronchus and as “displaced” when one brunch of the upper lobar bronchus is missed. The lung
parenchyma ventilated from tracheal bronchus has usually normal pulmonary arterial and venous supply.
Much frequent symptoms as reported by McLaughlin et al. are cough, stridor, and repeated pulmonary
infection.21 A radiograph of the chest obtained because of recurrent pneumonia or newborn respiratory
distress could lead to the suspicion of a tracheal bronchus. At this point, a CT scan is performed for a
better assessment of the anomaly and of the rest of the tracheobronchial tree (Fig. 76.5). At bronchoscopy,
the aberrant bronchus is often bronchiectasic or stenotic. Surgery is indicated when a history of recurrent
pneumonia or persistent atelectasis in presence of an aberrant bronchus supplying the area is observed.
Benign and malignant tumor has been sporadically described associated to a tracheal bronchus, albeit a
causal effect is far to be proved.
FIGURE 76.5 CT scan showing a “displaced” tracheal bronchus originating above the carina.
BRONCHIAL ATRESIA
Bronchial atresia is defined as a focal interruption of a main, lobar, segmental, or subsegmental bronchus.
The first case of bronchial atresia has been described by Ramsay and Byron.22 and the pathologic criteria
for the recognition of the malformation have been detailed in a case series of three patients reported by
Simon and Reid.23 The causes of the disease are not fully understood, but in the hypothesis of Waddell et
al., a focal vascular occlusion of a branch of the pulmonary artery during its growth toward the lung bud
is thought to be at the origin of the bronchial defect.24 Bronchial atresia as sole lung malformation is rare
and the prevalence in new born males has been reported to be of about 1 per 100,000 with about a 2 to 1
male predominance.25 On the other hand, the pathologic study of Riedlinger et al.26 using micro dissection
has shown that the features of a bronchial atresia are present in all cases of extralobar sequestration, in
most cases of intralobar sequestration and congenital cystic adenomatoid malformation, and in nearly half
of cases of lobar emphysema, which indicates that lung bud anomalies could share common
ethiopathogenetic mechanisms. On pathologic examination, an interrupted “blind” bronchus is usually
observed with mucus accumulation within the patent distal bronchial segment. The surrounding lung
parenchyma may appear normal or, alternatively, is more likely hyperinflated because of the trapped air
coming from collateral ventilation through the interalveolar canals of Lambert and Kohn. As reported by
Jederlinic et al.,25 up to 58% of patients are asymptomatic and the malformation is only incidentally
discovered. Although symptoms could develop early after birth, in a large group of patients they appear
only lately during the second and third decade of life. Symptomatic patients mainly present with recurrent
pulmonary infections which eventually become complicated by haemoptysis or, more rarely,
pneumothorax. On chest x-ray, a pulmonary rounded, ovoid, or tubular hilar opacity corresponding to the
mucocele can be observed (Fig. 76.6A). The opacity is surrounded by a zone of hyperaerated and
oligaemic lung parenchyma (Fig. 76.6A). On computed tomography, as reported by Lee et al.,27 a central
mass-like opacity is found, with a density between 10 and 25 HU, yielding the diagnosis of mucocele. CT
multiplanar reconstructions are helpful to visualize the typical tubular mucoid impaction (Fig. 76.6B,C).
The surrounding lung parenchyma is emphysematous and distended due to collateral air drift and a paucity
of pulmonary vessel can generally be observed. These features can also be observed in MRI imaging
(Fig. 76.7). In cases complicated by pulmonary infection, an air fluid level may be present in the
bronchocele surrounded by condensed parenchyma. Bronchial atresia is more frequently found in the left
upper lobe and more rarely two instances of bronchial atresia have been described in the same patients
(Fig. 76.6).
FIGURE 76.6 Bifocal bronchial atresia in the B4, B5, and B8 segments of the left lung: chest x-ray (A) and CT scan in axial
(B) and sagittal (C) planes; air-trapping in the anterior parts of the left lung, centered by tubular opacities corresponding to
bronchoceles (black asterisk) is evident. CT scan better shows the bifocal localization in the lingula and in the anterior segment
of the left lower lobe (B4, B5 + B8).
In the absence of symptoms, the patient should be informed on the risk of mucocele infection and a
simple clinical surveillance may be planned. On the other hand, in patients presenting with symptoms,
surgical resection of the affected portion of the lung should be performed. Recent surgical series, as the
one reported by Cappeliez et al., emphasize the role of video-assisted thoracic surgery as a major
determinant of a shorter postoperative stay and better cosmetic results.28 While in historical surgical
series, lobectomy was the most commonly performed procedure, in recent years, thanks to a better
delimitation of the lesion at preoperative imaging, parenchymal sparing resections were preferred, as
reported by Igai et al.29
FIGURE 76.7 Segmental bronchial atresia of right B2 segment: MRI T2-weighted fat suppressed in axial plane (A) and CT
coronal parenchymal reconstruction (B) B2 segmental air trapping. MRI better shows the liquid high signal intensity of the
bronchocele (black asterisk) in the center of low signal hyperinflated parenchyma.
FIGURE 76.8 Esophageal opacification (A) showing an esophageal apical bronchus (black arrow). A fistula between
pulmonary parenchyma connected to the esophageal bronchus and an upper lobe bronchus (white arrow), originating from
mainstem bronchus, is also present. CT scan in coronal minimal intensity projection (minIP) (B) shows the absence of ventilation
of the lung parenchyma next to the esophageal bronchus and the presence of extensive consolidations in the right upper lobe.
COMMUNICATING BRONCHOPULMONARY FOREGUT MALFORMATION

(OESOPHAGUS-LUNG OR OESOPHAGUS-BRONCHUS)
The most common congenital communication between the airway and the foregut is a tracheoesophageal
fistula. However, much rarer anomalies characterized by a fistula between an isolated portion of the
respiratory system (e.g., the lung, a lobe, or a segment) and the esophagus or the stomach do exist. Such
anomalies, including sequestration with a foregut communication, were firstly regrouped by Gerle et al.
under the term of congenital bronchopulmonary-foregut malformation.30 More recently, Srikanth et al.
proposed a four-group classification of conditions called communicating bronchopulmonary foregut
malformation.31 The first group is characterized by the presence of an esophageal atresia with the distal
esophagus originating from the trachea and a lung or a lobe originating from distal esophagus. The second
group refers to the malformation also known as “esophageal lung” which consists in the absence of the
main bronchus and a communication between the esophagus and the entire lung.32 The third group is
characterized by a pulmonary lobe or a segment arising from the esophagus or the stomach. The
malformation is also known as “esophageal bronchus” (Fig. 76.8).33 The fourth group includes those
cases characterized by a simple communication between a portion of the bronchial system and the
esophagus.
It should be noted that pulmonary sequestration could occasionally present with a communication with
the foregut. However, the presence of a systemic vascular supply would help the differential diagnosis.
Nonetheless, the boundaries between these malformations are not always clear and difficulties in
terminology and classification could arise. Communicating bronchopulmonary foregut malformations are
generally discovered in the workup for recurrent pneumonia. Historically, the diagnosis was confirmed
with an esophagogram (Fig. 76.8), whereas a CT scan with gastrointestinal contrast is currently
performed to characterize the malformation. Treatment is based on the resection of the chronically
infected portion of the lung, as well as the esophageal suture. In case of esophageal lung, a successful
reimplantation of the mainstem bronchus into the trachea has been reported by Lallemand et al.34
CONGENITAL LOBAR EMPHYSEMA

Congenital lobar emphysema, also known as infantile lobar emphysema or, more appropriately, congenital
lobar hyperinflation, refers to a malformation characterized by pulmonary over distension and air trapping
in one or more pulmonary lobes (Figs. 76.9 and 76.11). Pathologic features are alveolar overdistension
(emphysema) with a preserved alveolar anatomy. As detailed by Lincoln et al.,35 in most cases, complete
hypoplasia or the absence of a segment of bronchial cartilaginous rings is observed. This anomaly causes
the typical alveolar air trapping and overdistension secondary to a check valve phenomenon (Fig. 76.11).
Redundant mucosa and idiopathic bronchial stenosis have also been reported as being at the origin of the
bronchial air flow obstruction. The differential diagnosis of lobar overdistension includes extrinsic
causes of bronchial obstruction such as an abnormal vessel or compression from enlarged lymph nodes or
bronchogenic cysts. In older infants, the presence of an intrabronchial foreign body must also be ruled out.
Upper lobes and middle lobe are most commonly affected.
FIGURE 76.9 Middle lobe hyperinflation responsible of respiratory distress in a new born: x-ray (A) and axial CT scan (B)
show a compressive hyperinflation of the middle lobe responsible of displacement of mediastinum and atelectasis of surrounding
homolateral and contralateral lung parenchyma.
Congenital lobar emphysema is suspected in case of respiratory distress early after birth and during the
first year of life, whereas is rare after the second year of life. Chest x-ray (Fig. 76.9) shows a wide
radiotransparency of a hemithorax with a contralateral displacement of the mediastinal structures and
homolateral depressed diaphragm.36 In this setting, chest CT leads to a precise definition of the anatomic
lung area involved by emphysema and the possible extrinsic versus intrinsic causes of the disease can be
often ruled out (Fig. 76.9). Associated cardiac malformations are not rare and, lobar emphysema could be
generated by the compression of the bronchi from a distended aberrant pulmonary artery, as observed by
Isojima et al.37 In this case, the treatment is based on the repair of the vascular anomaly and lobectomy
could be sometime avoided.
FIGURE 76.10 Left upper lobe hyperinflation in a 6-month-old boy: CT scan in axial (A) and coronal (B) planes shows a
compressive hyperinflation of the left upper lobe with a displacement of mediastinum. The condition was well tolerated.
FIGURE 76.11 Hyperinflation of the whole right lung due to a focal stenosis of the right main bronchus in a 9-month-old girl.
CT scan in coronal minIP reconstruction (A) and in virtual bronchoscopy at the level of carina (B).
The clinical presentation is characterized by the development of an acute respiratory distress

syndrome (Fig. 76.9). In this situation, confirmation through imaging may not be possible since an urgent
intervention may be required. Conversely, in case of moderate respiratory syndrome, a bronchoscopic
examination could be performed prior to surgery, in order to identify the site of the bronchial
malformation and to exclude the presence of a foreign body. The treatment of symptomatic patients is
based on surgical excision of the affected lobe. In cases characterized by acute presentation with tension
intralobar emphysema, intubation and mechanical ventilation could lead to an increasing of the lung
overdistension with a supplemental impairment of gas exchange.38 At the urgent thoracotomy required for
decompression of the pleural cavity, the affected lobe is seen protruding through the incision and deflation
by perforation of the visceral pleura is indicated to decompress the lobe prior to lobectomy. In patients
presenting with a less acute clinical course (Figs. 76.10 and 76.11), the treatment timing and options can
be discussed, and, in asymptomatic patients, treatment may be conservative because the lesion often
stabilizes and/or regresses with time, as underlined by Laberge et al.11 Interestingly, the average age of
operated patients is around the fifth or sixth months of life whereas cases operated after the second year
of life are rare.
PULMONARY AGENESIS, APLASIA, AND HYPOPLASIA

Absence or underdevelopment of lung tissues, bronchi, and pulmonary vessels is known as the agenesis–
hypoplasia complex. The classification of Schneider, edited in 1912,39 and the one of Boyden,40 dated
1955, distinguish lung underdevelopment in three groups depending upon the degree of the lung defect. In
type I, termed agenesis or “true aplasia,” there is no trace of a lung, bronchus, or vascular supply to the
affected side. In type II, also called “pulmonary aplasia,” there is a rudimentary bronchus without
surrounding lung tissue (Fig. 76.12). Finally, in type III, referred as pulmonary hypoplasia, a variable
decrease in number and size of bronchi, vessels, and parenchymal structures is observed.
FIGURE 76.12 Pulmonary right aplasia in a newborn with prenatal diagnosis. MinIP coronal reconstruction (A) and axial (B)
and coronal (C) mediastinal window CT scan. Presence of a blind rudimentary bronchus; there is neither right lung parenchyma
nor venous return. There is a complete shift of the mediastinum to the right.
A newborn with unilateral pulmonary agenesis or aplasia may be asymptomatic or present with
tachypnea, dyspnea, and cyanosis. As reported by Sbokos and McMillan, more than 50% of patients with
pulmonary agenesis or aplasia die within the first 5 years of life but several patients may remain forever
asymptomatic.41 Older infants or children may present with wheezing that may mimic asthma or
bronchitis. On physical examination, the trachea and the mediastinal structures are shifted to the involved
side, and the overall shape of the chest is normal. Signs of airway obstruction and poor bronchial
drainage may be present. A radiograph of the chest reveals absence of lung markings and mediastinal shift
to the ipsilateral side. Contrast-enhanced CT scans allow for differential diagnosis with total lung
atelectasis or total lung sequestration (Fig. 76.12). Concomitantly, CT scan helps detecting other cardiac
(mainly patent ductus arteriosus or patent foramen ovale) or vascular thoracic anomalies. This is
especially important since the main causes of death in patients with left lung agenesis are related to
associated major cardiovascular anomalies, while main causes of death among patients with right
agenesis are due to airway complications, as reported by Chou et al.42 As a consequence of the
mediastinal shift occurring with right agenesis narrowing and compression of the trachea are observed.
Pulmonary hypoplasia can be unilateral or bilateral43 and encompasses a large spectrum of
malformations which include hypoplasia, aplasia, or agenesis of one or more lung segments or lobes.
Primary pulmonary hypoplasia is rare and is diagnosed when no obvious cause can be found. On the other
hand, secondary pulmonary hypoplasia has various established causes. The most common is the presence
of space-occupying lesions in the chest, such as misplaced abdominal organ as in congenital
diaphragmatic hernia, congenital cystic adenomatoid malformation, or in the case of pleural effusions.
Other causes include malformations of the chest wall resulting in a small thoracic cavity,
oligohydramnios, (which may result from lack of functioning renal tissue, urinary outflow obstruction, or
prolonged premature rupture of the membranes), and neuromuscular disorders which prevent normal fetal
respiratory movements.
SEQUESTRATION
In the classic definition proposed by Price in 1946, pulmonary sequestration corresponds to dysplastic
lung tissue not communicating with the rest of vascular or bronchial lung system but receiving an arterial
blood supply from systemic arteries.44 Boyden, reviewing data collected from embryos, proposed the
theory that sequestration would develop from a lung bud that is pinched off from the caudal foregut with
its own blood supply.45 Further studies by Iwai et al. corroborated these findings.46 A conventional
classification recognizes two main clinical and pathologic presentations, namely extralobar and intralobar
sequestrations. The boundaries of these two entities, however, may sometimes intertwine. In an extralobar
sequestration, the pulmonary dysplastic tissue is separated from the surrounding normal lung by its own
visceral pleura. The venous drainage of an extralobar sequestration is more frequently systemic, mainly in
the right atrium, vena cava, or azygous system. Conversely, an intralobar sequestration is recognized
because the pulmonary dysplastic tissue shares common pleura with the normal lung parenchyma and the
venous drainage is mostly through the pulmonary venous system. In the Price classification, the presence
of an aberrant systemic arterial supply to a normal lung was referred as Type I pulmonary sequestration.44
INTRALOBAR SEQUESTRATION
Intralobar sequestrations (Figs. 76.13 and 76.16) account for about 75% of cases of sequestrations
according to Savic et al.47 In as high as 97% of the patients with intralobar sequestrations, this
malformation is encountered in lower lobes and more often on the left side. Other congenital
abnormalities such as deformities of skeletal system, diaphragmatic hernia, or anomalies of heart or of
great vessels are associated to intralobar sequestrations in 13% of the cases (Fig. 76.17). The aberrant
artery is unique in about 80% of cases and originates from the thoracic aorta (Fig. 76.13), or, less
commonly, from abdominal aorta or its branches. The caliber of the aberrant arteries could vary from 1 to
16 mm and cases characterized by an aneurismatic dilatation of the vessel have been described.
Interestingly, the aberrant artery, unless originating from high pressure vascular system, shows a
predominance of elastic fibers and, even in young patients, various degrees of arteriosclerotic changes
are present.48 These pathologic characteristics should be considered during surgical manipulation of the
fragile arterial wall of the vessel which, if severed, tends to deeply retract in the mediastinum or in the
abdomen.
FIGURE 76.13 CT scan showing an intralobar left lower lobe sequestration. The systemic arterial supply from the thoracic
aorta is evident on contrast-enhanced CT scan on both axial (A) and coronal (B) reconstructions.
FIGURE 76.14 Prenatal diagnosis of intralobar pulmonary sequestration by MRI. The systemic arterial supply from the thoracic
aorta is evident.
Before the era of generalized gestational ultrasound surveillance, only a third of cases were
discovered before the age of 10 years, whereas the remaining cases were observed in adult age at the
onset of symptoms or as an incidental finding. Currently, the majority of sequestrations are discovered on
prenatal ultrasound and confirmed, when indicated, by MRI (Fig. 76.14). At ultrasounds, sequestrations
appear as a hyperechoic mass in the thorax that receives an atypical arterial blood supply from the
descending aorta, as detailed by Cavoretto et al.6 Interestingly, the detection and follow-up of such fetal
anomalies has led to observe that partial or complete regression after birth can occur in up to half of the
patients. A spontaneous obliteration of the artery of sequestration is also possible, as demonstrated by
Lababidi and Dyke.49 On the other hand, cases presenting with pleural effusion and mediastinal shift–
whether in association or not with hydrops and polyhydramnios—have been identified to be associated
with a severe prognosis, as reported by Mallmann et al.7 In such cases, an intrauterine treatment, such as
pleuroamniotic shunting or laser vascular ablation of the aberrant vessel, is recommended.
In older children and adults, characteristic symptoms are chronic cough and recurrent pneumonia
which are thought to be the consequence of the development of bronchiectasis both inside and outside the
dysplastic tissue (Figs. 76.15 and 76.16). Much rarer but dreaded complications are catastrophic
hemoptysis, as well as, bleeding into the pleural space, the esophagus, or into the sequestration itself.50,51
In infants, several cases of congestive heart failure, secondary to left-to-left shunt between the artery of
the sequestration and the pulmonary venous system, have been reported.52
When the anomaly is detected in a newborn, the surgical treatment is delayed if possible to the age of 6
months to decrease the surgical and anesthesiologic risk. By contrast, the management in the absence of
symptoms is less precisely defined. In the case of intralobar sequestration, the dysplastic tissue is not
separated from the normal parenchyma, and the risk of infection is thought to be extremely high and
preventative surgery is generally indicated.53 Moreover, the frequent association with adenoid cystic
malformation and its possible malignant potential leads to operate all patients presenting with a
pulmonary mass, even in absence of symptoms. Preoperative workup includes contrast-enhanced CT scan
to visualize the topography of systemic artery (Fig. 76.13); in young adult and children, MRI can represent
an option (Figs. 76.15 and 76.16).
FIGURE 76.15 Intralobar left lower lobe hybrid sequestration: T2 FS MRI in axial plane (A): voluminous left lower lobe lesion
composed by consolidated heterogeneous parenchyma with liquid components (high intensity signal) and aeric cysts (round
lesions with no signal); MRI angiography with injection of gadolinium (B): vascularization by two arteries emerging from the
descending aorta (white arrow) and early venous return to the left lower pulmonary vein (black arrow).
FIGURE 76.16 Intralobar right lower lobe sequestration: MRI without injection: T2 FS MRI in axial plane (A): posterobasal
right lower lobe lesion composed by consolidated parenchyma; MRI angiography without injection of gadolinium: vascularization
by a single artery emerging from the descending aorta (B).
Intralobar sequestration is classically treated with a lobar resection; however, less extended resection
could be planned on the basis of preoperative imaging. In recent years, the use of endoscopic technique in
treatment of sequestration is expanding.54
ABERRANT SYSTEMIC ARTERIAL SUPPLY TO A NORMAL LUNG
The case of an aberrant systemic arterial supply in a normal lung is generally included in the spectrum of
pulmonary sequestration as proposed by Price in 1953 (Fig. 76.18).44 Two main types could be
distinguished; the first is characterized by a dual vasculature, both systemic and pulmonary, in the affected
portion of lung. In the second type, a main feature is pulmonary artery hypoplasia or agenesis while the
lung is supplied by the sole aberrant systemic artery.55 Venous drainage is always through the pulmonary
bed, and a left-to-left shunt leading, in some extreme cases, to left ventricular failure is observed.56
FIGURE 76.17 Intralobar right lower lobe sequestration: Systemic arterial supply from a systemic artery originating from
abdominal aorta is evident. Hypoplastic pulmonary artery to middle and lower lobe coexists.
The anomaly is typically encountered in the lower lobes and predominantly on the left side.55 The
course can be asymptomatic, whereas the most common observed symptom is hemoptysis which is often
recurrent and, in some rare cases, massive. Historically, the treatment has been surgical, based on
anomalous vessel ligation and eventually pulmonary resection or, much rarely, vessel reimplantation in
the pulmonary artery vasculature.57 Since 1998, treatment by embolization has become widespread and
nowadays is probably to be considered as the best choice.58 Presence of a dual vasculature renders
arterial embolization relatively safe, with a low risk of postembolic pulmonary infarction.58
FIGURE 76.18 Aberrant systemic arterial supply to a normal lung. Contrast-enhanced CT scan with coronal reconstruction,
showing an aberrant large-caliber artery arising from the lower thoracic aorta.
FIGURE 76.19 Extralobar sequestration: T2FS MRI (A) and angio-MRI without injection: well-limited homogeneous lesion
within the left diaphragmatic cupola. A systemic artery is seen, emerging from the left side of descending aorta. Pleural fluid is
present on the left.
EXTRALOBAR SEQUESTRATION
Extralobar sequestrations (Figs. 76.19 and 76.21), also named in the past as “lower accessory lung,” are
more often associated to cardiopulmonary or other congenital anomalies than intralobar sequestrations,
and a diaphragmatic hernia can be seen in up to 30% of cases.47 Moreover, Conran and Stocker, in a
series of 50 patients presenting with extralobar sequestrations, found in half of cases a type II adenoid
cystic malformation.59 Extralobar sequestrations occur in up to 90% of patients in the left chest and
usually in the posterior costophrenic angle. In some cases, however, it may be located in the mediastinum
(Fig. 76.20) or within (Fig. 76.19) or beneath the diaphragm (Fig. 76.21). A possible communication with
the esophagus or stomach through an obliterated fibrous cord or with a patent tract can be observed.
Venous drainage is typically in the caval system. Symptoms are more rarely observed than in intralobar
sequestrations, because sequestrated lung does not communicate with normal lung thus rendering
infections uncommon. On the other hand, extralobar sequestrations are frequently associated to adenoid
cyst malformations and, since the latter are considered at risk for malignant degeneration, even
asymptomatic cases are considered for surgical treatment. It should be noted that associated lung vascular
anomalies are not infrequent and careful preoperative imaging and intraoperative inspection of lung
anatomy should be carried out. In addition, sequestrations could be associated to an anomalous pulmonary
venous connection.60
FIGURE 76.20 Extralobar pericardial sequestration: T2 FS MRI in axial plane (A) and CT angioscan in maximum intensity
projection (MIP) (B): solid lesion embedded in the pericardium behind the left ventricle, fed by a systemic artery emerging from
the descending.
FIGURE 76.21 Infradiaphragmatic sequestration: Angio-CT scan in coronal (A) and sagittal (B) planes: solid lesion of the left
hypochondrium vascularized by a systemic artery arising from the left edge of the abdominal aorta. In arteriography (C), venous
return is visualized to the portal system.
BRONCHOGENIC CYSTS
Bronchogenic cysts result from anomalous budding during primitive lung bud development.61 Mediastinal
centrally located cysts are thought to form early during first step of ventral diverticulum branching and
differentiation, whereas peripheral intrapulmonary cysts are thought to arise at a later date, when trachea
and main bronchi are formed. On pathologic examination, bronchogenic cysts closely resemble the
structure of a bronchial wall with representation of ciliated columnar epithelium, mucosal glands,
fibromuscular and cartilaginous tissue (Fig. 76.22).62 Centrally located bronchogenic cysts share a
common etiologic mechanism with the oesophageal duplication cysts which could be distinguished from
the former because they are found partially covered by oesophageal muscular layers. In addition,
esophageal duplication cysts are usually characterized by a cuboid or multistratified epithelium, albeit
gastric and ciliated cells can be at times found.63 The differentiation is not possible on clinical and
radiologic (Fig. 76.23) grounds, but this has no impact on management which is identical.
FIGURE 76.22 Histopathologic examination of a resected bronchogenic cyst showing a ciliated columnar epithelium, mucosal
glands, and walls containing fibro muscular and cartilage tissue.
Symptoms arise when the cysts, secondary to secretion from mucous glands, fill, expand, and compress
the adjacent structures. In infancy, life-threatening respiratory distress could result from compression of
central airway (Fig. 76.24), whereas in older children or young adults, milder respiratory symptoms such
as chronic cough and recurrent respiratory infection are generally reported (Figs. 76.25 and 76.26).
Intrapulmonary bronchogenic cysts (Fig. 76.27) can communicate with the tracheobronchial tree and the
risk of became infected is high. As detailed by McAdams et al., bronchogenic cysts on CT appear as
sharply outlined masses with either smooth or lobulated margins.64 Water or soft tissue homogeneous
attenuation could be measured and mural enhancement can be present. In doubtful cases, MRI, by
demonstrating markedly increased signal intensity within the lesions on T2-weighted images, can be
useful for suggesting the true cystic nature of the lesion.
All symptomatic cases require surgery unless major contraindication to anaesthesia is present. In
recent years, the rate of cysts incidentally discovered is increasing and, in such asymptomatic patients,
management by simple observation represents a viable option.65 Interestingly, a recent study of Kirmani et
al. has pointed out that 45% of incidentally discovered cases are expecting to further progress and
become symptomatic.66 Surgery is to be preferred to simple surveillance when the cyst is voluminous and
becomes a threatening mass exerting compression of contiguous structures or when a communication with
the bronchial tree is evident. Ultimately, it should be considered that several reports have described a
malignant tumor development in bronchogenic cysts; however, the rate of such condition is extremely rare
and it accounted for 0.7% of the analyzed cases.66
In the past, surgery was performed through a thoracotomic approach, whereas, nowadays, a primary
video-assisted approach can be considered at least in not complicated cases.67 The location of the cysts
and its relationship with adjacent organs should be taken into account. Intrapulmonary cysts require a
wedge resection, or, more frequently, segmentectomy or lobectomy.68 Centrally located cysts typically
occupy the posterior or middle mediastinum and are treated through a right-sided approach. The goal of
surgery is to remove the cyst entirely because residual mucosal and submucosal layer could be at the
origin of recurrence.67 However, difficult surgical conditions could be present, as in the situation when
the wall of the cyst is fused with the posterior tracheobronchial membrane or with the oesophageal layer
beyond the muscularis. In such cases, the opening of the airway or esophageal lumen must be avoided and
after cauterization or a chemical ablation of mucosal layer, the wall of the cyst could be left behind.67
Alternatives to surgical treatment have been proposed, such as aspiration or instillation of sclerosant
agents; however, these procedures could be useful in inoperable patients or when an urgent
decompression is necessary but they do not lead to a definitive cure.65,69
FIGURE 76.23 Mediastinal cyst: T2FS MRI (A) and axial angio-CT scan (B): fluid lesion with hypersignal in T2 MRI,
hypodensity in CT, adjacent to the esophagus, compatible with either bronchogenic cyst or esophageal duplication.
FIGURE 76.24 Subcarinal bronchogenic cyst : coronal scoot view (A), mediastinal (B) and parenchymal minIP projection (C)
windows: voluminous subcarinal fluid lesion responsible of stretching and compression of the carina and main bronchi.
Hyperinflated zones of air trapping are present in both lungs.
FIGURE 76.25 Thoracic CT scan of mediastinal bronchogenic cyst in subcarinal region revealed by persistent cough. Resection
by video-assisted thoracoscopy was performed.
FIGURE 76.26 Thoracic CT scan of mediastinal paraesophageal bronchogenic cyst revealed by dysphagia. Resection by video-
assisted thoracoscopy was carried out.
FIGURE 76.27 Intrapulmonary bronchogenic cyst. Adulthood onset of symptoms (cough and recurrent infection) led to thoracic
CT scan. Treatment involved right upper lobectomy.
CONGENITAL CYSTIC ADENOMATOID MALFORMATION

Congenital cystic adenomatoid malformation (CCAM) is the most common congenital lung anomaly and
its prevalence is reported at 1.05 cases every 10,000 births in the European surveillance network for
congenital anomalies.3 The disease is characterized by the presence of a cystic disease in a portion of
lung and, on pathologic examination, the cysts correspond to dilated airway lined by hyperplasia of
terminal bronchiolar-type tubular structures.70 The classification of Stocker et al. recognizes three
varieties of CCAM. In type I, one or more cysts with a diameter of at least 2 cm in size are present. The
type II is characterized by numerous small cysts not larger than 2 cm, whereas in the type III, microcysts
(<2 mm in size) are present while, macroscopically, the lesion appears as a bulky noncystic lesion. An
expanded classification into five subtypes has been proposed more recently by the same author.71 The
pathogenesis of the malformation is uncertain although it has been suggested that it is the result of a
maturation defect during lung embryogenesis.72 Most of cases of CCAM are now detected during in utero
surveillance of fetal development in form of echogenic lung masses (Figs. 76.3 and 76.28). Obviously, at
this time of fetal development, the true histopathologic nature of the lesion is uncertain and, as showed by
Tsai, definitive diagnosis of such echogenic masses at time of surgery could vary.73 On the other hand,
intrauterine surveillance of such lesions has to be planned because the growth of the mass, the presence of
a pleural effusion and/or of a mediastinal shift are features of an unfavorable outcome and a treatment
such as a fetal pleuro-amniotic shunt could be performed for decompression of the intrathoracic organs.74
At birth, most patients with CCAM are asymptomatic but, as reported by Sauvat et al., by the age of 13,
up to 86% of patients has experienced symptoms.75 In some cases, either the lesion or its complications
may be responsible for poor clinical tolerance (Fig. 76.29).
FIGURE 76.28 Right lower lobe CCAM with antenatal diagnosis: prenatal MRI showing hypersignal of the right lower lobe
containing a fluid cystic lesion is shown in Figure 76.2. Postnatal MRI at the age of 2 months (axial T2FS): multiple aeric lesions
of the apical segment of the right lower lobe. The content presents no signal while the walls show hypersignal. The fissure shows
hypersignal.
FIGURE 76.29 Large CCAM of the left lower lobe of prenatal diagnosis. Chest x-ray (A) and CT (B, C) scan carried out at
one day of life because of poor clinical tolerance: multiple large air-filled cystic lesions of the apical segment of the left lower
lobe are evident. Pneumothorax, complete shift of the mediastinum to the right and lung compression are associated.
CT scan is generally performed during the first year of life and the presence and size of cysts is
detected. In cases complicated by infection, the cysts fill with fluid and the areas of consolidation
increase. An aberrant systemic artery is to be searched to rule out an associated sequestration. This last
condition is much common in type II CCAM lesion. A large consensus exists on the attitude of operating
those cases of CCAM presenting with symptoms, while, in asymptomatic cases, different attitudes
coexists, as reported by Lo and Jones in a surveys among Canadian surgeons.76 The natural history of the
malformation is mainly characterized by the occurrence of recurrent pulmonary infections and, although
more rarely, hemoptysis and pneumothorax have also been reported.77 A surgical option is also advocated
to confirm the diagnosis and exclude the presence of malignant tumors. Epithelial malignant tumor such as
bronchoalveolar carcinoma, but also stromal tumors, such as pleuroblastoma have been observed in
association with the malformation.77 Nonoperative strategies claim that the operative risk is excessively
high in the face of such benign conditions and the risk of malignant transformation is excessively
exaggerated.77 In case of surgery, lobectomy is the more frequent type of lung resection because, even on
preoperative imaging, the burdens between the malformation and the normal lung are vanishing. Most
cases of CCAM are operated in infancy within the first 2 years of life and mini invasive techniques could
be employed even in such young patients.78 In recent years, video-assisted surgery is the preferred
technique in adult population.
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77
Pulmonary Complications of Cystic Fibrosis
Pascal A. Thomas
INTRODUCTION
Cystic fibrosis (CF) is the most common heritable genetic condition amongst Caucasian ethnicities,
affecting about 1 in 2,500 live births in Europe and European-derived populations and 1 in 3,500 in the
United States.1,2 CF is an autosomal recessive genetic disease caused by several mutations in a single
gene located on the long arm of chromosome 7 at position q31.23 that encodes the CF transmembrane
conductance regulator (CFTR) protein. More than 1,900 mutations in that gene have been described so
far, although this number can be folded into five classes of molecular lesions on the basis of their effect
on CFTR protein production, trafficking, function, and stability.4 Class I mutations are premature
transcription terminations causing a truncated nonfunctional CFTR, resulting in complete absence of
protein expression. Class II missense mutations consist of aberrantly folded CFTR protein that is
degraded by the cell quality–control system. Class III mutations lead to defective regulation of the CFTR
protein and, consequently, the absence of CFTR function. Class IV mutations lead to chloride channel
conduction defects. Class V mutations result in reduced amount of functional CFTR protein due to
abnormal gene splicing. Nevertheless, Phe508del (formerly F508del) is the most common CFTR
mutation, with approximately 45% of patients with CF being homozygous for this allele.5 This class II
mutation consists of a 3-bp deletion that codes for phenylalanine at position 508 of the CFTR protein.
Wild-type CFRT serves as a transmembrane channel located in the apical membrane of epithelial cells
responsible for the cAMP- and ATP-dependent transport of chloride and bicarbonate ions into and out of
the cell. CFTR influences the fluid composition of the mucus of exocrine glandular epithelia of the
paranasal sinuses, respiratory airways, gastrointestinal tract, and other organ systems, thus explaining the
major clinical manifestations of the disease.
In the respiratory epithelia of CF patients, chloride secretion is deficient and, as water passively
follows the chloride and sodium ions into the cells, this leads to dehydration of the mucous secretions6
and, in turn, dehydration of the airway surface liquid, increase in the viscosity of airway secretions, and
impaired mucociliary clearance that causes a decreased ability to clear bacterial infection.7 In addition,
deficiency of CFTR-mediated transport of bicarbonate and regulation of the pH of airway surface liquid
inhibits antimicrobial function in the CF airways.8 Therefore, the natural history of the lung disease
consists of early and persistent infection with pathogens such as Staphylococcus aureus and
Pseudomonas aeruginosa,9 exaggerated inflammatory response,10,11 and progressive airways obstruction.
Chronic infection and inflammation are punctuated by acute exacerbation episodes, following which lung
function fails to return to baseline levels, ultimately resulting in respiratory failure. Bronchiectasies and
progressive scarring, airway obstruction and air trapping, increased dead-space ventilation,
ventilation/perfusion mismatch, alveolar hypoventilation predominantly during sleep, exercise, and acute
respiratory exacerbations lead to hypoxemia and lastly hypercarbia. Chronic hypoxemia and hypercarbia
provoke muscular hypertrophy of the pulmonary vasculature, right ventricular hypertrophy, and eventually
cor pulmonale with right heart failure. Respiratory failure and pneumonia still account for more than 80%
of deaths in CF patients according to the most recent epidemiologic data.2,12 In some instances, several
acute complications, such as pneumothorax or massive hemoptysis, act as precipitating lethal events. The
genotype–phenotype relationship is actually complex and is affected by both environmental factors and
quality of care. Current fundamentals of CF care management are based upon early diagnosis, and
therapies include physiotherapy, mucolytic drugs and antibiotics to treat lung disease, pancreatic enzyme
replacement, and supplementary nutrition to overcome gastrointestinal dysfunction.
However, advances in the understanding of and treatments for CF continue to extend survival. Children
born and diagnosed with CF in the United States in 2010 are thus expected to live longer than those born
earlier, with a projected median survival of more than 50 years if mortality continues to decrease at the
rate observed between 2000 and 2010.13 Besides, the successful development of lung transplantation
provided a curative approach to life limiting pulmonary complications with the potential to significantly
extend survival and improve quality of life. These cumulated facts suggest that the thoracic surgeons’
community should anticipate greater numbers of adults with CF to deal with in the near future.
DIAGNOSIS
Even in the era of genetics and molecular biology, the diagnosis of CF should be based on clinical
grounds with a history of CF in a sibling or the presence of one or more characteristic phenotypic features
(Table 77.1), in a spectrum of pathology ranging from chronic sinusitis in adulthood to bowel obstruction
and severe lung, pancreatic, or liver disease in infancy, including typical radiologic features (Fig. 77.1).
Additionally, patients must have laboratory evidence of CFTR protein abnormality. This can be
demonstrated by the quantitative pilocarpine iontophoresis sweat test. A sweat chloride concentration of
more than 60 mmol/L on two separate occasions is consistent with the diagnosis of CF. The sweat test has
high sensitivity and specificity but its results must be interpreted in the context of the patient’s age and
clinical picture.14
TABLE 77.1 Phenotypic Features Consistent With a Diagnosis of CF
1. Chronic sinopulmonary disease, manifested by
a. Persistent colonization/infection with typical CF pathogens, including Staphylococcus aureus, nontypeable Haemophilus
influenzae, mucoid and nonmucoid Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia
b. Chronic cough and sputum production
c. Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation)
d. Airway obstruction, manifested by wheezing and air trapping
e. Nasal polyps; radiographic or CT abnormalities of the paranasal sinuses
f. Digital clubbing
2. Gastrointestinal and nutritional abnormalities, including
a. Intestinal: meconium ileus, distal intestinal obstruction syndrome, rectal prolapse
b. Pancreatic: PI, recurrent acute pancreatitis, chronic pancreatitis, pancreatic abnormalities on imaging
c. Hepatic: prolonged neonatal jaundice, chronic hepatic disease manifested by clinical or histologic evidence of focal biliary cirrhosis
or multilobular cirrhosis
d. Nutritional: failure to thrive (protein-calorie malnutrition), hypoproteinemia and edema, complications secondary to fat-soluble
vitamin deficiencies
3. Salt loss syndromes: acute salt depletion, chronic metabolic alkalosis
4. Genital abnormalities in males, resulting in obstructive azoospermia
Adapted from Farell PM, Rosenstein BJ, White TB, et al.; Cystic Fibrosis Foundation. Guidelines for diagnosis of cystic fibrosis in newborns
through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008;153:S4–S14. Copyright © 2008 Elsevier. With permission.
FIGURE 77.1 The cardinal finding of cystic fibrosis. Note the presence of diffuse thick-walled cylindrical and cystic
bronchiectasis, together with regions of consolidation and lymph node enlargement.
TABLE 77.2 Recommended Panel of CF-Causing Mutations
Missense, Deletion, Stop Mutations Splicing, Frame Shift Mutations
G85E I507del R560T 621_1G_T 2789_5G_A
R117H F508del R1162X 711_1G_T 3120_1G_A
R334W G542X W1282X 1717_1G_A 3659delC
R347P G551D N1303K 1898_1G_A 3849_10kbC_T
A455E R553X 2184delA
Adapted from Farell PM, Rosenstein BJ, White TB, et al.; Cystic Fibrosis Foundation. Guidelines for diagnosis of cystic fibrosis in newborns
through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008;153:S4–S14. Copyright © 2008 Elsevier. With permission.
Since 1989 and the availability of CFTR genotyping, the diagnosis can also be confirmed when
disclosing two disease-causing mutations in those patients with clinical suspicion but inconclusive sweat
test. CFTR genotyping is highly specific but not very sensitive because of the large number of known and
probably still unidentified mutations. Customizing mutation panels to match the patient’s ethnicity and
phenotype (i.e., pancreatic sufficiency) could increase the sensitivity of CFTR genotyping.15
Nevertheless, current commercially available mutation screening panels can identify a high percentage of
CFTR mutations, as they include the 23 (Table 77.2) that have been demonstrated by direct or empirical
evidence to cause sufficient loss of CFTR function to confer CF disease.
In patients with clinical features consistent with CF but a nondiagnostic sweat test result and only one
identified CF mutation, nasal potential difference (NPD) testing may be useful.16 The presence of a high
potential difference during baseline measurements plus a very low voltage response to zero-chloride
perfusate and isoproterenol provides a strong evidence for the diagnosis of CF. However, false-negative
result may occur in the presence of inflamed epithelium, a frequent condition in CF individuals. Thus, the
test must be duplicated on more than one occasion to be valid as a diagnostic adjunct. Its main limitation
is that access to the test remains limited to those rare centers having sufficient expertise with its use and
interpretation.
Ancillary tests may help to ascertain a diagnosis of CF either by identifying a phenotype, such as
exocrine pancreatic insufficiency, or by detecting microbiota of the airways. For instance, 72-hour stool
collection is very useful for determining pancreatic function. The highly specific monoclonal test for fecal
elastase, which is resistant to intraluminal degradation in contrast to trypsin, is preferred.17
Characterization of the respiratory microbiota can be diagnostically helpful in the evaluation of patients
with atypical features of CF. The tendency of P. aeruginosa to colonize the respiratory tract in CF is well
known, and its persistence is highly suggestive of CF, especially the mucoid phenotype. Persistent
colonization with other organisms such as S. aureus, Haemophilus influenzae, and Burkholderia cepacia
may support a diagnosis of CF18 although many of these pathogens are also found in other conditions.
Newborn screening has introduced a new complexity in the diagnostic algorithm. Figure 77.2
illustrates the current CF diagnostic process in screened newborns. It also led to isolate a new category of
individuals, that is, those asymptomatic infants with abnormal screening tests as the result of elevated
immunoreactive trypsinogen levels but inconclusive sweat tests and/or DNA results. Little is known on
how these infants should be managed. Close longitudinal monitoring has to be organized, weighting the
risk of delayed diagnosis of CF, and thus inadequate management early in life, against the risk of “over-
medicalization” of individuals who will perhaps never develop the disease.19
FIGURE 77.2 The CF diagnostic process for screened newborns. (Adapted from Farrell PM, Rosenstein BJ, White TB, et al.;
Cystic Fibrosis Foundation. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation
consensus report. J Pediatr 2008;153:S4–S14. Copyright © 2008 Elsevier. With permission.)
STANDARDS OF CARE
Multidisciplinary care in specialized centers is the current driving paradigm for the management of CF
patients worldwide. However, most available therapies target secondary aftermaths of the CFTR
deficiency, and very few the underlying processes of the disease. On the other hand, newborn screening
for CF, as implemented in many countries, gives the opportunity to diagnose CF individuals before
respiratory symptoms develop, and therefore to start treatment interventions earlier with the goal to delay
as far as possible and the hope to ultimately stop lung disease development, especially with the advent of
novel therapies aiming at the functional restoration of CFTR.
P. aeruginosa respiratory tract infections occur in almost all CF individuals. Once chronic infection is
established, P. aeruginosa is virtually impossible to eradicate and is associated with increased mortality
and morbidity. Eradication therapy of new P. aeruginosa infection, based on nebulized antibiotics, alone
or in combination with oral antibiotics, is effective and no alternative regimen has yet been shown to be
of superior efficacy.20 A recent cohort study demonstrated that sustained eradicators, defined as those who
maintained P. aeruginosa–negative cultures for 12 months after initial antipseudomonal therapy, had a
74% reduced risk of developing chronic infection (HR 0.26; 95% CI 0.17–0.40) compared with
nonsustained eradicators. However, there was no association between eradication status and clinical
outcomes such as rate of exacerbation and lung function decline.21 When eradication therapy has failed,
long-term maintenance therapy with inhaled antibiotics should be initiated.22 North American guidelines
recommend inhalation of tobramycin on alternate months, to be continued indefinitely irrespective of the
severity of lung disease.23 Colistin is used widely in Europe for this purpose.24 Inhaled aztreonam
lysine25 may be used as an alternative. Maintenance therapy with oral macrolids is also part of
recommended care,23 as azithromycin has been shown to improve lung function and reduce pulmonary
exacerbations not only in chronically infected patients with P. aeruginosa,26 but also in those who were
not.27 However, azithromycin can favor the development of resistance of common organisms such as S.
aureus and H. influenzae. In addition, it could predispose to lung infection by nontuberculous
mycobacteria (NTM).28
Methicillin-resistant S. aureus (MRSA) has emerged as a potentially harmful pathogen in CF and has
been increasing gradually in prevalence internationally. Chronic pulmonary infection of CF patients with
MRSA is thought to be associated with a worse outcome and a faster decline in lung function. Although
the results of several nonrandomized studies would suggest that eradication of MRSA is possible with
several combinations of topical, inhaled, oral, or intravenous antibiotics,29 whether this has a significant
impact on clinical outcome is still controversial.
Chest physiotherapy to assist airway clearance is pivotal. Positive expiratory pressure (PEP) devices
provide back pressure to the airways during expiration that enhances clearance by strengthening air
behind mucus via collateral ventilation. Other techniques include active cycle of breathing techniques,
autogenic postural drainage, oral oscillating PEP devices, high-frequency chest wall oscillation, and
bilevel PEP devices. There may be individual preferences and therefore different compliances with
respect to these airway clearance techniques as well as, in a given individual, varying preferences as
circumstances including developmental stages, pulmonary symptoms, and lung function change over time.
However, evidence-based medicine has shown a significant reduction in pulmonary exacerbations in
people using PEP in those studies where exacerbation rate was a primary outcome measure.30 A recent
randomized trial demonstrated that among patients hospitalized for an acute exacerbation of CF, the use of
noninvasive ventilation as an adjunct to the airway clearance regimen significantly improves FEV1 and
fatigue.31
Mucolytics and hydrators are complementary additives. The only mucolytic that has proven efficacy in
CF is inhaled recombinant human DNase (dornase alfa). Long-term maintenance therapy reduces
pulmonary exacerbations, regardless of disease severity32 and lung function decline.33 Inhaled nebulized
hypertonic saline improves mucociliary clearance in a dose-dependent way and has also been shown to
reduce pulmonary exacerbations and marginally improve lung function.34 Its routine use is therefore
currently recommended in CF patients with moderate to severe lung disease.23 Mannitol has been
introduced more recently and is also effective.35,36 Both agents act as irritants and require pretreatment
with a bronchodilator and initial tolerability testing.
Chronic and exaggerated neutrophilic inflammation promotes lung damage in CF patients. Since
infection and inflammation are strongly linked in most individuals, targeting inflammation may have
negative effects on defense against infections, especially systemic glucocorticoids. Nevertheless,
treatment with nonspecific anti-inflammatory drugs such as high-dose ibuprofen has been shown to have
beneficial effects on pulmonary function in older children with CF.37 Its routine use, however, lacks from
robust evidence-based arguments. Both systemic and inhaled corticosteroids are definitely not
recommended for routine use. On an individual basis, however, their handling may fit CF patients with
severe asthma and/or allergic bronchopulmonary aspergillosis (ABPA). Treatment using antiproteases
could also be a potential early intervention strategy in the prevention of lung damage. Indeed, treatment
with inhaled α1-antitrypsin has resulted in moderate reduction in activity of neutrophil elastase and
decreased Pseudomonas load in older patients.38
In spite of differences in clinical presentation, sino-nasal involvement occurs in almost all CF
patients.39 Chronic sino-nasal disease includes rhinosinusitis and nasal polyposis. Sinusal disease can
exacerbate lung disease, the upper airways serving as a bacterial reservoir because the bacterial florae in
the paranasal sinuses and lower airways are identical.40 Conservative management is considered the first
step in the treatment. In addition to the aforementioned measures that also act on the paranasal sinuses
mucosa, various topical treatments with nasal corticosteroid sprays, decongestants, antihistamines, and
saline irrigation are routinely used without a specific assessment of their efficacy. Endoscopic sinus
surgery should be considered when the noninvasive treatment fails, especially in case of persistent nasal
obstruction, or when there is a correlation between sino-nasal symptoms and pulmonary exacerbations.41
Although the impact of endoscopic sinusal surgery on pulmonary function is disappointing, surgery may
contribute to bacterial eradication.42 There is, however, a high rate of recurrences, leading to surgical
revision procedures.
Exercise and physical activity should be added in a comprehensive rehabilitation program,
irrespective of age and disease severity, since a decrease in exercise capacity is associated with a
decline in respiratory function and survival.43 Nutritional support is necessary, as CF patients require
increased caloric intake during pulmonary exacerbations due to higher metabolic demands. CF patients
often have a reduced appetite due to the respiratory discomfort caused by gastric distention after meals
and an impaired nutriment absorption due to exocrine pancreatic insufficiency. Accordingly, access to a
specialist dietician is crucial to prevent sarcopenia. Nutrition management includes a high-calorie/high-
fat diet, pancreatic enzyme replacement therapy, vitamin and mineral replacement, and enteral support as
needed, aiming at a goal body mass index of 22 for women and 23 for men.44
Vaccination guidelines in children with CF associate the usual vaccination schedule with specific
recommendations concerning influenza, pneumococcus, viral hepatitis A and B, and varicella. Live
attenuated vaccines must be administered before pulmonary transplantation. Development of new
vaccines against respiratory infections (S. aureus, P. aeruginosa and syncytial respiratory virus in
particular) is an important ongoing challenge for the medical management of these patients.45
There is a continual increase in the incidence of diabetes mellitus with advancing age, a condition that
concerns over one-third of CF individuals aged beyond 25 years. CF-related diabetes is not associated
with an increased risk of cardiovascular disease, and the prevalence of microvascular complications is
lower than diabetes mellitus type 1 and 2.46 The primary goal of insulin therapy is thus the preservation of
lung function and optimization of nutritional status. Indeed, the presence of CF-related diabetes is
associated with a worse pulmonary function in all age groups and an increased risk of mortality.47 There
is increasing evidence that appropriate screening and early intervention with insulin can reverse weight
loss and improve pulmonary function. Aggressive diagnosis and management of diabetes are thus
important components of CF care.
Liver failure usually occurs late, after the pediatric age. Annual screening for liver disease is
recommended to detect pre-symptomatic signs and initiate ursodeoxycholic acid therapy, which might halt
disease progression.48
Osteoporosis and osteopenia are also regarded as late symptomatic complications in adult CF patients,
although low bone densities and fractures may be seen early in children. Osteopenia is diagnosed in about
one-third of CF adults.49 CF-related bone disease consists of rib and vertebral compression fractures; its
mechanism is not well known, but contributing factors are severe pulmonary disease, malabsorption of
vitamin D, calcium, and other nutrients, hypogonadism, physical inactivity, and cytokines from chronic
infection.50 Major kyphosis and/or scoliosis is rare, but may be an obstacle to lung transplantation. Bone
mineral density measured by dual energy x-ray absorptiometry is part of the routine workup, especially
before registration on the waiting list, as osteoporosis may be worsened after lung transplantation due to
side effects of steroids. The basis of therapy is the correct calcium daily intake plus calcifediol that can
improve bone mineral density in some young CF patients. In those who do not respond to calcium and
calcifediol alone, alendronate can safely and effectively increase bone mineral density.51,52
Innovative therapies aim at targeting the CFTR protein dysfunction. Ivacaftor, a CFTR potentiator
studied in the gating mutation G551D, improves clinical outcomes in patients 6 years of age or older who
have CF and at least one copy of most class III (gating) mutations.53 Though this type of mutation is found
in less than 5% of patients worldwide, ivacaftor is now part of standard of care in those patients.
Lumacaftor is an investigational CFTR corrector that has been shown in vitro to correct p.Phe508del
CFTR misprocessing. Two recent phase III trials have demonstrated that lumacaftor in combination with
ivacaftor improved FEV1 and reduced the rate of pulmonary exacerbations in patients with CF who were
homozygous for the Phe508del CFTR mutation, with an acceptable tolerance profile.54 This combination
of a CFTR corrector and potentiator opens a new era in the standard of care, being a treatment milestone
for the 45% of patients with CF who are homozygous for this mutation.
Gene therapy to restore impaired CFTR function is a further promising path of research. The
respiratory epithelium is easy to access by inhaled aerosols, and various vectors for transfer of the CFTR
gene into respiratory epithelial cells have been tried. Viral approaches have failed so far because of
inefficient transduction from the luminal surface and immune responses restricting the efficacy of repeated
application.55 Among nonviral vectors are plasmid DNA–liposome complexes. A recent randomized trial
provided the first proof of concept while showing that monthly application of nebulized pGM169/GL67A
gene–liposome complex was associated with a significant, albeit modest, benefit in FEV1 compared with
placebo at 1 year, indicating a stabilization of lung function in the treatment group.56
As progressive respiratory insufficiency remains the major cause of mortality in CF patients, palliative
measures, that is, oxygen therapy and noninvasive ventilation, have to be implemented. Short-term oxygen
therapy during sleep and exercise has been shown to improve oxygenation in CF patients, but is
associated with modest and probably clinically inconsequential hypercapnia. There are also demonstrated
improvements in exercise duration, time to fall asleep, and regular attendance at school or work.
However, there is still a need for larger, well-designed clinical trials to assess the benefits of long-term
oxygen therapy in people with CF administered continuously or during exercise or sleep or both.57
Noninvasive ventilation was originally reported as a bridge to transplantation in CF patients with severe
respiratory failure but is now used earlier in the disease course as a long-term treatment modality for
patients with respiratory failure independent of transplant status, though its optimal timing remains
unclear. Noninvasive positive pressure ventilation (NPPV) has been shown to unload the respiratory
muscles in patients with CF, which increases alveolar ventilation and improves gas exchange. NPPV has
been shown to reduce oxygen desaturation during sleep, exercise, and chest physiotherapy and may
facilitate the recovery of a severe hypercapnic respiratory exacerbation in moderate to severe disease.58
Finally, lung transplantation is eventually required. Lung transplantation carries the paradox to be both a
high-risk and a potentially life-saving therapy for the end-stage lung disease of CF. The decision to carry
out transplantation remains difficult and needs to weigh for each individual the likelihood of survival with
and without transplantation as well as assessing the effect of wait-listing and transplantation on his or her
quality of life. Nevertheless, the advent of lung transplantation revolutionized the management of this
disease.59
LOCALIZED DISEASE: BRONCHIECTASIS AND LUNG ABSCESS

In the pretransplantation era, the so-called “localized” disease was quite liberally considered for elective
lung resection60 with the aim of removing the destroyed nonfunctioning parenchyma in order to prevent
bacterial spreading, enhance pulmonary function, and prevent more severe complications. Localized
disease covered bronchiectasis, acute or chronic atelectasis, and lung abscess (Figs. 77.3 to 77.5). In the
modern era, therapy and outcome for patients with CF have undergone marked improvement, and lung
transplantation has become an important therapeutic option for patients with end-stage lung disease.
Consequently, a more restrictive view about the role of lung resections is now shared among physicians
involved in CF care management. Only unilateral progressive localized disease that failed to respond to
conventional therapies may be selected for surgery to prevent disease progression in uninvolved areas.
Besides, emergent surgery may be performed anecdotally to manage life-threatening complications when
conservative treatment is unsuccessful.61 The available literature suggests a potential benefit in some
patients in terms of clinical symptoms and CF exacerbations, but with a substantial risk of postoperative
morbidity and mortality. This literature, however, is inconsistent in the lack of standardized indications
and because reported patients varied in age, severity of disease, study period, and therefore overall
medical care. Furthermore, almost all these studies were small sized, usually mixed elective and urgent
surgeries, and had a retrospective design with no control group and short follow-up.
In the 1970s, Mearns et al.62 reported on 23 pediatric CF patients of whom 12 were subjected to
elective surgery with radical intent, whereas 11 underwent pulmonary resection for palliation or as a life-
saving procedure, with one postoperative death. The majority of the patients showed some benefit from
surgery at 1 year in terms of improvement in symptoms. However, lung disease progression was
simultaneously registered in almost half of them. In the 1980s, Marmon et al.63 reported on 10 pediatric
CF patients of whom 9 had elective surgery and 1 had life-saving procedure, with no major postoperative
complication. These patients experienced decreased cough, sputum production, and incidence of
exacerbations, with a follow-up that ranged from 7 months to 13 years. In the 1990s, Smith and
colleagues64 reported on 14 pediatric and adult CF patients 10 underwent elective surgery and 4 urgent
surgery. The 12 surviving patients at a minimum follow-up of 1 year experienced a significant reduction
in the number of hospitalizations for pulmonary exacerbations despite a significant decline in pulmonary
function tests. A preoperative FEV1 less than 30% of the predicted value was consistently associated with
a poor outcome in this series. In the 2000s, Camargos et al.65 reported on 21 pediatric CF patients who
received elective surgery at a mean age of 8 years for chronic atelectasis and/or bronchiectasis over a 16-
year period. No significant differences were found when preoperative and postoperative indicators
related to nutritional and colonization status were compared. Consistently, there were no changes in
pulmonary function tests. However, a clear improvement in quality of life and reduction of number of
exacerbations were observed. The estimated 11-year survival probability was 93.8%. In the 2010s,
Sheikh et al.66 reported on 15 patients with a mean age of 20 years; 10 received surgery for progressive
lung disease and 5 life-threatening complications over a 15-year period. There were 3 deaths within the 2
following years. All of these 3 deaths occurred in patients with a FEV1 ≤40%. No improvement was
noted in nutritional status, hospital admissions, and antibiotics use over time.
FIGURE 77.3 Localized disease with bronchiectatic segmental destruction of the left lower lobe.
FIGURE 77.4 Localized disease with lung abscess in the right upper lobe.
FIGURE 77.5 Localized disease with a complete destruction and atelectasis of the whole right lung.
In the vast majority of cases, a lobectomy, and to a lesser extent a segmentectomy, typically of the right
upper lobe, were performed. Pneumonectomy was scarcely reported with only one patient in the paper by
Marmont et al.,63 four patients in the one by Smith,64 but none in the other above-mentioned papers.62,65,66
This is easily explained by the fear about the risks of bronchial stump fistula and respiratory failure or
death which remain significant hazards following pneumonectomy. Additional anatomical concerns
include development of scoliosis and the technical challenge of single lung transplantation after
contralateral pneumonectomy due to mediastinal shift. Haüsler et al.67 have specifically described two
cases of right pneumonectomy in children with complete lung atelectasis and abscess formation. These
two patients experienced a notable improvement in quality of life, as far as the follow-up limited to 2 and
4 years allows assessing it. Additionally, Ferrer González et al. described the remarkable 15-year
follow-up of a CF patient who underwent pneumonectomy at the age of 13 years.68 Even if definitive
conclusions are hazardous with such weak evidence, it may be summarized that the indication of elective
lobectomy or segmentectomy may be considered in every case of unilateral severe parenchymal localized
disease refractory to medical therapy, mainly in the infancy, provided that a preoperative FEV1 over 30%
to 40% of predicted is measured. In contrast, pneumonectomy remains a salvage option only in the very
selected patient with irreversible unilateral lung damages who is at high risk of dying while waiting for
lung transplantation.61 There is no data available on the possible use of VATS in this context, likely due to
the dense pleural adhesions and tissue fibrosis related to chronic inflammation that do not offer a
favorable ground for minimally invasive approaches.
Nowadays, the medical and surgical community is somewhat reluctant to consider elective lung
resection surgery in CF patients, mainly because of its probable futility in the setting of a systemic disease
and the risk to compromise the chances of lung transplantation in this population. With the advent of novel
therapies aiming at the functional restoration of CFTR in human CF airway epithelia, it may be speculated
on a possibly renewed role of surgery to remove residual destroyed lung area in patients whose disease
has been stabilized by these treatments, according to indications similar to those applied in non-CF
bronchiectatic patients.
PARAPNEUMONIC PLEURAL EFFUSION AND EMPYEMA

Despite the high incidence of bacterial infection of the respiratory tract, parapneumonic effusions and
pleural empyema are rarely encountered in CF patients. This observation undoubtedly relates to vigilant
microbiologic surveillance, early use of targeted antibiotic treatment, and intensive chest physiotherapy in
this population. Nowadays, empyema has been reported sporadically in CF patients following lung
transplantation,69 liver disease with portal hypertension,70 diabetes mellitus,71 or long-term use of oral
prednisolone.72
Significant parapneumonic effusions have to be evacuated with thoracentesis, whereas an empyema
requires pigtail catheter insertion or chest tube drainage. Indications of surgery are the same as for
patients without CF.61 VATS may be used to debride purulent collections and remove fibrin septa that
failed to be resolved by antibiotics and chest tube drainage with or without fibrinolytic therapy. VATS use
should be encouraged as early as possible to avoid the onset of an organized empyema. Indeed, an
organized, multiloculated empyema with pleural thickening and lung entrapment always requires a formal
decortication through thoracotomy. Besides its immediate risks, this surgery may also compromise the
technical feasibility of lung transplantation that may be eventually required.
PNEUMOTHORAX
Pneumothorax is a common surgical complication of pulmonary involvement by CF. Concomitant bilateral
pneumothoraces are not infrequent (Fig. 77.6). About 30% to 50% of all affected patients eventually
develop a metachronous contralateral pneumothorax. Spontaneous pneumothorax could be either a lethal
event or an incidental finding.73 Symptoms could be limited to pleuritic chest pain and acute shortness of
breath; some patients may even die.74 If pneumothorax represents only 2% of all causes of acute
respiratory failure,75 the related mortality in this setting may be considerable.76 Flume et al. reviewed the
data of 28,858 patients with CF who had been followed up over 10 years at CF centers across the United
States. Pneumothorax occurred in 3.4% of the whole cohort, with an average incidence of 0.64%
annually. According to this study, pneumothorax seems to occur in both genders equally, but it tends to be
more prevalent in older patients (median age of 21 years) and in those with a more severe obstructive
pulmonary disease (75% had a FEV1 <40%). During 1990 to 1999, there was an increased morbidity and
mortality following pneumothorax as illustrated by an increased number of hospitalizations and number of
days spent in the hospital, and a fourfold increased death rate in patients who experienced pneumothorax
when compared with those who did not. More than 30% of patients died in the first year following
pneumothorax. The 2-year mortality rate based on the severity of pulmonary impairment, which was
defined as the FEV1 percent of predicted, was always greater for patients with pneumothorax, with an
attributable risk for mortality due to pneumothorax between 6.3% and 14.3%. Finally, the median survival
time from the first episode of pneumothorax was approximately 4 years.74 This robust prognostic impact
leads to perceive pneumothorax as a surrogate of the severity of lung disease, and therefore to consider
the opportunity of lung transplantation in those patients.
FIGURE 77.6 Bilateral pneumothorax—incidental finding at CT scan in the workup of a pulmonary exacerbation.
PATHOGENESIS
The airways of CF lungs are typically obstructed by viscous purulent secretions and undergo a
progressive bronchiectatic remodeling process. In the parenchyma, there is the concomitant development
of multiple cavitations, bullae or cysts, patchy areas of bronchiolar consolidation, and fibrosis.77 Cysts,
blebs, and bullae predominate in the upper lobes (Fig. 77.7). Bronchiectatic cysts are not incriminated
because their thick walls are firm enough to prevent rupture. Smaller subpleural cysts are the likely sites
of pleural rupture, especially as pleural elastic fibers overlying air cysts are weakened by the actions of
neutrophil and bacterial elastase.78 Accordingly, the increased risk of pneumothorax in the CF population
seems to be related to the combination of a one-way valve phenomenon due to mucus retention that
increases upstream airway pressure with structural damage of peripheral lung parenchyma favoring
rupture of the blebs or bullae into the pleural space.79 Ruptured air cysts bordering interlobular septa may
cause air dissection that moves into the interstitium and backward along the bronchovascular bundle to the
hilum of the ipsilateral lung, resulting in pneumomediastinum, with or without pneumothorax.80 In
addition, iatrogenic causes related to lung wounds during invasive procedures such as venous line
placement or thoracentesis are not infrequent.61
FIGURE 77.7 Left loculated pneumothorax. Note the presence of multiple cavitations, bullae, and bronchiectactic cysts in both
upper lobes.
RISK FACTORS
In the CF cohort analyzed by Flume et al.,74 several risk factors for the occurrence of pneumothorax were
identified, including airways colonization with P. aeruginosa, B. cepacia, or Aspergillus, FEV1 <30% of
predicted, enteral feeding, pancreatic insufficiency, ABPA, and massive hemoptysis. A total of 10% to
20% of CF patients smoke tobacco and other substances including marijuana81; moreover, smoking is also
a well-known factor related to spontaneous pneumothorax. Inhaled medications (e.g., dornase-α,
tobramycin) could increase the risk of pneumothorax, probably due to the acute bronchial reactiveness
following inhalation.82 Likewise, NPPV increases the risk for pneumothorax.83 As already mentioned,
ABPA is clearly related to pneumothorax and prevalent (7.8%) in CF patients.84 Anecdotally, thoracic
endometriosis and catamenial pneumothorax may also be expected as in the overall young female
population.85
MANAGEMENT
Once suspected, the diagnosis of pneumothorax should be confirmed. Chest x-ray is the simplest
diagnostic method (Fig. 77.8). However, the existence of cysts, bullae, and pleural adhesions that is
frequent in CF patients may be misleading, rendering chest CT necessary for the differential diagnosis of
loculated effusions.86 Moreover, chest CT facilitates the choice of an appropriate management.87,88
Traditionally, pneumothoraces can be subdivided into first and recurrent episodes. A recurrent
pneumothorax is defined by the occurrence on the same side 7 days or more after initial resolution.
Conversely, a persistent pneumothorax is characterized by air leak lasting more than 5 days.89 The
severity of pneumothorax is judged on clinical grounds. The size of the pneumothorax is defined by the
distance between the apex and cupola, and described by convention as either small (≤3 cm) or large (>3
cm).90 However, one should keep in mind that, in the particular setting of CF, the size of the pneumothorax
might not reliably reflect intrapleural pressure, as CF lungs do not collapse as readily as healthy lungs.
FIGURE 77.8 Large right pneumothorax at chest x-ray.
In the absence of sufficiently strong data to elaborate evidence-based guidelines based on a systematic
review of the literature, the CF Foundation’s Pulmonary Therapies Committee formulated the following
recommendations on the basis of an expert panel’s consensus. Although the occurrence of pneumothorax is
suggested as a manifestation of a pulmonary exacerbation in many instances, additional evidence of
infection is required before routinely treating the patient with antibiotics. Noninvasive ventilatory support
should be suspended as long as the pneumothorax is present. Similarly, airway clearance therapies should
be stopped but may be reinstated once a chest tube has been inserted. In contrast, if cough and
bronchospasm are not elicited, inhaled therapy should not be interrupted. Clinically stable patients with a
small pneumothorax can be managed conservatively with a close observation. In all other circumstances,
a chest tube should be placed. Patients with persisting air leaks lasting between 5 and 7 days or a
recurrent large and/or symptomatic pneumothorax should undergo pleurodesis to ensure stabilization.
Surgical pleurodesis, performed by VATS or through a limited or full thoracotomy, is preferred over
chemical pleurodesis using sclerosing agents administered blindly via a chest tube (i.e., talc slurry).91
However, in the absence of randomized controlled studies, the issue of chemical versus surgical
pleurodesis for persistent or recurrent pneumothorax still remains an open debate.92 Moreover, early and
aggressive treatment is not always desirable, even in fit patients, and a tailored, more conservative
approach may be considered on an individual basis taking into account the need for limited invasiveness
and the possible technical implications of a previous pleural procedure for candidates to lung
transplantation. Indeed, even if pleural procedures are not seen as absolute contraindications to lung
transplantation,93 the presence of dense pleural symphysis makes the lungs difficult to remove with the
inherent risks of bleeding and/or phrenic nerves injury. Therefore, radical methods of pleurodesis such as
subtotal or total pleurectomy that precludes the possibility of using the extrapleural plane for freeing the
lung in case of further surgery should be avoided. Limited pleural abrasion with gauze or limited
pleurectomy, or thoracoscopic localized chemical or talc pleurodesis sparing the mediastinal and
diaphragmatic aspects of the pleural space seems preferable.
HEMOPTYSIS
Hemoptysis is also common in the course of CF, with a prevalence of about 9% in a 5-year period.94 It
occurs usually in older individuals with more severe pulmonary disease and impacts negatively on
patients’ prognosis. Pulmonary function significantly deteriorates over the year following the episode, and
there is an excess risk of dying within the following 2 years.95
Even if sometimes difficult to assess, the quantity of hemoptysis has been arbitrarily defined by current
guidelines as scant (<5 mL per 24 hours), mild to moderate (5 to 240 mL), and massive (>240 mL).91
Although typically the bleeding is scant or mild, more serious hemorrhage may cause either asphyxiation
or less commonly exsanguination. The so-called massive hemoptysis occurs in approximately 4% of all
patients with CF during their life span, what represents an average annual incidence of 1 on 115
patients.89,95 Pragmatically, this term also covers any life-threatening or recurrent bleeding of substantial
volume over a short period of time.94 Massive hemoptysis carries an obvious much higher risk of
mortality. Besides being an alarming clinical event, it also portends a very poor prognosis: up to one-
third of the patients die the same year due to massive hemoptysis.95 Therefore, the opportunity of lung
transplantation should be considered.
FIGURE 77.9 Massive hemoptysis in a 37-year-old CF male. A: Selective injection of a common bronchial-intercostal trunk
with marked hypervascularity, enlargement, and tortuosity. The bronchial artery follows the course of the mainstem bronchus,
whereas the intercostal artery follows the undersurface of the rib. B: After embolization of the artery, a repeat bronchial
injection shows almost complete occlusion of the artery. The bleeding stopped after the procedure. The patient eventually
received a combined double-lung and liver transplantation.
PATHOGENESIS
Hemoptysis in CF patients is nearly always of arterial origin, in particular from bronchial arteries and
their branches. Its pathogenesis, however, is not fully clarified and is possibly multifactorial. Chronic
inflammation and infection trigger bronchial arteries hypertrophy, angiogenesis, and microvascular
remodeling usually in the upper lobes where bronchiectases and lung abscesses are located. Moreover, an
enlargement of the normal systemic to pulmonary vasculature communications can be observed. Increased
blood flow at systemic pressure and neovascularization result in a tortuous, communicating, thin-walled
vascular network located closely to the bronchi with an attendant risk of rupturing into the airways.96
Genetic predisposition promoting vascular growth factors may also play a role. Hence, the increased
expression of vascular endothelial growth factor in some patients with CF might explain why massive
hemoptysis still occurs in young patients with near normal lung function.97
When bronchial artery embolization (BAE) or ligation is anticipated, consideration must be given to
the following points. First, although the bronchial arteries typically arise from the thoracic aorta at the T5
to T6 levels and consist of the combination of a single right intercostobronchial (ICB) trunk (Fig. 77.9)
with two left bronchial arteries,98 there are wide anatomic variations and anomalies described. As many
as 20% of bronchial arteries have aberrant origins other than the aorta, including the subclavian,
thyrocervical, internal mammary, innominate, pericardiophrenic, superior intercostals, abdominal aorta,
and inferior phrenic arteries.99–101 Second, in older CF patients with dense pleural adhesions, the
pulmonary parenchyma may also receive substantial arterial blood supply from transpleural systemic
collateral to the bronchial circulation via intercostals, mammary, phrenic, thyrocervical, axillary, and
subclavian arteries (Fig. 77.10).102 Third, there is possible communication between the bronchial arteries
and the arterial blood supply to the spinal cord. Indeed, in about 5% of cases, the major supply of the
anterior spinal artery arises from a right ICB trunk.103 Finally, bronchial arteries may have
transpericardial anastomoses with atrial branches of the coronary arteries.98 These anastomoses explain
the fewer incidences of tracheobronchial complications after heart–lung transplants (HLTxs) than after
grafting one or both lungs. In patients with severe coronary artery disease, a rare occurrence in CF
patients, bronchial to coronary arteries anastomoses may contribute to the preservation of systolic left
ventricular function. Conversely, these anastomoses may also lead to coronary steal in bronchiectatic
patients.104
FIGURE 77.10 Transpleural systemic collateral to the bronchial circulation via phrenic arteries.
RISK FACTORS
There is a clear association of this complication with older age due to the longer time for the
inflammation to alter the vascular system. Hemoptysis is thus rare in the pediatric population overall and
particularly exceptional below 10 years of age.105 Flume et al. showed that the average age at first
hemoptysis was 24.2 ± 8.7 years. Only 25% of patients with this complication had massive hemoptysis
prior to the age of 18 years, and half of the patients with this complication had their first episode between
the ages of 18 and 30 years. They also found that the mean age at the time of initial massive hemoptysis
for each year did not change during the 10 years analyzed. In addition, males and females are similarly
affected.95 In addition to the association with age, most patients presenting with hemoptysis have
moderate to severe pulmonary function impairment. In the US Cystic Fibrosis Foundation Patient Registry
(CFFPR), more than 60% of patients with a first episode of massive hemoptysis had a FEV1 of less than
40% of predicted. However, this complication also occurred in patients with mildly impaired to normal
measures of lung function in about 22% of cases.95
Hemoptysis has to be considered as an indicator of pulmonary exacerbation and a symptom of
infection.106 Flume et al. found an increased prevalence of massive hemoptysis when S. aureus was
present in sputum cultures.95 Life-threatening hemoptysis in the course of S. aureus–necrotizing
pneumonia has been reported in non-CF patients and attributed to the production of a particular
staphylococcal toxin called Panton–Valentine leukocidin.107 Meanwhile, the evaluation of chronic anti-
staphylococcal antibiotics in patients with CF failed to demonstrate any effect on reducing the risk for
massive hemoptysis in these patients.108 Flume et al. also found a paradoxically reduced incidence of
massive hemoptysis in patients with P. aeruginosa and B. cepacia,95 both agents being well known to be
associated with increased inflammation and a decline in lung function.109 They speculate that these
findings could be related to phenotypic features of these bacteria (e.g., mucoid phenotype, exotoxins).
However, other cohort analyses have not confirmed any reduction of P. aeruginosa infection in case of
hemoptysis.94,105 Other multidrug-resistant pathogens including Stenotrophomonas, Achromobacter,
Pandorea, and Ralstonia have emerged as promoting problematic infections. These bacteria may be
selected during therapy with colistin for chronic colonization with P. aeruginosa. Whether these bacteria
have an own contribution to the poor outcome of CF patients remains unclear; their association with
hemoptysis, however, has been reported.110
There has been recent growing awareness of the threat of NTM to individuals with CF. Despite scarce
specific available data, no relationship with hemoptysis, however, has been reported yet. Efrati et al.
found NTM in 5 of the 40 patients with hemoptysis versus in 11 of the 58 patients of the control group
(NS); 2 and 3 patients, respectively, were identified with Mycobacterium abscessus species.94
Chronic infection with Aspergillus species has not either been shown to be a risk factor for massive
hemoptysis.94,95 Aspergillomas, which are usually observed in patients with bullous and cavitary lung
diseases, are rare in CF patients.111
Malabsorption of fat-soluble vitamin K as well as liver cirrhosis consistently increase the risk of
massive hemoptysis due to an impaired clotting function. Accordingly, cirrhosis prevalence was
significantly higher in patients who experienced massive hemoptysis when compared with those who did
not in the CF cohort reported by Efrati et al.94 In contrast, cirrhosis was identified as a protective factor
against hemoptysis in the study from Flume et al.95 Both studies demonstrated that diabetes was a risk
factor for massive hemoptysis, the reason of which remains unclear.
MANAGEMENT
Patients should be admitted to hospital and treated with antibiotics because hemoptysis has to be
considered a result of pulmonary exacerbation, even in the absence of other features of infection.
Nonsteroidal anti-inflammatory medications, the use of which is recommended as chronic therapy in
young patients with CF,112 should be stopped because of their effect on platelet function. Except in
patients with massive hemoptysis, other routine treatments including aerosolized saline therapy, airway
clearance physiotherapy, and bilevel positive airway pressure (BiPAP) ventilation that may induce
bronchospasm and cough, and impair clot adherence, should be maintained because their benefits
outweighed their risks, even in this context. For the same reasons, other specific inhaled therapies, such
as bronchodilators, mucolytics, and aerosolized antibiotics, should be withheld only if they seem to
trigger or amplify bleeding.91
Airway safety and adequate blood volume resuscitation are the goals of emergency medical care of
massive hemoptysis before a conclusive treatment can be offered. In case of respiratory failure, the
patient should be intubated with a large endotracheal tube to allow for adequate suctioning and
ventilation.113 After hemodynamic and respiratory stabilization, the next urgency is to localize the source
of bleeding. Diagnostic bronchoscopy usually fails to meet this goal and is not recommended.91
Interventional bronchoscopy may be useful in some individuals. Rigid bronchoscopy should be used as
soon as it becomes apparent that bleeding is too active to permit successful airway exploration with
flexible bronchoscopy. Temporary control of hemoptysis with cold saline solution lavage, instillation of
topical vasoconstrictive or hemostatic agents, and balloon tamponade therapy to occlude the bleeding
bronchus may allow for improving the patient’s condition before definitive treatment.
Electrocardiographically synchronized, prospectively triggered multidetector row computed tomography
(ECG-MDR-CT) angiography of the aorta (Fig. 77.11) prior to BAE accurately predicts the location of
ectopic bronchial arteries in CF patients with massive hemoptysis. This diagnostic strategy could
potentially decrease the BAE radiation dose and contrast volume, and likely reduced table time.114
Treatment with the antifibrinolytic tranexamic acid can be considered alone, or in conjunction with
BAE, IV or orally. It may reduce both the duration and volume of bleeding, with low risk of short-term
thromboembolic complications even if the evidence base supporting its use for treating hemoptysis in
patients with CF is limited to single case reports.115 Likewise, the use of IV vasopressor agents (e.g.,
vasopressin, desmopressin, terlipressin) has been anecdotally reported to control massive hemoptysis in
a patient with CF.116 Their potential side effects (e.g., systemic hypertension, bronchoconstriction,
seizure) require close monitoring of the patient. Recombinant activated factor VII (rFVIIa), originally
developed for use in patients with hemophilia, is also potentially useful in the management of many life-
threatening bleeding conditions. Lau et al.117 reported on four CF patients with massive hemoptysis who
were treated successfully with rFVIIa, and suggested that its use can be considered in case of refractory
hemoptysis despite conventional therapy or as a temporizing therapy when BAE is not immediately
available.
FIGURE 77.11 Electrocardiographically synchronized, prospectively triggered multidetector row computed tomography (ECG-
MDR-CT) angiography of the aorta and bronchial arteries prior to planned BAE.
Indeed, the cornerstone of the treatment of massive hemoptysis is BAE. Bronchial arteries are
accessed via the femoral artery. Coils are usually preferred when embolization of large feeding arteries is
required, whereas polyvinyl alcohol (PVA) particles of different sizes are more commonly used for
smaller vessels.118 Overall, BAE is successful in achieving bleeding control in more than 90% of the
cases, even if several sessions may be required.119–121 Recurrences are common within the 12 following
months, concerning more than one patient among four.120,121 Lower recurrence rates could be achieved
with routine bilateral BAE and embolization of non-bronchial collateral vessels.102,121 The most
disastrous complication associated with BAE is spinal cord ischemia due to unintended embolization of
the anterior medullary artery. Large shunts and patent foramen ovale expose patients to the risk of
systemic brain and/or visceral ischemic accidents. Extensive procedures with bilateral BAE, subsequent
sessions, and combined non-bronchial collateral arteries embolization may lead to pulmonary infarction
(Fig. 77.12).122–124 The impact of BAE on long-term survival is debated. Barben et al. found in CF
children that median survival time following massive hemoptysis treated with BAE was twice as high as
if treated conservatively.125 In contrast, Vidal et al. reported in CF adults, a 5-year survival rate of 31%
for patients who received BAE compared to 84% in patients who had similar episodes of hemoptysis, but
were not treated with BAE.121 In the last study, it is likely that disease severity prior to treatment may
have confounded these results.
Surgery is an option of last resort, and only after other measures have failed,91 especially when
massive hemoptysis originates from cavitary lung disease, which is usually the most difficult to control
with BAE.119,122,125,126 Surgery may also be considered in those situations where there is a risk to the
spinal circulation. Extrapleural bronchial artery ligation has been reported as an effective method of
controlling hemoptysis in this context.127 This approach minimizes pleural adhesions, does not jeopardize
concomitant lung resection, and is, therefore, advantageous in the future prospect for lung transplantation.
However, most surgical experiences in patients with CF and life-threatening hemoptysis consist of
lobectomies. As previously mentioned, data from the literature suggest that major pulmonary resections
carry a significant mortality,61 even in the most recent series, especially in patients with an FEV1 of less
than 40%.66 Even in case of localized disease, the expectation to both control the bleeding and offer the
patient a palliation of the disease with fewer pulmonary exacerbations, and a better quality of life,
remains speculative. Lung transplantation should be a better option to be considered to achieve these
goals.128
FIGURE 77.12 Lung cavitations in the right lower lobe as the result of pulmonary infarction following extensive and subsequent
BAE sessions for massive hemoptysis.
DECLINE IN LUNG FUNCTION—LUNG TRANSPLANTATION

Despite the dramatic improvement of survival in patients with CF over the past decades, progressive
respiratory decline and acute pulmonary complications remain the major causes of mortality in this
population. Therefore, the vast majority (more than 60%) of thoracic transplant procedures are still
carried out in children with end-stage CF lung disease, while CF remains an indication in a substantial
proportion of adult patient recipients (16%) representing the third major indication for lung
transplantation after emphysema and pulmonary fibrosis according to the 2014 reports of the ISHLT
registry for the period 2000–2013.129,130 Indeed, lung transplantation has the potential to significantly
extend survival and improve quality of life provided that candidates are carefully selected. Moreover, CF
is reported as the condition associated with the highest long-term survival after lung transplantation when
compared to other indications both in children and in adults.129,130 For adult CF patients surviving to 1
year, conditional median survival was 11.1 years.130 Additionally, the Toronto group recently showed on
the basis of their prospective cohort study that lung transplantation also conferred the largest health-
related quality of life benefits in adult CF, when compared to other conditions.130 Finally, a study using
the data from the United Network for Organ Sharing Registry modeled the survival benefit of lung
transplantation in the United States taking into account disease evolution after registration on the waiting
list, and using the lung allocation score while on the waiting list as a surrogate for disease severity. This
study disclosed a significant improvement of the survival of adult CF patients thanks to lung
transplantation, with a 69% reduction in instantaneous risk of death.131 Conversely, the long-term benefit
of LTX in children with CF has been widely debated and remains controversial.132,133
Nevertheless, because CF is a systemic disease, it exposes the recipient to some CF-specific
complications that must be taken into consideration before, during, and after transplantation. This
dedicated pathway requires a tight collaboration between dedicated pediatricians/pulmonologists and the
transplant team. Timing of listing is also critical, because up to 15% of adult CF patients still die while
awaiting lung transplantation in the United States.131
Referral to the transplant center and registration on the waiting list are two separate decision steps.
TIMING OF REFERRAL
CF patients should be evaluated at transplant center when any of the following criteria are met134:
• FEV1 that has fallen to 30% or a patient with advanced disease with a rapidly falling FEV1 despite
optimal therapy, particularly in a female patient
• A 6-minute walk distance <400 m
• Development of pulmonary hypertension in the absence of a hypoxic exacerbation, as defined by a
systolic pulmonary arterial pressure (PAP) >35 mm Hg on echocardiography or mean PAP >25 mm Hg
measured by right heart catheterization
• Clinical decline characterized by increasing frequency of exacerbations associated with any of the
following:
• An episode of acute respiratory failure requiring noninvasive ventilation and/or ICU admission
• Increasing need for intravenous antibiotic therapy, increasing antibiotic resistance, and poor
clinical recovery from exacerbations
• Worsening nutritional status despite supplementation and/or diabetes
• Relapsing pneumothorax
• Life-threatening hemoptysis despite bronchial embolization
The patient’s individual motivation, current QoL, and social and familial environments need to be
taken into consideration as well. The patient and relatives must be fully informed about the immediate
risks of the procedure as well as its mid- and long-term consequences. Children and adolescents may not
be listed against their will.
TIMING OF LISTING
Registration on the waiting list becomes necessary when the estimated benefit/risk ratio of lung
transplantation compares favorably with that of the conservative medical treatment in the particular
patient. This consideration has to take into account the continuous improvement of life expectancy due to
the optimization of CF patients care, which allowed to decrease the adjusted mortality by 1.8% per year
along the last decade in the United States.135 Admission on the waiting list should happen when the
expected life expectancy is deemed reduced, but also at a time when it is thought still superior to the
expected waiting time. Transplantation should be considered for suitable CF patients who have a 2-year
predicted survival of less than 50%. Unfortunately, it remains very tough to consistently evaluate
prognosis for an individual patient, as statistical survival models have not been able to identify robust
predictors.136 One of the main explanations of that failure is that most of these models used a time-
dependent variable indicating whether or not a patient has received a transplant whereas other covariates
were measured at the time of registration and were not allowed to vary over time.
The expected waiting time may vary extensively according to some national particularities as are the
availability of lung donors and the organ allocation system that differ widely from a country to another
and some obvious individual parameters, that is, rare blood groups and marginal morphologies. Thus,
these parameters should also be integrated in the decision process. Obviously, listing should be
considered in case of chronic respiratory failure, with hypoxia (partial pressure of oxygen <8 kPa or <60
mm Hg) alone or with hypercapnia (partial pressure of carbon dioxide >6.6 kPa or >50 mm Hg),
necessity of long-term noninvasive ventilation therapy, development of pulmonary hypertension, frequent
hospitalization, rapid lung function decline, and World Health Organization Functional Class III or IV.137
The waiting period is definitely not a passive one. The patient should be engaged in an active lifestyle
in order to preserve muscle and bone mass through physiotherapy and rehabilitation and stabilize his/her
nutritional condition up to 80% of ideal body mass index. If necessary, feeding gastrostomy tube can be
inserted to achieve this goal. Psychological and emotional preparation to the transplantation should be
completed. Potential focus of infection (e.g., paranasal sinuses, teeth) should be treated. Other frequently
associated diseases such as diabetes mellitus, systemic hypertension, peptic ulcer, and gastroesophageal
reflux disease (GERD) also need optimized treatment prior to transplantation. Systemic steroid therapy, if
any, should be tapered to <20 mg prednisolone equivalent per day before transplantation. Finally, the
medical situation has to be continuously reevaluated to make sure that any worsening will be detected and
treated early. Eligibility should be regularly reconsidered, and the patient’s waiting list position possibly
adapted.134 The waiting period is a further opportunity for the patient and lung transplant team to develop
a productive working relationship based on mutual trust which will culminate in a long-term successful
outcome.
CONTRAINDICATIONS OF LUNG TRANSPLANTATION

Some absolute contraindications to lung transplantation exist that are not specific of CF recipients,137 as
are malignant diseases during the past 2 years with the exception of non-melanoma skin tumors such as
squamous cell and basal-cell carcinomas. Most transplant centers demand a disease-free interval of 5
years, even if such delay does not guarantee a definite remission status for most solid organs and
hematologic malignancies.
Other organ failure is another absolute contraindication unless a combined kidney, liver, or heart
transplantation is considered. Overall, the prevalence of coronary artery disease is low in candidates of
lung transplantation, and there is no specific data in the literature dealing with CF recipients. Thus,
routine coronary angiography and moreover coronary artery revascularization prior to LTX should be
reserved for patients with selected high-risk features, such as patients with significant left ventricular
dysfunction or objective evidence of ischemia.138
Active infections, such as chronic hepatitis B and C, are absolute contraindications. However, CF
patients without significant clinical, radiologic, or biochemical signs of cirrhosis or portal hypertension
and who are stable on appropriate combined immuno- and antiviral therapies may be considered for LTX
on an individual basis.139,140 Many transplant centers would include HIV infection in the contraindication
list although successful lung transplantation in this setting has been carried out successfully in a CF
recipient with a controlled disease with undetectable HIV-RNA and compliant on combined antiretroviral
therapy.141
Classic CF-associated organisms, such as S. aureus and P. aeruginosa, are generally manageable
posttransplantation and are associated with favorable outcomes. Colonization with multi- or panresistant
P. aeruginosa, Stenotrophomonas maltophilia, or Achromobacter species in CF patients does not also
result in inferior outcomes after lung transplantation and therefore does not constitute a rationale to deny
LTX to such patients.142 In contrast, B. cepacia complex infection is associated with a high mortality rate,
especially when it results in the so-called “cepacia syndrome,” a fatal necrotizing pneumonia that is
currently not curable. The B. cepacia complex, however, consists of nine genomic species called
genomovars, among which mainly three have been reported to cause the majority of infections: B.
cenocepacia, B. multivorans, and B. dolosa. Accordingly, dismal outcomes have been reported after LTX
in CF patients colonized with these last pathogens, as well as B. gladioli, a Gram-negative bacteria
closely related to B. cepacia complex.143–147 Though many LTX centers decline B. cepacia complex–
infected patients, an individualized approach remains mandatory.148
M. tuberculosis infection is infrequent in CF individuals, with a prevalence of about 1%,149,150 but
multidrug-resistant tuberculosis has been reported in this population.151 Active tuberculosis is obviously
an absolute contraindication to LTX if untreated. NTM infection has a higher prevalence in CF patients,
ranging from 3% to 19%. M. avium complex is most common in the United States, whereas M. abscessus
complex prevails in Europe. Macrolides remain the most effective agents available against M. avium and
M. abscessus. However, more than half of M. abscessus complex isolates have inducible macrolide
resistance.152 Despite concerns about NTM, especially M. abscessus, posttransplantation survival has not
been definitively shown to be less than average in patients with these infections. However, centers that
admit patients with M. abscessus infection for transplantation generally recommend aggressive treatment
before and after LTX.153
Some anatomical problems such as chest wall deformities may be of concern in the perspective of
LTX. Serious spinal deformations, especially scoliosis, are a frequent finding in CF, but do not preclude a
successful LTX.154 Severe acquired chest wall deformities and asymmetries may be encountered in
patients having had lung resections, that is, lobectomy or pneumonectomy, during their disease course.
Although rare, these patients have been identified as having an increased risk of perioperative mortality
and dialysis after LTX, but with no differences in terms of long-term survival when compared to other
recipients.155 From a technical point of view, those patients having received pneumonectomy on one side
may constitute a huge surgical challenge for single LTX on the other side, due to anatomical changes
caused by mediastinal shift, and distention of the remaining lung (Fig. 77.13).156 In contrast, previous
pleural procedures for pneumothorax should not be considered a contraindication in the assessment of
suitability for lung transplantation, even if dense pleural adhesions increase undeniably the risk of
bleeding and injury to the diaphragm or the phrenic nerves.93
BRIDGES TO TRANSPLANT
Pretransplant mechanical ventilation has to be seen chronologically as the first bridge to transplant in
patients with CF. Indeed, invasive ventilation is not associated with an increase in morbidity or mortality
after LTX.157,158 In the event of terminal failure of gas exchange despite mechanical noninvasive or
invasive ventilation, extracorporeal life support systems (ECLS) to improve blood oxygenation and/or
CO2 removal may be used if there is a realistic perspective of prompt LTX. ECLS technologies include
extracorporeal CO2 removal (ECCO2-R) by means of the interventional lung assist (iLA)159 and veno-
venous or veno-arterial extracorporeal membrane oxygenation (VV-/VA-ECMO)160 and are used
successfully as a bridge to transplant in CF individuals, albeit with considerable consumption of
resources. Donor lungs availability is a prerequisite in these situations, by any form of prioritization for
organ allocation.161,162 Perioperative mortality is high but 1-year survival reaches 60% to 80%. Long-
term functional results in these situations are still under investigation.
FIGURE 77.13 A 45-year-old CF female having had right pneumonectomy in the infancy. Note the marked mediastinal shifting.
This patient received a single left lung transplantation successfully.
ORGAN DONATION AND ALLOCATION

Bilateral pulmonary lower lobe transplants from two living donors were advocated by Starnes and
colleagues in the early 1990s,163 ideally in the pediatric CF population, in patients deemed unable to
await a cadaveric donor, and with notable long-term results.164 Development of lobar transplantation
using adult cadaveric lungs overcoming lung size–matching concerns,165 liberalizing cadaveric lung donor
acceptance criteria,166 donation after circulatory death (DCD),167 and, more recently, ex vivo lung
perfusion technique (EVLP)168 that allows to evaluate otherwise unacceptable donor lungs over several
hours after retrieval and to recondition them for subsequent LTX have led to a substantial increase in
available cadaveric donor organs over the last years, without compromising mid- and long-term results.
In combination with the implementation of various processes of prioritization in the allocation systems
worldwide, such as the lung allocation score131,162 or the high-emergency waiting list,161 the need for
living related lobar transplantation for the CF population has been reduced.
Donor lung allocation is principally based on blood group compatibility, size matching based on donor
and recipient predicted total lung capacity (TLC), and viral (CMV, EBV) status of donor and recipient. At
present, there is no matching for major histocompatibility antigens in the absence of pretransplant
allosensitization.
TYPE OF LUNG TRANSPLANTATION

The first thoracic transplantation in the setting of CF was a HLTx in 1983.169 According to the lastly
released data from the ISHLT registry, HLTx is now seldom performed in this indication, in both pediatric
and adult populations,129,130 unless a concomitant heart failure exists. Today, the standard operative
technique is bilateral sequential LTX.170 In some anecdotal circumstances, where there is a clear thoracic
asymmetry with a fixed mediastinal shift due to a previous lobectomy and/or retracted and destroyed lung
on one side, a single lung transplant combined with a pneumonectomy of the destroyed lung,171 a single-
lung transplantation combined to a contralateral lobar transplantation,172 or possibly a combined HLTx
can be performed, even if this last option remains strongly limited by donor shortage.173 In case of
previous pneumonectomy, single LTX may be performed but is associated with high perioperative
morbidity and mortality.156
OPERATIVE TECHNIQUE
The principles of lung transplantation and the operative techniques are presented in Chapter 88. Only
those specific aspects of CF will be focused. The most common approach for CF recipients is a bilateral
anterolateral thoracotomy in a patient positioned supine with abducted arms. The addition of a transverse
sternotomy, realizing the traditional “clamshell” incision,174 provides excellent exposure to the heart and
facilitates rapid central cannulation in case of hemodynamic compromise during the operation
necessitating the use of a cardiopulmonary bypass. Sparing the sternum, as well as both internal thoracic
arteries, is possible in many cases and results in a lower rate of wound infection and healing
complications than clamshell incisions and contributes to improve respiratory function in the early
postoperative period.175,176
In case of a previous pleurodesis or dense pleural adhesions, freeing the lungs via the extra pleural
space may be necessary. Special attention has to be paid to preserve phrenic and left recurrent laryngeal
nerves.
Once the lung is removed, the recipient bronchus is prepared centrally while avoiding denuding it
beyond the level of the planned anastomosis. This contributes to prevent ischemia of the bronchial
anastomosis, even if the main risk factors of this complication stay on the level of the donor bronchus.
Practically, it is often necessary to remove bulky lymph nodes, a frequent finding in CF recipients (Fig.
77.14) at the recipient hilum, to facilitate the exposure and dissection of the vessels. Nevertheless,
excessive lymphadenectomy should be avoided to prevent hardly controllable bleeding in the posterior
mediastinum or some catastrophic complications such as esophageal perforation.177 The only exception of
this rule is a history of an NTM infection in the recipient, because it has been suggested that extensive
lymphadenectomy in this situation has the potential to surgically remove all possibly infected foci.178 The
donor bronchus is shortened with only one cartilage ring remaining after the separation of the upper lobe
bronchus. Some authors recommend shortening the donor bronchus even more, until the plane of the lobar
carina.179 Peribronchial tissue is left untouched and some hilar fatty and pericardial donor tissues are
preserved to wrap the bronchial anastomosis once completed.
FIGURE 77.14 Bulky mediastinal lymph nodes. Note the presence of a huge adenopathy in the upper mediastinum on the
anatomical route of the left phrenic nerve.
Several techniques have been developed to accept oversized donor organs for short-stature patients,
that is, pediatric or small adult recipients. Available data show no adverse effect of lobar transplantation
on survival and pulmonary function.165,180–185 Accordingly, it is a safe and efficient response to donor
shortage for small CF recipients, especially if critically ill and in the urgent setting. Practically, the two
lower lobes are used, coming from a donor having a predicted TLC about twice higher than the measured
TLC of the recipient. Another technical option is represented by split lung transplantation that is
performed by subdividing the left donor lung and replacing the right recipient lung by the donor’s left
upper lobe with inverse anastomosis of the bronchus, while the recipient’s left lung is replaced by the
donor’s left lower lobe.186 In both cases, marginal donors ought to be avoided because preparation of the
lobar grafts enhances total ischemic time.
Hemodynamic instability may occur during the operation, especially because of the necessity of
retracting the heart to facilitate the exposure of the left hilum in the rather small chest cavities of these
patients. In this situation, when the operative approach consists of a bilateral anterolateral thoracotomy,
the sternum should be divided transversally and the pericardium opened anteriorly to expose the heart.
The heart is then lifted out of the pericardial sac and maintained gently in that position. This maneuver
generally improves hemodynamics while exposing the left hilum adequately for graft implantation.187,188
Nevertheless, intraoperative ECLS may become necessary during surgery, due to insufficient oxygenation
on single-lung ventilation, hemodynamic instability, or the onset of reperfusion edema in the first
implanted lung especially in patients with secondary pulmonary arterial hypertension. The most common
intraoperative support device is cardiopulmonary bypass (CPB). However, there is now a growing trend
to use veno-arterial or in some cases veno-venous ECMO with heparin-coated cannulas, instead of CPB,
which does not require full heparinization and therefore leads to decreased blood loss.189 This approach
can be especially recommended for CF patients who very often present with a high risk of pleural and
mediastinal bleeding. Intraoperative extracorporeal support can be provided by either central or
peripheral cannulation over the femoral vessels. Conversion to CBP may be mandatory in case of serious
bleeding, circulatory insufficiency, and complications in which full circulatory support is needed, such as
atrial tears.
OUTCOMES
LTX recipients are usually on a triple immunosuppressive therapy combining a calcineurin inhibitor
(tacrolimus or cyclosporine A), an antiproliferative agent (mycophenolate mofetil, mycophenolate
sodium, or azathioprine), and glucocorticoids. Postoperative complications of LTX, in general, include
ischemia/reperfusion injury, postoperative bleeding, wound infection, bronchial anastomosis dehiscence
and/or stenosis, vascular anastomosis stenosis and angio-occlusions, phrenic or recurrent nerve palsies,
acute rejection, acute renal failure, deep venous thrombosis, cerebrovascular events, and infection due to
bacterial, viral, or fungal organisms. These complications account for a 5% to 7% in-hospital mortality.
Long-term results are better in adults than in children: the reported 1-year, 5-year, and 10-year survival
rates are 84% versus 82%, 60% versus 50%, and 45% versus 36%, respectively.129,130 These rates are
better than those for patients with other diagnoses. Chronic lung allograft dysfunction (CLAD), especially
bronchiolitis obliterans (BO), remains the major medium- and long-term limiting condition in LTX and the
leading cause of death. Besides, chronic immunosuppression increases the risk of malignancy and
lymphoproliferative diseases. In CF LTX recipients the risk of cancer is about 6 times higher than in the
general population, with a substantial incidence of tumors involving the gastrointestinal tract (21-fold)
and skin and lymphoproliferative diseases (44-fold).190
Some events need emphasis in CF recipients. Immunosuppression favors the onset of secondary
diabetes, especially during treatment of acute rejection with high-dose steroids. The immunosuppressive
regimen may also decompensate already existing CF-related diabetes. The treatment aims at an optimal
blood glucose control with tailored nutritional counseling and insulin therapy. Nevertheless, if the
presence of diabetes is associated with significantly increased risk for death in patients with CF on the
wait list before lung transplantation, it does not seem to influence survival after transplantation.191
Gastrointestinal complications are common post-LTX in CF recipients. In the early postoperative
period, distal intestinal obstruction syndrome (DIOS) is common, particularly among patients with a
history of DIOS prior to the transplantation, abdominal surgery, or meconium ileus in infancy. DIOS may
itself be complicated by bowel perforation necessitating emergent surgery, therefore emphasizing the need
for a prophylactic management in the early posttransplant period, based on adequate fluid and dietary
fiber intake together with routine laxatives/enemas.192 Conversely, diarrhea posttransplant should
immediately trigger stool cultures and empirical treatment of a possible Clostridium difficile colitis,
especially in older CF patients, and when broad-spectrum antibiotics have been given to treat bacterial
infection. Indeed, C. colitis in the setting of immunosuppression may be devastating, with fulminant
pancolitis, surgical intervention and shock, especially in the first 6 months posttransplant.193 In general,
digestive problems are associated with malabsorption of immunosuppressive medications and, thus,
expose the patient to a risk of acute rejection and/or drugs toxicity with renal failure or encephalopathy.194
CF recipients also have a 90% prevalence of GERD, much higher than other LTX recipients.195 There is
growing evidence that demonstrates a relationship between GERD and bronchiolitis obliterans syndrome
(BOS).196 Simple acid neutralization by proton pump inhibitors is not adequate to protect these patients
from aspiration injury.197 Azithromycin does not also seem to protect against the long-term allograft
dysfunction caused by gastroesophageal reflux and bile acids aspiration.198 In fact, there are no
convincing data to indicate that medical therapies provide adequate treatment. In contrast, surgical
therapy by fundoplication is associated with reduced incidence of BOS and improvements in lung
function.199 In the absence of controlled studies, however, the precise indications, timing, and choice of
fundoplication are yet to be defined.200
Besides GERD, known risk factors for CLAD are recurrent episodes of acute rejection, the
development of anti-HLA antibodies, and CMV pneumonitis, but also bacterial/fungal colonization of the
graft, a pregnant problem in CF recipients. P. aeruginosa recolonization of the lung transplant is
considered an independent risk factor for the development of CLAD via the induction of neutrophilic
airway inflammation.201 Inhaled antibiotic therapy, combined with sinus surgery and daily nasal douching,
may reduce pseudomonal airway colonization after LTX.202
Overall, infections in the context of immunosuppression and particularly respiratory tract infections
constitute the major cause of morbidity after LTX. CF-specific pathogens persist in the paranasal sinuses
and upper airways and may cause recurrent infectious episodes. Aspergillus species colonization is also a
frequent event in CF recipients. Invasive necrotizing tracheobronchitis, typically starting at the level of
the bronchial anastomosis and then spreading distally, is particularly dangerous in the early postoperative
period with the possibility of potentially lethal complications such as bronchovascular fistula.203
Preventive management should be carried out up to 6 months after LTX and at times of increased
immunosuppression.204 Triazole-antimycotics (e.g., voriconazole, posaconazole) is nowadays the
standard therapy of invasive aspergillosis. When using these drugs, however, calcineurin inhibitors
should be monitored because their blood levels increase significantly due to pharmacologic interactions.
Echinocandins or lipid formulations of amphotericin B are less effective alternatives.134
MULTIORGAN TRANSPLANTATION
Liver disease in CF (CFLD) is diagnosed in one-third of adult CF patients, ends in multilobar cirrhosis,
and carries a high risk of liver decompensation and death during follow-up.205 Liver transplantation
(LiTX) is the curative treatment of advanced CFLD. The indication for this procedure in CF differs
notably compared to other diseases with chronic hepatic failure since extrahepatic factors, and
particularly worsening of the respiratory status, have to be considered. Therefore, there is a close
relationship between the respective likelihoods of liver and lung transplantation in these patients. Indeed,
CFLD at baseline appears as an independent factor associated with lung transplantation.48 Indication of
LiTX becomes under consideration in case of progressive hepatic dysfunction, uncontrollable ascites and
variceal hemorrhages, hepatopulmonary syndrome, severe malnutrition, and declining lung function. It is
rather consensual that LiTX alone may be performed when FEV1/FVC remains above the 50%
threshold.80 Stable cirrhosis caused by CFLD does not either constitute a definitive contraindication to
sole LTX, provided that hepatocellular function is conserved and portal hypertension is controlled.206 Of
note, when the existing liver disease is attributable to a cause other than CF, for example, alcohol abuse
or chronic hepatitis, a similar liver disease severity would be considered an absolute contraindication to
sole lung transplantation. In extremely selected cases, combined liver and lung transplantation has been
performed successfully, especially in the pediatric population, with similar long-term survival than after
sole LTX but with a higher complication rate.207,208
Although nephropathy is rare in CF, renal toxicity of various drugs that are used in the treatment of CF,
such as antibiotics, can lead to renal failure and the need for dialysis. However, such situation is mainly
encountered after LTX due to the implementation of immunosuppressive drugs that carry an additional
nephrotoxicity in the long run. Therefore, in clinical practice, sequential lung and kidney transplantation is
not that rare. In contrast, the experience of combined lung and kidney transplantation is limited to date to
one case report so far.209
Patients with end-stage CF and severe CF-related diabetes may benefit from combined lung–pancreas
transplantation,210 but combined lung–pancreatic islet transplantation seems a simpler alternative.211
LUNG RETRANSPLANTATION
Finally, CF does not relapse in the transplanted lung, and initial concerns that immunosuppression in these
patients would inexorably cause devastating postoperative infection have been unsupported by
worldwide experiences. Pulmonary function improves greatly, often to normal predicted values, thus
providing excellent quality of life. Nevertheless, CLAD remains to be the burden of lung transplantation
in the long term. Therapy attempts to address it include change/augmentation of immunosuppression, use
of neomacrolides and extracorporeal photopheresis, and finally redo lung transplantation in selected
candidates, explaining that survival rates for primary lung transplantation have historically been among
the lowest for all solid organ transplants. Lung retransplantation has reported survival rates that are much
lower than primary LTX, about 35% 5-year survival rate compared to 50%.212 There is no large initial
disease-specific data in the field of Re-LTX. Overall, poor candidates are those requiring
retransplantations more than once or within 1 year after the initial transplant. Moreover, CLAD is not a
homogeneous entity and different phenotypes exist, mainly BOS and restrictive CLAD (rCLAD). Survival
after retransplantation for rCLAD is likely to be worse compared to BOS, because patients retransplanted
for rCLAD were more likely to redevelop rCLAD.213
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78
Congenital Vascular Lesions of the Lungs
Antonio Bobbio ■ Laureline Berteloot ■ Audrey Lupo ■ Marco Alifano
Congenital vascular malformations of the lung include anomalies of the pulmonary arteries, the pulmonary
veins, and lymphatic vascular system. Most of these anomalies are associated to cardiac malformations
and are discovered and treated early after birth because of severe cardiorespiratory symptoms. In some
cases, however, the clinical course could be silent until adulthood.
ANOMALIES OF THE PULMONARY ARTERY
AGENESIS OF THE PULMONARY ARTERY (DUCTAL ORIGIN OF

PULMONARY ARTERY)
Agenesis of the pulmonary artery is defined as the unilateral absence of the proximal segment of the
pulmonary artery. In case of agenesis of the pulmonary artery, a perfectly normal pulmonary artery trunk
may be present as well as a normal but hypovascular distal intrapulmonary vasculature. In this setting, the
malformation has also been termed as “unilateral pulmonary artery discontinuity” or “proximal
interruption of pulmonary artery.”1 From an embryologic standpoint, the malformation is due to the
involution of the proximal sixth aortic arch—which is destined to become the proximal pulmonary artery
—and persistence of the connection of the intrapulmonary pulmonary artery with the distal sixth aortic
arch—which is destined to become the ductus arteriosus. Therefore, the proximal pulmonary artery is not
absent but undergoes progressive involution upon closure of the ductus arteriosus and the malformation is
also termed as “ductal origin of a pulmonary artery.”2,3 As a rule, intrapulmonary vasculature forms from
primitive lung buds and receives blood flow via the ductus arteriosus during intrauterine life. At birth,
however, the closure of fetal ductus arteriosus results in progressive loss of perfusion to the pulmonary
artery and blood to the affected lung is partially supplied through collateral systemic vessels, mainly
bronchial arteries, but also transpleural branches from the intercostal, internal mammary or subclavian
arteries. Vestigial embryonic connection of the intrapulmonary vasculature with the distal sixth aortic arc
is frequently observed as a diverticulum in the aortic arc or in the innominate artery.
Unilateral absence of pulmonary artery may occur as an isolated anomaly or in combination with other
cardiac or vascular lesions. Pulmonary artery agenesis on the right side is classically associated to a
patent ductus arteriosus while agenesis on the left side is frequently found in association to a tetralogy of
Fallot or a right-sided aortic arc.4
The malformation is not included in institutional registries on birth defect surveillance and, as a
consequence, its incidence among newborn is unknown. Bouros et al.5 reported six cases discovered on
chest x-ray among 6 hundreds of thousands medical visits performed in young adults for enrollment into
the army forces. Interestingly, among three of these patients, cardiac anomalies were also present. In the
review by Ten Harkel et al.,6 among the 108 cases published between 1978 and 2000, the rate of
asymptomatic patients was 14%. The clinical features, as well as prognosis of the malformation, are
related to the presence of pulmonary artery hypertension which is reported in between 19% and 44% of
the cases and could lead to congestive heart failure. Obviously, pulmonary hypertension is more
frequently observed in patients within the first year of age, while is generally absent in those patients in
whom the anomaly is discovered in adulthood. In the latter, signs and symptoms are often related to the
development of bronchiectasis on the affected lung with occurrence of recurrent pulmonary infections and
hemoptysis.
The radiologic features include pulmonary hypoplasia and shift of the heart and mediastinum toward
the affected side with hyperinflation of the contralateral lung.7 Angiography is useful in depicting the
absent pulmonary artery but also to evaluate the pulmonary vasculature through a pulmonary angiogram
(Fig. 78.1). On contrast-enhanced CT scan, the pulmonary artery may be completely absent or end within
1 cm of its origin. In addition, collateral systemic vascularization from bronchial arteries but also through
collateral arteries anastomosed with distal pulmonary arteries can be observed (Fig. 78.2).8
When diagnosis is established early after birth the goal is to restore the circulation in the distal
pulmonary artery prior to the development of hypoplasia of the lung and of its vasculature. It should be
noted that, early after birth, the ductal origin of the pulmonary artery is frequently patent and dilatation or
stenting of the ductus to maintain the systemic-ductal pulmonary artery shunt could be performed.9 A
modified Blalock Taussig shunting is a surgical option to restore patency of hypoplastic ductal pulmonary
artery. Ultimately, anastomosis of the pulmonary artery into the pulmonary trunk with interposition of
autologous or prosthetic material is generally performed. Patch augmentation of the caliber of the
pulmonary artery is useful to reduce the risk of stenosis of the anastomosis.10 When discovered in adult
age, the lung is often hypoplastic with diffuse bronchiectatic derangements and collateral systemic
vascularization. Hemoptysis is a common symptom and embolization could be the first step to control
recurrent bleeding. Pneumonectomy is the sole solution in adult patients with uncontrolled symptoms.
FIGURE 78.1 Right pulmonary arterial agenesis: Angiography showing an absence of the right pulmonary artery (A), important
collateral vasculature of the right lung by intercostal (B), diaphragmatic (C), and anterior thoracic (D) arteries.
ORIGIN OF THE LEFT PULMONARY ARTERY FROM THE RIGHT (LEFT

PULMONARY ARTERY SLING)
The anomalous origin of the left pulmonary artery from the right pulmonary artery is called pulmonary
artery sling because in such a case the artery encircles the distal trachea and right mainstem bronchus
(Fig. 78.3).11 Approximately half of the patients with pulmonary artery sling have an associated
congenital tracheal stenosis which could be either extended or localized. Stenosis is due to a complete
cartilaginous ring and the anomaly is termed as “ring-sling complex” (Fig. 78.4).12,13 Moreover, extrinsic
compression of the trachea is exacerbated by the ductus arteriosus which passes anteriorly and superiorly
to the left mainstem bronchus. A detailed classification of tracheobronchial anomalies seen in left
pulmonary artery sling has been reported by Wells and colleagues14 including the bridging bronchus
variant (Fig. 78.5) which is a right bronchus originating from the left bronchial tree with or without a
pseudocarina. Associated congenital heart defects are found in 50% of cases, the most common being
atrial and ventricular septal defects, patent ductus arteriosus, left superior vena cava, and tetralogy of
Fallot. Occasionally, the abnormality may be detected as an incidental finding in an asymptomatic adult or
in the adult with respiratory complaints but most patients present within the first month of life with
respiratory distress and signs of tracheal obstruction. Obviously, the presence of respiratory symptoms is
a marker of the severity of the condition in view of potential surgical correction. The division and
reimplantation of the anomalous left pulmonary artery could resolve an extrinsic tracheal compression
while, in patients with ring-sling complex, the tracheal lesion must be repaired. While a segmental
tracheal resection and direct anastomosis is performed in case of localized tracheal stenosis as shown by
Hraska and colleagues,15 in the event of an extended tracheal stenosis a tracheoplasty is warranted. In this
setting, slide tracheoplasty or patch tracheoplasty using various materials (fresh autologous pericardium,
free rib cartilage graft, or free tracheal autograft patch) have also been proposed.16
FIGURE 78.2 Right pulmonary arterial agenesis: CT scan in axial plane (A) and volume rendering reconstruction in posterior
(B) and anterior (C) views: normal pulmonary trunk and left pulmonary artery, no right pulmonary artery. Important collateral
circulation from dilated bronchial, anterior thoracic, intercostal, and diaphragmatic arteries.
ORIGIN OF ONE PULMONARY ARTERY FROM THE AORTA (HEMITRUNCUS

ARTERIOSUS)
While the origin of both pulmonary arteries from the aorta is called as truncus arteriosus (Fig. 78.6),
when only one pulmonary vessel is involved the anomaly is referred to as hemitruncus arteriosus.
The malformation is very rare and, as observed by Rosenberg and colleagues,17 two main types of the
anomalous vessel implantation could be distinguished which could be referred to different embryologic
cascade. When the aberrant implantation is observed in the ascending aorta closely to the innominate
artery, the fetal ductus could be considered as the proximal part of the pulmonary artery, while, when the
aortic implantation is at the level of the valvular plane, the malformation is due to an anomalous septation
of the truncus or an incomplete migration of the pulmonary artery.18
The affected lung(s) is perfused at systemic pressure and the remaining lung (in case of hemitruncus) is
exposed to the entire output of the right ventricle, possibly leading to pulmonary hypertension. The
development of the bilateral pulmonary hypertension is explained by postulating the presence of
circulating vasoconstrictor substances, neurogenic crossover from an unprotected lung, and left
ventricular failure.19 Because of such progressive pathologic changes in vascular lung pressures and to
prevent congestive heart failure, early repair of the anomaly is necessary. In the series of Fontana, 60% of
patients die during the first year if not operated.20 Surgical correction is generally achieved within the
first month of age and direct anastomosis between the pulmonary artery and the pulmonary trunk is
performed. Direct implantation is planned in those cases in which the pulmonary artery originates from
the posterior aspect of the aorta while, when the aberrant artery is implanted much higher in the aortic
arch, interposition of homologous or synthetic graft is frequently needed.21 Although characterized by a
severe clinical presentation, a good functional outcome is to be attended if no other cardiac anomalies
responsible for right ventricular outflow obstruction are present.
FIGURE 78.3 Pulmonary artery sling: CT scan in volume rendering reconstruction in posterior (A) and superior axial views (C)
and axial maximum intensity reconstruction (MIP) (B): The left pulmonary artery arises from the right, encircling and
compressing the carina and the origin of main bronchi. There is a hyperinflation of both lungs.
FIGURE 78.4 Pulmonary artery sling associated with an extended circumferential tracheal stenosis in a newborn. CT scan in
axial mediastinal plane (A), coronal minimum intensity projection (minIP) (B) and volume rendering reconstruction in several
posterior views (C). The trachea presents a reduced and round lumen due to circumferential cartilaginous rings spread over 2
cm. The carina has an aspect in inversed T, and is low-located, at the level of the vertebral body of the sixth thoracic vertebra.
The right upper bronchus is not visible at CT scan.
FIGURE 78.5 Bridging bronchus: CT scan in coronal minIP (A) and volume rendering (B) reconstructions. The right upper
bronchus arises from carina at the level of the fourth thoracic vertebral body while the right lower lobe bronchus arises from the
left main bronchus, at the level of the fifth vertebral body, and crosses the mediastinum from the ipsi- to the contralateral lung.
There is no middle lobe. There is a stenotic segment of airway (circumferential cartilaginous rings) between right upper and
lower bronchus origins.
FIGURE 78.6 Truncus arteriosus: CT scan in volume rendering reconstructions in posterior (A) and left (B) views and axial
plane (C).
ANOMALIES OF THE PULMONARY VEINS
PARTIAL ANOMALOUS PULMONARY VENOUS CONNECTION

Partial anomalous pulmonary venous drainage occurs when one or more (but not all) pulmonary veins
drain into the systemic venous circulation instead of left atrium. Abnormal connection of right pulmonary
veins is reported in up to 90% of cases, while left and bilateral cases account for 7% and 3% of cases,
respectively.23 The most common anomalous venous drainage is observed in association with a sinus
venous atrial septal defect (sinus venous syndrome, i.e., an interatrial communication caused by a
deficiency of the common wall between the superior vena cava and the right-sided pulmonary veins). The
anomalous pulmonary vein, usually the right upper or middle pulmonary vein, can either override the intra
atrial septum (anomalous drainage) or can drain separately into the superior vena cava (true anomalous
connection) (Fig. 78.7). When a right pulmonary vein draining the whole lung or sometimes only the
middle and lower lobe connects to the inferior vena cava, the malformation is termed as “scimitar
syndrome” because of the characteristic figure on chest x-ray. This syndrome, which is associated to a
wide panel of pulmonary and systemic vascular as well as bronchial anomalies, is discussed separately.
An anomalous venous connection on the left side includes drainage of one or both pulmonary veins into
the left brachiocephalic vein by an anomalous vertical vein (Fig. 78.8) or direct connection into the
coronary sinus or occasionally in a left superior vena cava. Partial anomalous venous connection may be
diagnosed at any time, from birth to old age. The severity of symptoms, and thus the likelihood of
diagnosis, vary significantly depending on the amount of partial left-to-right shunt through the anomalous
connections. Some authors have suggested that the defect becomes clinically significant when 50% or
more of the pulmonary veins demonstrates an anomalous return.24,25
Spiral CT enables a noninvasive assessment of pulmonary venous anomalies as well as of the likely
associated tracheobronchial and pulmonary artery malformation (Figs. 78.7 and 78.8).26 The surgical
procedure varies according to the type of anomalous connection. In cases involving superior vena cava
and right atrium, surgical correction demands redirection of the anomalous pulmonary venous return to the
left atrium without attenuation of pulmonary venous or superior vena cava–right atrium flow. In addition,
closure of the septal defect is required and, obviously, injury of to the sinus atrial node is to be avoided.
The technique described by Warden et al.27 includes the division of the vena cava above the higher
anomalous pulmonary vein and its reimplantation in the right appendage. A right atriotomy is than
performed for closure of the septal defect and redirection of the pulmonary venous flow into the left
atrium. In presence of intact septa, a high lining defect is created to redirect the pulmonary flow. An
autologous patch could also be employed to baffle the superior vena cava orifice. The technique proposed
by Duncan28 is characterized by an intra–superior vena cava autologous pericardial baffle. In case of
anomaly on the left side, the left appendage is amputated and the anomalous vein divided and reimplanted
in the atrial stump.
Scimitar Syndrome
Anomalous pulmonary venous connection of the right lung to the inferior vena cava is frequently termed as
scimitar syndrome as proposed by Neill et al.29 in 1960 because of the characteristic Turkish saber sign
often present on chest x-ray. However, this type of partial anomalous venous connection is associated to a
wide constellation of cardiac and pulmonary anomalies. As a consequence, to describe this complex of
malformations, Felson has proposed the term of congenital pulmonary venolobar syndrome.30 The terms
Halasz syndrome, mirror-image lung syndrome, epibronchial right pulmonary artery syndrome or vena
cava bronchovascular syndrome have also been used.31,32 The right anomalous pulmonary vein which
connects to the inferior vena cava or to the cavoatrial junction usually drains the right lower lobe,
sometimes also the middle lobe, and in the 20% to 30% of cases the whole right lung. The connection
with the inferior vena cava can be observed above or below the diaphragm. In those rare cases in which
the anomalous pulmonary vein connects to the left atrium, the anomalous vein is termed as “meandering”
(Fig. 78.9).30 Concomitantly, a right lobar/pulmonary agenesis, aplasia, or hypoplasia (Fig. 78.10)—often
collectively referred to as “hypogenetic” lung—are almost always present.30 Absence or hypoplasia of a
pulmonary artery (Fig. 78.10), pulmonary sequestration, systemic arterialization of the lung without
sequestration, absence of the inferior vena cava, and duplication of the diaphragm are likely part of the
syndrome. Interestingly, a horseshoe lung (Figs. 78.11 and 78.12), which is diagnosed when the
pulmonary parenchyma connects in the midline posterior to the pericardium and anterior to the aorta and
esophagus, is not infrequently observed.33 A classification has been proposed according to age of
presentation. The childhood form is diagnosed in the first year of life, characterized by major cardiac
anomalies associated to pulmonary hypertension, and it generally portends a poor prognosis. Conversely,
in the “adult” form, the symptoms are mild or absent and the prognosis is favorable.34,35 Symptoms are
related to the degree of left-to-right shunting, pulmonary hypertension, parenchymal lung disease, and
associated intracardiac lesions. Kiely et al.36 documented in 70 cases that common symptoms were
fatigue, dyspnea, decreased exercise tolerance, cough, recurrent respiratory tract infections, and failure to
thrive. The A-P chest x-ray shows, in less than 50% of the patients, the half crescent sign often in
association with a small right lung and cardiac displacement. CT scan provides, in a noninvasive fashion,
detailed information upon the anatomy of the pulmonary veins and easily detects the presence of an
aberrant systemic artery.37 Tracheobronchial anatomy is also completely explored. Echocardiography is
performed to assess associated intracardiac anomalies and cardiac catheterization is indicated for both
diagnostic and therapeutical procedures. In recent years, embolization of the systemic artery but also of
the scimitar vein in those cases with a double venous connection have been successfully performed.38
FIGURE 78.7 Partial anomalous venous connection: CT scan in coronal (A) and axial (B) planes and volume rendering
reconstruction (C): The right upper pulmonary vein presents an anomalous return to the superior vena cava. There is no anomaly
of right lower and left pulmonary venous connections.
FIGURE 78.8 Partial anomalous venous connection of the left superior pulmonary lobe via a vertical vein connecting to the
anonymous vein.
FIGURE 78.9 Pseudoscimitar syndrome; the anomalous vein connects to the left atrium and is termed as “meandering.” Return
of left lower vein into left atrium is also present.
FIGURE 78.10 Scimitar syndrome: CT scan in axial plane at the level of pulmonary artery (A) and pulmonary veins (B),
coronal reconstruction in minIP (C) and oblique coronal reconstruction in MIP (D). Hypoplasia of the right pulmonary artery (A),
hypoplasia of the right lung which presents only one dysplastic lobar bronchus (C), dextroposition of the heart, right anomalous
pulmonary venous return by two veins to the inferior vena cava (D), and no right pulmonary vein connecting to the left atrium
(B) are observed in the same case. A left superior vena cava is also present.
The decision for operative intervention should be based on the presence of associated cardiac
anomalies, the degree of left-to-right shunt, the presence of scimitar vein obstruction, and of bronchial
anomalies eventually responsible for recurrent infections or hemoptysis. In infants, if a systemic aberrant
artery is present its division reduces the blood shunting and improves pulmonary artery pressure. Repair
of the scimitar vein consists of redirecting the pulmonary vein in the left atrium. Kirklin et al.39 reported
that either the anomalous vessel can be anastomosed directly to the left atrium or an intracardiac patch can
be used to tunnel the flow from the anomalous vein to the left atrium through an atrial septal defect.
Lobectomy or pneumonectomy could be necessary in those cases in which recurrent pulmonary infection
and hemorrhage are present.40 Results depend mainly on the degree of preoperative pulmonary
hypertension and associated cardiac lesions. Older patients with minimal symptoms have an excellent
prognosis while, as reported by Canter et al.,41 infants with cyanosis, failure to thrive, and severe
pulmonary hypertension have a high mortality rate.
FIGURE 78.11 Scimitar syndrome associated with right pulmonary sequestration and horse-shoe lung: CT scan in axial (A) and
coronal (B) MIP projections, axial plane (C), coronal minIP projection (D) and VR reconstruction (D) in anterior views.
Hypoplasia of the right pulmonary artery and lung, which is dysplastic and contains cystic lesions, dextroposition of the heart, no
right pulmonary vein connecting to the left atrium are present. An additional hyperinflated lung segment is evident, straddling right
and left sides, between the aorta and esophagus.
TOTAL PULMONARY ANOMALOUS VENOUS CONNECTION

Total anomalous pulmonary venous connection is diagnosed when all four pulmonary veins drain into the
systemic venous circulation. The malformation is subdivided into four types: supracardiac, cardiac,
infracardiac, and mixed types.42 In the supracardiac type, which is the more frequent (45% of cases in the
series of Bove and Hirsch43), a common pulmonary vein drains superiorly into the innominate vein,
superior vena cava, or azygous vein via an ascending vertical vein (Fig. 78.13). Conversely, the cardiac
type is defined by a pulmonary venous drainage into the coronary sinus or, on rare occasions, individual
pulmonary veins connect directly into the right atrium. The infracardiac type is characterized by a
common pulmonary vein draining through the diaphragm into the inferior vena cava, portal vein, or in
ductus venosus (Fig. 78.14). Finally, in the mixed type, the features of the previous types could coexist.
Obviously, the coexistence of an atrial septal defect is the rule.
Signs and symptoms of the malformation vary upon the presence of an obstruction to the pulmonary
venous drainage. Venous obstruction is always present in the infracardiac type, because of the intrahepatic
obstacle, and is sometimes present in the supracardiac type in the form of extrinsic compression on the
vertical vein. The presence of venous flow obstruction is associated to a severity of clinical presentation
because of the rapid development of pulmonary venous hypertension and pulmonary edema, whereas
patients without venous pulmonary obstruction could be asymptomatic.
FIGURE 78.12 Three-dimensional reconstruction of the horse-shoe lung (case illustrated in Fig. 78.11).
The diagnosis can be made on echography by the identification of the anomalous pulmonary venous
confluence to the systemic venous system. Cardiac catheterization is useful for the measurement of
pulmonary vascular resistance. Obviously, spiral CT allows for noninvasive assessment not only of
pulmonary venous anomalies but also of the associated tracheobronchial and pulmonary arterial
malformations.
The objectives of surgery are the division of the anomalous communications between pulmonary and
systemic circulation, redirection of the pulmonary veins drainage into the left atrium, and the closure of
the atrial septal defect.
FIGURE 78.13 Supracardiac total anomalous pulmonary venous connection, type I. CT scan in coronal MIP projection (A) and
posterior view in VR reconstruction (B): The four pulmonary veins drain via a large common collector tube to the superior vena
cava.
FIGURE 78.14 Infracardiac total anomalous pulmonary venous connection. CT scan in coronal MIP projection: The four
pulmonary veins drain via a large common collector to the left suprahepatic vein.
Advances in diagnosis, intensive care medicine, and surgical technique have led to improved survival.
Early diagnosis and repair has brought to excellent long-term survival and functional status. Although a
reduction in surgical mortality from over 30% in the 1970s to less than 10% in the last decade has been
observed, it remains a main concern in the event of recurrent venous obstruction, which develops in 5%
to 15% of patients.44,45 In such cases, the results of balloon angioplasty and/or stent insertion have been
disappointing and recurrent stenoses are the rule. Individual patch angioplasty of the ostia has also been
utilized with poor long-term results.
PULMONARY ARTERIOVENOUS FISTULAS

Pulmonary arteriovenous malformations (PAVMs) are anomalous communication between the pulmonary
arteries and pulmonary veins. They are characterized by aberrant capillary bed development with
incomplete formation or disintegration of the vascular septa that normally divide the primitive
connections between the arterial and venous plexus. The most common cause of pulmonary arteriovenous
fistulae is hereditary hemorrhagic telangiectasia (HHT) also called Rendu–Osler–Weber disease, an
autosomal dominant disorder which accounts for approximately 70% of cases of PAVMs.46 In those cases
of HHT, in which mutation in ENG gene is present, pulmonary arteriovenous fistula in found in nearly
60% of cases.47 Other much more infrequent causes of arteriovenous fistula are trauma, cavopulmonary
shunt and gestational trophoblastic disease. However, as pointed out by Tobin,48 some pulmonary
arteriovenous shunting exists in normal lungs and in absence of a recognized pathologic condition these
malformations are often termed as sporadic. The incidence of sporadic arteriovenous fistula is difficult to
estimate but data extrapolated from cancer screening programs have reported about 1 case in every 2000
CT scans.49 Signs and symptoms are related to size and number of the lesions as well as to the presence
of a Rendu–Osler–Weber disease. In the latter, the first signs of the disease are epistaxis and
gastrointestinal manifestations often preceding cardiorespiratory manifestations. In any case, the presence
of arteriovenous malformation configures a syndrome of right-to-left shunting which is characterized by
hypoxemia and compensatory polycythemia. Dyspnea is generally observed in association with clubbing
and cyanosis.50 Hemoptysis or hemothorax are feared complications and they are much frequently seen in
presence of systemic arterial feeding which could develop as a consequence of arterial embolization. As
a consequence of the absence of capillary bed filtration, central nervous system complications, such as
ischemic stroke, cerebral abscess, transient ischemic attacks, are frequent. During pregnancy, because of
increased blood volume, increased cardiac output, and increased blood flow through the fistulas, an
enhanced risk of complication and mortality is observed.51 Contrast-enhanced CT scan is sufficient to
demonstrate the anatomy of the malformation (Fig. 78.15); coronal reconstruction allows better
visualization of the anatomy of afferent and efferent vessels (Fig. 78.16), while angiography is performed
at time of embolization.52
FIGURE 78.15 CT scan of a right congenital pulmonary arteriovenous fistula. The afferent artery and efferent vein are evident
upon MIP reconstruction.
Since the risk of stroke has been demonstrated to be independent of the size of the arteriovenous
fistulas, the treatment of the lesion has been recommended for all malformation amenable to the
procedure.53 Pulmonary resection centered on the PAVMs has been the sole treatment for decades, up to
1977, when the first case of arterial coil embolization was reported by Porstmann.54 Nowadays, large
series of patients treated with balloon and plug embolization have been published, demonstrating the
safety of the procedure which eliminates the risk and the costs of surgery. In last decade, the use of the
Amplatzer vascular plug (AGA Medical, Plymouth, MN, USA), a self-expanding cylindrical nitinol
occlusive device, has led to the amelioration of the results of embolization.55,56 These nitinol devices
have been reported to be useful when positioned very distally in the feeding pulmonary arterial branch
thus leading to a complete vessel occlusion with a single device. Indeed, the rate of recanalization using
these devices seems very low.
THORACIC LYMPHANGIOMAS, LYMPHANGIECTASIS,

LYMPHANGIOMATOSIS, AND LYMPHATIC DYSPLASIA SYNDROME
Primary pulmonary lymphatic disorders are derived from abnormal embryogenesis and development of
lymphatic vasculature. The lymphatics vascular system forms as an outgrowth of the venous system and
from mesenchymal tissue to constitute the two-paired juguloaxillary and inguinal sacs, as well as the
retroperitoneal and the cisterna chili sacs.57 The pulmonary lymphatics and the surrounding mesenchymal
tissue are prominent till the 20th week of fetal development while they regress and are replaced by the
alveolar tissue.
FIGURE 78.16 CT scan of a right congenital pulmonary arteriovenous fistula. Coronal reconstruction allows better visualization
of afferent artery and efferent vein.
A classification of the disorder of the lymphatic system has been proposed by Hilliard et al. in 1990
and has been partially modified by Faul et al. in 2000.58,59 Four main nosologic types are recognized:
lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome.
Lymphangiomas are localized proliferation of lymphatic tissue (Figs. 78.17 to 78.19), while
lymphangiectasis indicates the presence of dilated lymphatics. Lymphangiomatosis (Fig. 78.20) refers to
multiple lymphangiomas and, when they are found exclusively in the lung, the term of pulmonary
lymphangiomatosis is employed. The term lymphatic dysplasia syndrome includes primary lymphedema
syndrome, congenital chylothorax, and the yellow nail syndrome.
LYMPHANGIOMAS
Lymphangiomas are localized proliferation of well-differentiated lymphatic tissue which represents a
remnant of embryonic lymphatic tissue. They are typically found at the sites of primordial lymphatic sacs
(juguloaxillary, inguinal, retroperitoneal, or mediastinal), whereas intrapulmonary lymphangiomas are
extremely rare. Lymphangiomas are classified in three types upon their pathologic features. “Simple”
lymphangiomas presents thin-walled lymphatics channels, while “cavernous” lymphangiomas is
characterized by the association of lymphatics channels with stroma. The lesion has no well-defined
margins and insinuates surrounding tissues. The “cystic” lymphangiomas presents large multiloculated
cysts lined by endothelium and with connective tissue and hyperplastic smooth muscle; a fibrous pseudo
capsule is the rule (Fig. 78.17). Cavernous and cystic pathologic features could coexist. Simplex
lymphangiomas is exclusively cutaneous while thoracic lymphangiomas could be found as masses in the
thoracic wall (Fig. 78.18) or in any mediastinal compartment (Fig. 78.19), with possible intrathoracic
spread (Fig. 78.19). On CT scan, they could present as well limited multiloculated mass with hydric
density but sometimes the limits of the lesion are not well defined and the density is heterogeneous.60 MRI
could be helpful in differential diagnosis with other mediastinal mass (Fig. 78.19).60,61 Lymphangiomas
are frequently diagnosed before the first 2 years of life but, when they are deeply located, they are not
discovered until adult age as incidental findings or when symptoms appear. The natural history is
characterized by slow growth and possible compression of adjacent structures. In this context, various
symptoms are associated to thoracic lymphangiomas such as cough, dyspnea, stridor, dysphagia, or even
vena cava syndrome. Surgical excision is performed to obtain a definitive diagnosis, to relieve symptoms
and, in any case, to avoid further complication resulting from adjacent organ compression. Surgery is
often challenging because the tumor has no well limited margins and involves the structures in the
mediastinum but also in the neck. Total extirpation is not always possible without functional impairment
which is undesired for such benign lesions.
FIGURE 78.17 Histopathological examination of a sample of pulmonary cystic lymphangioma: At lower magnification (A), the
lesion in close contact with lung parenchyma is evident. At higher magnification (B), multiloculated cysts (A) lined by
endothelium and with connective tissue and hyperplastic smooth muscle (B) are evident; a fibrous pseudo capsule is also present
(C). Lymphocytes inside the lymphatics are visible (D).
FIGURE 78.18 MRI T2-weighted sequences in coronal (A) and axial planes (B); right thoracic parietal lymphangioma
insinuating through the whole chest wall into the pleural cavity. Lesions presents heterogenous hyperintensity, because of
intracystic bleeding..
FIGURE 78.19 A 25-year old women complaining of persistent cough and sus-clavicular swelling. CT scan, axial view (A)
showing the pulmonary component of a cervicothoracic cystic lymphangioma. CT scan, coronal view (B), showing the
mediastinal component of the lesion who insinuates between vessels. Treatment involved resection through a combined cervical
and transpleural approach.
FIGURE 78.20 MRI assessment of left pulmonary lymphangiomatosis by T2-weighted sequences in axial plane (A, B) and
coronal plane (C), showing diffuse hyperintensity as well as thickening of pleura and interlobular lines.
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79
Chronic Pulmonary Emboli
Nathaniel B. Langer ■ Philippe Dartevelle ■ Elie Fadel
INTRODUCTION
In most survivors of acute pulmonary embolism, the clot is resorbed by local fibrinolysis, eventually
restoring patency to the pulmonary arterial bed. In a small proportion of patients, however, this process
fails. Instead, the clot undergoes a fibrotic organization within the pulmonary arteries that results in
chronic occlusion of the pulmonary arterial tree.1 Over time, this leads to chronic thromboembolic
pulmonary hypertension (CTEPH), a form of pre-capillary pulmonary hypertension, and without effective
therapy, patients develop progressive, lethal right heart failure. Management of this disease has markedly
improved over the past two decades, largely due to a better understanding of the pathophysiology of
CTEPH, along with its diagnosis and treatment. CTEPH is potentially curable with surgical pulmonary
endarterectomy (PEA), and despite its complexity, mortality following PEA is less than 5% at
experienced centers.2 Long considered rare, CTEPH is increasingly recognized as an important cause of
pulmonary hypertension, and improvements in awareness, diagnostic techniques, and availability of
treatment continue to increase appropriate diagnosis.
EPIDEMIOLOGY
The precise prevalence and annual incidence of CTEPH remain unknown. However, estimates from the
United States suggest there are between 500 and 2,500 patients with this condition annually.1 Studies from
the United Kingdom have estimated the incidence at about 5 per million population per year.3 This makes
CTEPH one of the most common forms of pre-capillary pulmonary hypertension. However, only 1.7 and
0.9 patients per million population undergo PEA in Europe and the United States, respectively, suggesting
that the condition remains significantly underdiagnosed.
PATHOPHYSIOLOGY AND NATURAL HISTORY

Although there has been some debate within the literature regarding the relationship between venous
thromboembolism (VTE) and CTEPH, recent studies have largely confirmed VTE as the initiating event.
Early retrospective reports by Wolf, Bonderman, Lang, and others reported no history of VTE in 40% to
60% of CTEPH patients.4–6 However, more recent studies from Bonderman and Condliffe found 70% and
58% of CTEPH patients had a history of VTE, respectively.7,8 These findings are supported by results
from the prospective European CTEPH registry, where 74.8% of the 679 CTEPH patients had a previous
pulmonary embolism and 56.1% had a prior deep vein thrombosis, as well as the registry maintained at
the University of California San Diego where 70.6% of their 2,700 CTEPH patients had a history of acute
pulmonary embolism.9,10 It is now accepted that CTEPH is a consequence of VTE, albeit CTEPH as a
direct result of symptomatic pulmonary embolism remains uncommon.
Despite the connection between VTE and CTEPH, there is no uniform association between classical
risk factors for VTE and increased risk for CTEPH. Wolf and colleagues examined the prevalence of
genetic risk factors for VTE, including antithrombin, protein C, protein S, and plasminogen deficiencies,
factor V Leiden, and anticardiolipin antibodies, and found that their prevalence was not increased in
CTEPH patients compared to either patients with idiopathic pulmonary hypertension or controls.4
However, other VTE risk factors such as prior splenectomy, ventriculoatrial shunts, indwelling catheters
or device leads, and thyroid replacement therapy, as well as malignancy, osteomyelitis, and inflammatory
bowel disease, are associated with CTEPH.5,7,11
The pathologic hallmark of CTEPH is the fibrosis of pulmonary artery clot leading to chronic
occlusion of the pulmonary arteries. Under normal conditions, blood clots within the pulmonary arteries
are dissolved through a two-phase process. The first phase is one of fibrinolysis, followed by a second,
cellular phase when monocytes and endothelial progenitor cells induce thrombus neovascularization and
recanalization.12,13 The exact defects in this process that occur in CTEPH and cause clot fibrosis are not
well understood. However, recent studies have implicated endothelial dysfunction and inflammation in
CTEPH pathogenesis. In a mouse model, Alias and colleagues demonstrated that impaired thrombus
resolution results from impaired angiogenesis, and Sakao and colleagues found that myofibroblast-like
cells isolated from PEA surgical specimens can induce endothelial cell dysfunction.14,15 Several other
groups have additionally shown that monocytes, pro-inflammatory cytokines, and cellular adhesion
molecules impact the timing and success of clot resolution.16–19
As clot fibrosis progresses and portions of the pulmonary arterial tree become partially or completely
occluded, blood flow increases in the non-occluded vessels. This overflow generates higher local arterial
pressures and increased shear stress, which together contribute to the vascular remodeling and endothelial
dysfunction seen in the patent pulmonary arteries in CTEPH patients.20 The medial hypertrophy, intimal
thickening, and plexiform lesions found in these vessels are similar to what is seen in idiopathic
pulmonary arterial hypertension (PAH) and explain the poor correlation between the extent of central
pulmonary artery occlusion and the severity of patients’ pulmonary hypertension.21,22 Continued
remodeling of the non-occluded arteries also explains the progression of pulmonary hypertension seen in
CTEPH despite the absence of additional thromboembolic episodes.23
In most patients, the mean pulmonary artery pressure is lower in CTEPH than in PAH patients with
similar degrees of pulmonary vascular resistance (PVR). This is thought to result from less effective right
ventricular adaptation and the increased ventricular stroke work required to overcome the severe
obstruction and stiffness of the pulmonary arteries present in CTEPH patients.24,25
The time required to progress from an initial thromboembolic event to symptomatic CTEPH is not well
known, but there is usually a honeymoon period following the initial event during which patients remain
asymptomatic. It is estimated that this symptom-free period can last anywhere from months to years.26 The
best data currently available from the European CTEPH registry show a median time from last known
pulmonary embolus to CTEPH diagnosis of 12.5 months and a median time from initial symptoms to
diagnosis of 14 months.9 Diagnosis is often made only after patients develop dyspnea, which along with
syncope, hemoptysis, and other signs of right heart failure are both common presenting symptoms and
markers of advanced disease. This makes early diagnosis difficult, a challenge underscored by the fact
that most patients present with NYHA class III or IV symptoms.9 Nevertheless, timely diagnosis and
treatment are essential. Without treatment, 5-year survival is only 30% for patients with a mean
pulmonary artery pressure greater than 40 mm Hg and 10% if it exceeds 50 mm Hg.1
DIAGNOSIS
The initial clinical presentation of CTEPH is most often progressive dyspnea on exertion, which is
similar to many other forms of cardiopulmonary disease, including PAH and congestive heart failure. In
the European CTEPH registry, patients were a median of 63 years old at the time of diagnosis, with males
and females equally affected.9 Findings on physical exam are nonspecific, as accentuation of the pulmonic
component of the second heart sound can be difficult to appreciate and is easily overlooked. Other
potential physical exam findings, such as a tricuspid insufficiency murmur and lower extremity edema, are
likewise shared with other cardiopulmonary conditions.
There are no specific laboratory tests for CTEPH, although multiple abnormalities can be seen.
Patients may manifest secondary polycythemia due to chronic hypoxemia, elevated liver function tests
from hepatic congestion, and increased blood urea nitrogen resulting from a low cardiac output.
Electrocardiography is similarly nonspecific and is often normal, although general patterns associated
with pulmonary hypertension, right ventricular hypertrophy, or right ventricular strain can be seen. These
include a right axis deviation, right bundle branch block, or nonspecific ST–T wave changes in leads V1–
V3.27 Klok and colleagues reported that an electrocardiogram without evidence of right heart strain and a
normal N-terminal pro-brain-type natriuretic peptide level have, when taken together, a negative
predictive value of 99% for CTEPH in patients with acute pulmonary embolism.28
While it is not part of the specific algorithm for diagnosing CTEPH, patients often undergo pulmonary
function testing as part of a larger dyspnea evaluation or a more general investigation of pulmonary
hypertension. In CTEPH, spirometry and lung volumes are often normal, although mild restrictive or
obstructive defects are possible. For example, Morris and colleagues reported a series of CTEPH
patients in which 22% had a restrictive defect.29 Additionally, most patients will have a reduced single
breath diffusing capacity for carbon monoxide out of proportion to any spirometric abnormalities. Severe
obstructive or restrictive defects should raise suspicion for alternative causes of dyspnea. With chest
radiography, enlargement of central pulmonary arteries and right heart enlargement may be detectable, but
these findings are also nondiagnostic.
FIGURE 79.1 Basic algorithm for the diagnosis and evaluation of CTEPH. Initial confirmation of pulmonary hypertension is
best achieved with transthoracic echocardiography, after which CTEPH is specifically investigated with ventilation/perfusion
(V/Q) scan and, if the V/Q scan is consistent with CTEPH, subsequent pulmonary angiography and right heart catheterization.
All CTEPH patients should be evaluated for pulmonary endarterectomy at a CTEPH center.
Given these nonspecific signs and symptoms, clinical suspicion must be high, and all patients with
unexplained dyspnea or pulmonary hypertension, as well as any who remain symptomatic following an
acute pulmonary embolism, should be evaluated for CTEPH. This is especially important if there is a
positive history of VTE, though it must be remembered that a significant portion of CTEPH patients
present with no such history.
In all suspected cases, the general diagnostic approach should be to establish the presence of
pulmonary hypertension first and then determine its cause (Fig. 79.1). The preferred initial test is a
transthoracic echocardiogram, which allows for both the identification of pulmonary hypertension and
assessment of the heart. Possible echocardiographic findings in CTEPH include right atrial and
ventricular enlargement, impaired right ventricular function, tricuspid regurgitation, leftward
displacement of the interventricular septum, decreased left ventricular size, and abnormal left ventricular
systolic and/or diastolic function.30 Furthermore, a patent foramen ovale has been reported in up to 25%
of CTEPH patients, and consequently all echocardiographic exams should include agitated saline contrast
in order to identify significant shunts that should be closed during future surgery.31
Once the presence of pulmonary hypertension is established by echocardiogram, ventilation/perfusion
(V/Q) scanning is the best subsequent test in evaluating a patient for CTEPH. In a review of 227 patients,
Tunariu and colleagues found V/Q scans to be 96% sensitive and 90% to 95% specific for CTEPH, with
a negative predictive value of virtually 100%.32 This is significantly better than the 51% sensitivity and
99% specificity of multidetector CT pulmonary angiography (CTPA) reported in the same study.32 To
fully evaluate for CTEPH, and potentially exclude it, scans should consist of planar images on at least six
views plus SPECT.33,34 In addition to better sensitivity, V/Q scans require lower radiation exposure than
CTPA and avoid potential complications resulting from the use of intravenous contrast. Furthermore, V/Q
scanning can differentiate between diseases of the proximal, large pulmonary arteries, such as CTEPH
and pulmonary artery sarcoma, and distal small vessel diseases, such as PAH, that often are the most
likely alternative diagnoses.35,36 V/Q scans in CTEPH reveal segmental or larger, and usually bilateral,
perfusion defects with normal ventilation, whereas the V/Q abnormalities are mostly homogenous in PAH
(Fig. 79.2). It is essential to differentiate between primary pulmonary hypertension and CTEPH. While
highly sensitive for CTEPH, V/Q scans often underestimate the severity of central obstructions due to
some blood flow reaching the lung periphery via channels through or around central lesions.
FIGURE 79.2 V/Q scan consistent with CTEPH. V/Q scans in CTEPH typically demonstrate normal ventilation with
segmental or larger perfusion defects that are frequently bilateral.
If the V/Q scan is indeterminate, further evaluation with CTPA is warranted, as CTPA can provide
additional evidence for CTEPH by demonstrating strictures, stenoses, intimal irregularities, or complete
obstruction (Fig. 79.3).37–39 However, a normal CTPA does not exclude a diagnosis of CTEPH.37 CT
scanning can also exclude rare conditions that may present with similar symptoms, including fibrous
mediastinitis, mediastinal carcinoma, and sarcoma of the pulmonary artery. CT scans can also delineate
atheromatous calcifications of the pulmonary artery in long-standing disease, which increases the
technical difficulty of the endarterectomy. Several groups have reported using magnetic resonance
imaging (MRI) or magnetic resonance angiogram (MRA) to evaluate the pulmonary arteries and right
heart in CTEPH patients. While initial results are encouraging and have shown sensitivity and specificity
to be similar to V/Q scanning, further study is needed before they can be routinely used in the evaluation
of CTEPH patients.40,41
With a V/Q scan suggestive of CTEPH, patients should be referred to a center with expertise in the
medical and surgical management of CTEPH.42 Subsequently, evaluation should continue with a
pulmonary angiogram and right heart catheterization. Pulmonary angiography allows for visualization of
both the proximal and distal elastic pulmonary arteries and remains the gold standard for diagnosing
CTEPH and assessing for proximal versus distal disease, an essential part of determining a patient’s
operability. Pulmonary angiogram should be performed with both anterior and lateral views using
selective nonionic contrast injections and a biplane digital subtraction system. There are five distinct
patterns seen on pulmonary angiogram in CTEPH: pouch defects, pulmonary artery webs or bands, intimal
irregularities, abrupt narrowing, and complete obstruction (Fig. 79.4).43 Pulmonary angiography can also
visualize subpleural perfusion, which has been shown to be correlated with poor surgical outcomes.44
While concern has been raised regarding the safety of pulmonary angiography in patients with
pulmonary hypertension due to potential systemic hypotension from contrast-induced vasodilation, this
has not been demonstrated in the literature. Pitton and colleagues showed no adverse hemodynamic
effects from multiple bolus injections of nonionic contrast, including in patients with systolic pulmonary
artery pressures greater than 60 mm Hg.45 Ideally, pulmonary angiography should be performed
simultaneously with hemodynamic assessment by right heart catheterization. Furthermore, all patients at
risk for coronary artery disease should be evaluated by coronary angiography, as coronary artery bypass
grafting can be performed at the time of PEA, if needed.1 Carotid artery stenosis should also be excluded
by duplex scanning in at-risk patients. Together, these studies allow for a comprehensive assessment of
disease burden and the status of the cardiovascular and pulmonary systems. When possible, this
evaluation should be performed at a specialized CTEPH center so as to minimize repetition of exams.
FIGURE 79.3 CT pulmonary angiogram of a patient with CTEPH demonstrating pulmonary artery stenoses and occlusions.
FIGURE 79.4 Pulmonary angiogram consistent with CTEPH. There are five classical patterns seen in pulmonary angiograms
from CTEPH patients, including pouch defects, pulmonary artery webs or bands, intimal irregularities, abrupt narrowing, and
complete obstruction.
DIAGNOSTIC CRITERIA
As per the 2009 guidelines for the diagnosis and treatment of pulmonary hypertension, a diagnosis of
CTEPH requires that a patient must have pre-capillary pulmonary hypertension (mean pulmonary artery
pressure >25 mm Hg, pulmonary capillary wedge pressure <15 mm Hg, PVR >2 Wood units) in the setting
of multiple chronic/organized occlusive thrombi/emboli in the elastic pulmonary arteries (main, lobar,
segmental, or subsegmental) despite at least 3 months of anticoagulation.42
EVALUATION OF SURGICAL CANDIDACY

Once a patient is diagnosed with CTEPH, the first step should be to initiate life-long anticoagulation. This
is most commonly done using a bridge of either intravenous unfractionated heparin or subcutaneous low
molecular weight heparin followed by a vitamin K antagonist, with a target international normalized ratio
of 2.0 to 3.0.46 After initiation of anticoagulation, all patients diagnosed with CTEPH should be evaluated
for PEA, as surgery remains the only potentially curative therapy. It is essential that this evaluation occur
even if a patient’s symptoms or hemodynamic derangements are mild, as arteriopathy can develop in the
unobstructed territories over time. If allowed to occur, this arteriopathy can lead to persistent
postoperative pulmonary hypertension, a strong predictor of poor outcomes.1,38
While most patients who present for PEA evaluation will show severe hemodynamic compromise,
some will appear normal. This may indicate unilateral obstruction.47 However, even if unilateral
obstruction is absent, these patients will likely demonstrate an abnormal response to exercise. Even at
rest, studies suggest that the right ventricle is not adapted to the increased afterload in CTEPH, regardless
of normal pressures.48 As progressive pulmonary hypertension can develop from elevated pulmonary
artery pressure and right ventricular workload during daily activities, these patients can significantly
benefit from PEA. In order to identify this subset of patients, some centers have incorporated exercise
testing into their diagnostic evaluation.
Indications for PEA directly relate to the accessibility of the lesions and the experience of the surgeon.
As outlined by Fedullo and colleagues, indications can generally be approached through four categories:
surgical accessibility, correlation of thrombi with hemodynamic derangement or ventilatory impairment,
presence and severity of patient comorbidities, and the patient’s willingness to proceed with surgery.1
The primary determination that must be made is whether or not the thrombi are surgically accessible. Only
thrombi that originate within the main, lobar, or segmental arteries are removable during PEA. Second,
successful PEA depends on the hemodynamic compromise being proportional to the degree of vascular
occlusion. This is critical, because if a patient’s hemodynamic compromise is due mostly to inaccessible,
distal disease, the PVR is likely to be minimally reduced by PEA. Failure to reduce the PVR is associated
with poor short- and long-term outcomes, including failure to wean from cardiopulmonary bypass,
hemodynamic instability, and death.1,38,49,50 Currently, there are no standardized metrics for assessing the
contribution of thrombi to hemodynamic compromise, further underlining the need for expert consultation.
As experience with CTEPH has grown, contraindications for PEA have decreased. The only current,
absolute contraindication for PEA is severe restrictive or obstructive lung disease.1 Severely elevated
PVR (>900 to 1,000 dynes/cm/sec−5) has been associated with increased perioperative mortality in
several series.38,51 However, no degree of PVR elevation or functional status impairment should be
considered a contraindication for PEA. Severity of disease and symptoms should be included in the
preoperative risk assessment, however. The same is true for other comorbidities, which are likewise not
absolute contraindications but must be considered when comprehensively evaluating a patient’s overall
health and assessing operative risk. Importantly, advanced age is not in and of itself a contraindication for
PEA. Berman and colleagues reported early mortality in septuagenarian patients that is comparable to
younger patients, and successful PEA has been reported for patients over 80.2,52
The final decision to proceed with surgery is complex and requires expertise in CTEPH surgery,
pulmonology, intensive care, and radiology. Only an expert, multidisciplinary CTEPH team should make
the final decision regarding operative candidacy.37 No patient should be considered inoperable until
independently evaluated by at least two expert centers.
Once a patient is determined to be a candidate for surgery, some centers routinely place an inferior
vena cava (IVC) filter unless there is a clear non-leg, non-pelvic source for a patient’s emboli. This is in
order to provide protection against further emboli during the sensitive postoperative period or intervals
of inadequate anticoagulation. There is no consensus, however, as to the efficacy of this practice and
debate continues.53 To date, there have been no randomized trials evaluating the use of IVC filters.
However, in the European CTEPH registry, the placement of an IVC filter did not affect 1-year survival
after PEA.54 If a filter is placed, a transjugular approach is preferable, and the procedure should be
performed several days prior to surgery in order to avoid potential bleeding complications in the
perioperative period.
PULMONARY ENDARTERECTOMY
Patient monitoring during surgery is similar to general cardiac surgery and includes continuous monitoring
of the electrocardiogram, bladder temperature, pulse oximetry, and arterial blood pressure, as well as the
degree of diuresis. For PEA, a femoral artery catheter may be placed in addition to the routine radial
artery catheter in order to avoid aberrant values resulting from peripheral vasoconstriction following
hypothermic circulatory arrest.55 The head is wrapped in a cooling jacket for direct cerebral cooling, and
near-infrared spectroscopy used to monitor brain oxygenation during cardiopulmonary bypass and
circulatory arrest. Lastly, a Swan–Ganz catheter is placed to monitor the cardiac output, mixed venous
oxygen saturation, and PVR, and a transesophageal echocardiography probe is inserted to perform routine
cardiac evaluation and a detailed assessment of the right heart and inter-atrial septum.55
The surgical approach for PEA is via a median sternotomy and vertical pericardiotomy (Video 79.1).
This allows for direct access to both pulmonary arteries without opening the pleura and avoids the highly
vascularized tissue that surrounds blood vessels outside of the pericardium. After systemic heparinization
to prolong the activated clotting time beyond 400 seconds (300 units/kg, given intravenously), full
cardiopulmonary bypass is instituted via the superior vena cava and IVC and the aorta. This strategy is
used in order to allow access to the right atrium, if needed. Once cardiopulmonary bypass is instituted,
cooling is begun in order to lower the patient’s core temperature to 18° to 20°C. A 10°C gradient should
be maintained between the arterial blood and the central temperature (rectal or bladder) during
cooling.55,56 Complete cooling usually requires 45 minutes to 1 hour, so as the temperature is decreasing,
the superior vena cava is completely dissected to grant access to the right pulmonary artery, and a vent is
placed in the main pulmonary artery, approximately 1 cm distal to the pulmonary valve. A second vent is
inserted through the right superior pulmonary vein into the left atrium. Sufficient decompression of the left
heart is especially important during PEA due to the large amount of venous return resulting from enlarged
bronchial arteries.38
Browser issues
Video 79.1 Correct development of the endarterectomy plane and distal extension of the endarterectomy
such that the specimen releases under gentle tension
Once the patient’s core temperature has reached 18° to 20°C, both vena cavae are snared, an aortic
cross-clamp is applied to the ascending aorta, and cardioplegia is instilled via the aortic root. A
longitudinal arteriotomy is made along the anterior aspect of the right pulmonary artery between the aorta
and the superior vena cava. The incision should be carried distally in order to access the lower lobe
branch, just proximal to the takeoff of the middle lobe artery.55 Any gross, loose thrombotic material can
be removed at this stage; however, it must be emphasized and clearly understood that embolectomy alone
will not improve PVR in CTEPH patients, and a true endarterectomy must be performed.
As long as there is no excessive back bleeding, the endarterectomy is now begun. If such bleeding is
present, circulatory arrest should commence, as an unobstructed view during endarterectomy is required.
Identification of the correct endarterectomy plane is essential to a successful operation, and the initial
plane should be developed on the posterior surface of the pulmonary artery. This allows for the best
chance of repair if there is an injury. The correct plane is located between the intima and media and
appears pearly white and smooth. Easy stripping of the endarterectomy specimen layer further confirms
the correct plane. By contrast, a red to pink color suggests that the plane is in the adventitia and is too
deep.55 This risks potentially fatal perforation of the artery. However, equal care must be taken to avoid
too shallow a plane, as this will result in an inadequate endarterectomy and a poor hemodynamic result.
Once the correct plane is identified, it is developed circumferentially and extended into the
mediastinal and intermediary arteries and their branches. Normally, the initial opening of the arteries
leads to significant back bleeding that necessitates initiating deep hypothermic circulatory arrest in order
to provide a bloodless field and allow safe continuation of the endarterectomy into the lobar and
segmental arteries. Without circulatory arrest, progressive clearing of the arterial obstructions leads to
more significant back bleeding, which makes visualization impossible and increases the risk of arterial
injury. Once cardiopulmonary bypass is stopped and circulatory arrest is initiated, the endarterectomy
should be continued into each subsegmental artery individually until the specimen releases spontaneously
and there is no further distal obstruction.55 Carrying the endarterectomy to an appropriately distal extent is
important, as the length and number of PEA specimen tails have been shown to inversely correlate with
postoperative PVR.57 Once the right-sided endarterectomy is complete, cardiopulmonary bypass is
reinstituted and the arteriotomy closed with a running 6-0 polypropylene suture. With experience, a
complete, one-sided endarterectomy should be achievable in a single period of circulatory arrest lasting
less than 20 minutes.
After reperfusion of the patient for 15 minutes, attention is turned to the left side. An arciform
arteriotomy is made starting in the main pulmonary artery and extending into the left pulmonary artery to
the level of the pericardial reflection. No improvement in visibility is obtained with more lateral
dissection, and doing so makes repairing the arteriotomy more difficult and may risk the left phrenic
nerve.55 Endarterectomy of the left is performed according to the same guiding principles used on the
right, with circulatory arrest again instituted when back bleeding prevents perfect visualization. A
complete, bilateral endarterectomy must be the goal in all patients, and should be achievable with a total
circulatory arrest time of less than 55 minutes.38
As an addition to the standard technique initially developed at the University of California, San Diego,
Dartevelle and colleagues described the use of an angioscope during the endarterectomy.58 With the
angioscope, they reported improved illumination of the vessel lumen as well as visualization of the distal
arterial segments. Furthermore, the angioscope allowed the entire surgical team to view the procedure,
facilitating the work of assistant surgeons as well as surgical teaching.
FIGURE 79.5 Pulmonary endarterectomy specimen. Specimen shows appropriate distal extension with inclusion of intact tails
from each segmental and subsegmental artery.
Once the bilateral endarterectomy is completed, the specimen should be examined and the disease
classified according to the Jamieson system (Fig. 79.5). As proposed by Thistlethwaite and colleagues in
2002, patients are classified according to the location and type of disease. Specifically, type I is fresh
thrombus in the main to lobar arteries, type II is organized thrombus with intimal thickening proximal to
the segmental arteries, type III is intimal thickening and fibrosis in the distal segmental arteries, and type
IV is distal arteriolar vasculopathy with removal of the normal intimal layer and no intraluminal
disease.59 The type and location of disease, as described by this classification, is predictive of
postoperative outcome, with significantly higher perioperative survival, lower incidence of postoperative
complications, lower NYHA functional class, and shorter overall hospital length of stay in patients with
types I and II disease compared to those with types III and IV.59
With completion of the endarterectomy, cardiopulmonary bypass is again restarted and rewarming
begun while the left arteriotomy is closed. Keeping a 10°C gradient between the warmed perfusate and
body temperature, rewarming generally requires 90 to 120 minutes.55 During this period,
methylprednisolone and mannitol are administered and any other required procedures, such as patent
foramen ovale repair, coronary artery bypass grafting, or cardiac valve repair, are performed.
Importantly, while many CTEPH patients will have severe tricuspid valve regurgitation preoperatively,
tricuspid valve repair is rarely required unless there is evidence of damage to the valve itself. Significant
right ventricular remodeling occurs following successful PEA, and this usually ameliorates any
preoperative tricuspid insufficiency.47
After all procedures are completed, the heart is de-aired and the aortic cross-clamp removed.
Rewarming is allowed to finish, after which the patient is carefully weaned from cardiopulmonary
bypass, meticulous hemostasis is achieved, temporary atrial and ventricular pacing wires and drains are
placed, and the chest is closed.
Of note, there have been several reports of groups performing PEA under moderate hypothermia or
using alternative cannulation strategies that avoid deep hypothermic circulatory arrest or provide
selective cerebral perfusion.60–62 These attempts arose out of concern for the potentially negative
cognitive effects and other complications associated with deep hypothermic circulatory arrest. However,
the PEACOG (Circulatory Arrest Versus Cerebral Perfusion During Pulmonary Endarterectomy Surgery)
trial, a randomized study of 74 patients who underwent PEA with either deep hypothermic circulatory
arrest for periods of up to 20 minutes at 20°C or antegrade cerebral perfusion with a 1:1 ratio, found no
difference in cognitive function or rate of adverse events between the groups.63 In fact, cognitive function
improved in both groups, and nine patients crossed over from antegrade cerebral perfusion to deep
hypothermic circulatory arrest to allow for complete endarterectomy. Consequently, it is recommended
that PEA continue to be performed with deep hypothermic circulatory arrest in order to obtain the best
possible visualization during endarterectomy.
POSTOPERATIVE MANAGEMENT
Many of the postoperative challenges following PEA, including bleeding, pericardial effusion,
arrhythmias, atelectasis, delirium, and wound infection are similar to those encountered after general
cardiac surgery. However, PEA causes unique physiologic changes that can lead to specific management
challenges. Early postoperative care should focus on minimizing systemic oxygen consumption and
optimizing right heart function through appropriate preload and, if necessary, inotropic support. As
outlined by Mayer, postoperative patients usually fall into one of three general hemodynamic categories.64
Approximately 70% of patients will experience a profound decrease in mean pulmonary artery pressure
and PVR with an increase in cardiac output and systemic vasodilation. In this subset, postoperative
management is likely to be routine, although significant increases in cardiac output can result in
pulmonary overflow, so the cardiac output must be monitored and reduced if necessary. Roughly 20% of
patients will continue to have elevated pulmonary artery pressures but with the increased cardiac output
and systemic vasodilation seen in the first group. These patients are at increased risk for reperfusion
pulmonary edema and right heart failure and frequently require diuresis in addition to close monitoring of
their cardiac output. Finally, up to 10% of patients will have elevated pulmonary pressures and low
cardiac output with right heart failure and possible progression to multi-organ failure. In this critically ill
subset, intensive therapies including extracorporeal membrane oxygenation (ECMO) and/or continuous
venovenous hemodialysis may be required.64
All patients require life-long anticoagulation after PEA. This is begun with prophylactic dose
subcutaneous heparin as soon as possible on the day of surgery once it is clear there is no significant
postoperative bleeding.65 Patients at high risk for recurrent VTE, including those with lupus anticoagulant
or antiphospholipid antibody, should instead begin with full anticoagulation using intravenous
unfractionated heparin to a goal activated partial thromboplastin time (aPTT) at the lower end of the
therapeutic range. Otherwise, full anticoagulation, usually with a vitamin K antagonist to a goal INR of
2.0 to 3.0, should begin once the pacing wires and mediastinal drains are removed.65
Two unique physiologic changes can occur after PEA, both of which may significantly impact a
patient’s postoperative course. The most common is pulmonary artery steal or the redistribution of
pulmonary blood flow away from previously well-perfused areas and into the newly endarterectomized
vessels. This was originally reported by Olman and colleagues and occurs in up to 70% of patients
following PEA.66 As CTEPH preferentially affects the lower lobe arteries, steal causes disproportionate
perfusion of the lower lobes and can lead to hypoxemia from V/Q mismatch or venous admixture if care is
not taken to maintain proper lower lobe ventilation.65 Consequently, higher tidal volumes are often
required to maintain oxygenation in PEA patients. Positive end expiratory pressure (PEEP) can also be
increased if oxygenation remains problematic; however, peak inspiratory pressures should be kept below
30 mm Hg to avoid potential barotrauma.65
In up to 30% of patients, the postoperative period is marked by reperfusion pulmonary edema.67 Non-
cardiogenic in origin, reperfusion pulmonary edema usually develops in the lung areas impacted by PEA
during the initial 72 hours after surgery. The severity can vary widely, from mild hypoxemia to
hemorrhagic pulmonary edema and death. Treatment is largely supportive, consisting of mechanical
ventilation and supplemental oxygen. Several groups have published individual cases or small case series
reporting the use of inhaled nitric oxide to treat hypoxemia from reperfusion edema in an attempt to
redirect blood flow to well-ventilated alveoli and decrease V/Q mismatch.68–71 While the results are
encouraging, there are no data from large series or randomized studies to support its use.
The successful use of ECMO has also been reported in cases of severe postoperative reperfusion
pulmonary edema and right heart failure. Thistlethwaite and colleagues reported using venovenous ECMO
in 20 patients who developed respiratory failure from reperfusion pulmonary edema after PEA, with an
in-hospital survival of 30%.72 Berman and colleagues used venoarterial ECMO in seven PEA patients
with early postoperative cardiopulmonary failure, with five of these patients (71%) successfully weaned
from mechanical support.73 Despite limited published reports, ECMO represents a potentially life-saving
option for patients with severe cardiopulmonary compromise following PEA, and ECMO capability has
been recommended for all CTEPH centers.35
Rarely, weaning from cardiopulmonary bypass may be impossible in patients with severe persistent
postoperative pulmonary hypertension. In these situations, mechanical circulatory support provides a
potential bridge to either recovery or transplantation for highly selected patients. Venoarterial ECMO or a
centrally cannulated device, such as the Novalung, can allow a patient to be weaned from
cardiopulmonary bypass and transferred to the intensive care unit, where further evaluation for double
lung or heart–lung transplant listing can occur.74
Regardless of postoperative pulmonary artery pressure, significant hemodynamic instability can occur
following PEA. Successful stabilization largely depends on optimizing right ventricular function, as the
right ventricle in CTEPH patients is poorly compliant and heavily dependent on appropriate preload,
right atrial function, and heart rate in the postoperative period.65 The intraoperative placement of
temporary atrial and ventricular pacing wires allows for modulation of the heart rate and treatment of
specific arrhythmias. Left ventricular function may also be affected, as the interventricular septum returns
to its normal configuration after a significant decrease in right ventricular afterload. The initial
postoperative period is frequently marked by profound diuresis, and while this is physiologic and
generally advantageous, extreme diuresis can result in insufficient right or left ventricular preload and
systemic hypotension. Judicious fluid administration can restore appropriate preload in these cases.65
Despite the management challenges posed by hemodynamic instability and respiratory complications,
the postoperative course is usually similar to general cardiac surgery, and it is appropriate to aim for
extubation of stable patients on the first postoperative day. Accepted protocols for weaning mechanical
ventilation should be followed and extubation delayed until patients are fully awake and cooperative with
stable hemodynamics and an appropriate respiratory status. However, there is no reason to delay
extubation if these criteria are met. In fact, Fedullo and Jamieson report successful extubation in
approximately 50% of PEA patients on the first day following surgery, with a subsequent 30% to 40%
successfully extubated on postoperative day two.51,65 In their review of 1,500 cases, Jamieson and
colleagues report a median ICU stay of approximately 96 hours and a median overall hospital stay of 10
days.51
OUTCOMES FOLLOWING PULMONARY ENDARTERECTOMY

When performed at an experienced CTEPH center, current outcomes for PEA are excellent. The European
CTEPH registry reported a 4.7% in-hospital mortality rate for 386 patients who underwent PEA between
2007 and 2009, which is consistent with other recently published series.9 In a retrospective review of
500 PEA patients operated on between 2006 and 2010, Madani and colleagues reported an in-hospital
mortality of 2.2%.2 For patients operated on during 2006, Condliffe and colleagues reported an in-
hospital mortality of 5.4%.75 Importantly, published series show a significant learning curve for
successfully performing PEA. Both Madani and Condliffe show approximately 50% decreases in in-
hospital mortality between their early and most-recent cohorts.2,75
Long-term survival is also excellent, with death due to CTEPH occurring rarely after the early
postoperative period. Corsico et al. reported 4% CTEPH-related mortality at 4 years in patients who
survived to 3 months following surgery.76 In Condliffe and colleagues’ series, 1- and 3-year survival
were 88% and 76% for 236 patients treated with PEA, while Madani and colleagues reported 5- and 10-
year postoperative survival for 1,410 patients of 82% and 75%, respectively.2,75 Recurrence of CTEPH
after PEA is rare, with Mo and colleagues reporting a reoperation rate of 1.5% in their series of 870
patients. Importantly, 85% of patients undergoing reoperation had either a unilateral PEA as an initial
operation or insufficient postoperative anticoagulation, suggesting the postoperative recurrence rate
would be even lower with appropriate initial surgical and medical therapy.77
When successful, PEA has a profound impact on the postoperative hemodynamics of patients, with the
potential for near normalization of postoperative pulmonary artery pressure and PVR. However, 5% to
35% of patients have persistent pulmonary hypertension following surgery, most often due to either the
presence of surgically inaccessible distal disease unappreciated during preoperative evaluation or
irreversible arteriopathy.1,78–80 The wide range in estimated occurrence is likely due to differences in the
definition of persistent pulmonary hypertension between groups; however, despite these differences,
persistent pulmonary hypertension remains a common causes of postoperative death and negatively
impacts symptom and functional status following PEA.38,78 Patients with persistent postoperative
pulmonary hypertension present a management challenge and should be evaluated for medical therapy or
lung transplantation, depending on overall clinical status.
For the majority of PEA patients, hemodynamic improvements are immediate, and they can be
dramatic. In a retrospective review of 500 patients, Jamieson et al. reported a mean decrease in PVR
from approximately 890 to 285 dynes/s/cm−5 and mean pulmonary artery pressure from a mean of 46 to
28 mm Hg. Cardiac output increased from a mean of 2.8 to 5.5 L/min.51 Similar results have been
reported by multiple other groups.57,58,81,82 With these significant improvements in hemodynamics, the
right ventricle remodels following PEA. Echocardiographic studies demonstrate that the position of the
interventricular septum normalizes, right atrial and ventricular size decreases, and tricuspid regurgitation
decreases or resolves.83–85
Perhaps most importantly, patient functional status and quality of life improve following PEA. Reesink
and colleagues reported an increase in the 6-minute walk distance of 100 m in 35 PEA patients 1 year
following surgery.86 Archibald et al. found significant improvements in shortness of breath, NYHA class,
and scores on the Rand SF-36 quality of life metric, with 62% of preoperatively unemployed patients
able to return to work.87 Overall, while PEA is a highly complex procedure with potential for severe,
life-threatening complications, survival at experienced centers is excellent, and the operation offers
significant, and often immediate, improvements in hemodynamics that correspond with durable
improvements in patient symptoms, overall functional status, and quality of life.
LUNG TRANSPLANT
For patients who have severe, persistent pulmonary hypertension following surgery or who are not
candidates for PEA due to distal disease, lung or heart–lung transplantation is the final surgical option.74
Evaluation for transplantation in CTEPH is generally similar to PAH, with double lung transplant or
heart–lung transplant the procedure of choice.53 To date, there have been no studies that specifically
examine lung or heart–lung transplantation in CTEPH; however, some series that report results following
transplantation for multiple types of pulmonary hypertension include CTEPH patients. Fadel and
colleagues reported on 219 patients undergoing double lung or heart–lung transplant for pulmonary
hypertension, of which 21 had CTEPH.88 Of these patients, 11 underwent heart–lung transplantation and
10 received a double lung transplant. Overall survival for the CTEPH patients was 76% at 1 year and
57% at 5 years, with no difference in survival between the heart–lung and double lung transplant groups.
There is currently no evidence to suggest that CTEPH patients fare worse than other pulmonary
hypertension patients following either lung or heart–lung transplantation; however, postoperative
mortality is higher for patients with pulmonary hypertension as compared to other lung diseases. Due to
the scarcity of available donor organs, high postoperative mortality, and risks associated with life-long
immunosuppression, transplantation should only be considered as a last resort for CTEPH patients.
BALLOON PULMONARY ANGIOPLASTY

While first reported by Feinstein et al. in 2001, there has been renewed interest in balloon pulmonary
angioplasty (BPA) as a therapeutic option for CTEPH patients. In this approach, standard balloon
angioplasty techniques are utilized to open segmental and subsegmental pulmonary arteries. Early results
have been encouraging. In their initial series, Feinstein and colleagues reported outcomes from 18
patients with either surgically inaccessible disease or severe medical comorbidities that precluded
PEA.89 Patients underwent a median of three catheterizations with 2.3 dilations per catheterization. At a
mean follow-up of 34 months, survival was 89% with a decrease in mean pulmonary artery pressure from
42 to 33 mm Hg and total pulmonary resistance from 22 to 17 Wood unit/m−2. The average NYHA class
improved from 3.3 to 1.8 and mean 6-minute walk distance increased from approximately 191 to 454 m.89
However, 11 patients (61%) developed reperfusion pulmonary edema, with three requiring mechanical
ventilation.89
In subsequent series in both Japan and Europe, multiple groups reported success with BPA. In the
largest series, Mizoguchi et al. reported results from 68 patients with inoperable CTEPH, with 97%
survival at 2 years and a decrease in PVR and mean pulmonary artery pressure from 942 to 326
dynes/s/cm−5 and 45 to 24 mm Hg, respectively.90 Mean World Health Organization (WHO) functional
class improved from three to two.90 In a report of 20 patients with inoperable CTEPH or persistent post-
PEA pulmonary hypertension, Andreassen and colleagues also showed significant hemodynamic and
functional improvement after BPA.91 Mean pulmonary artery pressure decreased from 45 to 33 mm Hg,
PVR decreased from 8.8 to 5.9 Wood units, and cardiac output increased from 4.9 to 5.4 L/min, with an
improvement in NYHA class from an average of class three to class two symptoms. Overall survival was
85% at an average follow-up of 4.25 years.91 However, peri-procedural death was 10%, and 35% of
patients developed reperfusion pulmonary edema.91
Taken together, results from early BPA series are encouraging and suggest significant potential.
However, the procedure is not without risk given the requirement for multiple interventions and reports of
serious adverse events, including both pulmonary hemorrhage and significant rates of reperfusion
pulmonary edema. The long-term durability of BPA is also not yet fully defined. Consequently, further
study is required to determine the appropriate clinical application of BPA, and until such studies are
performed, it should not be considered an alternative to PEA.35
MEDICAL THERAPY
It must be emphasized that CTEPH is currently a surgical disease. All patients should undergo evaluation
for PEA at an expert center prior to any treatment decisions, as PEA is the only potentially curative
therapy. However, despite advances that have made PEA available to more CTEPH patients, significant
percentages remain inoperable, choose to forego surgery, or have persistent pulmonary hypertension
following surgery. In the European CTEPH registry, 31% of patients referred to CTEPH centers were
deemed inoperable and 17% had persistent postoperative pulmonary hypertension.9 In these cases, it is
appropriate to consider medical therapy. The goal of medical therapy in CTEPH is to utilize pulmonary
vasodilators and remodeling agents to reduce both pulmonary artery pressure and PVR in order to
improve patients’ functional status and quality of life. However, the benefits of medical therapy are small
compared to successful PEA, and medical therapy is not curative.
Medical therapy for CTEPH involves the use of medications initially developed to treat PAH, and this
rationale is based on the observation that patients can have significant distal arteriopathy. Distal
arteriopathy in CTEPH is similar to that seen in PAH, and it is a common cause of patients being declared
inoperable. There is a well-established literature supporting the safety and efficacy of prostacyclin
analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors in treating PAH, and
consequently they have been applied to CTEPH.92
To date, there have been two large, randomized trials of medical therapy for CTEPH. The first was the
BENEFIT trial (bosentan effects in inoperable forms of CTEPH).93 BENEFIT was a double-blind,
randomized, placebo-controlled study involving 157 CTEPH patients who were either inoperable or had
persistent postoperative pulmonary hypertension more than 6 months following PEA. Patients were
randomized to receive bosentan, an endothelin receptor antagonist, or placebo for 16 weeks. The primary
end points were percent change in PVR from baseline and change in 6-minute walk distance.93 One
primary endpoint was achieved in the study, with a 24% decrease in PVR seen in patients treated with
bosentan versus placebo. Several hemodynamic metrics also improved, including total pulmonary
resistance and cardiac index; however, no significant difference in 6-minute walk distance was found
between the two groups.93 Subsequent studies generally corroborate these findings, with a systematic
review of 10 smaller, observational studies plus BENEFIT by Becattini and colleagues reporting that
patients with CTEPH treated with bosentan had increases in 6-minute walk distance and cardiac index
and a decrease in pulmonary artery pressure, after 3 to 6 months.94
The second large, randomized trial was the CHEST-1 study published in 2013.95 CHEST-1 was a
phase 3, multicenter, randomized, double-blind, placebo-controlled trial of riociguat, a soluble guanylate
cyclase stimulator, in 261 patients with inoperable CTEPH or persistent pulmonary hypertension
following PEA. After 16 weeks of therapy, the primary endpoint of change in 6-minute walk distance was
met, as patients treated with riociguat had a statistically significant increase of 39 m in mean 6-minute
walk distance compared to patients receiving placebo, whose distance decreased by an average of 6 m.
PVR, N-terminal pro-brain natriuretic peptide levels, and WHO functional class also improved
significantly in the treatment group compared to placebo. Minimal adverse effects were noted, with 3% of
patients developing right heart failure and 2% to 3% experiencing syncope in both the placebo and
treatment groups.96 CHEST-2, a follow-up study with long-term extension of riociguat treatment to 1-year
reported similar efficacy and safety results.95 Riociguat is currently approved to increase exercise
tolerance in patients with inoperable CTEPH or persistent post-PEA pulmonary hypertension in the
United States and Europe.
Aside from BENEFIT and CHEST, there are no other large, randomized trials examining medical
treatment for CTEPH. Suntharalingam and colleagues performed a randomized, double-blind, placebo-
controlled trial of sildenafil in 19 patients with inoperable CTEPH.97 After 12 weeks of treatment, no
significant difference was seen in the primary endpoint of 6-minute walk distance, but there were
statistically significant improvements in PVR and WHO functional class. The study was extended to 1
year in an open-label format, after which significant improvements were seen in 6-minute walk distance,
hemodynamics, and both activity- and symptom-related quality of life.97 While the study was
underpowered to assess the primary endpoint and only demonstrated significant functional improvements
after an open-label period, it is consistent with results from other, nonrandomized studies of
sildenafil.98,99
Additionally, several smaller studies and series have been performed examining the use of prostanoids
in CTEPH. Cabrol and colleagues retrospectively reviewed 27 patients with inoperable CTEPH treated
with intravenous epoprostenol and found significant improvements in 6-minute walk distance, NYHA
functional class, and mean pulmonary artery pressure after a mean treatment period of 20 months.100 An
uncontrolled trial of subcutaneous treprostinil by Skoro-Sajer et al. in 25 patients with inoperable
CTEPH also showed significant improvement in 6-minute walk distance, WHO class, and hemodynamics
after a mean period of 19 months.101 Finally, inhaled iloprost has been shown to improve hemodynamics
and functional status in CTEPH. While these results are encouraging, the studies are, unfortunately, either
nonrandomized, involve combination therapy with other pulmonary hypertension medications, or include
PAH patients.102–105
There are currently no specific guidelines or protocols for determining appropriate medical therapy in
inoperable patients or those with persistent postoperative pulmonary hypertension. Given the evidence,
however, it is appropriate to offer such patients medical therapy. The most recent guidelines from the
American College of Cardiology Foundation Task Force, American Heart Association, European Society
of Cardiology, and European Respiratory Society do not address specific strategies of medical treatment
in CTEPH, but the European guidelines do recommend medical therapy for patients who are not surgical
candidates or those with persistent postoperative pulmonary hyperetension.106,107 Notably, these
guidelines were published prior to the CHEST-1 and CHEST-2 trials.
The fact that a high preoperative PVR is associated with increased postoperative mortality has led
some to begin medical therapy preoperatively in an attempt to reduce the PVR, and such use of PAH
medications prior to PEA is increasing. Jensen and colleagues reported an increase in PEA patients
receiving preoperative medical therapy from 19.9% in 2005 to 37% in 2007, and the European CTEPH
registry reported 28.3% of operative patients receiving at least one PAH medication at the time of
surgery.9,108 While there is now evidence from randomized trials that supports specific medical therapy
for inoperable CTEPH or persistent postoperative pulmonary hypertension, no such evidence exists for
this use of medical therapy as a bridge to PEA. Nagaya and colleagues reviewed 12 patients with a PVR
greater than 1,200 dynes/s/cm−5 treated with intravenous prostacyclin prior to PEA and found treatment
significantly decreased PVR.109 Bresser and colleagues retrospectively analyzed nine patients treated
with continuous intravenous epoprostenol and also found improvement in PVR by an average of 28%;
however, three patients experienced clinical deterioration despite therapy.110 Lastly, in an investigator-
initiated, randomized, controlled, single-blind study, Reesink and colleagues found that 16 weeks of
bosentan treatment prior to PEA significantly increased 6-minute walk distance and cardiac index and
reduced PVR and mean pulmonary artery pressure.111
While these studies reported improvements in preoperative hemodynamics, none showed improved
postoperative outcomes in patients who were medically treated prior to surgery. In fact, in a retrospective
review of 355 patients referred for PEA, Jensen et al. found no difference in postoperative hemodynamics
or numerous patient outcome measures, including mortality, reperfusion lung injury, or length of ICU or
hospital stay, between patients who were or were not medically treated with bosentan, sildenafil,
epoprostenol, or combination therapy prior to surgery.108 However, they found that preoperative medical
therapy nearly doubled the time between diagnosis and surgical referral from approximately 4 to 9
months.108 Given the vital importance of timely surgical referral and absence of high-quality data
demonstrating convincing benefit, there is currently insufficient evidence to support routine preoperative
medical therapy, and it may in fact be harmful.
There are have been no studies of medical therapy in patients with surgically accessible disease who
are deemed inoperable due to comorbidities or refuse surgery, and as these patients are specifically
excluded from most clinical trials, it is inappropriate to extrapolate potential effects. However, as the
general biologic mechanisms of CTEPH hold true in these patients, and PAH medications are generally
well tolerated, such patients are often treated despite the lack of evidence.20
SUMMARY
In a small subset of patients, venous thromboembolic disease transforms into a chronic state of thrombus
fibrosis and pulmonary arterial remodeling that progressively obstructs the pulmonary arteries. This
pathologic process leads to CTEPH and eventually lethal right heart failure. The precise mechanisms
underlying this transition are unknown and being investigated. Currently, the only potentially curative
therapy is PEA. While complex, PEA performed at an experienced center results in excellent
postoperative survival and profound improvement in patients’ hemodynamics, functional status, and
overall quality of life. Consequently, it remains the standard of care. The experimental use of medications
developed for PAH has shown promise in those patients who are not candidates for surgery or have
persistent postoperative pulmonary hypertension; however, current evidence does not support their
preoperative use in surgical patients. BPA is another developing option for nonsurgical patients. Despite
these advances, however, surgical PEA remains the treatment of choice for CTEPH, and all patients
should be evaluated for surgery at an expert center before any alternative treatment decisions are made.
REFERENCES
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2. Madani MM, Auger WR, Pretorius V, et al. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than
2,700 patients. Ann Thorac Surg 2012;94(1):97–103.
3. Pepke-Zaba J, Jansa P, Kim NH, et al. Chronic thromboembolic pulmonary hypertension: role of medical therapy. Eur Respir J
2013;41(4):985–990.
4. Wolf M, Boyer-Neumann C, Parent F, et al. Thrombotic risk factors in pulmonary hypertension. Eur Respir J 2000;15(2):395–399.
5. Bonderman D, Jakowitsch J, Adlbrecht C, et al. Medical conditions increasing the risk of chronic thromboembolic pulmonary
hypertension. Thromb Haemost 2005;93(3):512–516.
6. Lang IM. Chronic thromboembolic pulmonary Hypertension—not so rare after all. N Engl J Med 2004;350(22):2236–2238.
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2009;33(2):325–331.
8. Condliffe R, Kiely DG, Gibbs JSR, et al. Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension. Eur
Respir J 2009;33(2):332–338.
9. Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH) results from an international
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venous thrombi. J Vasc Surg 1999;30(5):894–900.
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20. Hoeper MM, Madani MM, Nakanishi N, et al. Chronic thromboembo

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Volume

One & Two

Yolonda L. Colson, MD, PhD

Gaetano Rocco, MD, FRCSEd

Copyright © 2019 Wolters Kluwer.

Printed in The United States of America

Library of Congress Cataloging-in-Publication Data

Dedication to Dr. Carolyn E. Reed, MD

To my family and to all succeeding generations of knowledge-seeking, innovative healers around

PART A Evolution of General Thoracic Surgery

PART B The Lung, Pleura, Diaphragm, and Chest Wall

PART C The Esophagus

PART D The Mediastinum

EVOLUTION OF GENERAL THORACIC

HISTORY AND PIONEERS IN

“Let me repeat what history teaches, history teaches.”

BRONCHOSCOPY AND BRONCHOGRAPHY

CONTROL OF THE PLEURAL SPACE

FURTHER PROGRESS WITH VENTILATION AND ANESTHESIA

DRAINAGE OF LUNG CAVITIES AND ABSCESSES

EVARTS GRAHAM AND THE US ARMY EMPYEMA COMMISSION

PERMANENT OPEN DRAIN

TABLE 1.1 Variations of Collapse Therapy and Terminology Used

CARLO FORLANINI AND PNEUMOTHORAX THERAPY

JACOBEUS AND PNEUMOLYSIS

JOHN ALEXANDER AND THORACOPLASTY

TABLE 1.2 Variations of Thoracoplasty (Main Proponents)

EXTRAPLEURAL APICAL PROCEDURES

UNUSUAL OPERATIONS UNDERTAKEN IN AN EFFORT TO CONTROL

TABLE 1.3 Concerns Regarding Pulmonary Resection

ENTRY INTO THE CHEST

LIGATION OF PULMONARY ARTERIES

AVOIDANCE OF SPREAD TO THE CONTRALATERAL LUNG

HOW TO CLOSE THE BRONCHIAL STUMP

HOW TO SEAL THE RAW SURFACE OF THE LUNG

WHAT WILL HAPPEN TO THE SPACE PREVIOUSLY OCCUPIED BY LUNG

EVOLUTION OF SURGICAL PROCEDURES AND THE EXTENT OF SURGERY

CONGENITAL ESOPHAGEAL ATRESIA

HIATAL HERNIA SURGERY

DEVELOPMENT OF POSITIVE PRESSURE VENTILATION

THORACIC SURGERY FOR TUBERCULOSIS

COLLAPSE THERAPY FOR TUBERCULOSIS

TECHNIQUES OF EARLY PULMONARY RESECTIONS

LOBECTOMY VS. PNEUMONECTOMY

HISTOLOGIC CLASSIFICATION OF PULMONARY CARCINOMA

THE TNM STAGING SYSTEM

ASSESSING PERIOPERATIVE RISK FACTORS

SIGNIFICANT ANESTHESIA DEVELOPMENTS AFFECTING THORACIC

DEVELOPMENT OF ENDOBRONCHIAL BLOCKING DEVICES

DOUBLE LUMEN ENDOTRACHEAL TUBES

VATS ANATOMIC LUNG RESECTIONS

THE LUNG, PLEURA, DIAPHRAGM,

STRUCTURE AND FUNCTION OF THE

SURFACE ANATOMY OF THE THORAX

FIGURE 4.3 Surface relations of pleura and lungs (lateral view).

SUPERFICIAL CHEST WALL MUSCULATURE

THE THORACIC SKELETON

FIGURE 4.7 Typical rib. A: Inferior view. B: Superior view.

THE INTERCOSTAL SPACE

Shield's General Thoracic Surgery

Shield's General Thoracic Surgery

Shield's General Thoracic Surgery