Surgical Management of Hepatobiliary

Poston • D’Angelica • Adam

With a Foreword by
and Pancreatic Disorders Yuji Nimura, MD, President
of the Aichi Cancer Center,
Japan, and Past President
Second Edition of the IHPBA
Edited by Graeme J. Poston, Michael D’Angelica, and René Adam This book

Surgical
demonstrates the
About the book
wisdom of the
Hepato-Pancreato-Biliary (HPB) surgery is now firmly established within the repertoire
of modern general surgery. This new edition has been completely rewritten by
new knowledge

Management of
world-leading surgeons to reflect the considerable advances made in the surgical and technical skills
management of HPB disorders since the highly successful first edition.
of these diverse
This new edition includes: disciplines where

Hepatobiliary
• An in-depth coverage of benign and malignant disorders of the liver, pancreas, and cooperative efforts

and Pancreatic Disorders

Surgical Management of Hepatobiliary
bile ducts and gallbladder
• A comprehensive section on anatomy, imaging, and surgical technique
contribute toward
• Over 20 new chapters, including a complete account of pediatric HPB disorders the benefit of the
• Almost 300 high-resolution images, many in full color patients with HPB

and Pancreatic
Surgical Management of Hepatobiliary and Pancreatic Disorders, Second Edition, disorders.
comprehensively covers the full spectrum of common HPB diseases and associated
surgical techniques to assist not only the general surgeon in regular practice,
but also surgical trainees and those in related specialties of oncology, radiology, Also Available
gastroenterology, and anesthesia.
Hepatocellular Carcinoma:
A Practical Approach

Disorders
About the Editors Edited by Bandar Al Knawy, K. Rajendra Reddy
and Luigi Bolondi
Graeme j. Poston, MS, FRCS (Eng), FRCS (Ed), is Director of Surgery and Hepatobiliary ISBN: 9780415480802
Surgeon, University Hospital Aintree, Liverpool, UK. He is the President of the Association e-ISBN: 9780203092880
of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS), President-
Elect of the European Society of Surgical Oncology (ESSO), Past President of the British Improved Outcomes in Colon
Association of Surgical Oncology (BASO), and author of numerous publications and and Rectal Surgery
national/international guidelines relating to the practice of HPB surgery. Edited by Charles B. Whitlow, David E. Beck, David A.
Margolin, Terry C. Hicks and Alan E. Timmcke

Second Edition
Michael D’Angelica, MD, is an Associate Attending at Memorial Sloan-Kettering ISBN: 9781420071528
Cancer Center and an Associate Professor at Cornell University/Weill Medical Center. e-ISBN: 9781420071535
He is currently the Program Chairman of the American Hepato-Pancreato-Biliary
Association and a writing member of the National Comprehensive Cancer Network Textbook of Surgical Oncology
(NCCN) practice guidelines for hepatobiliary malignancy. Edited by Graeme J. Poston, R. Daniel Beauchamp,
and Theo J. M. Rogers
René Adam, MD, PHD, is Hepatobiliary Surgeon and Professor of Surgery, Hôpital Paul ISBN: 9781841845074
Brousse, Université Paris-Sud, Villejuif, France. e-ISBN: 9780203003220

Second
Edition
Edited by
Graeme J. Poston
Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK Michael D’Angelica
52 Vanderbilt Avenue, New York, NY 10017, USA

www.informahealthcare.com René Adam

Surgical Management of Hepatobiliary
and Pancreatic Disorders
Surgical Management of Hepatobiliary
and Pancreatic Disorders
Second Edition

Edited by
Graeme J. Poston MS, FRCS (ENG), FRCS (ED)
Centre for Digestive Diseases
University Hospital Aintree
and
Department of Surgery
The Royal Liverpool University Hospitals
Liverpool, UK

Michael D’Angelica MD
Weill Medical College of Cornell University
and
Memorial Sloan-Kettering Cancer Center
New York, New York, USA

and

René Adam MD, PHD

AP-HP Hôpital Paul Brousse
Centre Hépato-Biliaire
Villejuif, France
First published in 2003 by M. Dunitz Ltd, United Kingdom
This edition published in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK.

Simultaneously published in the USA by Informa Healthcare, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017, USA.

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Contents

List of contributors vii 16 Management of neuroendocrine tumor

Foreword x hepatic metastasis 154
Preface xi Kaori Ito

17 Noncolorectal, nonneuroendocrine metastases 166

I ANATOMY/IMAGING/SURGICAL TECHNIQUE C. Kahlert, R. DeMatteo, and J. Weitz
1 Surgical anatomy of the liver and bile ducts 1 18 Chemotherapy-associated hepatotoxicity 173
Robert Jones and Graeme J. Poston Martin Palavecino, Daria Zorzi,
2 Anatomy of the pancreas 17 and Jean-Nicolas Vauthey
Margo Shoup and Jason W. Smith 19 Thermal ablation of liver metastases 180
Samir Pathak and Graeme J. Poston
3 Hepatic resection 24
Ajay V. Maker and Michael D’Angelica
ii. Primary
4 Ultrasound for HPB disorders 36
Duan Li and Lucy Hann 20 Resection for hepatocellular carcinoma 192
Rajesh Satchidanand, Stephen W. Fenwick,
5 Liver surgery in elderly patients 46 and Hassan Z. Malik
Gerardo Sarno and Graeme J. Poston
21 Treatment of laparoscopically discovered
6 Small solitary hepatic metastases: when and how? 53 gallbladder cancer 197
David L. Bartlett and Yuman Fong Jason K. Sicklick, David L. Bartlett, and Yuman Fong
7 Managing complications of hepatectomy 63 22 Liver transplantation for HCC: Asian perspectives 208
Fenella K. S. Welsh, Timothy G. John, and Myrddin Rees Shin Hwang, Sung-Gyu Lee, Vanessa de Villa,
and Chung Mao Lo
8 Pancreatic resection 73
Thilo Hackert, Moritz Wente, and Markus W. Büchler 23 Non-surgical treatment of hepatocellular
carcinoma 216
9 Surgical complications of pancreatectomy 81 Ghassan K. Abou-Alfa and Karen T. Brown
Steven C. Katz and Murray F. Brennan
24 Resection of intrahepatic cholangiocarcinoma 223
10 Laparoscopy in HPB surgery 89 Junichi Arita, Norihiro Kokudo, and Masatoshi Makuuchi
Nicholas O’Rourke and Richard Bryant
25 Transplantation for hilar cholangiocarcinoma 229
11 Cross-sectional imaging for HPB disorders Julie K. Heimbach, Charles B. Rosen,
(MRI and CT) 100 and David M. Nagorney
Lawrence H. Schwartz
26 Rare vascular liver tumors 233
II LIVER Jan P. Lerut, Eliano Bonaccorsi-Riani,
Giuseppe Orlando, Vincent Karam, René Adam,
A. Malignant and the ELITA-ELTR Registry

i. Metastases
12 Liver metastases: detection and imaging 109 B. Benign
Valérie Vilgrain, Ludovic Trinquart, and Bernard Van Beers 27 Management of recurrent pyogenic cholangitis 242
13 Surgery for metastatic colorectal cancer 118 W. Y. Lau and C. K. Leow
René Adam and E. Hoti 28 Liver abscess: amebic, pyogenic, and fungal 253
14 Chemotherapy for metastatic colorectal cancer 135 Purvi Y. Parikh and Henry A. Pitt
Derek G. Power and Nancy E. Kemeny 29 Benign solid tumors of the adult liver 261
15 Multimodal approaches to the management Mark Duxbury and O. James Garden
of colorectal liver metastases 148 30 Liver trauma 271
Gerardo Sarno and Graeme J. Poston Timothy G. John, Myrddin Rees, and Fenella K. Welsh

v
 CONTENTS

31 Portal hypertension 280 IV PANCREAS

Michael D. Johnson and J. Michael Henderson
A. Malignant
32 Liver transplantation for acute and chronic 42 Adenocarcinoma of the pancreas 380
liver failure 288
André L. Mihaljevic, Jörg Kleeff, and Helmut Friess
Vincent Kah Hume Wong and J. Peter A. Lodge
43 Palliation of pancreas cancer 401
33 Benign cystic disease of the liver 301
Michael G. House and Keith D. Lillemoe
Stephen W. Fenwick and Dowmitra Dasgupta
44 Cystic tumors of the pancreas 407
34 Management of hydatid disease of the liver 308
Peter J. Allen and Murray F. Brennan
Adriano Tocchi
45 Neuroendocrine pancreatic tumors 414
35 Surgical management of primary sclerosing
Stephen N. Hochwald and Kevin Conlon
cholangitis 324
Jason A. Breaux and Steven A. Ahrendt 46 Rare tumors of the pancreas 432
Jooyeun Chung, Lisa J. Harris, Hamid Abdollahi,
and Charles J. Yeo
III BILE DUCTS AND GALLBLADDER
A. Malignant B. Benign
36 Management of advanced gallbladder cancer 329 47 Acute pancreatitis 439
Hiromichi Ito and William R. Jarnagin
C. Ross Carter, A. Peter Wysocki, and Colin J. McKay
37 Extrahepatic cholangiocarcinoma 333 48 Chronic pancreatitis 451
Yuji Nimura
Jakob R. Izbicki, Oliver Mann, Asad Kutup,
38 Endoscopic management of malignant and Kai A. Bachmann
biliary obstruction 343 49 Pancreatic injury 463
Nick Stern and Richard Sturgess Demetrios Demetriades, Beat Schnüriger,
and Galinos Barmparas
B. Benign
50 Pancreas transplantation 470
39 Choledochal cyst detected in adulthood 354 Khalid Khawaja
Bilal Al-Sarireh and Hassan Malik

40 Bile duct injuries and benign biliary strictures 360

V PEDIATRIC HPB DISORDERS
Steven M. Strasberg
51 Pediatric HPB disorders 478
41 Gallstones and common bile duct
Maureen McEvoy and Michael P. La Quaglia
stones—surgical and non-surgical approaches 373
Matthew P. Dearing and Michael Rhodes Index 489

vi
List of contributors
Ghassan K. Abou-Alfa MD
Assistant Attending, Memorial Sloan-Kettering Cancer Center, and
Assistant Professor, Weill Medical College at Cornell University,
New York, New York, USA
Hamid Abdollahi MD
Senior Resident (General Surgery), Department of Surgery, Thomas
Jefferson University, Philadelphia, Pennsylvania, USA
René Adam MD, PhD
AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm,
Unité 785, and Université Paris-Sud, UMR-S 785, Villejuif, France
Steven A. Ahrendt MD
Associate Professor of Surgery, University of Pittsburgh
Medical Center, UPMC Passavant Cancer Center, Pittsburgh,
Pennsylvania, USA
Peter J. Allen MD
Department of Surgery, Memorial Sloan-Kettering Cancer Center,
New York, New York, USA
Bilal Al-Sarireh MBBCh, FRS, PhD
Consultant Hepatopancreatobiliary and Laparoscopic Surgeon,
Swansea University, and Department of Surgery, Morristown Hospital,
Swansea, UK
Junichi Arita MD, PhD
Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and
Transplantation Division, Department of Surgery, Graduate School of
Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Kai A. Bachmann
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
Galinos Barmparas
Division of Trauma and Surgical Critical Care, University of Southern
California, Los Angeles, California, USA
David L. Bartlett
Department of Surgery, University of Pittsburgh, Pittsburgh,
Pennsylvania, and National Cancer Institute, National Institutes
of Health, Bethesda, Maryland, USA
Eliano Bonaccorsi-Riani
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires
St Luc Université catholique de Louvain, Department of Abdominal
and Transplantation Surgery, Brussels, Belgium
Jason A. Breaux MD
Surgical Oncology Fellow, University of Pittsburgh Medical Center,
UPMC Cancer Pavilion, Pittsburgh, Pennsylvania, USA
Murray F. Brennan
Benno C. Schmidt Clinical Chair in Oncology, Department of Surgery,
Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Karen T. Brown MD
Attending Radiologist, Memorial Sloan-Kettering Cancer Center, and
Professor of Clinical Radiology, Weill Medical College at Cornell
University, New York, New York, USA
Richard Bryant MBBS, FRACS
Royal Brisbane Hospital, Brisbane, Queensland, Australia
Markus W. Büchler
Department of General Surgery, University of Heidelberg, Heidelberg,
Germany
C. Ross Carter
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow,
Scotland, UK
Jooyeun Chung MD
Department of Surgery, The Methodist Hospital, Houston, Texas, USA
Kevin Conlon
Professor of Surgery, University of Dublin, Trinity College Dublin, and
Professorial Surgical Unit, Education Centre, AMNCH, Dublin,
Ireland
Michael D’Angelica MD
Weill Medical College of Cornell University and Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Dowmitra Dasgupta MD, FRCS
Consultant Hepato-Pancreatico-Biliary Surgeon, Department of Upper
GI Surgery, Castle Hill Hospital, Cottingham, UK
Matthew P. Dearing
Department of Surgery, Norfolk & Norwich University Hospital,
Norwich, UK
R. DeMatteo
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New
York, New York, USA
Demetrios Demetriades
Division of Trauma and Surgical Critical Care, University of Southern
California, Los Angeles, California, USA
Mark Duxbury
Clinical Surgery, University of Edinburgh Royal Infirmary,
Edinburgh, UK
Stephen W. Fenwick MD, FRCS
Consultant Hepatobiliary Surgeon, North Western Hepatobiliary Unit,
University Hospital Aintree, Lower Lane, Liverpool, UK
Yuman Fong MD
Hepatobiliary Service, Department of Surgery, Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Helmut Friess
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar,
Technische Universität München, Munich, Germany
O. James Garden
Regius Professor of Clinical Surgery, Clinical and Surgical Sciences
(Surgery), University of Edinburgh, Royal Infirmary, Edinburgh, UK
Thilo Hackert
Department of Surgery, University of Heidelberg, Heidelberg, Germany
Lisa J. Harris MD
Senior Resident (General Surgery), Department of Surgery, Thomas
Jefferson University, Philadelphia, Pennsylvania, USA
J. Michael Henderson
Chief Quality Officer, Cleveland Clinic, Cleveland, Ohio, USA
Stephen N. Hochwald MD
Chief, Division of Surgical Oncology, University of Florida, Gainesville,
Florida, USA
Michael G. House MD
Assistant Professor, Department of Surgery, Indiana University School
of Medicine, Indianapolis, Indiana, USA
vii
 LIST OF CONTRIBUTORS

Lucy Hann MD W. Y. Lau

Professor of Radiology, Weill Cornell Medical Center, and Director of
Ultrasound Memorial Sloan-Kettering Cancer Center, New York,
New York, USA
Julie K. Heimbach
Mayo Clinic, Rochester, Minnesota, USA
Steven N. Hochwald
University of Florida Medical School, Box 100286, Gainesville,
FL 32610–0286, USA
E. Hoti
AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France,
and Liver Transplant Unit, Saint Vincent’s University Hospital,
Dublin, Ireland
Shin Hwang
Professor, Division of Hepatobiliary Surgery and Liver
Transplantation, Department of Surgery, University of Ulsan College
of Medicine, Seoul, Korea
Hiromichi Ito MD
Department of Surgery, Michigan State University,
Lansing, Michigan, USA
Kaori Ito MD
Department of Surgery, Michigan State University, Lansing, Michigan,
USA
Jakob R. Izbicki FACS
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
William R. Jarnagin MD
Hepatobiliary Service, Department of Surgery, Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Timothy G. John MD, FRCSEd (Gen)
Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS
Foundation Trust, Basingstoke, UK
Michael D. Johnson MD
Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
Robert Jones MB, ChB, MRCS
Clinical Fellow, North Western Hepatobiliary Centre, Aintree
University Hospital, Liverpool, UK
C. Kahlert
Department of Surgery, University of Heidelberg, Heidelberg, Germany
Vincent Karam
Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France
Steven C. Katz MD
Director of Surgical Immunotherapy, Roger Williams Medical Center,
Providence, Rhode Island, USA
Khalid Khwaja MD
Director of Kidney and Pancreas Transplantation, Senior
Staff Surgeon, Lahey Clinic, Burlington, Massachusetts, USA
Nancy E. Kemeny MD
Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Jörg Kleeff
Department of Surgery, Klinikum rechts der Isar, Technische
Universität München, Munich, Germany
Norihiro Kokudo MD, PhD
Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and
Transplantation Division, Department of Surgery, Graduate School of
Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Asad Kutup
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
Faculty of Medicine, The Chinese University of Hong Kong, Prince of
Wales Hospital, Shatin, New Territories, Hong Kong, SAR
C. K. Leow
Mount Elizabeth Medical Centre, Singapore, Singapore
Keith D. Lillemoe MD
Jay L. Grosfeld Professor and Chairman, Department of Surgery,
Indiana University School of Medicine, Indianapolis, Indiana, USA
Sung-Gyu Lee
Professor, Division of Hepatobiliary Surgery and Liver Transplanta-
tion, Department of Surgery, University of Ulsan College of Medicine,
Seoul, Korea
Michael P. La Quaglia MD
Department of Surgery, Pediatric Surgery Service, Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Jan P. Lerut MD, PhD, FACS
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires
St Luc Université catholique de Louvain, Department of Abdominal
and Transplantation Surgery, Brussels, Belgium
Duan Li MD
Assistant Attending Radiologist, Memorial Sloan-Kettering Cancer
Center, New York, New York, USA
Chung Mao Lo
Professor, Department of Surgery, Queen Mary Hospital,
The University of Hong Kong, Hong Kong, China
J. Peter A. Lodge MD, FRCS
Professor and Clinical Director, HPB & Transplant Unit, St. James’
University Hospital, Leeds, UK
Ajay V. Maker MD
Director of Surgical Oncology, Creticos Cancer Center–Advocate
Illinois Masonic Medical Center; Departments of Surgery and
Microbiology/Immunology, University of Illinois at Chicago, Chicago,
Illinois, USA
Masatoshi Makuuchi MD, PhD
Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and
Transplantation Division, Department of Surgery, Graduate School of
Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Hassan Malik MD, FRCS
Hepatobiliary Unit, Department of Surgery, University Hospital
Aintree, Liverpool, UK
Oliver Mann
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
Maureen McEvoy MD
Department of Surgery, Pediatric Surgery Service, Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Colin J. McKay
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow,
Scotland, UK
André L. Mihaljevic
Department of Surgery, Klinikum rechts der Isar, Technische
Universität München, Munich, Germany
David M. Nagorney
Mayo Clinic, Rochester, Minnesota, USA
Yuji Nimura MD
President, Aichi Cancer Center, Chikusaku, Nagoya, Japan
Giuseppe Orlando
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St
Luc Université catholique de Louvain, Department of Abdominal and
Transplantation Surgery, Brussels, Belgium

viii
 LIST OF CONTRIBUTORS
Nicholas O’Rourke MBBS, FRACS
Royal Brisbane Hospital, Brisbane, Queensland, Australia
Martin Palavecino MD
Department of Surgical Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, USA
Purvi Y. Parikh MD
Department of Surgery, Albany Medical College, Albany, New York,
USA
Samir Pathak MD, ChB, MSC, MRCS
Clinical Fellow, North Western Hepatobiliary Centre, Aintree
University Hospital, Liverpool, UK
Henry A. Pitt MD
Indiana University, Indianapolis, Indiana, USA
Graeme J. Poston MS, FRCS (Eng), FRCS (Ed)
Centre for Digestive Diseases, University Hospital Aintree, and
Department of Surgery, The Royal Liverpool University Hospitals,
Liverpool, UK
Derek G. Power MD
Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Myrddin Rees MS, FRCS, FRCS (Ed)
Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS
Foundation Trust, Basingstoke, UK
Michael Rhodes
Department of Surgery, Norfolk & Norwich University Hospital,
Norwich, UK
Charles B. Rosen
Mayo Clinic, Rochester, Minnesota, USA
Gerardo Sarno MD
Clinical Fellow, North Western Hepatobiliary Centre, Aintree
University Hospital, Liverpool, UK
Rajesh Satchidanand MD, FRCS
Clinical Fellow, North Western Hepatobiliary Centre, Aintree
University Hospital, Liverpool, UK
Beat Schnüriger
Division of Trauma and Surgical Critical Care, University of Southern
California, Los Angeles, California, USA
Lawrence H. Schwartz
Department of Radiology, Columbia University College of Physicians and
Surgeons, and Radiologist-in-Chief, New York–Presbyterian Hospital/
Columbia University Medical Center, New York, New York, USA
Margo Shoup MD, FACS
Chief, Division of Surgical Oncology, Department of Surgery, Loyola
University Medical Center, Maywood, Illinois, USA
Jason K. Sicklick
Department of Surgery, Memorial Sloan-Kettering Cancer Center,
New York, New York, USA
Steven M. Strasberg MD, FRCS(C), FACS, FRCS (Ed)
Pruett Professor of Surgery and Head Hepato-Pancreato-Biliary and
Gastrointestinal Surgery, Washington University in Saint Louis and
Barnes-Jewish Hospital, Saint Louis, Missouri, USA
Jason W. Smith MD
Chief Resident, Department of Surgery, Loyola University Medical
Center, Maywood, Illinois, USA
Nick Stern
Consultant Gastroenterologist, Digestive Diseases Department,
University Hospital Aintree, Liverpool, UK
Richard Sturgess
Consultant Gastroenterologist and Clinical Director, Digestive Diseases
Department, University Hospital Aintree, Liverpool, UK
Adriano Tocchi
Head of 1st Department of Surgery and Chief of the Gastro-intestinal
and Hepato-biliary Surgical Service, University of Rome Sapienza
Medical School, Rome, Italy
Ludovic Trinquart
Department of Radiology, Assistance-Publique Hôpitaux de Paris,
Hôpital Beaujon, Clichy, France
Bernard Van Beers
Department of Radiology, Assistance-Publique Hôpitaux de Paris,
Hôpital Beaujon, Clichy; Université Paris; and Centre de recherche
biomédicale Bichat-Beaujon, Paris, France
Jean-Nicolas Vauthey MD
Department of Surgical Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, USA
Valérie Vilgrain
Department of Radiology, Assistance-Publique Hôpitaux de Paris,
Hôpital Beaujon, Clichy; Université Paris; and Centre de recherche
biomédicale Bichat-Beaujon, Paris, France
Vanessa de Villa
Assistant Professor, Department of Surgery, Queen Mary Hospital,
The University of Hong Kong, Hong Kong, China
J. Weitz MD
Department of Surgery, University of Heidelberg, Heidelberg, Germany
Fenella K. S. Welsh MA, MD, FRCS (Gen Surg)
Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS
Foundation Trust, Basingstoke, UK
Moritz Wente
Department of Surgery, University of Heidelberg, Heidelberg, Germany
Vincent Kah Hume Wong MBCB, MRCS
Research Fellow in Hepatopancreatobiliary & Transplant Surgery, HPB
& Transplant Unit, St. James’ University Hospital, Leeds, UK
A. Peter Wysocki
Department of Surgery, Logan Hospital, Meadowbrook, Queensland,
Australia
Charles J. Yeo MD
The Samuel D. Gross Professor and Chair, Department of Surgery,
Thomas Jefferson University, Philadelphia, Pennsylvania, USA
Daria Zorzi MD
Department of Surgical Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, USA
ix
Foreword
As recent progress in hepato-pancreato-biliary (HPB) surgery
has been evident since the first edition of this book was pub-
lished eight years ago, Dr. Graeme Poston, Dr. Mike
D’Angelica, and Dr. René Adam, internationally recognized
authorities in HPB surgery, have attempted to rewrite the sec-
ond edition, joined by selected numerous worldwide special-
ists renowned as expert authors in each field to present a
current view of the surgical and non-surgical management of
benign and malignant HPB disorders.
This book demonstrates the wisdom of the new knowledge
and technical skills of these diverse disciplines where cooperative
x
efforts contribute toward the benefit of the patients with HPB
disorders.
The general surgeon will find this volume to be a useful source
of current thoughts on how to manage the diverse HPB diseases.
Yuji Nimura MD
President, Aichi Cancer Center
Professor Emeritus, Nagoya University Graduate
School of Medicine
Past President, International Hepato-Pancreato-Biliary
Association (IHPBA)
Preface
Hepato-pancreato-biliary (HPB) surgery is now firmly
established within the repertoire of modern general surgery.
Indeed, in many major tertiary centers there are now specific
teams for both pancreatic and liver surgery. However, in most
hospitals outside these major centers the day-to-day manage-
ment and decision-making for patients with these disorders
remains the remit of the general surgeon.
Following the launch of the highly successful first edition of
this book eight years ago there have been considerable
advances in the surgical management of HPB disorders. Many
of these relate to related specialties (radiology, oncology, gas-
troenterology, and anesthesia) and also directly to surgery
(liver transplantation, caval bypass and replacement, laparo-
scopic surgery to name but a few). As such the second edition
has been completely rewritten from scratch.
As with the first edition, the purpose of this edition is
twofold. First, it is intended to cover the spectrum of common
HPB diseases that will confront the general surgeon in his or
her regular practice. Second, we hope that this work will be
sufficiently comprehensive to cover the broad spectrum of
HPB surgery for candidates coming to examinations at the
completion of surgical training.
We are indebted to the many international contributors for
their perseverance and patience over the gestation of this proj-
ect, which is greatly appreciated. Lastly, we are grateful to our
publishers, Informa Healthcare, for their help during the
preparation of this project.
Graeme J. Poston
Michael D’Angelica
René Adam
September 2010
xi
1 Surgical anatomy of the liver and bile ducts
Robert Jones and Graeme J. Poston
The success of any surgical intervention on the liver and bile
ducts is totally dependent on a thorough working knowledge
of their anatomy. As the number of patients undergoing hepa-
tobiliary surgery is increasing, good understanding of the
anatomy of this area is increasingly important for any surgeon
with an interest in the gastrointestinal tract. Command of this
anatomy is also essential for the successful interpretation of
functional imaging of hepatobiliary anatomy.
When operating on the liver and biliary tree, the surgeon has
to obey three basic tenets.
● Remove all pathologically involved tissue.
● Preserve the maximal amount of functioning non-
pathological liver tissue.
● Perform safe resection, while ensuring adequate
blood supply to the remaining hepatic parenchyma.
Historically, the liver was described according to its mor-
phological appearance (1,2). However, these three tenets have
altered the approach to surgery, and the liver is now consid-
ered from a functional and therefore surgical perspective.
morphological anatomy
Historically, when viewed at laparotomy, the liver appears
divided into a larger “right” lobe, and a smaller “left” lobe by
the umbilical fissure and falciform ligament (Figs. 1.1 and
1.2) (3). Situated on the inferior surface of the right lobe is the
transverse hilar fissure, which constitutes the posterior limit of
the right lobe. The “quadrate” lobe was defined as the portion
of the right lobe lying anterior to this transverse hilar fissure
and to the right of the umbilical fissure, its other margin being
defined by the gallbladder fossa. The “caudate” lobe, which is
anatomically and functionally separate from the rest of the
liver, lies posterior to the hilum, between the portal vein and
the inferior vena cava (IVC) (4).
This historical anatomical approach does not consider the
vasculature or biliary drainage of the liver and is of only lim-
ited use when planning surgical resection.
early application of the functional
anatomy
Isolated liver wounds, usually as a result of military action,
had been successfully treated since the early seventeenth
century (5,7), but the first attempt at resection of a liver tumor
was not made until 1886, when the French surgeon Luis
excised a solid liver tumor by ligating and cutting through a
pedunculated left lobe “adenoma.” Attempts to suture the sev-
ered pedicle were unsuccessful, and the stump was returned to
the peritoneal cavity. Not surprisingly, the patient succumbed
some six hours later (8).
In 1888, Rex reported a “new” arrangement of the right and
left lobes of the liver and further refined our understanding of
lobar anatomy (2). The first successful elective liver resection
was performed two years later by von Langenbuch, who
excised a portion of the left lobe of the liver containing an
adenoma in 1888 (9). He had to reopen the abdomen several
hours after the operation because of reactionary hemorrhage,
but was able to ligate the bleeding vessels and return the over-
sewn liver to the abdomen.
Two years later in 1890, the Baltimore surgeon McLane
Tiffany reported the successful removal of a benign liver
tumor (10), and the following year Lucke described the
successful resection of a cancerous growth of the liver (11).
Surgery was now becoming a recognized treatment for liver
pathology. Advances in surgery closely mirrored increased
understanding of the functional anatomy of the liver (12–14).
The first attempt to define the functional anatomy of the
liver, which could possibly guide current surgical practice, was
made by Cantlie in 1898, while working in Hong Kong. He dis-
sected the livers of executed prisoners (15) and making vascu-
lar casts, he demonstrated that the main division between the
right and left lobe in fact extended from approximately the
gallbladder fossa, to the right side of the IVC, posterosuperi-
orly. Cantlie’s line, therefore, follow a line drawn from the gall-
bladder fossa, along the middle hepatic vein, to the IVC
(Figs. 1.2 and 1.3) (3). In 1911, Wendel reported the first case
of right lobectomy for a primary tumor (16), however this
procedure did not follow the precise anatomical plane
described by Cantlie.
In 1939, while working in Paris, the Vietnamese surgeon Ton
That Tung described the venous drainage of the liver in rela-
tion to the true lobar anatomy (Fig. 1.4) (17). The first ana-
tomically correct description of a left lateral segmentectomy
was made by Raven in 1948 while resecting metastatic colon
cancer (18). Four years later, Lortat-Jacob and Robert finally
described a similar approach to the true right hepatic lobec-
tomy, based on the anatomical principles described by Cantlie
(Fig. 1.6) (19).
Healey and Schroy were the first to demonstrate in 1953 that
the right lobe was further divided into an anterior and a pos-
terior sector (20). They also showed that the left lobe was
divided into a medial and lateral sector by the line of the falci-
form ligament and umbilical vein (Fig. 1.5). Understanding of
the functional anatomy of the liver continued to develop, and
in 1957, Goldsmith and Woodburne described a number of
anatomical planes through the liver parenchyma that followed
this functional anatomy. Their paper finally defined true right
lobectomy (right hepatectomy), left lobectomy (left hepatec-
tomy), and left lateral segmentectomy (Fig. 1.6) (21).
appreciation of segmental anatomy
Probably the most important anatomical contribution to
modern liver surgery comes from the work of the late Claude
1
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
IVC
Left lobe
Right lobe
IVC Right free border of
lesser omentum
Figure 1.1 Morphological anatomy.
Gallbladder
Cantlie's line
Quadrate lobe
Transverse
hilar fissure
Gastrohepatic
omentum
Common bile duct, IVC Caudate lobe
hepatic artery
and portal vein
Figure 1.2 Anatomical features.
Couinaud, who in 1957 produced a huge number of vasculo-
biliary casts of the liver (23,24). Couinaud was able to demon-
strate that the liver appeared to consist of eight anatomical
segments, each of which could potentially be separately resected
without affecting the physiological viability of the other seg-
ments. Couinaud redefined the caudate lobe as segment 1 and
Goldsmith and Woodburne’s left lobe as segments 2 and 3. The
quadrate lobe was termed segment 4, and more recently has
been subdivided by further studies of its portal blood supply
into 4A (superiorly) and 4B (inferiorly). The right liver consists
of segments 5 (anteroinferiorly), 6 (posteroinferiorly), 7 (pos-
terosuperiorly), and 8 (anterosuperiorly) (Fig. 1.7). Couinaud
later suggested a further clarification, in which the caudate lobe
to the left of the IVC remained segment 1, with that to the right
being redefined as segment 9 (25).
Resections based on these anatomical segments enable the
surgeon to safely operate following the three central tenets
described above; remove all pathologically involved tissue,
preserve the maximal amount of nonpathological liver tissue,
and perform safe resection, while ensuring an adequate blood
2
Middle hepatic vein lying IVC
among Cantlie's line
IVC
Cantlie's line Gallbladder
Figure 1.3 Cantlie’s line.
Umbilical supply (inflow and outflow), and therefore viability, to the
fissure remaining hepatic parenchyma.
The description of Couinaud is the most complete and
exact, and also the most useful for the operating surgeon, and
therefore it is this description that will be used throughout
this book.
segmental anatomy of the liver
These anatomical studies of the functional anatomy of the
liver allow us to define hepatic segments based upon both
the distribution of the portal pedicles and the drainage of the
hepatic veins (Fig. 1.5). The three main hepatic veins (right,
middle, and left) divide the liver into four sectors, each of
which receives a portal pedicle containing branches of the
hepatic artery, hepatic duct, and portal vein; thus producing
an alternation between hepatic veins and portal pedicles.
These four sectors, demarcated by the hepatic veins, are the
portal sectors, each sector therefore receiving an independent
portal supply. For the same reason, the scissurae containing
the hepatic veins are termed the portal scissurae while the scis-
surae containing portal pedicles are the hepatic scissurae
(Fig. 1.5). Thus, the liver is divided by the main portal scissura
along the line of the middle hepatic vein into two discrete
hemilivers, along the line previously described by Cantlie (15).
We therefore refer to these hemilivers as right and left livers,
rather than right and left lobes, to avoid confusion with the
anatomical lobes, particularly since there is no visible surface
marking that permits individualization of the “true” lobes.
As described by Cantlie, the main portal scissura runs poste-
riorly from the middle of the gallbladder fossa to the right side
of the IVC (Fig. 1.5). Therefore, the right and left livers, demar-
cated by the main portal scissura, are independent in terms of
their portal and arterial vascularization and their biliary
drainage.
These right and left livers are both further divided into two
by the other two portal scissurae, delineated by the right and
left hepatic veins. Goldsmith and Woodburne refer to these
further divisions as “segments” (21), but for the rest of this
book, we will use the more generally accepted nomenclature of
Couinaud, which refers to these divisions as “sectors” (23). The
 SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS

Right liver Left liver

IVC
Middle hepatic vein
(usually enters left vein Left heptic vein
before IVC)

Right
hepatic vein
Caudate hepatic veins
(variable)

Right inferior
hepatic vein
(variable)
IVC

Gallbladder, note that the middle vein

may lie superficially in the gallbladder fossa
Figure 1.4 Venous drainage of the liver.

IVC Middle hepatic vein in

main portal scissura
following Cantlie's line

Left hepatic vein

in left portal
7 2 scissura

Right hepatic
vein in right 8 Lateral
3 segment of
portal scissura
1 left lobe
4
Right
posterior Falciform ligament
sector 6
5
Medial segment of left lobe

Right anterior sector Portal vein

Right liver Left liver

Figure 1.5 Functional sectoral anatomy and relationship to hepatic scissurae.

right liver is divided by the right portal scissura (right portal
vein) into an anteromedial (or anterior) sector containing
segments 5 inferiorly and 8 superiorly, and a posterolateral (or
posterior) sector containing segments 6 inferiorly and 7 supe-
riorly (Fig. 1.5). When the liver lies in its normal position
within the upper abdominal cavity, the right posterolateral
sector lies directly behind the right anteromedial sector, and
this scissura is therefore almost in the coronal plane. Therefore
in the clinical setting (particularly when imaging the liver), it
is better to speak of these anterior and posterior sectors
(Fig. 1.5). The exact location of the right portal scissura is
imprecise, because it has no external landmarks. According to
Couinaud (23), it extends from the edge of the liver at the mid-
dle point between the back of the liver and the right side of the
gallbladder bed along the right hepatic vein posteriorly to the
confluence of the right hepatic vein and the IVC (26–28).
The venous drainage of the right liver is variable in that, in
addition to the right and middle hepatic veins, there are often
a number of smaller hepatic veins draining directly into the
IVC from segments 6 and 7. Not infrequently (63–68%) seg-
ment 6 drains directly into the IVC through a distinct inferior
right hepatic vein, larger than these other venous tributaries to
the IVC, which can be a significant bonus in the preservation
of residual hepatic function when undertaking extended left
hepatectomies (Fig. 1.4) (29,30).
The left portal scissura, along the left hepatic vein, divides
the left liver into two sectors: an anterior sector containing
segments 3 and 4 and a posterior sector containing segment 2

3
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A) (B)

(C) (D)

(E)
Figure 1.6 Formal hepatectomies: (A) right hepatectomy; (B) left hepatectomy; (C) left lateral segmentectomy; (D) extended left hepatectomy; (E) extended right
hepatectomy.

8 2
8
7
7
2 1
3
1
3 4
5 4
6 5
6

(A) (B)
Figure 1.7 Functional division of the liver and of the liver segments according to Couinaud’s nomenclature (A) as seen in the patient and (B) in the ex vivo position.

4
 SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS
(Fig. 1.5). It is important to note that the left portal scissura
does not follow the umbilical fissure; this portal scissura
contains a hepatic vein and the umbilical fissure contains
a portal pedicle. Therefore the left portal scissura lies poste-
rior to the ligamentum teres, inside the left lobe of the liver
(Fig. 1.5).
The middle hepatic vein (defining the main portal scissura)
usually enters the left hepatic vein some 1 to 2 cm before the
left hepatic vein joins the IVC (Fig. 1.4) (30). Occasionally the
middle and left hepatic veins enter the IVC separately, and in 2
out of 34 of Couinaud’s casts, the middle vein and left veins
joined at more than 2.5 cm from the IVC (30). Such an anom-
aly must be detected and excluded during isolated resection of
segment 4, since if it is not seen, and the last 2 cm of the left
vein is damaged, segments 2 and 3 will be needlessly sacrificed
(and in the case of extended right hepatectomy, threaten future
remnant liver viability).
The caudate lobe (segments 1 and 9) is the dorsal portion of
the liver, lying posteriorly and surrounding the retrohepatic
IVC. It lies directly between the portal vein (anteriorly) and
the IVC (posteriorly). The main bulk of the caudate lobe lies to
the left of the IVC, with its left and inferior margins being free
in the lesser omental bursa (Fig. 1.2). The gastrohepatic (lesser)
omentum separates the caudate from segments 2 and 3 of the
left liver. The left portion of the caudate lobe lies inferior to the
right between the left portal vein and the IVC, as the caudate
process. This process then fuses inferiorly with segment 6 of
the right liver. The amount of caudate lobe that lies on the
right side is variable, but usually small. The anterior surface of
the caudate lobe lies within the hepatic parenchyma against
the posterior intrahepatic surface of segment 4, demarcated by
an oblique plane slanting from the left portal vein to the left
hepatic vein.
The caudate lobe must be considered functionally as an iso-
lated autonomous segment, since its vascularization is inde-
pendent of the portal division and of the three main hepatic
veins. It receives a variable arterial and portal blood supply
from both the right and left portal structures, although the
right caudate lobe consistently receives an arterial supply from
the right posterior artery. Biliary drainage is likewise into both
the right and left hepatic ducts. However, the left dorsal duct
can also join the segment 2 duct. The small hepatic veins of the
caudate lobe drain directly into the IVC. This independent
functional isolation of the caudate lobe is clinically important
in Budd–Chiari syndrome; if all three main hepatic veins are
obliterated, the only functioning hepatic venous drainage is
through the caudate lobe, which therefore undergoes compen-
satory hyperplasia.
anatomical classification of hepatectomies
Hepatic resections can be classified as “anatomical” and
“nonanatomical.” Anatomical hepatectomies (hepatectomies
reglees) are defined by resection of a portion of liver paren-
chyma defined by the functional anatomy. These resections
are called left or right hepatectomies, sectorectomies, and seg-
mentectomies. Nonanatomical hepatectomies involve resec-
tion of a portion of hepatic parenchyma not limited by
anatomical scissurae. Such resections are usually inappropriate,
as they will leave behind devascularized residual liver and will
also probably not adequately excise all the pathologically
involved parenchyma.
The usual anatomical hepatectomies can be considered in
two groups: right and left hepatectomies in which the line of
transection is the main portal scissura separating the right and
left livers along the middle hepatic vein, and right and left
hepatectomies in which the line of transection commences in
the umbilical fissure.
For some time the latter definition, initially proposed by
Goldsmith and Woodburne (21), has been the accepted conven-
tion. We would encourage the use of the former definition, as
segment 4 (quadrate lobe) is anatomically part of the left liver
(Fig. 1.9), and this convention was adopted universally at the
2000 Brisbane Congress of the IHPBA (Brisbane Convention),
and will be used hereafter in this book. Using this functional
approach to liver anatomy, we can define numerous potential
liver resections based upon the order (first, second, third) of
the hepatic divisions (main portal scissura, anterior and poste-
rior right portal scissurae, left portal scissura) (28).
With regard to the first order division, right hepatectomy or
hemihepatectomy (removal of the right liver/hemiliver) there-
fore consists of the resection of segments 5 to 8 (stipulating ±
segment 1). Left hepatectomy or hemihepatectomy (removal
of the left hemiliver or liver) is the removal of segments 2–4
(stipulating ± segment 1) (Fig. 1.6). In certain pathologies
(multiple liver metastases or large tumors transgressing the
main portal scissura) hepatectomies can be extended to
include adjacent segments and sectors of the other liver. There-
fore extended right hepatectomy (right trisegmentectomy or
extended right hemihepatectomy) will also include resection
of segment 4 (stipulating ±segment 1), taking portal struc-
tures to the right of the falciform ligament (Fig. 1.6). Similarly,
extended left hepatectomy (left trisegmentectomy or extended
left hemihepatectomy) would include resection of segments 5
and 8 en bloc with segments 2 to 4 (stipulating ± segment 1)
(Fig. 1.6).
When discussing second order divisions, individual sectors
can be resected in isolation or in adjacent pairs depending
upon the distribution of pathology. Therefore right anterior
sectionectomy refers to the en bloc resection of segments 5
and 8 (between the main portal scissura (middle hepatic vein)
and right portal scissura (right portal vein) on their pedicle of
the anterior division of the right portal vein). Right posterior
sectionectomy (previously referred to as right posterior or lat-
eral sectorectomy) is the contiguous resection of segments 6
and 7, posterior to the right portal scissura (on the pedicle of
the posterior division of the right portal vein) (Fig. 1.8). On
the left side, isolated excision of segment 4 can be described as
left median sectionectomy, although it is also legitimate to
refer to it as resection segment 4 or segmentectomy 4.
One area of confusion in these definitions of hepatectomies
comes in the simultaneous resection of segments 2 and 3
(Fig. 1.10). Goldsmith and Woodburne originally described
this procedure as a left hepatic lobectomy (21). Describing this
as left lateral segmentectomy is technically wrong since the
true left lateral segment (and sector) comprises no more than
segment 2 (excision of which in isolation can therefore be
5
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
described as left lateral or posterior sectorectomy). It is now
accepted convention that resection of segments 2 and 3 is
regarded as a left lateral sectionectomy (but can also legiti-
mately be referred to as bisegmentectomy 2–3).
With regard to the third order divisions, resection is now at
the level of the individual hepatic segment(s). Therefore these
resections are referred to as segmentectomy (classified
according to the segment being removed: 1–9). Similarly,
segments 5 and 6 can be resected en bloc (and this used to be
described as a right inferior hepatectomy) and this should now
be described as bisegmentectomy 5–6. If there is a significant
right inferior hepatic vein draining segments 5 and 6, then
segments 7 and 8 can be resected with the right hepatic vein
(bisegmentectomy 7–8) (Fig. 1.8).
surgical approach to the caudate lobe
This resection (segmentectomy 1 or 9, or 1 and 9 en bloc) is
initially achieved by dissection of the coronary ligament up to
the right of the IVC, being careful to avoid the right hepatic
vein. The falciform ligament is then dissected to the IVC, the
(A)
(C)
(E)
Figure 1.8 Other hepatic sectorectomies: (A) right posterior sectorectomy; (B) right anterior sectorectomy; (C) left medial sectorectomy (segments 4A and 4B);
(D) right inferior hepatectomy; (E) right superior hepatectomy.
6
lesser omentum being incised close to the liver. Opening the
left coronary ligament allows ligation of the inferior phrenic
vein. The caudate veins running directly to the IVC are now
exposed and can be divided between ligatures as they run up
the back of the caudate lobe. After the hilar plate is lowered to
expose the right and left portal pedicles, the portal inflow to
both the right and left caudate segments can be identified,
ligated, and divided. The caudate lobe is now isolated and the
main portal fissure is divided to separate segments 4, 7, and 8.
Note that the caudate segment 1s not defined macroscopically
from segment 6.
the biliary tract
Accurate biliary exposure and precise dissection are the two
most important steps in any biliary operative procedure and
are both totally dependent on a thorough anatomical under-
standing of these structures. Several authors have described
the anatomy of the biliary tract (17,22,23), but unfortunately
the surgical implications have been incompletely described
and continue to be misunderstood by many surgeons.
(B)
(D)
 SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS
intrahepatic biliary anatomy
The right liver and left liver are respectively drained by the
right and the left hepatic ducts. The caudate lobe (segments 1
and 9) is drained by several ducts joining both the right and
left hepatic ducts (20). The intrahepatic ducts are tributaries
of the corresponding hepatic ducts, which form part of the
major portal tracts invaginating Glisson’s capsule at the hilus
and penetrating the liver parenchyma (Fig. 1.11). There is vari-
ation in the anatomy of all three components of the portal
triad structures (hepatic ducts, hepatic arteries, and portal
vein), but it is the portal vein that shows the least anatomical
variability. In particular, the left portal vein tends to be consis-
tent in location (23). Bile ducts are usually located above the
portal vein whereas the corresponding artery will lie below.
Each branch of the intrahepatic portal vein corresponds to one
or two intrahepatic bile ducts, which converge outside the liver
to form the right and left hepatic ducts, in turn joining to form
the common hepatic duct.
The left hepatic duct drains segments 2, 3, and 4, which con-
stitute the left liver. The duct draining segment 3 is found a lit-
tle behind the left horn of the umbilical recess, from where it
passes directly posteriorly to join the segment 2 duct to the left
Figure 1.9 Completion of segment 4 resection with portal bifurcation lying
inferiorly in front of the inferior vena cava.
Figure 1.10 Left lateral segmentectomy immediately prior to division of the
portal structure lying inferiorly and the left hepatic vein lying superiorly.
of the main portal branch to segment 2. At this point, the left
branch of the portal vein turns forward and caudally in the
recessus of Rex (23) (Figs. 1.12 and 1.13). As the duct draining
segment 3 begins its posterior course it lies superficially in the
umbilical fissure, often immediately under Glisson’s capsule. As
such it is usually easily accessible at surgery to allow a biliary–
enteric (segment 3 hepaticojejunostomy) anastomosis for bili-
ary drainage if such access is not possible at the porta hepatis.
The left hepatic duct then passes beneath the left liver at the
posterior base of segment 4, lying just above and behind the left
branch of the portal vein. After the left duct crosses the anterior
edge of that vein it joins the right hepatic duct to form the com-
mon duct at the hepatic ductal confluence. In this transverse
portion, where it lies below the liver parenchyma, it receives
one to three small branches from segment 4 (23).
The right hepatic duct (Fig. 1.14) drains segments 5 to 8 and
arises from the convergence of the two main sectoral (anterior
5 and 8, and posterior 6 and 7) tributaries. The right posterior
sectoral duct runs almost horizontally (26) and comprises the
confluence of the ducts from segments 6 and 7 (Fig. 1.15). The
right posterior duct joins the right anterior sectoral duct
(formed by the confluence of the ducts from segments 5 and 8)
Figure 1.11 Exposing the hilar plate by raising the inferior surface of segment
4B, thus demonstrating the condensation of Glisson’s capsule, which will
cover the extra hepatic confluence of the right and left hepatic ducts.
Figure 1.12 Exposing the recessus of Rex by distraction of the falciform liga-
ment to demonstrate the bifurcation of segment 3 and segment 4 bile ducts.
7
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

4 as it descends vertically (26). This right anterior sectoral duct

RPV lies to the left of the right anterior sectoral branch of the intra-
2 hepatic portal vein as it ascends within the parenchyma
(Fig. 1.15). The junction of the two main right biliary ducts
RHD
usually occurs immediately above the right branch of the por-
RHA
tal vein (23). The right hepatic duct is considerably shorter
than its counterpart on the left, which it joins to form the com-
mon hepatic duct in front of the right portal vein (Fig. 1.15).
The caudate lobe (segments 1 and 9) has its own separate
biliary drainage. This segment comprises two anatomically
4
(ant.) and functionally distinct portions, a caudate lobe proper
(which consists of a right and left part) located at the posterior
CHD 3 aspect of the liver, and a caudate process passing behind the
portal structures to fuse with segment 6 of the right liver. In
nearly half of individuals, three separate bile ducts drain these
PV HA
Recessus of Rex distinct parts, while in a quarter of individuals, there is a com-
mon biliary duct between the right portion of the caudate lobe
Figure 1.13 Biliary and vascular anatomy of the left liver. Note the position of proper and the caudate process, while the left part of the cau-
segment 3 duct above the corresponding vein and its relationship to the reces-
sus of Rex.
date lobe is drained by an independent duct. However, the site
of drainage of these ducts is variable. Most authors advocate
en bloc resection of the caudate lobe during resection of hilar
cholangiocarcinoma (31), since the tumor usually infiltrates
these ducts draining the caudate lobe. Certainly these authors
have demonstrated that in 88% of cases of hilar cholangiocar-
cinoma coming to resection there is histological evidence of
tumor infiltration of the caudate lobe along these ducts.

extrahepatic biliary anatomy

The detail of this section will be confined to the upper part of
the extrahepatic biliary tree, above the common bile duct,
since the common bile duct is also covered in chapter 2. The
right and left hepatic ducts converge at the right of the hilum
Figure 1.14 Demonstration of the right hepatic duct lying within the gallblad- of the liver, anterior to the portal venous bifurcation and over-
der fossa. lying the origin of the right portal vein. The biliary confluence

Anterior sectoral duct

5
7

Posterior
sectoral LHD
duct

LPV
6
LHA

CHD HA

PV
Figure 1.15 Biliary and vascular anatomy of the right liver. Note the horizontal course of the posterior sectoral duct and the vertical course of the anterior sectoral duct.

8
 SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS
is separated from the posterior aspect of the base of segment 4
by a fusion of connective tissue investing from Glisson’s cap-
sule to form the fibrous hilar plate. This hilar plate has no vas-
cular interposition and, when opened behind the posterior
aspect of the base of segment 4, will display the extrahepatic
confluence of the right and left hepatic ducts (Fig. 1.16).
The main bile duct is divided into its upper part, the com-
mon hepatic duct, and lower part, the common bile duct, by
the entry of the cystic duct from the gallbladder. This point of
confluence of hepatic and cystic ducts to form the common
bile duct is widely variable, and any surgeon performing the
operation of cholecystectomy has a duty of care to their patient
to be fully aware of this anatomic variability (lest they mistake
the common bile duct, or less frequently the common or right
hepatic ducts for the cystic duct, resulting in catastrophic con-
sequences for the patient). The main bile duct normally has a
diameter of up to 6 mm and passes downward anterior to the
portal vein in the right free border of the lesser omentum. The
bile duct is closely related to the hepatic artery as it runs
upwards on its left side before dividing into its left and right
branches, the right hepatic artery usually passing posteriorly
to the bile duct. The cystic artery, which usually arises from the
right hepatic artery, crosses the common hepatic duct as fre-
quently anteriorly as it does posteriorly (Figs. 1.17 and 1.18).
Calot’s triangle was originally defined by the common
hepatic duct lying medially, inferiorly by the cystic duct and
superiorly by the cystic artery (32). However, the usually
accepted surgical definition of this triangle has been modified
to that of the “cholecystectomy” triangle, which defines the
Segment 4
Glisson's
capsule
Lig.teres
Umbilical
fissure
Line of incision of
hilar plate to expose
left hepatic duct
Cystic plate Hilar plate
Figure 1.16 Demonstration of the relationship between the posterior aspect
of the base of segment 4 and the biliary confluence. Note the extension of Glis-
son’s capsule to invest the portal structures at the hilum (hilar plate) and
extending over the hepatic surface of the gallbladder (cystic plate). Exposure
of the extrahepatic left hepatic duct is achieved by incising the hilar plate at the
base of segment 4 medially as far as the umbilical fissure.
upper border as the inferior surface of the liver (and therefore
contains the cystic artery) (33). The junction of the cystic duct
and common hepatic duct varies widely and may even occur
behind the pancreas. The retropancreatic portion of the bile
duct approaches the duodenum obliquely, accompanied by
the terminal part of the duct of Wirsung (see chap. 2). These
two ducts join to enter the duodenum through the sphincter
of Oddi at the papilla of Vater (34,35).
gallbladder and cystic duct
The gallbladder lies within the cystic fossa on the underside of
the liver in the main liver scissura, thereby defining the junc-
tion between the right and left hemilivers. It is separated from
the hepatic parenchyma by the cystic plate, which is an exten-
sion of connective tissue from the hilar plate (described previ-
ously). The anatomical relationship of the gallbladder to the
liver ranges from hanging by a loose peritoneal reflection to
being deeply embedded within the liver parenchyma. The gall-
bladder varies in size and consists of a neck, body, and fundus,
which usually reaches the free edge of the liver, still closely
applied to the cystic plate. Large gallstones impacting within
the neck of the gallbladder may create a Hartmann’s pouch
(33), and inflammation secondary to this can obscure the ana-
tomical plane between the gallbladder and the common
hepatic duct (thus obliterating the cholecystectomy triangle).
This degree of inflammation can make dissection during cho-
lecystectomy difficult, increasing the risk of damage to the
common hepatic duct (36). Other structures similarly threat-
ened during this dissection as part of cholecystectomy for
LPV
RHD
LHD
RHA LHA
RPV
Cystic artery
Cystic duct
Gallbladder
CHD
HA
Retroduodenal
artery
Gastroduodenal
CBD artery
Splenic
vein
Superior mesenteric artery and vein
Figure 1.17 Anterior aspect of biliary anatomy. Note the hepatic duct conflu-
ence anterior to the right hepatic artery and origin of the right portal vein.
Note also the course of the cystic artery, arising from the right hepatic artery
and passing posteriorly to the common hepatic duct.
9
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

chronic cholecystitis include the right hepatic artery (in up to
50% of cholecystectomy bile duct injuries, so rendering the
upper bile duct ischemic with ramifications for the timing of
bile duct repair), the right hepatic duct, and in exceptional cir-
cumstances, a low-lying middle hepatic vein lying superficially
just below the gallbladder fossa.
The cystic duct arises from the neck of the gallbladder and in
80% of people descends to join the common hepatic duct in its
supraduodenal course. Its length varies widely but its luminal
diameter is usually between 1 and 3 mm. The mucosa of the
cystic duct is arranged in spiral folds (valves of Heister) (33).
In a small number of cases, the cystic duct joins the right
hepatic duct or occasionally a right hepatic sectoral duct.
The gallbladder receives its blood supply by the cystic artery,
the anatomy of which varies widely (Fig. 1.18). The most com-
mon variant arises directly from the right hepatic artery, then
dividing into an anterior and posterior branch. The venous
drainage of the gallbladder is directly through the gallbladder
fossa to the portal vein in segment 5 (Fig. 1.19).

(A) (B) (C) biliary anomalies

The biliary anatomy described above, comprising a right and
left hepatic duct joining to form a common hepatic duct
occurs in between 57% (23) and 72% (8) of cases. This vari-
ance may be explained by Couinaud’s (23) description of a
triple confluence of right posterior sectoral duct, right ante-
rior sectoral duct, and left hepatic duct in 12% of cases, which
Healey and Schroy do not describe.
(D) (E) (F)
There are many other abnormalities in biliary anatomy.
Couinaud described a right sectoral duct joining the main bile
duct in 20% of individuals (right anterior sectoral in 16%,
right posterior sectoral in 4%). In addition, a right sectoral
duct (posterior in 5%, anterior in 1%) may join the left hepatic
duct in 6% of cases. In 3% of cases, there is an absence of a
defined hepatic duct confluence with all the sectoral ducts
(G) (H) joining separately and in 2% the right posterior sectoral duct
may join the neck of the gallbladder or be entered by the cystic
duct (23) (Fig. 1.20).
Similarly, there are common variations of the intrahepatic
Figure 1.18 The eight most common variations in the anatomy of the arterial biliary anatomy. Healey and Schroy (20) describe the classical
supply (cystic artery) to the gallbladder. intrahepatic biliary arrangement outlined above in 67% of

(A) (B)
Figure 1.19 (A) Venous drainage of the gallbladder. (B) The lymphatic drainage of the gallbladder towards the coeliac axis.

10
 SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS

cases, with ectopic drainage of segment 5 in 9%, segment 6 in duplicated gallbladder (39,40), septum and diverticulum of
14%, and segment 8 in 20% of the cases. In addition, they the gallbladder, and variations in cystic duct anatomy includ-
describe a subvesical duct in 20% to 50% of the cases (8,37). ing a double cystic duct (41). More rare is agenesis of the gall-
This subvesical duct may lie deeply embedded in the cystic bladder (42,43) (Fig. 1.22). Furthermore, the gallbladder may
plate and can join either the common or right hepatic ducts. be abnormally positioned, either lying deep within the liver
This duct does not drain any specific area of the liver and never parenchyma or lying under the left liver (44).
communicates with the gallbladder, but may be damaged dur- The union of the cystic duct with the common hepatic duct
ing cholecystectomy and therefore contribute to postoperative may be angular, parallel, or spiral. The most frequent union is
biliary leak. On the left side, the commonest anomaly is a com- angular (75%) (45), while the cystic duct may run parallel with
mon union of ducts of segments 3 and 4 (25% of cases), and in the hepatic duct in 20%, both encased in connective tissue. In
only 2% does the segment 4 duct independently join the 5% of cases, the cystic duct may approach the hepatic duct in
common hepatic duct (Fig. 1.21). a spiral fashion, usually passing posteriorly to the common
Gross described a number of anomalies of the accessory hepatic duct before entering on its left side (Fig. 1.23).
biliary apparatus in 1936 (38). These include bilobed and
the arterial blood supply of the bile ducts
The hepatic artery usually arises as one of the three named
ra ra
branches of the coeliac trunk, along with the left gastric and
rp
splenic arteries (Fig. 1.24). The first named branch of the
Ih rp Ih
hepatic artery is the gastroduodenal artery and either of these
arteries may then give rise to the right gastric and retroduode-
nal arteries (Fig. 1.24). The hepatic artery then divides into
57% 12% right (giving rise to the cystic artery) and left hepatic arteries.
(A) (B) This arrangement holds true for 50% of cases.
In nearly 25% of cases, the right hepatic artery arises sepa-
ra ra
Ih rately from the superior mesenteric artery, indicative of the
joint fore- and mid-gut origin of the liver (Fig. 1.25). In the
rp Ih
remaining 25% of cases, the left hepatic artery arises from the
rp
left gastric artery. Occasionally, other variations will occur.
These variations will be readily apparent to an experienced
20% 16% 4% surgeon at operation. The authors do not advocate preopera-
C1 C2
tive angiography to delineate these anomalies prior to routine
(C)
hepatectomy.
ra The extrahepatic biliary system receives a rich arterial blood
ra
supply (46), which is divided into three sections. The hilar sec-
rp tion receives arterioles directly from their related hepatic arter-
rp Ih
Ih ies and these form a rich plexus with arterioles from the
supraduodenal section. The blood supply of the supraduodenal
section is predominantly axial. Most vessels to this section arise
6% 5% 1% from the retroduodenal, right hepatic, cystic, gastroduodenal,
D1 D2
and retroportal artery. Usually, eight small arteries, each 0.3 mm
(D)
4 3 in diameter, supply the supraduodenal section. The most
4
ra important of these vessels run along the lateral borders of the
3
rp ra duct and are referred to as the 3 o’clock and 9 o’clock arteries.
Of the arteries supplying the supraduodenal section, 60% run
2 rp 2 upward from the major inferior vessels while 38% run down-
1 1 ward from the right hepatic artery. Only 2% are nonaxial, aris-
3% 2% 1% ing directly from the main trunk of the hepatic artery as it runs
E1 E2 parallel to the bile duct. The retropancreatic section of the bile
(E) duct receives its blood supply from the retroduodenal artery.
ra
The veins draining the bile duct mirror the arteries and also
rp
Ih
drain the gallbladder. This venous drainage does not enter the
portal vein directly but seems to have its own portal venous
pathway to the liver parenchyma (47).
It has been proposed that arterial damage during cholecys-
tectomy may result in ischemia leading to postoperative stric-
2% ture of the bile duct (47), although it seems unlikely that
(F) ischemia is the major mechanism in the causation of bile duct
Figure 1.20 Main variations of the hepatic duct confluence. stricture after cholecystectomy.

11
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

7 8 7

6
91% 86%
8 5
7 8 7 7
7 8 7
8 8
6 8
6
5% 4%
5 5 5
10% 2% 2%
(A) seg V (B) seg VI

7 7 2 2

6
6 3 3
5
5
80% 20% a 67% b 1%
2
(C) seg VIII
3

c 1%
2 2

3
3

d 25% e 1%
2

f 1%
2

3
g 4%
(D) seg IV
Figure 1.21 Variations of the intrahepatic biliary anatomy.

the anatomy of biliary exposure
Although intraoperative ultrasound has made easier the loca-
tion of dilated intrahepatic biliary radicals, surgical exposure
of the extrahepatic biliary confluence and the segment 3 duct
demands knowledge of precise anatomical landmarks. Biliary–
enteric anastomosis necessitates precise bile duct exposure to
facilitate the construction of a mucosa to mucosa apposition
(36,48–50).
To expose the extrahepatic biliary confluence, the base of the
quadrate lobe (segment 4) is lifted upward and Glisson’s cap-
sule is incised at its base (see Fig. 1.16) (51). This technique is
also sometimes referred to as “lowering the hilar plate.” In only
1% of cases is this made difficult by any vascular imposition
between the hilar plate and the inferior aspect of the liver. This
maneuver will expose considerably more of the left hepatic
duct than the right, which runs a shorter extrahepatic course.
Contraindications to this approach include patients with a
very deep hilum, which is displaced upward and rotated later-
ally (36), and those patients who have undergone removal or
atrophy of either the right or left livers resulting in hilar rota-
tion. In this situation, the bile duct may come to lie behind the
portal vein.
When approaching the segment 3 duct (segment 3 hepati-
cojejunostomy), follow the round ligament (in which runs
the remnant of the obliterated umbilical veins) through the
umbilical fissure to the point where it connects with the left
branch of the portal vein within the recessus of Rex. This
junction may sometimes be deeply embedded within the
parenchyma of the fissure. The bile ducts of the left liver are
located above the left branch of the portal vein, whereas the
corresponding arteries lie below the portal vein. Dissection of
the round ligament on its left side allows exposure of either

12
 SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS
1 2 3 the right side is to the segment 5 duct (52), which runs on the
(A)
1 2
(B) (C)
1 2
(D)
Figure 1.22 Main variations in gallbladder and cystic duct anatomy:
(A) bilobed gallbladder; (B) septum of gallbladder; (C) diverticulum of gall-
bladder; (D) variations in cystic duct anatomy.
(A) 75% (B) 20% (C) 5%
Figure 1.23 Different types of union of the cystic duct and common hepatic
duct: (A) angular (75%); (B) parallel (20%); (C) spiral (5%).
the pedicle or anterior branch of the duct from segment 3.
This dissection is achieved by mobilizing the round ligament
and pulling it downwards, thereby freeing it from the depths
of the umbilical fissure. This procedure usually requires the
preliminary division of the bridge of liver tissue that runs
between the inferior parts of segments 3 and 4. The umbilical
fissure is then opened and with downward traction of the
ligamentum teres an anterior branch of the segment 3 duct is
exposed on its left side.
Sometimes it may be necessary to perform a superficial liver
split to gain access to this duct. In the usual situation of chronic
biliary obstruction with dilatation of the intrahepatic bile ducts,
the segment 3 duct is generally easily located above the left
branch of the portal vein. However, in the situation of left liver
hypertrophy, it may be necessary to perform a more extensive
liver split to the left of the umbilical fissure in order to widen the
fissure to achieve adequate access to the biliary system.
Access to the right liver system is less readily achieved than
to the left as the anatomy is more imprecise. However, intraop-
erative ultrasonography greatly enhances the ability of the sur-
geon to locat e these ducts at surgery. The ideal approach on
left side of its corresponding portal vein (23). The duct is
exposed by splitting the liver over a short distance to the right
of the gallbladder fossa, commencing at the right side of the
porta hepatis. The segment 5 duct should lie relatively superfi-
cially on the left aspect of the portal vein to that segment.
radiological anatomy of the liver
1 Accurate preoperative localization of liver pathology using
radiological techniques is of increasing importance, as any
potential resection depends largely on the segmental loca-
lization. Imaging is generally performed using ultrasound,
computed tomography (CT), and magnetic resonance (MR).
Ultrasound is excellent for imaging bile ducts, cysts,
abscesses, and tumors. Hepatic circulation can also be accu-
rately assessed using a Doppler technique. Ultrasound is also
the imaging modality of choice for the biliary tree. However,
the accuracy of ultrasound imaging is very operator depen-
dent, and fine detail can be limited. Examination is limited by
body habitus, and can be restricted by overlying bowel gas.
CT scanning is an excellent method of assessing the liver
parenchyma. It is able to identify a variety of different patholo-
gies, and CT with IV contrast is the most commonly used
method of imaging liver metastases. MR is excellent for the
imaging and characterizing primary liver tumors, and is useful
for the identification of hemangiomas, which can resemble
metastases on CT scanning.
Methods for defining segmental anatomy on ultrasound,
CT, and MR images follow the anatomical landmarks previ-
ously described (53). These methods generally involve using
three vertical planes along the lines of the main hepatic veins
to divide the liver into its four sectors, with a transverse scis-
sura along the portal vein further subdividing these four sec-
tors to give the eight Couinaud segments. These anatomical
landmarks are generally easily identifiable on standard imag-
ing. The middle hepatic vein, left hepatic vein, and ligamen-
tum teres provide good landmarks for dividing the left liver
into its four segments. The right hepatic vein can usually be
clearly seen dividing the right liver into its two sectors.
hepatic veins
In an oblique ultrasonic view, the three hepatic veins join the
IVC to form a characteristic W, with its base on the IVC. A
similar view can be seen on CT scan. These veins are usually
easily seen: the left hepatic vein separating segment 2 from seg-
ments 3 and 4, the middle hepatic vein separating segment 4
from 5 and 8, and the right hepatic vein separating 5 and 8
from 6 and 7.
portal system
The portal supply to the left lobe, when viewed obliquely, can
be seen as a side-on “H,” with the left portal vein giving its
13
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Left branch of the hepatic artery

Right branch of
the hepatic artery

Hepatic artery

3 o'clock artery
9 o'clock artery

Common hepatic artery

Retroduodenal artery
Gastroduodenal artery

(A)

M.H. artery
L.H. artery
R.H. artery Left gastric

Cystic
Aorta
Proper hepatic Celiac trunk
Right gastric

Supraduodenal Splenic

Gastroduodenal Common hepatic

(B)
Figure 1.24 (A) The biliary duct blood supply; (B) conventional arterial anatomy of the liver (50%).

branch to segment 2, before dividing into the terminal
branches to 3 and 4.
The portal supply to the right lobe also demonstrates a side-
on “H” in the oblique view. The right branch of the portal vein
forms the cross bar of the H, with the branches to segment 5 to
8 forming the arms.
identified using the landmarks outlined above. The scans were
then reviewed, with the lesion being attributed to the nearest
portal branch. Sixteen percent of lesions had a different seg-
mental location if the portal branch was used instead of the
conventional technique (Fig. 1.29) (54).

gallbladder, ligamentum venosum, key points

and falciform ligament
Radiological landmarks of these structures are fallible
● A full understanding of the lobar, sectoral, and seg-
(Figs. 1.26–1.28). Significant variations in intrahepatic vascu- mental anatomy of the liver and biliary system is
lar anatomy may result in incorrect identification of lesion an essential prerequisite for successful liver surgery.
location. A study by Rieker et al. looked at CT scans of patients
● The surgeon must appreciate the wide variation in
who underwent liver resection. The location of the lesion was extrahepatic biliary anatomy.

14
 SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS

4a 2

8 IVC
(A) (B)

Figure 1.27 CT scan of upper liver in venous phase showing the left, middle
and right hepatic veins draining into the inferior vena cava (IVC).
(C) (D)

(E) (F)
Figure 1.25 Variations in anatomy of hepatic arterial supply.

Figure 1.28 CT scan of the liver in portal phase showing the left portal vein
passing anteriorly between segments 3 and 4 within the recessus of Rex.

RAPV

LPV

RPPV
MPV

Figure 1.26 Portal phase CT scan through porta hepatis showing the left Figure 1.29 Percutaneous direct portogram showing the relationships of the
portal vein (L) lying centrally and the anterior (RA) and posterior (RP) anterior (RAPV) and posterior (RPPV) to the main (MPV) and left (LPV)
divisions of the right portal vein (R). portal veins.

15
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
references
1. Glisson F. Anatomia Hepatis. London: Typ. Du-Gardianis, 1654.
2. Rex 1888. Cited in Hobsley M. The anatomical basis of partial hepatec-
tomy. Proc R Soc Med Engl 1964; 57: 550–4.
3. Schwartz SI. Historical Background. In: McDermott WV Jr, ed. Surgery of
the liver. Boston, MA: Blackwell Scientific, 1989: 3–12.
4. McIndoe AH, Counsellor VX. A report on the bilaterality of the liver. Arch
Surg 1927; 15: 589.
5. Lau WY. The history of liver surgery. J R Coll Surg Edin 1997; 42: 303–9.
6. Mikesky WE, Howard JM, DeBakey ME. Injuries of the liver in three hun-
dred consecutive cases. Int Abstr Surg 1956; 103: 323–4.
7. Dalton HC. Gunshot wound of the stomach and liver treated by laparot-
omy and suture of the visceral wounds. Ann Surg 1888; 8: 81–100.
8. Luis A. Di un adenoma del fegato. Centralblatt fur chirg 1887; 5: 99.
Abstract from Ganzy, delle cliniche 1886, 23, No 15.
9. Langenbuch C. Ein Fall von Resektion eines linksseitigen Schnurlappens
der Leber. Berl Klin Wosch 1888; 25: 37–8.
10. Tiffany L. The removal of a solid tumor from the liver by laparotomy.
Maryland Med J 1890; 23: 531.
11. Lucke F. Entfernung der linken Krebsiten Leber Lappens. Cantrallbl Chir
1891: 6: 115.
12. Cattell RB. Successful removal of liver metastasis from carcinoma of the
rectum. Lehey Clin Bull 1940; 2: 7–11.
13. Wangensteen OH. The surgical resection of gastric cancer with special
reference to: (1) the closed method of gastric resection; (2) coincidental
hepatic resection; and (3) preoperative and postoperative management.
Arch Surg 1943; 46: 879–906.
14. Keen WW. Report of a case of resection of the liver for the removal of a
neoplasm with a table of seventy six cases of resection of the liver for
hepatic tumor. Ann Surg 1899; 30: 267–83.
15. Cantlie J. On a new arrangement of the right and left lobes of the liver. J
Anat Physiol (Lond) 1898; 32:4–9.
16. Wendel W. Beitrage zur Chirurgie der Leber. Arch Klin Chir Berlin 1911;
95: 887–94.
17. Ton That Tung. La vascularisation veineuse du foie et ses applications aux
resections hepatiques. These, Hanoi, 1939.
18. Raven RW. Partial hepatectomy. Br J Surg 1948; 36: 397–401.
19. Lortat-Jacob JL, Robert HG. Hepatectomie droite regle. Presse Med 1952;
60: 549–50.
20. Healey JE Jr, Schroy PC. Anatomy of the biliary ducts within the human
liver. Arch Surg 1953; 66: 599–616.
21. Goldsmith NA, Woodburne RT. Surgical anatomy pertaining to liver
resection. Surg Gynaecol Obstet 1957; 195: 310–18.
22. Hjortsjo CH. The topography of the intrahepatic duct systems. Acta Anat
1951; 11: 599–615.
23. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Paris: Masson,
1957.
24. Couinaud C. Lobes et segments hepatiques. Note sur l’architecture
anatomiques et chirurgicales du foie. Presse Med 1952; 62: 709–12.
25. Couinaud C. Anatomy of the dorsal sector of the liver. In: Couinaud C, ed.
New Considerations on Liver Anatomy. Paris: Couinaud, 1998: 39–61.
26. Ton That Tung. Les Resections Majeures et Mineures Du Foie. Paris: Mas-
son, 1979.
27. Caprio G. Un caso de extirpacion die lobulo izquierdo die hegado. Bull
Soc Cir Urag Montevideo 1931; 2: 159.
28. Bismuth H, Houssin D, Castaing D. Major and minor segmentectomies
“reglees” in liver surgery. World J Surg 1982; 6: 10–24.
29. Mancuso M, Nataline E, Del Grande G. Contributo alla conoscenza della
struttura segmentaria del fegato in rapportto al problema della resezione
epatica. Policlinico, Sez Chir 1955; 62: 259–93.
16
30. Couinaud C. Surgical anatomy of the liver revisited. C Couinaud, 15 rue
Spontini, Paris, 1989.
31. Mizumoto R, Kawarada Y, Suzuki H. Surgical treatment of hilar carci-
noma of the bile duct. Surg Gynecol Obstet 1986; 162: 153–8.
32. Rocko JM, Swan KG, Di Gioia JM. Calot’s triangle revisited. Surg Gynecol
Obstet 1981; 153: 410–14.
33. Wood D. Eponyms in biliary tract surgery. Am J Surg 1979; 138: 746–54.
34. Byden EA. The anatomy of the choledochaoduodenal junction in man.
Surg Gynecol Obstet 1957; 104: 641–52.
35. Delmont J. Le sphincter d’Oddi: anatomie traditionelle et fonctionelle.
Gastroenterol Clin Biol 1979; 3: 157–65.
36. Bismuth H, Lazorthes F. Les Traumatismes Operatoires de la Voie Biliaire
Principale. Paris: Masson, Vol 1, 1981.
37. Champetier J, Davin JL, Yver R, Vigneau B, Letoublon C. Aberrant bili-
ary ducts (vasa aberrantia): surgical implications. Anat Clin 1982;
4: 137–45.
38. Gross RE. Congenital anomalies of the gallbladder. A review of a hundred
and forty-eight cases with report of a double gallbladder. Arch Surg 1936;
32: 131–62.
39. Hobby JAE. Bilobed gallbladder. Br J Surg 1979; 57: 870–2.
40. Rachad-Mohassel MA, Baghieri F, Maghsoudi H, Nik Akhtar B. Duplica-
tion de la vesicule biliaire. Arch Francais des Maladies de l’Appareil Diges-
tif 1973; 62: 679–83.
41. Perelman H. Cystic duct duplication. J Am Med Assoc 1961; 175: 710–11.
42. Boyden EA. The accessory gallbladder. An embryological and compara-
tive study of aberrant biliary vesicles occurring in man and the domestic
mammals. Am J Anat 1926; 38: 177–231.
43. Rogers HI, Crews RD, Kalser MH. Congenital absence of the gallbladder
with choledocholithiasis. Literature review and discussion of mecha-
nisms. Gastroenterology 1975; 48: 524–9.
44. Newcombe JF, Henley FA. Left sided gallbladder. A review of the literature
and a report of a case associated with hepatic duct carcinoma. Arch Surg
1964; 88: 494–7.
45. Kune GA. The influence of structure and function in the surgery of the
biliary tract. Ann R Coll Surg Engl 1970; 47: 78–91.
46. Northover JMA, Terblanche J. A new look at the arterial blood supply of
the bile duct in man and its surgical implications. Br J Surg 1979; 66:
379–84.
47. Northover JMA, Terblanche J. Applied surgical anatomy of the biliary
tree. In: Blumgart LH, ed. Biliary Tract, Vol 5. Edinburgh: Churchill Liv-
ingstone, 1982.
48. Bismuth H, Franco D, Corlette NB, Hepp J. Long term results of Roux-en-
Y hepaticojejunostomy. Surg Gynecol Obstet 1978; 146: 161–7.
49. Voyles CR, Blumgart LH. A technique for construction of high biliary
enteric anastomoses. Surg Gynecol Obstet 1982; 154: 885–7.
50. Blumgart LH, Kelley CJ. Hepaticojejunostomy in benign and malignant
bile duct stricture: approaches to the left hepatic ducts. Br J Surg 1984; 71:
257–61.
51. Hepp J, Couinaud C, L’abord et L’utilisation du canal hepatique gauche
dans le reparations de la voie biliaire principale. Presse Med 1956; 64:
947–8.
52. Smadja C, Blumgart LH. The biliary tract and the anatomy of biliary
exposure. In: Blumgart LH, ed. Surgery of the Liver and Biliary Tract, 2nd
edn. Edinburgh: Churchill Livingstone, 1994: 11–24.
53. Strunck H, Stuckmann G, Textor J et al. Limitations and pitfalls of Couin-
auds segmentation of the liver in transaxial imaging. Eur Radiol 2003; 13:
2472–82.
54. Rieker O, Mildenberger P, Hintze C et al. Segmentanatomie der Leber in
der Computertomographie: Lokalisieren wir die Lasionen richtig. Rofo
2000; 171: 147–52.
2 Anatomy of the pancreas
Margo Shoup and Jason W. Smith
topography of the pancreas
The shape and size of the pancreas are highly variable but in
general it has a roughly trapezoidal shape and lies in the retro-
peritoneum of the upper abdomen (1). It is a finely lobular
structure with a tan to dull yellow color that reaches from the
medial concavity of the duodenum up and to the left termi-
nating at the hilum of the spleen. The volume of the pancreas
increases rapidly during childhood, plateaus from 20 to
60 years, and then steadily decreases; however, the percentage
of parenchyma versus fat in the pancreas continues to increase
during life slowly replacing functional tissue (2) (Fig. 2.1).
The pancreas is divided into three major regions, the head
and uncinate, the neck, and the body and tail (3). The head is
the most medial portion of the gland. It is the widest and
thickest part, having the most globular ultrastructure and is
cradled in the concavity of the duodenum lying just to the
right of the second lumbar vertebra (1). There is an inferior
projection to the head of the pancreas that lies posterior to the
superior mesenteric vessels, which makes up the uncinate pro-
cess. The head and uncinate are intimately associated with the
duodenum, sharing an abundant network of anastomosing
vessels. The posterior surface of the head of the pancreas is in
apposition to the inferior vena cava, aorta, right spermatic and
ovarian vessels, and right renal vessels and separated from
them by the avascular fusion fascia of Treitz (4). The ante-
rior surface is covered by the transverse colon and its
mesentery (5,6).
The neck of the pancreas is 2 to 3 cm in length and overlies
the confluence of the superior mesenteric vein (SMV) and
splenic vein by which it is grooved. It is related superiorly to
the pylorus and first portion of the duodenum (3,4).
The body of the pancreas extends from body of the second
lumbar vertebra over the left kidney and begins to taper into
the tail as it reaches the hilum of the spleen. The prismatic
shape of the pancreas flattens in the tail. The splenic vein runs
the length of the pancreas on the posterior surface, while the
artery courses along the superior edge of the body. The body
of the pancreas lies over the aorta and the left renal pedicle and
kidney and is separated from these structures by the fusion
fascia of Toldt (4). Inferiorly, it abuts the mesentery of the
transverse mesocolon, while superiorly and anteriorly it abuts
the stomach but is separated from it by the posterior parietal
peritoneum (7).
ductal anatomy of the pancreas
There are numerous configurations of the ducts of the pan-
creas and their relationships to each other, the duodenum and
the common bile duct. The significance of the pancreas
became understood only after the discovery of the main pan-
creatic duct by Wirsung in 1643. He noted that there was a
duct that traversed the length of the organ with numerous
tributary ducts coming off at near right angles and that this
duct opened into the duodenum, and he saw that there were
occasionally two ducts in the gland (1). It was Santorini who
finally concluded that, in the normal condition, there existed
two ducts with the smaller of the two emptying into the duo-
denum by way of a small papilla approximately 2 cm nearer to
the stomach than the major duct and this smaller duct bears
his name (5). The smaller duct is patent all the way to the duo-
denum in only 60% of specimens and the duct of Wirsung
represents the larger of the two; however, in about 10% of
specimens, the duct of Santorini is the main drainage for the
pancreas. Also in about 10% of cases, the two ducts are not in
communication with each other (1) (Fig. 2.2). The paren-
chyma of the pancreas consists of small lobules divided by
connective tissue. These lobules are centered around the main
tributary ducts that run to the main pancreatic duct. Smaller
branches off of these tributaries define further septated regions
within the lobules of pancreatic tissue. The main branches of
the pancreatic duct tend to meet the main duct on its superior
and inferior aspect. The diameter of the main pancreatic duct
is reported to be between 2.6 and 4.8 mm in the head, 2.0 and
4.0 mm in the body, and 0.9 and 2.4 mm in the tail (3). The
duct runs in a relatively superficial position in the tail and after
traversing the neck of the pancreas it dives deep into the paren-
chyma as it crosses the head and is near the dorsal surface of
the pancreas as it nears the confluence with the common bile
duct (CBD) and the duodenum (1).
The lower portion of the CBD lies in contact with the head
of the pancreas for between 2 and 7 cm and 40% of the time it
lies in a groove between the surface of the pancreas and the
duodenum. In the remainder of cases, it lies within the paren-
chyma of the pancreas (7). During embryological develop-
ment, the lower duct of Wirsung arises in the ventral pancreatic
bud adjacent to the early hepatic duct. Therefore, the associa-
tion of the duct of Wirsung with the CBD is a consistent fea-
ture of the ductal anatomy of the pancreas (1). The duct of
Wirsung and the CBD unite 6 to 8 mm within the papilla and
form a common channel, which is slightly dilated and referred
to as the ampulla of Vater. In just over 10% of cases, the two
ducts do not form a short common channel and instead enter
the duodenum independently on the papilla (5).
arterial anatomy of the pancreas
The pancreas enjoys an abundant arterial blood supply that
draws from both the celiac axis and the superior mesenteric
artery (SMA). The pancreas is supplied from the celiac axis by
the superior pancreaticoduodenal artery from the gastroduo-
denal artery (GDA), and the dorsal pancreatic and pancreatica
magna arteries from the splenic artery (Fig. 2.3). The distal
and inferior borders of the pancreas are supplied by the caudal
and inferior pancreatic arteries, which are formed by
17
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Figure 2.1 Overview of the relationship of the pancreas to other important structures in the upper abdomen. Plate 1098, From Anatomy of the Human Body,
Henry Gray 1918.

(A) (B) (C)

Figure 2.2 (A) Duct of Santorini is patent all the way to the duodenum. (B) Duct of Santorini is the main drainage. (C) The two ducts are not in communication
with each other.

ramifications with the dorsal pancreatic, pancreatica magna,
and splenic arteries. The SMA gives rise to the more variable
inferior pancreaticoduodenal (IPD) artery, which divides into
branches to form both an anterior and posterior anastomotic
arcade with branches from the superior pancreaticoduodenal
artery (8).
Superior Pancreaticoduodenal Artery
The superior pancreaticoduodenal is a short branch of the
GDA that arises after the takeoff of the right gastroepiploic
artery (Fig. 2.4). It is angiographically identifiable in about
10% of specimens and is generally about 8 mm in length (9).
Although rare, it is reported to occasionally arise from the left
hepatic artery. When present, the superior pancreaticoduode-
nal artery divides into anterior and posterior branches, which
anastomose with the inferior branches from the SMA. In the
remaining cases, the posterior superior pancreaticoduodenal
(PSPD) artery is seen arising from the GDA prior to the right
gastroepiploic takeoff. The anterior superior pancreaticoduo-
denal (ASPD) artery has a caliber between 1 and 3 mm and is
considered the most important blood supply to the head of the
pancreas. In the majority of cases, it is a terminal branch of the
GDA after it has given off the PSPD and the right gastroepi-
ploic arteries. The ASPD can be duplicated in up to 7% of
cases and rarely is absent. Case reports of extremely rare
anomalies exist, reporting the origin of this artery from almost
all of the major branches of the celiac and SMAs (9).
Posterior Superior Pancreaticoduodenal Artery
This artery forms the superior portion of the posterior arcade
that forms anastomoses with the posterior branch of the IPD
artery. The PSPD artery is most commonly found as a branch
of the GDA 1 to 2 cm after the takeoff of the hepatic artery (10).
Up to 10% of cases may see the PSPD arise from the superior

18
 ANATOMY OF THE PANCREAS
Cystic artery
Probe passed through epiploie foramen
C r e
a t o
r O x e n t e
Figure 2.3 Arterial anatomy of the pancreas, the celiac axis and its major branches. Plate 532, From Anatomy of the Human Body, Henry Gray 1918.
pancreaticoduodenal and in rare instances may arise from any
of the hepatic arteries. The most common course of the PSPD
after it leaves the GDA posteriorly is it runs over the portal vein
(PV) and the anterior edge of the top of the pancreas where it
enters the gland and finds the common bile duct and makes a
right-handed spiral around the duct passing posterior to it just
above the ampulla. It then runs deep in the parenchyma of the
pancreas to find its connection with the posterior inferior
artery. The PSPD gives off collateral branches to form the blood
supply to the intrapancreatic portion of the common bile duct,
it generally gives off the supraduodenal artery and occasionally
the retroduodenal artery, rarely it may give a branch to the gall-
bladder or an accessory right hepatic artery (10).
Inferior Pancreaticoduodenal Artery
The IPD artery is present in about 70% of cases and is the
common trunk that gives rise to the anterior and posterior
inferior pancreaticoduodenal (AIPD and PIPD) arteries that
form the anastomotic arcades supplying the head of the pan-
creas (11). In the remaining 30% of cases, the AIPD and PIPD
arise directly from the SMA. The IPD may arise directly from
the SMA as the first collateral branch from 2 to 5 cm distal to
the origin and take a short course from its posterior takeoff
into the inferior edge of the pancreatic parenchyma, or alter-
natively, it may arise as a common trunk with the first jejunal
h
c
a
m
o
t
S
branch, the pancreaticoduodenaljejunal (PDJ) trunk in which
case it takes a longer course to the pancreas. The IPD crosses
posterior to the SMV and the posterior surface of the pancreas
and does not give off any branches prior to dividing into its
anterior and posterior termini (11).
Anterior and Posterior Inferior Pancreaticoduodenal Arteries
These arteries supply the inferior part of the anastomotic
arches that supply the head of the pancreas. They arise most
often from a common IPD artery. They may also originate
directly from the SMA or less commonly directly from the first
jejunal artery or from a replaced hepatic artery. The main
course of the AIPD is to follow the inferior curve of the pan-
creas and find its partner the ASPD (12). It may give off a
branch to the duodenal–jejunal flexure or to form a transverse
pancreatic artery. The PIPD runs more posterior and cephalad
than the AIPD and ultimately finds the PSPD or alternatively
terminates as small end arteries. It may supply a collateral
branch to the transverse pancreatic artery when present (12).
Dorsal Pancreatic Artery
The main blood supply to the neck and body of the pancreas is
the dorsal pancreatic (DP) artery. It most commonly arises
from the splenic artery near its origin at the celiac axis (13). It
may also take its origin from the celiac trunk itself, the
19
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

S t o m a c h

Figure 2.4 Arterial anatomy of the pancreas, demonstrating the gastroduodenal and its branches of the anterior and posterior pancreaticoduodenal arteries form-
ing the anastomotic arcades with the branches from the superior mesenteric artery. Plate 533, From Anatomy of the Human Body, Henry Gray 1918.

common hepatic or the GDA. Alternatively, the DP may arise
from the SMA. The course of the DP artery is usually in the
form of an inverted “T” with a right and left branch that form
after a short 1 to 3 cm course. When the artery arises from the
splenic artery, it tends to angle back to the right, if it takes off
from the celiac, hepatic, or GDA, then it transverses the neck in
a leftward direction. When coming from the SMA it comes up
from the bottom of the pancreas. The right branch of the DP
forms an anastomosis with left anastomotic pancreatic artery
from the ASPD. The left branch becomes the transverse pan-
creatic artery (13).
Caudal and Great Pancreatic Arteries
The great pancreatic artery is often present and is given off
from the splenic artery at the junction of the body and tail. It
collateralizes with the transverse pancreatic artery. The caudal
pancreatic artery takes its origin from the left gastroepiploic,
the distal splenic artery or a branch from the splenic hilum
and forms anastomotic connections with the great pancreatic
and transverse pancreatic arteries (3).
The arterial blood supply to the pancreas is rich and
complex. Most of the primary arterial conduits form some
anastomotic connection and this shared blood supply is one of
the challenges of pancreatic surgery. When operating in the
deepest recesses of the abdomen, having an intimate knowl-
edge of the standard arterial anatomy as well as the most com-
mon alternatives will allow the pancreatic surgeon to maximize
patient safety. That same surgeon must keep in mind that the
arterial anatomy in this area is subject to wide variation and
that one must always be prepared to address the aberrant anat-
omy. To that end, having good preoperative imaging to estab-
lish before the operation what the arterial anatomy is can be a
valuable aid whether by angiography or by computed tomog-
raphy (CT) angiography.
Venous Drainage of the Pancreas
The veins of the pancreas follow the course of the correspond-
ing arteries in most cases. They are generally more superfi-
cially located than the arteries and depending on the location
in the pancreas drain into the PV, SMV, the inferior mesenteric
vein, or the splenic vein. In the head of the pancreas, there is a
venous arcade that mirrors the arterial anastomoses and of the
four main veins all, but the PSPD vein, which empties directly
into the PV, find their way to the SMV. In addition, there are

20
 ANATOMY OF THE PANCREAS
12 12p1
12b1 12a1
1 9
12p2
12a2
3
8a
5
8p
2
6
4
13a 14b
17a
17b
13b
Figure 2.5 Lymphatic drainage of the pancreas.
numerous small bridging veins between the head of the pan-
creas and the SMV and PV as they course behind the pancreas,
which must be carefully ligated during a resection. The fact
that there are rarely venous branches that enter the SMV or PV
on their anterior surfaces makes the dissection along the plane
anterior to these vessels possible during pancreaticduodenec-
tomy. Two large veins drain the body and tail of the pancreas,
the splenic vein, which courses along the superior edge of the
pancreas and the transverse pancreatic vein along the
inferior margin.
The portal vein is formed on the posterior surface of the
neck of the pancreas by the confluence of the splenic vein and
the SMV. The inferior mesenteric vein may join at this point as
well, but more commonly joins the splenic vein or SMV prox-
imal to the confluence (Fig. 2.4).
lympatic drainage of the pancreas
The lymphatic drainage of the pancreas is rich and drains each
lobular division with frequent anastomotic connections and
the ultrastructure is similar to that in other solid organs of the
abdomen(14) (Fig. 2.5). These lobular lymphatics coalesce to
form several trunks that empty into the primary lymph node
basins for the pancreas before quickly reaching the thoracic
duct (15). The drainage of the pancreas can be roughly divided
into right and left side based on the ventral and dorsal anlage
of the primordial pancreas. The left side of the system drains
the upper portion of the head, the neck, and body and tail,
10
11
7
16
10
14a
18
14d
14c
14V
14d
15
while the right side drains the lower portion of the head, which
developed from the ventral bud and constitutes the retroportal
lymphatics (15,16). The superior pancreatic nodes drain the
upper half of the neck, body and tail of the pancreas, and a
portion of the head. They primarily lie along the superior bor-
der of the gland or in the gastropancreatic fold and gastrohe-
patic ligament (17). The inferior pancreatic nodes similarly
drain the inferior half of the gland and lie along the inferior
border as well as draining into the superior mesenteric nodes
or the periaortic nodes. The anterior nodes are located along
the surface of the pancreas that lies adjacent to the duodenum
and are called the infrapyloric lymph nodes and the pancreati-
coduodenal nodes. These anterior nodes may also drain into
nodes along the root of the transverse colonic mesentery that
is adjacent to the head of the pancreas. The posterior nodes
run along the posterior pancreaticoduodenal border and
include the nodes along the lower portion of the common bile
duct, portal vein and nodes at the origin of the SMA. The tail
of the pancreas forms several lymphatic trunks that reach out
into the hilum of the spleen and form the superior and inferior
lymph nodes (3,16). This simplified lymphatic mapping sys-
tem is that adapted by the International Union against Cancer
(UICC). A more comprehensive and clinically useful system
was developed by the Japanese Research System, which divides
lymph node stations into 18 different designations and rates
them according to the likelihood of metastatic spread. Nodal
stations 13 and 17 are the most likely to harbor disease with
21
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Right gastroepiploic vein
Portal vein Splenic vein
PSPD-V
Gastrocolic trunk
Superior mesenteric vein
AIPD-V
PIPD-V First jejunal
tributary
ASPD-V
Figure 2.6 Major venous drainage for the pancreas.
47% and 29%, respectively (18,19) (Fig. 2.6). Classification of
lymphatic involvement will become increasingly important as
increasing numbers of targeted therapies become available in
pancreatic cancer.
innervation of the pancreas
The pancreas receives fibers from both the sympathetic and
parasympathetic nervous systems. The sympathetic innerva-
tion is via the splanchnic nerves, which carry both afferent
fibers and efferent fibers, while the parasympathetic innerva-
tion is via the vagus nerve, which also has afferent and efferent
supply to the pancreas. Parasympathetic innervation provides
stimulatory signals to the islet cells to increase insulin secre-
tion in response to food intake, while increased sympathetic
tone suppresses insulin secretion and stimulates the secretion
of glucagon (20,21). Efferent pain fibers are found in both the
splanchnic and vagal nerves and localization of these fibers has
been a difficult clinical problem in the management of pain in
both inflammatory and malignant diseases of the pancreas.
The right, and more prominently the left, celiac ganglion pro-
vide the majority of the direct innervation to the posterior
head, body, and tail of the pancreas via fibers that course along
the splenic artery (16). Neural ganglia around the common
hepatic artery also provide fibers that course along the GDA to
the head and uncinate process of the pancreas (22). Recently, it
has been shown that the celiac ganglion bearing the splanchnic
efferent fibers can be identified by endoscopic ultrasound and
precise localization of neurolytic therapies can be applied to
improve the success of these approaches (23,24).
Enteropancreatic nervous connections have also been dem-
onstrated from both the stomach and proximal duodenum to
the pancreas (24–26). These connections suggest that there is
crosstalk directly from the gastrointestinal tract to the pancreas
coordinating exocrine and/or endocrine secretions with
gut function.
22
The pancreas lies in the recesses of the upper abdomen and
remains one of the most challenging organs to manage from
a clinical or operative standpoint. Its rich blood supply, close
associations with major vascular structures, intimate relation
to the common bile duct, and the attachments to the duode-
num and spleen all contribute to the complexity of surgical
intervention in both malignant and benign disease (7). A
thorough understanding of the three dimensional relation-
ship of the arterial blood supply and major veins in proxim-
ity to the pancreas make approaching pancreatic resection
possible. As we move into an era of minimally invasive sur-
gery, being able to recognize the anatomy and its variations
with minimal cues from adjacent structures will become
increasingly important and continued study of these com-
plex relationships allows the mind to know, so that the eye
may see.
references
1. Opie EL. Anatomy of the Pancreas and its Variations. Disease of the Pan-
creas: Its Cause and Nature, 1st edn. Philadelphia, PA: J.B. Lippincott
Company, 1903: 359.
2. Saisho Y, Butler AE, Meier JJ, et al. Pancreas volumes in humans from
birth to age one hundred taking into account sex, obesity, and presence of
type-2 diabetes. Clin Anat 2007; 20: 933–42.
3. Skandalakis LJ, Colborn GL, Skandalakis JE. Surgical anatomy of the pan-
creas. In: Baker RJ, Fischer JE, eds. Mastery of Surgery, Vol. 2, 4th edn.
Philadelphia, PA: Lippincott Williams & Wilkins, 2001: 2448.
4. Kuroda A, Nagai H. Surgical anatomy of the pancreas. In: Howard J,
Idezuki Y, Ihse I, Prinz R, eds. Surgical Diseases of the Pancreas, 3rd edn.
Baltimore, MD: Lippincott Williams & Wilkins, 1998: 869.
5. Cattell RB, Warren KW. The anatomy and physiology of the pancreas. In:
Cattell RB, Warren KW, eds. Surgery of the Pancreas. Philadelphia, PA:
Saunders, 1953.
6. Hollinshead WH. The thorax, abdomen and pelvis. In: Hollinshead WH,
ed. Anatomy for Surgeons. Vol. 2. New York: Medical Department, Harper
and Row Publishers, 1971: 430.
7. Anson BJ, McVay CB, Callander CL. The Abdomen. Surgical Anatomy.
Philadelphia, PA: Saunders, 1971.
8. Woodburne RT, Olsen LL. The arteries of the pancreas. Anat Rec 1951;
111: 255–70.
9. Bertelli E, Di Gregorio F, Bertelli L, Mosca S. The arterial blood supply of
the pancreas: A review. I. The superior pancreaticoduodenal and the ante-
rior superior pancreaticoduodenal arteries. An anatomical and radiologi-
cal study. Surg Radiol Anat 1995; 17: 97–106, 101–3.
10. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood sup-
ply of the pancreas: A review. II. The posterior superior pancreaticoduodenal
artery. An anatomical and radiological study. Surg Radiol Anat 1996; 18: 1–9.
11. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood
supply of the pancreas: A review. III. The inferior pancreaticoduodenal
artery. An anatomical review and a radiological study. Surg Radiol Anat
1996; 18: 67–74.
12. Bertelli E, Di Gregorio F, Bertelli L, Orazioli D, Bastianini A. The arterial
blood supply of the pancreas: A review. IV. The anterior inferior and pos-
terior pancreaticoduodenal aa., and minor sources of blood supply for the
head of the pancreas. An anatomical review and radiologic study. Surg
Radiol Anat 1997; 19: 203–12.
13. Bertelli E, Di Gregorio F, Mosca S, Bastianini A. The arterial blood supply
of the pancreas: A review. V. The dorsal pancreatic artery. An anatomic
review and a radiologic study. Surg Radiol Anat 1998; 20: 445–52.
14. Navas V, O’Morchoe PJ, O’Morchoe CC. Lymphatic system of the rat pan-
creas. Lymphology 1995; 28: 4–20.
15. Pissas A. Anatomoclinical and anatomosurgical essay on the lymphatic
circulation of the pancreas. Anat Clin 1984; 6: 255–80.
16. Donatini B, Hidden G. Routes of lymphatic drainage from the pancreas:
A suggested segmentation. Surg Radiol Anat. 1992; 14: 35–42.
 ANATOMY OF THE PANCREAS
17. Hartley M, Finch-Jones M. Anatomy of the pancreas. In: Poston G,
Blumgart L, eds. Surgical Management of Hepatobiliary and Pancreatic
Disorders, 1st edn. London: Martin Dunitz, 2002: 19–28.
18. Bogoevski D, Yekebas EF, Schurr P, et al. Mode of spread in the early phase
of lymphatic metastasis in pancreatic ductal adenocarcinoma: Prognostic
significance of nodal microinvolvement. Ann Surg 2004; 240: 993–1000,
discussion 1000–1.
19. Sakai M, Nakao A, Kaneko T, et al. Para-aortic lymph node metastasis in
carcinoma of the head of the pancreas. Surgery 2005; 137: 606–11.
20. Benthem L, Mundinger TO, Taborsky GJ, Jr. Parasympathetic inhibition
of sympathetic neural activity to the pancreas. Am J Physiol Endocrinol
Metab 2001; 280: E378–81.
21. Jarhult J, Falck B, Ingemansson S, Nobin A. The functional importance of
sympathetic nerves to the liver and endocrine pancreas. Ann Surg 1979;
189: 96–100.
22. Yoshioka H, Wakabayashi T. Therapeutic neurotomy on head of pancreas
for relief of pain due to chronic pancreatitis; a new technical procedure
and its results. AMA Arch Surg 1958; 76: 546–54.
23. Levy MJ, Topazian MD, Wiersema MJ, et al. Initial evaluation of the effi-
cacy and safety of endoscopic ultrasound-guided direct Ganglia neuroly-
sis and block. Am J Gastroenterol 2008; 103: 98–103.
24. Kirchgessner AL, Liu MT, Gershon MD. In situ identification and visual-
ization of neurons that mediate enteric and enteropancreatic reflexes. J
Comp Neurol 1996; 371: 270–86.
25. Holst JJ, Schwartz TW, Knuhtsen S, Jensen SL, Nielsen OV. Autonomic
nervous control of the endocrine secretion from the isolated, perfused pig
pancreas. J Auton Nerv Syst 1986; 17: 71–84.
26. Kirchgessner AL, Gershon MD. Innervation and regulation of
the pancreas by neurons in the gut. Z Gastroenterol Verh 1991; 26:
230–33.
23
3 Hepatic resection
Ajay V. Maker and Michael D’Angelica
introduction
Though liver anatomy and physiology have been studied for
centuries, liver surgery still is a relatively young field. Just
30 years ago, the mortality of major hepatic resection neared
25%. This high mortality limited its utility and deterred
patients and referring physicians from considering surgery.
The current generation of hepatobiliary surgeons has an
increased understanding of the segmental anatomy of the
organ and has seen a dramatic decrease in the mortality of
liver surgery to nearly 1% largely due to a dramatic decrease in
blood loss (1). This chapter will address the basic principles
and techniques to safely approach liver resection.
basic principles
Surgical Indications: Benign vs. Malignant Disease
Though this chapter focuses on the technical aspects of
hepatic resection, an understanding of when liver resection
is indicated is of paramount importance. Due to advances
in modern imaging techniques and an increased knowl-
edge of the natural history of liver lesions, tumors that may
have been resected in the past for diagnostic uncertainty
are now often observed. Similarly, malignant lesions that
were not resected in the past but referred for nonsurgical
therapy are now being treated with resection. Indications
for specific benign and malignant processes are outlined
in other chapters; however, the general principles are
mentioned here.
Benign Disease
Partial hepatectomy for benign conditions should be paren-
chymal preserving and reserved for lesions that are symptom-
atic, have premalignant potential, or carry an unclear diagnosis.
Wide margins are not necessary, therefore in some cases, for
example, focal nodular hyperplasia (FNH) or hemangiomas,
enucleation may be safely performed, although in some ins-
tances an anatomic segmental resection may be the safest
approach (2–4). This is addressed at the end of the chapter and
detailed in other chapters.
Malignant Disease
Partial hepatectomy for malignant conditions must obtain a
clear surgical margin, and is suitable for well-selected patients
with both primary and metastatic cancer. We have found
increased patient survival with margins of at least 1 cm in
patients undergoing resection for metastatic colorectal cancer
(5–13), though other series suggest that a negative margin,
regardless of the distance, is sufficient (14,15). The exception
may be in slow-growing tumors with multiple liver metasta-
ses, such as neuroendocrine tumors, where tumor debulking
may be of value. As long as the functional remnant liver is
adequate, usually about 25% liver volume in otherwise
24
healthy individuals, excision of tumor can prolong life and in
some cases provide long-term disease-free survival.
Patient Selection
Proper patient selection is critical to both the safety and effi-
cacy of hepatic resection. One should evaluate the patient’s
general state of health, the condition of the liver, and the
volume of the future liver remnant to properly assess the risk
of general anesthesia, major abdominal surgery, and liver
resection. Subcostal and upper abdominal incisions are pain-
ful and may result in respiratory splinting and increased pul-
monary complications compared to other incisions (16). For
this reason, assessment of the patient’s ability to mobilize early
and ambulate postoperatively must not be underestimated.
Though there are many algorithms to evaluate liver function
in patients with chronic liver disease, the Child-Pugh classifi-
cation is a useful preoperative indicator, and patients with a
Pugh score of B or C should generally not undergo liver resec-
tion. Hepatic resection in cirrhotic patients is particularly dif-
ficult with operative mortality increasing with advanced Child
classification. Hepatic resection in the setting of portal hyper-
tension is generally not recommended (17), as this condition
predisposes the liver to higher portal pressures and diminished
ability to increase portal flow to the liver remnant postopera-
tively, thereby inhibiting normal liver regeneration and
increasing the risk of life-threatening bleeding. The cirrhotic
liver has decreased regenerative capacity and impairment in
liver function is greater, lasts longer, and can result in perma-
nent liver failure. A low platelet count, splenomegaly, ascites,
or evidence of varices on preoperative radiography may be the
only findings to alert the surgeon to hepatic dysfunction.
Many noncirrhotic patients that present for hepatic resec-
tion have abnormal liver function due to chemotherapy, dia-
betes, or obesity. These diseased livers carry an increased risk
of functional impairment with large resections and may also
have impaired function despite retained volume (18,19). In
these livers, careful preoperative planning must be done to
achieve a parenchymal sparing resection. Biopsy, if per-
formed, can give clues to the fat content of the liver, as can
preoperative imaging (20). Early data suggest that MRI spec-
troscopy can also accurately quantify hepatic fat content, and
this may prove to be a useful tool in preoperative liver assess-
ment and operative planning (20,21). In cases where liver
function may be impaired, or where extended resection is
necessary to gain tumor-free margins, portal vein emboliza-
tion is being employed to induce hypertrophy of the proposed
liver remnant (22,23). No absolute guidelines for emboliza-
tion can be made; however, preoperatively induced liver
hypertrophy is a valuable tool in planning and executing
major liver resections (24). Furthermore, chronic biliary
obstruction inhibits liver function and, thus patients with
 HEPATIC RESECTION
hilar cholangiocarcinomas are also at increased risk of liver
failure postoperatively.
The functional residual liver volume should be calculated to
insure adequate liver function postresection. A healthy, non-
cirrhotic individual requires a functional hepatic reserve of at
least 20% of the original nontumoral liver volume. The regen-
erative capacity of the liver should enable full functional com-
pensation within weeks of resection; once greater than 70% of
liver volume is resected, however, there is a risk of clinically
significant liver insufficiency. This risk is minimal if specimen
volume has been replaced with tumor, in which case compen-
satory hypertrophy will have already occurred.
Preoperative Imaging (See Also Chapters 3, 4, and 11)
Fine-cut triphasic helical computed tomography (CT) with
CT angiogram is the single most useful study in preoperative
evaluation of liver tumors. When the study includes the chest,
abdomen, and pelvis, preoperative staging is reliable and can
identify areas outside of the liver that may need further evalu-
ation or confirm nonoperative candidates. CT can define the
vascular anatomy, identify anatomical variants, determine
resectability, estimate the functional liver residual volume, and
identify preoperative biliary drainage strategies, thereby obvi-
ating the need for further radiographic studies. CT angiogra-
phy in particular has almost prevented the need for traditional
angiography. 3-D reconstruction of the vasculature is particu-
larly helpful in identifying vascular anomalies quickly and
temporally. Furthermore, 3-D reconstruction of the vascular
anatomy may lead to more accurate visualization of tumor–
vessel relationships and may be a more accurate study to pre-
determine the operative line of transection (25). Magnetic
resonance imaging can also provide high-quality vascular and
volumetric assessments of the liver but its principal role is in
characterizing liver tumors of unclear etiology.
In experienced hands, ultrasound is a fast, inexpensive, and
noninvasive modality that can quickly obtain information
regarding tumor size and the amount of liver involvement,
particularly in gallbladder and biliary tumors. It is especially
helpful in distinguishing cysts from solid tumors and should
be used in addition to CT to evaluate cysts for the presence of
septations or mural thickening, which would suggest cystade-
noma or a cystadenocarcinoma. Duplex ultrasound is also
particularly helpful as a dynamic study to identify vasculature
in relation to tumor masses.
Anesthetic Techniques
Operative and perioperative morbidity and mortality have
been decreased in part due to changes in anesthetic practices
over the evolution of hepatic resection. A focus on maintain-
ing low central venous pressure (CVP) can greatly reduce
blood loss and keep the operative field clean for proper visual-
ization of the biliary and vascular anatomy during paren-
chymal transaction. This is accomplished by positioning the
patient in mild Trendelenberg and minimizing intravenous
fluid to maintain systolic blood pressures above 90 mmHg and
urine output to about 25 mL/h. If the IVC is still distended
after mobilization of the liver, parenchymal transection can
wait until central venous pressure is decreased through use of
narcotics, vasodilatory inhalation agents, or direct vasodila-
tors. A central venous pressure of less than 5 mmHg can be
maintained during the periods of liver mobilization and
parenchymal transection. Though a cental venous catheter is a
useful tool to follow the CVP, the surgeon can also look for a
nondistended IVC and for blood coursing through flat intra-
hepatic veins. If transection is performed under Pringle con-
trol, bleeding is generally from hepatic veins, therefore, with a
low hepatic venous pressure, even large tears in hepatic veins
can be visualized to allow ligation or repair without massive
hemorrhage. By Poiseuille’s law, blood flow is exponentially
proportional to the radius of the vessel; therefore, even minor
decreases in venous distention can decrease blood loss expo-
nentially. With these techniques, the risk of postoperative renal
failure has not been shown to be significant, nor has the risk of
air embolism, which can be minimized, regardless, by keeping
the patient in about 15° of Trendelenberg (26,27). Normal
resuscitation is performed after the resection is completed and
hemostasis has been achieved.
basic techniques
Positioning, Skin Incision, and Exposure
The patient should be positioned supine with the arms
extended at right angles to the body. Any self-retaining retrac-
tor can be utilized, however, we prefer the Goligher retractor to
elevate the costal margin, and this crossbar can be fitted to the
table to form a 45° angle from top of the crossbar to the
xyphoid. The patient should be prepped from the mid-chest to
below the umbilicus, and draped to expose the right chest in
the event a right thoracotomy is necessary to gain additional
exposure. Though some groups routinely make a J-shaped tho-
racoabdominal incision, in our experience a thoracoabdominal
incision was rarely necessary in over 1800 cases (2). We employ
selective use of diagnostic laparoscopy based on the risk of
unresectable disease (28), and conform the type of incision to
the expected resection. For access to both lobes of the liver, a
bilateral subcostal incision can be used with or without vertical
midline extension. For the great majority of liver resections, we
employ a “hockey stick” incision, which includes a right sub-
costal incision with vertical midline extension to the xyphoid.
These incisions, when combined with the Goligher retractor,
provide good exposure of the suprahepatic IVC, even with large
right-sided tumors. We have found a higher rate of incisional
hernia with a “Mercedes” incision compared to a “hockey stick”
incision (29). For left-sided resections, a midline incision may
suffice. Occasionally, when there is severe right-sided hepatic
atrophy or exposure to the suprahepatic IVC is necessary for
safety, extension into the right chest can be helpful (Fig. 3.1).
Mobilization
The ligamentum teres is divided between clamps and ligated,
leaving a long secure ligature that is used as a handle to further
expose the porta hepatis. The thin veil of the falciform liga-
ment is incised along its length to free it from the anterior
abdominal wall and expose the ligamentum teres. In obese
individuals, the area where the falciform is fused to the ante-
rior abdominal wall may be invested within a large fat pad.
This fat pad can be removed with diathermy from beneath
25
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
both sides of the exposed fascia, improving exposure and
aiding with fascial reapproximation at the end of the case.
The falciform ligament is divided up to the suprahepatic
IVC (Fig. 3.2).
Bimanual palpation of the liver should be performed to
assess the extent of hepatic disease. Segment 4 should be
carefully retracted cephalad to expose the clear veil of lesser
omentum anterior to the caudate lobe and attaching to the
ligamentum venosum. This is incised, allowing palpation of
F A
D
B E
C
Figure 3.1 Incisions for liver resection. B-D, initial upper midline exploration.
A-B-C, ideal for exposure of the whole liver (hockey stick). C-D-E, the classic
chevron incision with A-D (Mercedes) extension. C-D, right subcostal inci-
sion. F, thoracoabdominal extension. Source: Blumgart; Surgery of the Liver,
Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
Figure 3.2 Mobilization of the liver begins with downward traction on the liver and division of the falciform ligament to the inferior vena cava. Source: Blumgart;
Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
26
the caudate and celiac axis, and providing access through the
foramen of Winslow to the porta hepatis. Intraoperative ultra-
sound is used at this point to define the extent of disease, vas-
cular relationships, and to confirm resectability.
To mobilize the right liver, the leaf of the right coronary liga-
ment is dissected from the falciform ligament and carefully
incised over the IVC and territory of the right hepatic vein.
This should be done sharply with downward traction on the
liver and superior traction on the diaphragm. Once the right
hepatic vein is identified, the right coronary ligament is taken
close to the liver surface to its furthest extent laterally and the
right triangular ligament is divided. To complete the mobiliza-
tion, the right liver must be freed inferiorly. Omental and peri-
toneal attachments to the liver and gallbladder are divided to
expose the inferior extent of the right triangular ligament. The
retroperitoneal attachments are incised off the right adrenal
gland and the liver can then be rotated medially to expose the
retrohepatic IVC.
If the right liver is to be resected or control of the right
hepatic vein is needed, the multiple small venous branches
from the IVC to the posterior liver must be individually dis-
sected, controlled, and divided. Large accessory inferior right
hepatic veins are common and may require division with a
vascular stapler or control with vascular clamps and ligatures.
It is critical for the surgeon on the left side of the table to
retract the right liver medially to expose these branches and
prevent injury to the cava. When all of these branches are
ligated and divided, all that is left to expose the right hepatic
vein will be a fibrous band of tissue that runs lateral to the
vein, encircles the IVC, and courses posteriorly to the left and
posterior border of the caudate, known as the caval ligament
(Fig. 3.3). A tunnel can be safely created medial to this liga-
ment and lateral to the right hepatic vein with a Kelly clamp or
renal pedicle clamp in order to allow either a ligature or a
 HEPATIC RESECTION

vascular load endo-GIA staple fire. Once this is divided, the
right liver is mobile and the lateral aspect of the right hepatic
vein is exposed.
The left liver is mobilized similarly, however since it does not
lie on the vena cava, an extensive caval dissection is not neces-
sary. Sharp and blunt dissection over the suprahepatic IVC will
expose the groove between the right vein and the common
trunk of the middle and left and middle hepatic veins. Down-
ward traction on the liver and cephalad traction on the dia-
phragm help expose the left coronary ligament. The groove
between the left and middle hepatic veins can be exposed with
sharp dissection if there is no long intrahepatic common
channel (Fig. 3.4). Care must be taken here to identify the
phrenic vein as it courses on the underside of the diaphragm
to enter the IVC, as it can be inadvertently injured if the trian-
gular ligament is not properly exposed or not divided close to
the liver surface (Fig. 3.5). As the left lateral segment is released
from its peritoneal attachments, it is also useful to place a hand
or laparotomy pad under the left lateral segment and anterior
to the caudate to provide traction and to protect the stomach,
bowel, and spleen from diathermic injury. Further mobiliza-
tion of the left liver can be accomplished by dividing the lesser
omentum as well as the ligamentum venosum either at the left
portal vein or left hepatic vein insertions to expose these ves-
sels and the underlying caudate lobe.
vascular isolation
Once the liver is mobilized, there are essentially three steps to
safely perform a hepatectomy. These involve vascular inflow
control, vascular outflow control, and parenchymal transection.
Inflow Control
All major hepatic resections require control of the vascular
inflow to be accomplished safely. Furthermore, adequate

Figure 3.3 Multiple small venous branches from the IVC to the posterior liver must be individually dissected and divided. When all of these branches are controlled,
all that is left to expose the right hepatic vein will be a fibrous band of tissue, the caval ligament. A tunnel can be safely created behind this ligament and above the
right hepatic vein with a Kelly clamp. Once this is divided, the entire right liver is mobile and the venous outflow can be encircled and controlled. Source: Blumgart;
Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

27
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

hepatic arterial and portal venous inflow must be maintained structures in the hilum, but risks injury to the pedicle before
to the remnant liver. Selective inflow control may be achieved encircling the triad, or hemorrhage from coursing veins, which
extrahepatically (30), intrahepatically during parenchymal commonly run close to the pedicles.
transection (1,31), or by intrahepatic pedicle control via hepa- Though total vascular isolation has been employed by some
totomies (32,33). groups (35–38), we have found that total vascular isolation
In the extrahepatic approach, the hepatic artery and portal techniques were not necessary in more than 1800 consecutive
vein branches are dissected at the porta hepatis and controlled liver resections (2).
outside of the liver. In this approach, the individual artery and
portal vein have to be separately identified and ligated since Outflow Control
they have not yet entered the liver as a portal pedicle. The Though there are multiple small veins that drain the right lobe
advantages of this approach are early vascular control prior to and segment I directly into the retrohepatic vena cava, the
transection and demarcation of the liver on its surface. The majority of hepatic blood flow drains into the inferior vena
disadvantages are a somewhat tedious dissection and the cava (IVC) via the left, middle, and right hepatic veins. In
potential for injury to contralateral structures. The presence of
tumor abutting the hilum may mandate extrahepatic inflow
control. The right hepatic artery usually courses posterior to
the common hepatic bile duct and can be dissected from the
right side of the porta hepatis and controlled. Once divided,
the proximal artery stump can be retracted anteriorly expos-
ing the underlying portal vein. All branches must be carefully
dissected and identified prior to division to insure that there is
no compromise of flow to the future liver remnant, a poten-
tially fatal complication. There is typically a small branch to
the caudate process coming off the right portal vein proxi-
mally that may have to be controlled. As opposed to the short
extrahepatic course from the hilum to the right liver, the vas-
cular inflow to the left liver can be controlled in the umbilical
fissure (34). The left portal vein and duct are mobilized by
lowering the hilar plate. Here the left hepatic artery is typically
found running cephalad along the left side of the porta hepatis
anteriorly. It is prudent to insure that one has not inadver- Figure 3.4 Sharp and blunt dissection over the suprahepatic IVC exposes the
tently ligated the artery proximal to the right hepatic artery right, middle and left hepatic veins. Source: Blumgart; Surgery of the Liver,
takeoff by confirming a pulse to the right liver. Once the left Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
hepatic artery is divided, the underlying left portal vein can be
dissected behind it. A branch to caudate lobe is very constant
and should be preserved if the caudate is not going to be Left phrenic Left triangular
resected. Proximal dissection and identification of the right vein Diaphragm ligament
portal vein from the left side is worthwhile to confirm anatomy.
Unless mandated by tumor proximity, we prefer to transect the
bile duct (left or right) intrahepatically during parenchymal tran-
section to absolutely avoid contralateral injury. This is especially
important on the left side where there is often variant drainage
of the major right sectoral ducts to the left hepatic duct.
An alternative to extrahepatic inflow control at the hilum is
intrahepatic control using a pedicle ligation technique. This
technique is most appropriate for right-sided tumors not
encroaching on the hilus. The portal triads carry Glisson’s cap-
sule with them into the liver substance forming a sturdy pedic-
ular sheath that can be dissected and clamped. Exposure of the
pedicles can be accomplished by parenchymal transection Diathermy
down to the sheaths or by hepatotomies in the liver substance
above the pedicle. For exposure of the right-sided inflow
pedicle(s), hepatotomies are typically made along the inferior Figure 3.5 Downward traction on the liver and cephalad traction on the
part of the gallbladder fossa and the caudate process and a diaphragm help expose the left coronary ligament. Care must be taken here
large clamp is used to encircle the inflow structures. The whole to identify the phrenic vein as it courses on the underside of the diaphragm
to enter the IVC, as it can be inadvertently injured if the triangular ligament
right pedicle can be controlled this way or the right anterior is not properly exposed or not divided close to the liver surface. Source:
and posterior sectoral pedicles can be encircled separately. The Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition;
approach is rapid and avoids dissection of the contralateral Chapter 80; copyright Elsevier.

28
 HEPATIC RESECTION
major hepatectomy, extrahepatic control of these vessels is
preferred. Standard anatomy consists of a single right hepatic
vein entering the vena cava, and a left and middle hepatic vein
that is joined and entering the cava as a single trunk. Autopsy
studies of the left and middle hepatic venous trunk have eluci-
dated at least five types of hepatic vein trunk variants (39).
The right hepatic vein is typically encircled after the dissec-
tion of the vena cava and caval ligament has been carried out
as described earlier. The base of the right hepatic vein should
be dissected sharply and once exposed, a clamp can be passed
between the right and middle hepatic veins. Exposure of the
left and middle hepatic vein extraheaptically can be challeng-
ing. The groove between the right and middle hepatic veins is
initially developed from above the liver. The left liver is mobi-
lized and the ligamentum venosum is divided just before its
insertion into the left hepatic vein. Here a tunnel is carefully
developed underneath the middle and left hepatic vein and
they are encircled (Fig. 3.6). It is often difficult to individually
encircle the left or middle hepatic vein extrahepatically but
this depends on the anatomy of the common trunk. It is
important to identify the hepatic venous anatomy on preopera-
tive imaging and recognize variations in the branching patterns,
since bleeding in this area can be difficult to control. Ligation
of the hepatic venous outflow of the liver can also be accom-
plished during parenchymal transection with careful exposure
of the cava and the origin of these veins once the liver has
been transected to expose them. The exposures for specific
resections are discussed later in the chapter.
Parenchymal Transection
Once vascular inflow and outflow to the lobe or segment has
been controlled, all that remains is division of the liver paren-
chyma. There are many techniques to accomplish this. The
instruments used are left to the surgeon’s preference, but it is
imperative that the vessels and ducts divided be identified
and dissected before division. Transection of the liver should
be a deliberate dissection of intrahepatic structures rather
than simply coagulation of liver tissue. In addition to the
ability to confidently ligate each branch on the transection
(A)
Figure 3.6 (A) Medial retraction of the left lateral segment exposes the ligamentum venosum. (B) The ligamentum venosum is divided sharply where it is tethered
to the left hepatic vein, releasing the vein and enabling a tunnel to be dissected under the middle and left hepatic veins and anterior to the IVC. Source: Blumgart;
Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
line, it allows one to identify the venous drainage and pedicle
inflow to the remnant liver. Moreover, in cases where the
tumor margin is adjacent to major hepatic veins and portal
pedicles, it allows precise extirpation of the tumor. For these
reasons, we prefer a simple crushing technique. Glisson’s
capsule is scored with diathermy along the transection line
and a Kelly clamp is used to crush the liver tissue and expose
the vessels and ducts for clipping, ligation, or bipolar energy
sealing. Larger pedicles are suture ligated or stapled (40). The
operative surgeon crushes the tissue in small linear planes,
the assistant clips or seals the vessels, and the surgeon divides
the structures. In this fashion, the transection line is quickly
and efficiently completed. Though not always necessary,
inflow occlusion with a Pringle maneuver may be used to
decrease blood loss, and an entire lobe can often be tran-
sected with three to four sessions of 10–15 minutes on Prin-
gle with 5 minutes off. After removal of the specimen, the
raw surface is carefully inspected for bile leaks, which are
suture ligated or clipped. Some groups advocate injection of
dye or intralipid via the cystic duct to identify open biliary
tributaries for ligation. Since drainage is associated with pro-
longed hospital stay, increased infection, and no change in a
need for interventional radiology directed drainage, we do
not routinely place drains after hepatic resection in the
absence of biliary reconstruction (41).
major hepatic resection: definitions and
specific considerations
Multiple descriptions of liver anatomy and resections by anat-
omists and surgeons have resulted in terminologies that can be
confusing and imprecise. A recent consensus conference in
Brisbane, Australia, with the American Hepato-Pancreato-
Biliary Association has published new guidelines to clarify this
nomenclature. When unclear, or if there is confusion about the
description of a resection, one should revert to naming
the numerical segments involved. The right liver is comprised
of segments V–VIII and the left liver is comprised of
segments II–IV. Appropriate terms for resection of the right or
left liver would be “hepatectomy” or “hemi-hepatectomy.”
(B)
29
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Extending a right hepatectomy to include segment IV or a left
hepatectomy to include segments V and VIII would be
described as a “right/left trisectionectomy” or “trisegmentec-
tomy.” Resection of segments II and III is often referred to as a
“left lateral segmentectomy” or “sectionectomy.” There are
essentially five types of major resection. The nomenclature of
these resections is based on the anatomical classification
(Table 3.1) (Fig. 3.7) (42–45).
Right Hemihepatectomy (Right Hepatectomy, Right
Hepatic Lobectomy)
A right hemihepatectomy involves excision of segments
V–VIII. The right lobe is completely mobilized and the
right hepatic vein is isolated. The peritoneum overlying the
common bile duct and extending into Calot’s triangle is
incised to expose the cystic artery and duct. These are
ligated and divided. A long tie is left on the proximal cystic
stump and used as a retractor to help expose the common
bile duct and dissect the vasculature. The hilar plate is low-
ered to protect the left hepatic duct. We typically do not
dissect the right hepatic duct extrahepatically, but address it
during parenchymal transection to absolutely avoid any
potential for injury to the left hepatic duct. The right
hepatic artery usually passes posterior to the common bile
duct (Fig. 3.8) and is sharply dissected, ligated, and divided
to the right of the common duct.
Superior traction on the right hepatic artery stump will
help expose the portal vein. The portal bifurcation is
approached laterally and posteriorly. When dissecting the
right portal vein, care should be taken to identify the first
posterior branch to the right side of the caudate. Circumfer-
ential control of the right portal vein should not be
attempted until this branch is identified and dissected as
bleeding from this vein can be troublesome. Once a few cen-
timeters of right portal vein are fully exposed and the left
portal vein has been visualized, it is encircled and divided.
Clamping of the right portal vein at this point should con-
firm demarcation of the right liver. Occasionally, the right
anterior and posterior sectoral portal vein branches arise
independently from the portal vein. In this instance, they
must be individually dissected and ligated after confirming
flow to the left liver.
The right hepatic vein is isolated and divided as described
previously. It is important that all the retrohepatic veins are
first controlled and divided, that the dissection extends to the
Table 3.1 Anatomy and Classification of Major Hepatic Resections
Anatomic Classification
Couinaud Goldsmith and Woodburne
Right hepatectomy Right hepatic lobectomy
Right lobectomya Extended right hepatic lobectomy
Left hepatectomy Left hepatic lobectomy
Extended left hepatectomya Extended left lobectomy
Left lobectomy Left lateral segmentectomy
a
Often referred to as trisegmentectomy.
b
May also include segment I.
30
left of the IVC, and that the right hepatic vein is skeletonized
completely right at the liver surface. It is especially important
to gain extrahepatic control of the vein with large tumors near
the hepatic venous confluence or in the posterior sector near
the vena cava, where it can be difficult to obtain tumor clear-
ance without excessive traction on the vein. Alternatively, the
right hepatic vein can also be controlled from within the liver
during parenchymal transection, however, this usually forces
the hepatic transection to the right of the true principal
midliver plane.
After inflow ligation, a line of demarcation becomes evi-
dent. Figure-of-eight stay sutures are placed to either side
of this line and parenchymal transection can begin safely.
The surgeon’s left hand lifts the left lobe from above the
IVC carefully as the transection plane is deepened. This
will expose the middle hepatic vein, and division of the
specimen can proceed to the right or left of the vein
depending on tumor clearance. As the dissection proceeds
superiorly, the segment V and then VIII hepatic veins are
divided along the middle hepatic vein. The main right por-
tal pedicle is exposed and divided with the endo-GIA sta-
pler. This will control the right hepatic duct if it was not
controlled extrahepatically.
Alternatively, an anterior approach can be used to resect
the right lobe of the liver. This approach is advantageous
when the right lobe cannot be mobilized due to a large
right-sided tumor, or there is a large mass adherent to the
diaphragm or IVC (46). In this approach, after extrahepatic
inflow division, the liver is transected without mobilization.
It is then freed from its venous and ligamentous attachments
to the IVC and peritoneum. The parenchyma is transected
from the anterior liver surface to the IVC along the line of
demarcation, and venous tributaries are controlled from the
front, including the right hepatic vein (47,48). To help con-
trol bleeding in the deeper parenchymal plane, the “hanging
maneuver” may be employed (49). In this maneuver, the
anterior plane of the IVC is dissected from the liver under-
surface. The most inferior veins draining the caudate are
ligated and divided, and a tunnel is carefully created ante-
rior to the IVC to the space between the right and middle
hepatic veins with a Kelly clamp. This is a blind tunnel of 4
to 6 cm. A tape is passed that can then be used to elevate the
liver away from the anterior surface of the IVC, helping to
define the plane of transection and facilitating exposure of
the deeper tissues. In this technique, the right portal pedicle
Brisbane Segments resected
Right hemihepatectomy V, VI, VII, VIII
Right trisectionectomy IV,V,VI, VII, VIIIb
Left hemihepatectomy II, III, IV
Left trisectionectomy II, III, IV, V, VIIIb
Left lateral sectionectomy II, III
 HEPATIC RESECTION
is divided, parenchymal transection is completed to the
IVC, the lateral venous attachments to the IVC are ligated
and divided, the right hepatic vein is stapled, the coronary
and triangular ligaments are divided, and the specimen is
removed.
Right Trisectionectomy (Right Lobectomy, Extended Right
Lobectomy, Right Trisegmentectomy)
A right trisectionectomy is a right hemihepatectomy extended
to include segment IV. The liver is mobilized as described for a
right hepatectomy. To approach the inflow and outflow of seg-
ment IV, the ligamentum teres is elevated to expose the umbil-
ical fissure. If a bridge of tissue between segments III and IV is
present concealing the fissure, this should be divided with
diathermy. Here, the ligamentum teres can be traced to its
embryologic origin at the left portal vein. Incising the fibrous
tissue that tethers the left main pedicle to the base of the
umbilical fissure releases the left-sided structures from the
(A)
(C)
(E)
Figure 3.7 The anatomy and classification of major hepatic resections. (A) right hepatectomy, (B) left hepatectomy, (C) left lobectomy, (D) extended left hepatectomy,
(E) right lobectomy.
undersurface of segment IV, and it opens up the fissure. To
safely perform a right trisectionectomy, the left hepatic duct
should be freed clear of the proposed plane of transection.
This is accomplished by lowering the hilar plate as previously
described. The inflow and outflow to the right liver are
controlled and divided as previously described. Once the right
hepatic vein has been divided, the middle vein can usually be
encircled. The liver tissue is divided to the right of the falci-
form ligament and the pedicles feeding segments IVa and IVb
are ligated and divided as they come off the main left pedicle
(Fig. 3.9). Unless tumor mandates, a deliberate dissection
within the umbilical fissure is usually not necessary. As the
plane of transection is deepened toward the IVC superiorly,
the middle hepatic vein is encountered, dissected, and divided
with a stapler. It is absolutely critical to protect the left hepatic
vein as narrowing or transection of this vein will likely result in
liver failure or massive hemorrhage secondary to a lack of
other venous return from the liver.
(B)
(D)
31
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 3.8 During right hepatectomy, the right hepatic artery usually passes
posterior to the common bile duct and is sharply dissected, ligated, and
divided to the right of the duct. After cholecystectomy, retraction of the cystic
duct will expose the underlying artery. Source: Blumgart; Surgery of the Liver,
Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
Left Hemihepatectomy (Left Hepatectomy, Left Hepatic
Lobectomy)
A left hemihepatectomy involves excision of segments II–
IV. The left lobe of the liver is mobilized, the umbilical fis-
sure is exposed, and the hilar plate is lowered as previously
described. The gastrohepatic ligament is entirely divided,
with care taken to identify any accessory or replaced left
hepatic arteries not identified on preoperative imaging. The
left hepatic artery is dissected at the base of the umbilical
fissure and divided. The caudate branch of the portal vein is
identified before the left main portal vein enters the umbil-
ical fissure. If the caudate lobe is to be spared, the portal
vein is ligated and divided distal to this vein. A line of
demarcation marking the right-sided border of segment IV
corresponds with a plane that usually extends from the IVC
to the base of the gallbladder fossa (“Cantlie’s line”). This
“principle plane” is the same as that seen in a right hemi-
hepatectomy. Segments II and III are reflected medially and
the middle and left hepatic veins are identified, encircled
and divided extrahepatically as described earlier. The left
hepatic vein is often not amenable to circumferential extra-
hepatic exposure initially but can be exposed after splitting
the liver back to its origin. Parenchymal transection com-
pletes the excision.
Left Trisectionectomy (Extended Left Hepatectomy,
Extended Left Lobectomy, Left Trisegmentectomy)
A left trisectionectomy involves removal of segments II,
III, IV, V, and VIII. The entire liver is mobilized. The inflow
and outflow to the left lobe are controlled as previously
32
Figure 3.9 To expose and control the portal pedicles to segment IV, the liver
tissue is divided to the right of the falciform ligament and the pedicles feeding
segments IVA and IVB are ligated and divided as they come off the main left
pedicle. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th
Edition; Chapter 80; copyright Elsevier.
described for a left hemihepatectomy. The inflow to seg-
ments V and VII can be addressed in a few ways. The ante-
rior sectoral pedicle can be encircled intrahepatically either
through hepatotomies or after transection in the right scis-
sura to the left of the right hepatic vein. The pedicle can be
encircled and clamped confirming flow the posterior sector.
Alternatively, an extensive hilar dissection can be carried
out to identify and divide the arterial and portal branches
to the right anterior sector. It is critical that preoperative
imaging is reviewed for anatomic variations in the inflow
and outflow to the right liver. Once the anterior sectoral
inflow is divided, a near horizontal line of demarcation
becomes evident anterior to the right hepatic vein and
dividing the right anterior and posterior sectors. Parenchy-
mal transection continues anterior to the right hepatic vein
and the specimen is removed. The middle hepatic vein is
necessarily taken as part of this resection and is addressed
as described earlier. A left trisectionectomy is a challenging
operation that requires significant experience with major
hepatic resections.
Left Lateral Sectionectomy (Left Lobectomy, Left Lateral
Segmentectomy)
A left lateral sectionectomy involves removal of segments II
and III. The left lobe of the liver is mobilized and the hilar
plate is lowered as previously described. Just to the left of the
umbilical fissure, the portal pedicles to segments II and III are
identified and divided. These can be identified and controlled
through multiple hepatotomies or during parenchymal trans-
action in a plane just to the left of the falciform ligament. A
deliberate dissection in the umbilical fissure is usually not
necessary. The left hepatic vein is usually divided after paren-
chymal resection back to its origin but can also be controlled
extrahepatically as described in the “outflow control” section
of the chapter.
 HEPATIC RESECTION
wedge vs. segmental resection
The segmental anatomy of the liver, as defined by Couin-
aud, divides the liver into eight independent segments, each
with its own inflow and biliary drainage (see chapter 1)
(42,50). As a result, each segment can be individually
resected without affecting the inflow or outflow to the rest
of the liver. Segment-oriented hepatectomy spares normal
parenchyma and is particularly useful when bilateral non-
contiguous segments are involved or in patients with
chronic liver disease. Nonanatomic wedge resections can be
useful for small peripheral tumors that are not close to
major inflow pedicles or venous branches for which ade-
quate tumor margins can be obtained. Though some groups
have shown that anatomical resection is not superior to
wedge resection for tumor clearance, pattern of recurrence,
or survival (51), in our experience anatomic segmental
resection resulted in improved tumor clearance and patient
survival compared to wedge resection (52). Wedge excision
may risk fracturing the plane between the tumor and nor-
mal liver, margin positivity, and intraoperative hemor-
rhage (12,53). Anatomic resection may provide better
visibility, decrease the risk of major hemorrhage, and in
many cases provide a wider margin of resection.
Segmentectomy I (Caudate Resection)
The caudate lobe is often resected with a right or left hemi-
hepatectomy, however, isolated caudate resection may be per-
formed for solitary tumors in segment I. The anatomy of the
caudate lobe between the IVC, portal triad, and hepatic veins
can make resection tedious and challenging. The caudate lobe
straddles both hepatic lobes and therefore receives vascular
inflow from both the right and left portal pedicles (54). Venous
drainage is directly into the IVC via one to nine short hepatic
veins (55). The left edge of the caudate fuses with the IVC via
a fibrous band of tissue that encircles the IVC and attaches to
segment VII. In many patients, this caval ligament may be
composed of liver parenchyma.
Dissection at the base of the umbilical fissure exposes the
caudate branches of the left portal vein and hepatic artery
for ligation and division. Segments II and III of the liver
are mobilized and reflected to the right, exposing the cau-
date where it lies on the IVC. The left lateral attachments
of the caudate to the IVC are divided (56). Exposure and
division of the left caval ligament can be challenging and
care should be taken to avoid injury to the cava inferio-
medially and the base of the left and middle hepatic veins
superiorly. With anterior traction on the caudate, the short
hepatic veins draining into the IVC on the posterior aspect
of the caudate can be visualized and controlled. If there is
a bulky tumor in the caudate or anterior traction of the
lobe is difficult, the retrohepatic veins can be approached
from the right side, by mobilizing the right lobe and turn-
ing it to the left, then dissecting and dividing all the veins
starting below the caudate and continuing onto the ante-
rior surface of the IVC (57). The caudate branch from the
right portal vein should also be identified and ligated. To
complete the resection, the tissue joining the caudate to
segment VII must be transected. Anteriorly and superiorly,
care must be taken to avoid injury to the middle and left
hepatic veins.
Segments II or III
The approach to excising either segment II or III is the same as
that for a left lateral segmentectomy, except the plane between
the segments needs to be defined. This plane is identified by
the course of the left hepatic vein, segment 3 being anterior
and segment 2 being posterior. Inflow control to either seg-
ment is achieved in the umbilical fissure. Ligation of the portal
pedicle will guide resection along the plane of demarcation.
Care must be taken to divide the branches of the left hepatic
vein draining the excised segment, but to leave the main left
hepatic vein intact to drain the remnant liver.
Segment IV
As described in a right trisectionectomy, the inflow to
segment IV is found to the right of the umbilical fissure.
The hilar plate is lowered to protect the left bile duct and to
provide access to the multiple pedicles to segment IV. Liga-
tion of these pedicles will provide a line of demarcation
along Cantlie’s line. During parenchymal transection, the
venous drainage of segments IVa and IVb are divided
sequentially to the left of the middle vein on the lateral bor-
der of the segment, and along the umbilical fissure on the
medial border of the segment, where the umbilical vein
often courses. The middle hepatic vein can be sacrificed in
this operation if necessary with adequate drainage of the
right liver and segments 2 and 3.
Segments V and VIII (Anterior Sector)
The inflow to segments V and VIII are from the right anterior
sectoral pedicle. This can be approached and controlled extra-
hepatically or intrahepatically as described for a left trisectio-
nectomy. If the anterior and posterior sectoral pedicles branch
within the liver parenchyma, a hepatotomy over the anterior
pedicle is necessary. Alternatively, the liver can be transected
in the principal plane down to the base of the anterior sector
where its origin can be controlled, typically posterior to ter-
minal middle hepatic vein branches. The anterior sector lies
between the right and middle hepatic veins, i.e., between
Cantlie’s line and a transverse plane anterior to segments VI
and VII. This horizontal plane of transection can be better
defined by clamping the anterior pedicle to demarcate the
right, left, and posterior borders. The transection line between
V and VIII is demarcated and defined intrahepatically when
control of the isolated segmental inflow is obtained. The mid-
dle hepatic vein can usually be safely divided in this operation
if necessary, but in the absence of a large accessory right
hepatic vein, the right hepatic vein must be preserved for
adequate drainage of the posterior sector.
Segments VI and VII (Posterior Sector)
The inflow to segments VI and VII are from the posterior sec-
toral pedicle. This can often be approached and controlled in
the fissure of Ganz, though the anatomy of anterior and pos-
terior pedicles can be highly variable. If the anterior and pos-
terior sectoral pedicles branch within the liver parenchyma,
33
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
the portal pedicles must be approached during parenchymal
transection. The medial plane of transection can be better
defined by clamping the posterior pedicle to demarcate the
border. The classic description of a single pedicle from the
posterior sectoral pedicle feeding either segment VI or VII is
the exception rather than the rule (58), therefore, careful
parenchymal dissection, preoperative study of the CT, and
intraoperative ultrasound are critical to these resections. If a
posterior sectorectomy is to be performed, the right hepatic
vein can be sacrificed since the anterior sector drains into the
middle hepatic vein.
Central Hepatectomy (Segments IV, V, and VIII)
A central hepatectomy with various amount of extension into
any of the three segments can be performed combining the
techniques described above. Typically this requires dividing
the middle hepatic vein intrahepatically near its origin. The
techniques of a segment IV resection and anterior sectorec-
tomy are essentially combined. This is a challenging operation
that requires a substantial surface of liver to be transected but
can be very useful to spare parenchyma while removing cen-
trally placed tumors.
enucleation of benign tumors
₍see chapters 28, 32, and 33₎
When indicated, hepatectomy for benign conditions should be
parenchymal preserving. Though anatomic resection along seg-
mental planes is sometimes necessary, some benign tumors may
be enucleated, for example, adenomas, fibronodular hyperpla-
sia, metastatic neuroendocrine tumors, and hemangiomas (2,4).
Hemangiomas in particular push liver tissue away as they grow,
and create a fibrolamellar plane of tissue that defines the border
between cavernous tissue and normal liver parenchyma (2). The
arterial supply to the hemangioma can be determined from pre-
operative imaging and is clamped, allowing the tumor to
decompress via the venous outflow. The hepatic tissue over the
mass is then incised to enter an avascular plane surrounding the
tumor. Small vessels that traverse this plane are ligated and
divided. The majority of the dissection can be done with the
surgeon’s finger, and the mass is shelled out. This approach pre-
serves normal parenchyma, eliminates the need for hepatic
venous outflow control, limits blood loss, and has fewer compli-
cations than lobectomy (3,4). Management of benign lesions is
covered in further detail in other chapters.
conclusion
Major hepatic resections for benign and malignant tumors can
be accomplished safely and efficaciously. Proper patient selec-
tion, precise preoperative imaging, specific anesthetic techniques,
and knowledge of the principal complications are essential.
Study of each patient’s segmental anatomy will allow inflow and
outflow control and the ability to tailor the resection needed for
each individual.
references
1. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative out-
come after hepatic resection: Analysis of 1,803 consecutive cases over the
past decade. Ann Surg 2002;236(4):397–407.
34
2. Baer HU, Dennison AR, Mouton W, et al. Enucleation of giant hemangio-
mas of the liver: Technical and pathologic aspects of a neglected proce-
dure. Ann Surg 1992;216(6):673–6.
3. Gedaly R, Pomposelli JJ, Pomfret EA, Lewis WD, Jenkins RL. Cavernous
hemangioma of the liver: anatomic resection vs. enucleation. Arch Surg
1999 Apr;134(4):407–11.
4. Yoon SS, Charny CK, Fong Y, et al. Diagnosis, management, and outcomes
of 115 patients with hepatic hemangioma. J Am Coll Surg 2003;197(3):
392–402.
5. Are C, Gonen M, Zazzali K, et al. The impact of margins on outcome after
hepatic resection for colorectal metastasis. Ann Surg 2007 Aug;246(2):
295–300.
6. Cady B, Jenkins RL, Steele Jr GD, et al. Surgical margin in hepatic resec-
tion for colorectal metastasis: A critical and improvable determinant of
outcome. Ann Surg 1998;227(4):566–71.
7. Cady B, Stone MD, McDermott Jr WV, et al. Technical and biological fac-
tors in disease-free survival after hepatic resection for colorectal cancer
metastases. Arch Surg 1992;127(5):561–9.
8. Ekberg H, Tranberg KG, Andersson R. Determinants of survival in liver
resection for colorectal secondaries. Br J Surg 1986;73(9):727–31.
9. Elias D, Cavalcanti A, Sabourin JC, et al. Resection of liver metastases
from colorectal cancer: The real impact of the surgical margin. Eur J Surg
Oncol 1998;24(3):174–9.
10. Kato T, Yasui K, Hirai T, et al. Therapeutic results for hepatic metastasis of
colorectal cancer with special reference to effectiveness of hepatectomy:
Analysis of prognostic factors for 763 cases recorded at 18 institutions.
Dis Colon Rectum 2003;46:522–31.
11. Ohlsson B, Stenram U, Tranberg KG. Resection of colorectal liver metas-
tases: 25-year experience. World J Surg 1998;22(3):268–77.
12. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal
liver metastases. World J Surg 1995;19(1):59–71.
13. Shirabe K, Takenaka K, Gion T, et al. Analysis of prognostic risk factors in
hepatic resection for metastatic colorectal carcinoma with special refer-
ence to the surgical margin. Br J Surg 1997;84(8):1077–80.
14. Hamady ZZR, Cameron IC, Wyatt J, et al. Resection margin in patients
undergoing hepatectomy for colorectal liver metastasis: A critical
appraisal of the 1 cm rule. Eur J Surg Oncol 2006;32(5):557–63.
15. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on
survival and site of recurrence after hepatic resection for colorectal metas-
tases. Ann Surg 2005;241(5):715–24.
16. Mimica Z, Pogorelic Z, Perko Z, et al. Effect of surgical incision on pain
and respiratory function after abdominal surgery: a randomized clinical
trial. Hepatogastroenterology 2007;54(80):2216–20.
17. Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging,
and treatment of hepatocellular carcinoma. Liver Transpl 2004;10
(2 Suppl 1):S115–20.
18. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepato-
toxicity and surgery for colorectal liver metastases. Br J Surg. 2007;94(3):
274–86.
19. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on perioperative
outcome following hepatic resection. J Gastrointestinal Surg 2003;7(8):-
1034–44.
20. Siegelman ES, Rosen MA. Imaging of hepatic steatosis. Semin Liver Dis
2001;21(1):71–80.
21. Orlacchio A, Bolacchi F, Cadioli M, et al. Evaluation of the severity of
chronic hepatitis C with 3-T1H-MR spectroscopy. AJR Am J Roentgenol
2008;190(5):1331–9.
22. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embo-
lization for major liver resection: a meta-analysis. Ann Surg
2008;247(1):49–57.
23. Covey AM, Brown KT, Jarnagin WR, et al. Combined portal vein emboli-
zation and neoadjuvant chemotherapy as a treatment strategy for resect-
able hepatic colorectal metastases. Ann Surg 2008;247(3):451–5.
24. Belghiti J. Arguments for a selective approach of preoperative portal vein
embolization before major hepatic resection. J Hepatobiliary Pancreat
Surg 2004;11(1):21–4.
25. Lamade W, Glombitza G, Fischer L, et al. The impact of 3-dimensional
reconstructions on operation planning in liver surgery. Arch Surg
2000;135(11):1256–61.
 HEPATIC RESECTION
26. Cunningham JD, Fong Y, Shriver C, et al. One hundred consecutive
hepatic resections: Blood loss, transfusion, and operative technique. Arch
Surg 1994;129(10):1050–6.
27. Melendez JA, Arslan V, Fischer ME, et al. Perioperative outcomes of major
hepatic resections under low central venous pressure anesthesia: Blood
loss, blood transfusion, and the risk of postoperative renal dysfunction. J
Am Coll Surg 1998;187(6):620–5.
28. D’Angelica M, Fong Y, Weber S, et al. The role of staging laparoscopy in
hepatobiliary malignancy: prospective analysis of 401 cases. Ann Surg
Oncol 2003 Mar;10(2):183–9.
29. D’Angelica M, Maddineni S, Fong Y, et al. Optimal abdominal incision for
partial hepatectomy: increased late complications with Mercedes-type
incisions compared to extended right subcostal incisions. World J Surg
2006;30(3):410–8.
30. Blumgart L. Hepatic resection. In: Dudley HAF, Rob C, Smith of Marlow
RS, Pories WJ, eds. Rob & Smith’s operative surgery, 4th edn. London,
Boston: Butterworth Scientific, 1982:v.
31. Tung TT. Les Re?sections Majeures et Mineures du Foie. 1979.
32. Launois B, Jamieson GG. The posterior intrahepatic approach for hepa-
tectomy or removal of segments of the liver. Surg Gynecol Obstetrics
1992;174(2):155–8.
33. Launois B, Jamieson GG. The importance of Glisson’s capsule and its
sheaths in the intrahepatic approach to resection of the liver. Surg Gyne-
col Obstetrics 1992;174(1):7–10.
34. Hepp J, Couinaud C. [Approach to and use of the left hepatic duct in
reparation of the common bile duct.]. Presse Med. 1956;64(41):947–8.
35. Delva E, Camus Y, Nordlinger B, et al. Vascular occlusions for liver resec-
tions. Operative management and tolerance to hepatic ischemia: 142
cases. Ann Surg 1989;209(2):211–8.
36. Emond J, Wachs ME, Renz JF, et al. Total vascular exclusion for major
hepatectomy in patients with abnormal liver parenchyma. Arch Surg
1995;130(8):824–30; discussion 30–1.
37. Emre S, Schwartz ME, Katz E, Miller CM. Liver resection under total vas-
cular isolation. Variations on a theme. Ann Surg 1993;217(1):15–19.
38. Hannoun L, Borie D, Delva E, et al. Liver resection with normothermic
ischaemia exceeding 1 h. Br J Surg. 1993;80(9):1161–5.
39. Nakamura S, Tsuzuki T. Surgical anatomy of the hepatic veins and the
inferior vena cava. Surgery Gynecol Obstetrics 1981;152(1):43–50.
40. Fong Y, Blumgart LH. Useful stapling techniques in liver surgery. J Am
Coll Surgeons 1997;185(1):93–100.
41. Fong Y, Brennan MF, Brown K, Heffernan N, Blumgart LH. Drainage is
unnecessary after elective liver resection. Am J Surg 1996;171(1):158–62.
42. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Le Foie: Etudes
Anatomiques et Chirurgicales. 1957.
43. Goldsmith NA, Woodburne RT. The surgical anatomy pertaining to liver
resection. Surg Gynecol Obstet 1957;105:310–8.
44. Starzl TE, Iwatsuki S, Shaw BW, Jr, et al. Left hepatic trisegmentectomy.
Surg Gynecol Obstet 1982;155(1):21–7.
45. Starzl TE, Koep LJ, Weil R, 3rd, et al. Right trisegmentectomy for hepatic
neoplasms. Surg Gynecol Obstet 1980;150(2):208–14.
46. Chik BH, Liu CL, Fan ST, et al. Tumor size and operative risks of extended
right-sided hepatic resection for hepatocellular carcinoma: implication
for preoperative portal vein embolization. Arch Surg 2007;142(1):63–9;
discussion 9.
47. Lai EC, Fan ST, Lo CM, Chu KM, Liu CL. Anterior approach for difficult
major right hepatectomy. World J Surg 1996;20(3):314–7; discussion 8.
48. Lai ECS, Fan ST, Lo CM, et al. Hepatic resection for hepatocellular carci-
noma: An audit of 343 patients. Ann Surg 1995;221(3):291–8.
49. Belghiti J, Guevara OA, Noun R, Saldinger PF, Kianmanesh R. Liver hang-
ing maneuver: a safe approach to right hepatectomy without liver mobili-
zation. J Am Coll Surg 2001;193(1):109–11.
50. Couinaud C. Bases anatomiques des hepatectomies gauche et droite
reglees. J Chir 1954;70:933–66.
51. Zorzi D, Mullen JT, Abdalla EK, et al. Comparison between hepatic wedge
resection and anatomic resection for colorectal liver metastases. J Gastro-
intest Surg 2006;10(1):86–94.
52. DeMatteo RP, Palese C, Jarnagin WR, et al. Anatomic segmental hepatic
resection is superior to wedge resection as an oncologic operation for
colorectal liver metastases. J Gastrointest Surg 2000;4(2):178–84.
53. Polk W, Fong Y, Karpeh M, Blumgart LH. A technique for the use of
cryosurgery to assist hepatic resection. J Am Coll Surg 1995;180(2):-
171–6.
54. Mizumoto R, Suzuki H. Surgical anatomy of the hepatic hilum with
special reference to the caudate lobe. World J Surg 1988;12(1):2–10.
55. Heloury Y, Leborgne J, Rogez JM, et al. The caudate lobe of the liver. Surg
Radiol Anat 1988;10(1):83–91.
56. Takayama T, Makuuchi M. Intraoperative ultrasonography and
other techniques for segmental resections. Surg Oncol Clin N Am
1996;5(2):261–9.
57. Lerut J, Gruwez JA, Blumgart LH. Resection of the caudate lobe of the
liver. Surgery Gynecol Obstetrics 1990;171(2):160–2.
58. Hata F, Hirata K, Murakami G, Mukaiya M. Identification of segments VI
and VII of the liver based on the ramification patterns of the intrahepatic
portal and hepatic veins. Clin Anat 1999;12(4):229–44.
35
4 Ultrasound for HPB disorders
Duan Li and Lucy Hann
introduction
Ultrasound is the initial study of choice in most clinical situa-
tions due to the lack of ionizing radiation, relatively low cost,
and accessibility in varied settings such as at the bedside or in
the operating suite. Ultrasound differs from other cross-
sectional imaging techniques in that it uses sound propagation
and reflection from interfaces within tissue for imaging.
Images are generated by piezoelectric material within the
transducer that transmits and receives the sound signal. Higher
frequency transducers provide the best resolution, but high
frequencies are attenuated more rapidly in tissue. For that rea-
son, transducer frequency is selected for the application.
Superficial structures are evaluated at frequencies in the range
of 6 to 18 MHz and transabdominal ultrasound, which
requires better penetration, typically uses frequencies ranging
from 3 to 6 MHz.
Doppler is a unique feature of ultrasound for imaging ves-
sels and blood flow. When moving blood is insonated, the fre-
quency of the returning signal is proportional to blood
velocity. A cursor is placed over a specific blood vessel and
images are obtained in both gray scale and Doppler (termed
“Duplex scanning”). The Doppler information can then be
displayed in three different formats: (1) spectral Doppler, (2)
color Doppler, and (3) power Doppler. Spectral Doppler shows
a waveform with velocity changes and flow direction over
time. Color Doppler displays mean velocities and direction of
flow within vessels. The color codes assigned for velocities are
usually displayed in the upper left aspect of the image. Power
Doppler gives the amplitude of the Doppler signal without
direction or frequency information; since it is not angle-
dependent, it is very useful for imaging low flow and
tortuous vessels.
Ultrasound contrast agents further improve applications for
vascular imaging. Current contrast agents use microbubbles
encapsulated within thin lipid spheres. After intravenous
injection, the microbubbles remain intravascular and do not
diffuse into the interstitium as do MRI and CT contrast agents.
After a low-power ultrasound signal is applied, the microbub-
bles oscillate (expand and contract) at harmonic frequencies
that are detected by the transducer (1,2). With these ultra-
sound contrast agents, it is now possible to image tumor vas-
culature in exquisite detail (3–7) (Fig. 4.1).
Despite the versatility of ultrasound, there are limitations.
Sound is reflected at bone and air interfaces so scans are
obtained from different positions to avoid intestinal air or rib
artifact. This lack of standardized perspective compared to
axial imaging format of CT and MRI may present difficulty for
referring clinicians who are unfamiliar with the technique. To
lessen bowel gas interference, 6-hour fast is recommended to
improve visualization of the pancreas and liver and to provide
sufficient gallbladder distension. Another significant limitation
36
is that ultrasound is operator-dependent; skilled technologists
and radiologists are essential since diagnosis is made at image
acquisition. For best results, the surgeon should communicate
to the radiologist the specific clinical questions so that appro-
priate targeted images can be obtained at the time of the
examination.
This chapter will discuss ultrasound applications for diag-
nosis of hepatic, gallbladder, biliary, and pancreatic abnormal-
ities. The role of specialized ultrasound techniques such as
endoscopic ultrasound and intraoperative ultrasound will also
be addressed.
liver
Anatomically the liver is divided into sectors that are defined
by the scissurae that contain the hepatic veins; these sectors are
then subdivided into individual hepatic segments that each
contain intact portal and arterial inflow and hepatic venous
outflow and draining bile ducts (8,9). Ultrasound hepatic
anatomy is shown in Fig. 4.2.
Diffuse Liver Disease
Diffuse liver abnormalities include fatty infiltration, hepatitis,
and cirrhosis. Hepatic steatosis is present in 17% to 33% of the
general population and in 70% of overweight individuals (10).
On ultrasound, the liver has diffusely increased echogenicity
and in advanced cases significant sound beam attenuation
obscures the deep liver. Areas of focal sparring may be seen
anterior to the portal confluence and adjacent to the gallblad-
der. Hepatic steatosis impacts perioperative outcome and
accurate preoperative diagnosis would be useful (11). Fatty
infiltration increases liver stiffness, which can be measured by
tissue displacement in response to the transmitted ultrasound
wave. These elastography techniques hold promise for diagno-
sis of diffuse infiltrative liver diseases such as hepatic steatosis
and early-stage hepatic fibrosis (12–14).
Focal Hepatic Lesions
Cystic lesions
Ultrasound is the best modality to differentiate cystic from
solid liver masses and to determine the internal architecture
of cystic lesions. Simple cysts, found in 2% to 3% of patients
(15), have thin wall, no internal echoes, and bright posterior
enhancement. Even if the cyst is lobulated or has thin septa-
tion, benign diagnosis can be made (16). Symptomatic large
simple cysts may be treated with ultrasound-guided aspira-
tion and sclerosis (15,17), but it is extremely important to
assess the cyst wall. Mural nodularity, thick tumor rim, and
internal vascularity may indicate neoplasm such as biliary
cystadenoma and these lesions should not be unroofed or
aspirated since complete surgical resection is required. Cystic
liver metastases present as complex cysts often with solid or
 ULTRASOUND FOR HPB DISORDERS
(A)
Figure 4.1 Microbubble contrast enhanced ultrasound image of a hypervascular liver mass. (A) Contrast enhanced image shows the intense hypervascularity of
this liver lesion (arrow) that proved to be focal nodular hyperplasia. (B) The lesion (arrows) is subtle on the corresponding grayscale image. (Complements of
Siemens Medical Solutions, Ultrasound Division. Malvern, PA.)
irregular rim. These are typically from sarcoma, cystadeno-
carcinomas of the ovary and pancreas, and mucinous colon
carcinoma primaries (16,18). Ovarian metastases are charac-
teristically peripheral implants. Squamous cell tumors with
necrosis appear as cystic masses and other metastases may
cavitate in response to chemotherapy.
The appearance of cyst contents on ultrasound can be used
for differential diagnosis. Pyogenic abscess initially may be
echogenic and later liquified with debris, fluid-fluid levels, and
irregular wall (Fig. 4.3). Echogenic reflections with reverbera-
tions, seen in 20% to 30% of cases, suggest air within the
abscess (18). The classic echinococcal cyst is a complex cyst
with well-defined wall, containing double echogenic lines.
Multiple, internal echogenic foci, “snowstorm signs” settle in
the dependent portions of the cyst. Localized splits in the cyst
wall, with floating, undulating membranes, are also character-
istic and the cyst wall may calcify (19,20). Hematomas in the
acute stage may be echogenic and then they have layering low-
level echoes from blood, and later become honeycombed with
septation. When a preexisting cyst becomes hemorrhagic,
internal septation may be thick and irregular, but they float
freely in real-time and are not rigid.
Solid Liver Lesions
Solid liver lesions are further characterized by lesion echo-
genicity, vascularity, and peripheral halo. Definitive diagnosis
of benignity can be made for hemangiomas, focal fatty infiltra-
tion, and focal fatty sparing because of their classic ultrasound
features. Benign focal nodular hyperplasia can also be identi-
fied when the characteristic “spokewheel” vascular pattern, tor-
tuous feeding artery, and marked hypervascularity are seen on
contrast-enhanced ultrasound or Doppler images (Fig. 4.1).
Hypoechoic liver masses and lesions with a peripheral halo are
suspicious for malignancy. Although CT and MRI are used for
tumor staging, there can be added benefit from ultrasound to
(B)
(1) assess lesions that are “too small to characterize” by CT,
(2) define the relationship of tumor to bile ducts, and (3) evalu-
ate vascular encasement and tumor margin (Fig. 4.4).
Typical hemangioma, seen in 70% to 80% of cases, is a uni-
formly echogenic mass with sharp margin (21) (Fig. 4.5A). The
multiple vascular interfaces within the hemangioma cause the
increased echogenicity and margin is well-demarcated since
histopathologically hemangiomas lack a capsule. Hemangio-
mas have absent or minimal flow on Doppler imaging; they are
never hypervascular. Another common appearance of heman-
gioma is a mass with thin peripheral echogenic rim with mixed
central echogenicity (Fig. 4.5B). Giant hemangiomas > 5 cm
often lack these characteristic ultrasound features because of
central fibrosis, necrosis, and myxomatous degeneration. A
study of 213 patients with typical hemangioma appearance and
without risk for hepatic malignancy found only one patient
with malignancy on long term follow-up and concluded that
typical hemangiomas in low-risk patients do not require fol-
low-up (22). This rule does not apply to patients with cirrhosis,
hepatitis, or chronic liver disease that places them at increased
risk for hepatocellular carcinoma, nor does it apply to patients
who already have malignancies, and particularly not to those
with primary tumors that exhibit echogenic metastases.
Caturelli et al. (23) studied 2,000 patients with cirrhosis. Of
these, 44 had hemangioma-like lesions. On follow-up, half
proved to be hepatocellular carcinomas and half hemangiomas.
Thus, in patients at risk for hepatocellular carcinoma, any
echogenic lesion merits further evaluation or follow-up.
Other benign conditions such as focal fatty infiltration and
focal sparing are diagnosed by geographic margins and typical
location in segment 4 anterior to the portal vein bifurcation or
less commonly, adjacent to the gallbladder. Focal fat appears
echogenic relative to normal liver and areas of focal sparing are
less echogenic than fatty infiltrated liver. A useful finding
on Doppler evaluation is that vessels cross undisturbed
37
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

without displacement through areas of focal fat or focal
sparring (24,25).
A hypoechoic halo around a liver lesion indicates a clinically
significant mass, suspicious for malignancy, including hepato-
cellular carcinoma and hepatic adenoma and metastases from
colorectal, gastrointestinal, neuroendocrine, renal cell, chorio-
carcinoma, and vascular primaries such as Kaposi sarcoma
(Fig. 4.4). Pathologically, the halo is caused by proliferating
malignant cells, compression of the liver parenchyma, and
dilated sinusoids. The hypoechoic halo sign has a 95% positive
predictive value and an 87% negative value for differentiating
metastases from hemangioma (26,27). A hypoechoic halo may
be seen even in small lesions <1.5 cm. The halo is detected
when the tumor is hyperechoic relative to the surrounding
liver. In hypoechoic tumors, the lesion and the halo have the
similar echogenicity and therefore the halo sign is not evident.
Hepatocellular carcinoma (HCC) has a variable sonographic
appearance ranging from hypoechoic to echogenic, but a
hyperechoic lesion with hypoechoic halo is the common pre-
sentation. Small satellite tumors are typically hypoechoic.
Doppler evaluation is the key in diagnosing HCC since the
tumor is hypervascular and invasion of the portal or hepatic

(A) (B)

(C) (D)

(E)
Figure 4.2 Normal liver anatomy. (A) Transverse view of the right lobe. The middle hepatic vein separates the right from left hepatic lobes. The right hepatic vein
divides the right anterior sector (segments 8 and 5) and the right posterior sector (segments 7 and 6). R = right hepatic vein, M = middle hepatic vein, IVC =
inferior vena cava. (B) Longitudinal view of the right lobe reveals the right hepatic vein RHV and the hepatic segments. RK = right kidney. (C) Transverse view of
the portal vein bifurcation. Segments are numbered. R = right portal vein, L = left portal vein, RK = right kidney, IVC = inferior vena cava, A = aorta. (D) Longi-
tudinal view of the left lobe. The left hepatic vein separates the posterior left sector segment 2 from the anterior sector (segments 3 and 4). The caudate, segment 1,
is demarcated anteriorly by the fissure for the ligamentum venosum (arrowhead) and the inferior vena cava posteriorly. IVC = inferior vena cava. RPV = right
portal vein. (E) Color Doppler sagittal image of the portal vein reveals hepatopetal flow.

38
 ULTRASOUND FOR HPB DISORDERS

veins is very common; about 40% of patients have portal
venous involvement and 25% show hepatic venous involve-
ment (28). Flow within the tumor is usually of high velocity
and low resistance due to arterial-venous shunting within the
tumor. Tumor thrombus from HCC can be distinguished from
bland thrombus when arterial flow is detected within the
thrombus (29). With ultrasound contrast agents, the hyper-
vascularity and dysmorphic vessels in HCC are more apparent
and there is washout in the portal venous phase.
Hypoechoic liver masses are suspicious for malignancy.
Liver metastases that are hypoechoic are most commonly from
breast, lung, esophagus, stomach, pancreas, and non-Hodgkin
lymphoma.

gallbladder and bile ducts

Figure 4.3 A 50-year-old woman several years postpancreaticoduodenectomy
for duodenal carcinoid developed fever after hepatic artery embolization for
control of hepatic metastases. Right hepatic liquified abscess (asterisk) with
posterior acoustic enhancement (arrowhead). Small posterior solid metastases
(small arrows) are also seen.
Ultrasound is the procedure of choice for evaluation of the
gallbladder and bile ducts. Gallstones are mobile, echogenic,
and have posterior acoustic shadows (Fig. 4.5). The shadow-
ing is present with or without gallstone calcification; it is
due to the acoustic mismatch between stone and surround-
ing bile. Stones <3 mm may not generate a shadow because
of small size. Gallstones move quickly with positional varia-
tion in contrast to sludge, which moves slowly and lacks an
acoustic shadow. Gallbladder polyps do not shadow and
they are fixed in position. Management of gallbladder pol-
yps depends on size and sonographic appearance. Choles-
terol polyps, usually <5 mm and multiple, do not progress as
shown in long-term studies, but larger polyps 1 cm or
greater or those with irregular margins are at risk for malig-
nancy (30,31).

(A) (B)
Figure 4.4 Colorectal metastasis to left hepatic lobe was evident on ultrasound but not by CT done the same day. (A) The lateral left lobe was considered negative
on CT. (B) Longitudinal ultrasound revealed a segment II metastases with peripheral halo (calipers) consistent with malignant lesion.

(A) (B)
Figure 4.5 Hemangioma. (A) Typical hemangioma (arrow) is uniformly echogenic with no surrounding halo. (B) An atypical hemangioma with a thin bright rim
(arrow) is shown in this longitudinal view of the right hepatic lobe. Another hemangioma (arrowhead) is noted peripherally.

39
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Normal gallbladder wall thickness is <3 mm. Mural thicken-
ing may occur with adenomyomatosis, inflammation, or neo-
plasm. Adenomyomatosis may be focal mass (adenomyoma)
or diffuse thickening and gallbladder deformity with hour-
glass configuration. Ring down artifact from cholesterol crys-
tals in Aschoff–Rokitansky sinuses is a diagnostic ultrasound
feature of adenomyomatosis. Acute cholecystitis causes diffuse
or focal gallbladder wall thickening with a layered appearance
and in severe cases, the sloughed mucosa may be seen (Fig. 4.6).
Marked edema in the pericholecystic space may mimic
acute cholecystitis in patients with pancreatitis or hepatic
inflammation.
It is essential to carefully evaluate the gallbladder wall to
exclude gallbladder carcinoma that may coexist with stones
(Fig. 4.7). This is particularly important in patients being con-
sidered for laparoscopic cholecystectomy since surgical man-
agement of gallbladder carcinoma usually requires hepatic
resection and recurrences in laparoscopic port sites are fre-
quent (32). Gallbladder carcinoma may cause focal thickening
or may obliterate the gallbladder lumen. Associated tumor
extension into hepatic segments 4 and 5 and biliary obstruc-
tion at the hilus are common.
Ultrasound is sensitive for detection of biliary dilation and
to determine level of obstruction. Dilated intrahepatic bile

(A) (B)

(C)
Figure 4.6 Acute cholecystitis in a 56-year-old woman with abdominal pain. (A) Longitudinal view reveals a laminated appearance to the anterior gallbladder wall
(arrowheads) and gallstone (arrow) with posterior acoustic shadow. (B) Transverse view shows thickened wall at 6 mm (calipers). (C) Longitudinal color Doppler
image reveals vascular flow within the gallbladder wall.

(A) (B)
Figure 4.7 Gallbladder carcinoma. (A) Longitudinal and (B) transverse sonogram of the gallbladder reveals a stone (arrowhead) with acoustic shadowing. The
anterior fundus is narrowed and surrounded by hypoechoic soft tissue that infiltrates the adjacent liver (arrows).

40
 ULTRASOUND FOR HPB DISORDERS
ducts produce the double duct sign and dilation of the com-
mon bile duct >6 mm is considered abnormal. There has been
controversy regarding the size of the common bile duct with
increasing age and postcholecystectomy, but recent studies
have shown that even in the elderly, 98% of ducts are <6 mm
and there is no compensatory dilation of the common duct
after cholecystectomy (33–36).
Cholangiocarcinomas cause biliary obstruction in character-
istic patterns. Intrahepatic cholangiocarcinoma arises from the
peripheral bile ducts and bile duct obstruction peripheral to
the tumor is seen in almost one third of the cases. These tumors
are also typically hypovascular, in contrast to HCC. Hilar chol-
angiocarcinoma are typically smaller since their critical loca-
tion produces early jaundice. Associated vascular encasement is
evident in nearly 50% of the cases (37). Ultrasound is useful for
tumor staging that is determined by location of tumor along
the ducts and the extent of vascular involvement (38).
pancreas
The echotexture of the normal pancreas is uniform and slightly
higher echogenicity than liver. With aging and obesity, fatty
infiltration of the pancreas may further increase echogenicity.
The pancreatic duct is best seen transversely and is normally
less than 2 mm in the body and 3 mm in the head (39).
Diffuse Pancreatic Diseases
In acute pancreatitis, the pancreas may become enlarged and
hypoechoic with indistinct margins from edema. The edema
may involve the entire gland or only a portion, usually the
head. Peripancreatic fluid is a useful diagnostic feature; fluid
and vascular mural thickening may also be observed (40)
(Fig. 4.8). Pancreatic duct may be dilated. In the most acute
stage, ileus limits ultrasound visualization and CT is more use-
ful, but ultrasound has a role to exclude biliary calculi as an
etiology for the pancreatitis (41–44). Severe inflammation
progresses to inflammatory pancreatic mass or phlegmon with
fluid collection, hemorrhage, and necrosis. Fluid is commonly
seen within the lesser sac, anterior pararenal spaces, transverse
mesocolon, small bowel mesentery, and parapancreatic spaces
(45). Pseudocysts may persist for a minimum of 4 weeks after
Figure 4.8 Acute pancreatitis in a patient with AIDS. Transverse sonogram of
the pancreas reveals heterogeneous pancreatic parenchyma and edema of the
splenic vein (arrow). The vein has a layered appearance with a ring of
hypoechoic fluid within the wall of the vessel. Fluid also is seen in the peripan-
creatic space (arrowheads).
the onset of pancreatitis (46). Identification of infected pseu-
docyst is limited, but the presence of echogenic foci corre-
sponding to gas bubbles is suggestive of infection. If there is
clinical suspicion, ultrasound can provide image guidance for
fluid aspiration or drainage. Venous thrombosis and pseudoa-
neurysms that occur secondary to pancreatitis can also be
evaluated sonographically.
Ultrasound findings in chronic pancreatitis include altera-
tion of texture, calcification, pancreatic duct, and/or bile duct
dilation, and chronic pseudocyst. The gland is usually atrophic
and heterogeneous. Calcification, either focal or diffuse, and
pancreatic duct dilation are the most classic sonographic fea-
tures (47). When findings of chronic pancreatitis mimic neo-
plasm with ductal dilation, CT or MRI is needed to make the
distinction.
Pancreatic Neoplasms
Characterization of pancreatic masses, aspiration and biopsy
are increasingly being done with endoscopic ultrasound
(EUS). Miniature ultrasound transducers mounted on endo-
scopes display radial or linear images of the pancreas. EUS is
more sensitive for detection of small masses and biopsy can be
performed through the posterior gastric wall (48).
Adenocarcinoma appears on ultrasound as a focal mass with
atrophy and pancreatic duct dilation distal to the mass. Vascu-
lar invasion is frequent and bile ducts are dilated commonly
for masses in the pancreatic head. Ultrasound is considered
reliable for diagnosis of nonresectable tumors and in such
cases further imaging is not required; evaluation can proceed
directly to biopsy for tissue diagnosis (40,49) (Fig. 4.9). Stag-
ing of pancreatic adenocarcinoma by EUS and CT were com-
pared in a prospective study by DeWitt (50). EUS had higher
sensitivity than CT for tumor detection (98% vs. 86%), better
staging accuracy (67% vs. 41%), and both techniques were
equivalent for nodal status. EUS is also useful for biopsy espe-
cially when CT-guided biopsy is negative. In a prospective
study of patients with negative CT-guided biopsy of pancre-
atic masses, EUS biopsy had 95% sensitivity and 100% speci-
ficity for diagnosis (51).
Neuroendocrine tumors such as insulinomas and gastrino-
mas usually have classical symptoms. When tumors are small,
abdominal ultrasound is limited, but laparoscopic ultrasound
and intraoperative ultrasound are extremely useful for tumor
detection (52,53). Approximately one-third of endocrine
tumors are nonfunctioning and these tumors are more likely
malignant.
Cystic pancreatic neoplasms (serous microcystic adenomas,
mucinous adenomas, and solid and cystic pseudopapillary
tumors) are best evaluated with EUS. Serous microcystic ade-
nomas are benign tumors with multiple cysts ranging in size
from 1 mm to 2 cm. These tumors may appear solid on ultra-
sound because of numerous interfaces produced by the micro-
scopic cyst walls (54–57). Macrocystic mucinous tumors of the
pancreas are malignant or potentially malignant and have
cysts >2 cm. The cysts may have thick septation, mural nod-
ules, and calcification may be present (47,56). It is not possible
to distinguish between benign and malignant mucinous
tumors, but in general, larger cysts and cystic masses with
41
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
(A)
(C)
Figure 4.9 Unresectable pancreatic adenocarcinoma. (A) Longitudinal ultrasound image of the pancreas shows an enlarged pancreatic head (m) and dilated com-
mon bile duct (arrow), PV = portal vein, IVC = inferior vena cava. (B) Transverse sonogram reveals the pancreatic head mass (m) and dilated pancreatic duct
(arrows) anterior to the splenic vein (SV). IVC = inferior vena cava, a = aorta. (C) Transverse sonogram reveals a left hepatic metastasis (arrows). R = right hepatic
vein, M = middle hepatic vein, IVC = inferior vena cava.
significant solid component are more likely to be malignant
(47,55,58). Aspirates of cystic lesions are relatively acellular
but fluid analysis for tumor markers is useful. Brugge et al.
(59) reported that elevated cyst fluid CEA level had 79%
accuracy for diagnosis of mucinous tumors.
intraoperative ultrasound
Intraoperative ultrasound (IOUS) is an important tool for (1)
assessment of tumors at the time of resection, (2) vascular map-
ping during hepatic resection or live split liver donor transplan-
tation, and (3) guidance during intraoperative tumor ablation
or biopsy (60–64) (Fig. 4.10). During hepatic resection, IOUS is
used to characterize liver lesions that are indeterminate or occult
on preoperative imaging. IOUS can accurately assess tumor
extent relative to vascular structures and bile ducts (65–68); this
is important since approximately 1 to 2 cm margin should be
available between the tumor and vessels for optimal surgical
outcome and vessel encasement or thrombosis may alter surgi-
cal approach (69–72). A prospective study by Cerwenka et al.
(73) evaluated the role of IOUS in patients who had partial hep-
atectomy after standardized hepatic protocol preoperative MRI.
Small additional lesions with mean size of 1.5 cm were found by
IOUS in 7% of patients and in 5% of patients IOUS findings
altered surgical strategy (73,74). IOUS altered management in
20% of patients who had resection for primary or secondary
hepatic malignancies. Even with recent improvements in cross-
sectional imaging, there was no significant difference in resection
42
(B)
rate (72%), detection of unrecognized additional tumors (20%
vs. 14% p=0.70), or detection of vascular involvement when
groups in the years1999 to 2003 and 2003 to 2005 were
compared (68,74–76).
Special dedicated high-frequency (5–10 MHz) transducers
are required for IOUS; these transducers can be applied
directly on the area of interest to improve resolution com-
pared to transabdominal ultrasound, which is limited by dis-
tance and abdominal wall artifact. Typically IOUS probes are
small T-shaped linear and hockey-stick-shaped probes, which
are easy to manipulate within restricted operative fields.
Transducer specifications should include good near field res-
olution and Doppler capabilities. It is preferable to have the
scanner connected to the hospital network to provide (1)
access for consultation at remote sites during real-time scan-
ning and (2) permanent image archiving in the electronic
record.
Review of preoperative imaging is essential before IOUS since
preoperative planning increases the efficiency of the procedure.
While performing IOUS, the surgeon should avoid applying
excessive pressure. If vessels become compressed, it is difficult to
assess patency or encasement. Light touch with the transducer
can be used as a palpation method to differentiate between soft
benign lesions such as hemangiomas, focal fat, and fat sparing
versus malignant lesions, which are usually firm (77,78).
IOUS may be limited for lesions in the high right lobe or in
the posterior subdiaphragmatic location where access is
 ULTRASOUND FOR HPB DISORDERS

(A) (B)

(C)
Figure 4.10 Intraoperative ultrasound reveals additional hepatic lesions. (A) A 2 cm segment 7 liver lesion (arrows) with peripheral halo and (B) an 8 mm
segment 6 lesion (arrow) were seen on preoperative imaging. (C) A nonpalpable 6 mm lesion (arrow) in segment 4A was not evident on preoperative imaging.
Lesions were resected with diagnosis of metastatic neuroendocrine carcinoma; primary site later identified in the pancreas. (Complements of Robert A. Kane,
M.D., Professor of Radiology, Harvard Medical School, Chief, Body and Abdominal Ultrasound Imaging, Beth Israel Deaconess Medical Center, Boston, MA.)

difficult. In that situation, scanning from the opposite surface
of the liver may improve visualization. Artifacts in the near
field of the image may also obscure lesions near the hepatic
surface. If this occurs, the surgeon can immerse the liver in a
sterile saline bath, thereby changing the focus zone to better
visualize the superficial anatomy. Another difficulty may be
encountered when attempting to visualize lesions near a surgi-
cal margin. Echogenic foci from air bubbles in the parenchyma
after cauterization or radiofrequency ablation may mimic
echogenic mucin-containing colorectal metastases. This pitfall
can be mitigated by imaging before intervention to accurately
determine number, size, and location of lesions (79–81).
New advances in intraoperative and interventional ultra-
sound techniques now allow fusion of ultrasound, CT, and
MRI images and electromagnetic tracking to more precisely
localize lesions for biopsy and thermal ablation procedures.
For example, after initial CT data is entered, information
from electromagnetic sensors is applied onto the needle
device and the patient can guide the needle track in real time
even when the needle is out of the ultrasound imaging plane.
This process brings two data sets into spatial alignment. Such
techniques have shown improved needle tracking for
interventional procedures and better three-dimensional visu-
alization of tumor and treatment zone during radiofrequency
ablation (63,82–84).
references
1. Cosgrove D. Ultrasound contrast agents: an overview. Eur J Radiol 2006;
60(): 324–30.
2. Wilson SR, Burns PN, Muradali D,et al. Harmonic hepatic US with
microbubble contrast agent: initial experience showing improved charac-
terization of hemangioma, hepatocellular carcinoma, and metastasis.
Radiology 2000;215(1):153–61.
3. Albrecht T, Blomley MJ, Burns PN, et al. Improved detection of hepatic
metastases with pulse-inversion US during the liver-specific phase of
SHU 508A: multicenter study. Radiology. 2003; 227(2): 361–70.
4. Ascenti G, Mazziotti S, Zimbaro G, et al. Complex cystic renal masses:
characterization with contrast-enhanced US. Radiology 2007; 243(1):
158–65.
5. Burns PN, Wilson SR. Focal liver masses: enhancement patterns on con-
trast-enhanced images--concordance of US scans with CT scans and MR
images. Radiology 2007; 242(1): 162–74.
6. Correas JM, Claudon M, Tranquart, et al. The kidney: imaging with
microbubble contrast agents. Ultrasound Q 2006; 22(1): 53–66.
7. Kabakci N, Igci E, Secil M, et al. Echo contrast-enhanced power Doppler
ultrasonography for assessment of angiogenesis in renal cell carcinoma. J
Ultrasound Med 2005; 24(6): 747–53.

43
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
8. Couinaud C. Le Foi: Etudes Anatomogiques et Chirurgicales. Paris:
Masson, 1957.
9. Lafortune M, Madore F, Patriquin H, et al. G. Segmental anatomy of the
liver: a sonographic approach to the Couinaud nomenclature. Radiology
1991; 181(2): 443–8.
10. Caballeria L, Auladell MA, Toran P, et al. Risk factors associated with non-
alcoholic fatty liver disease in subjects from primary care units. A case-
control study. BMC Gastroenterol 2008; 8: 44.
11. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on periopera-
tive outcome following hepatic resection. J Gastrointest Surg 2003; 7(8):
1034–44.
12. Fahey BJ, Nightingale KR, Nelson RC, et al. Acoustic radiation force
impulse imaging of the abdomen: demonstration of feasibility and utility.
Ultrasound Med Biol 2005; 31(9): 1185–98.
13. Kim DY, Kim SU, Ahn SH, et al. Usefulness of FibroScan for detection of
early compensated liver cirrhosis in chronic hepatitis B. Dig Dis Sci 2008;
54(8): 1758–63.
14. Yoneda M, Mawatari H, Fujita K, et al. Noninvasive assessment of liver
fibrosis by measurement of stiffness in patients with nonalcoholic fatty
liver disease (NAFLD). Dig Liver Dis 2008; 40(5): 371–8.
15. Marn CS, Bree RL, Silver TM. Ultrasonography of liver. Technique and
focal and diffuse disease. Radiol Clin North Am 1991; 29(6): 1151–70.
16. Middleton W. There are nonhyperechoic lesions in the liver: What does
that mean? In: RSNA, editor. Categorical Course in Diagnostic Radiology:
Findings at US—What do they mean? Oak Brook, IL: Radiological Society
of North America, 2002. pp. 79–90.
17. Saini S, Mueller PR, Ferrucci JT, Jr.,et al. RJ. Percutaneous aspiration of
hepatic cysts does not provide definitive therapy. AJR Am J Roentgenol
1983; 141(3): 559–60.
18. Mortele KJ, Ros PR. Cystic focal liver lesions in the adult: differential CT
and MR imaging features. Radiographics 2001; 21: 895–910.
19. Czermak BV, Unsinn KM, Gotwald T, et al. Echinococcus multilocularis
revisited. AJR Am J Roentgenol 2001; 176(5): 1207–12.
20. Pedrosa I, Saiz A, Arrazola J, et al. . Hydatid disease: radiologic and patho-
logic features and complications. Radiographics 2000; 20(3): 795–817.
21. Charboneau J. There is a hyperechoic mass in the liver. What does that
mean? Categorical Course in Diagnostic Radiology: Findings at US—
What Do They mean? RSNA; 2002: 73–8.
22. Liefer KM, Koster MI, Wang XJ, et al. Down-regulation of p63 is required
for epidermal UV-B-induced apoptosis. Cancer Res 2000; 60(15): 4016–20.
23. Caturelli E, Pompili M, Bartolucci F, et al. Hemangioma-like lesions in
chronic liver disease: diagnostic evaluation in patients. Radiology 2001;
220(2): 337–42.
24. Quinn SF, Gosink BB. Characteristic sonographic signs of hepatic fatty
infiltration. AJR Am J Roentgenol 1985; 145(4): 753–5.
25. Ralls PW, Mack LA. Spectral and color Doppler sonography. Semin Ultra-
sound CT MR 1992; 13(5): 355–66.
26. Kruskal JB, Thomas P, Nasser I, et al. Hepatic colon cancer metastases in
mice: dynamic in vivo correlation with hypoechoic rims visible at US.
Radiology 2000; 215(3): 852–7.
27. Wernecke K, Vassallo P, Bick U, et al. The distinction between benign and
malignant liver tumors on sonography: value of a hypoechoic halo. AJR
Am J Roentgenol 1992; 159(5): 1005–9.
28. Reinhold C, Hammers L, Taylor CR, et al. Characterization of focal
hepatic lesions with duplex sonography: findings in 198 patients. AJR Am
J Roentgenol 1995; 164(5): 1131–5.
29. Wilson SR, Withers CE. The liver. In: Rumack CM, Wilson SR, Char-
boneau JW, Johnson JM, eds. Diagnostic Ultrasound. St. Louis: Elsevier
Mosby, 2005: 77.
30. Levy AD, Murakata LA, Abbott RM, et al. From the archives of the AFIP.
Benign tumors and tumorlike lesions of the gallbladder and extrahepatic
bile ducts: radiologic-pathologic correlation. Armed Forces Institute of
Pathology. Radiographics 2002; 22(2): 387–413.
31. Terzi C, Sokmen S, Seckin S, et al. Polypoid lesions of the gallbladder:
report of 100 cases with special reference to operative indications. Surgery
2000; 127(6): 622–7.
32. Winston CB, Chen JW, Fong Y, et al. Recurrent gallbladder carcinoma
along laparoscopic cholecystectomy port tracks: CT demonstration. Radi-
ology 1999; 212(2): 439–44.
44
33. Perret RS, Sloop GD, Borne JA. Common bile duct measurements in an
elderly population. J Ultrasound Med 2000; 19(11): 727–30; quiz 31.
34. Wilkinson ML. Are dilating bile ducts a cause for concern? Gut 1999;
45(5): 637–8.
35. Skalicky M, Dajcman D, Hojs R. Effect of cholecystectomy for gallstones
on the surface of the papilla of Vater and the diamter of the common bile
duct. Eur J Gastroenterol Hepatol 2002; 14(4): 399–404.
36. Majeed AW, Ross B, Johnson AG. The preoperatively normal bile duct
does not dilate after cholecystectomy: results of a five year study. Gut
1999; 45(5): 741–3.
37. Are C, Gonen M, D’Angelica M, et al. Differential diagnosis of proximal
biliary obstruction. Surgery 2006; 140(5): 756–63.
38. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and out-
come in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;
234(4): 507–17; discussion 17–19.
39. Hadidi A. Pancreatic duct diameter: sonographic measurement in normal
subjects. J Clin Ultrasound 1983; 11: 17–22.
40. Ralls PW, Wren SM, Radin R, et al. Color flow sonography in evaluating
the resectability of periampullary and pancreatic tumors. J Ultrasound
Med 1997; 16(2): 131–40.
41. Balthazar EJ, Freeny PC, vanSonnenberg E. Imaging and intervention in
acute pancreatitis. Radiology 1994; 193(2): 297–306.
42. Balthazar EJ, Ranson JH, Naidich DP, et al. Acute pancreatitis: prognostic
value of CT. Radiology 1985; 156(3): 767–72.
43. Balthazar EJ, Robinson DL, Megibow AJ, et al. Acute pancreatitis: value of
CT in establishing prognosis. Radiology 1990; 174(2): 331–6.
44. Clavien P, Hauser H, Meyer P, et al. Value of contrast-enhanced computer-
ized tomography in the early diagnosis and prognosis of acute pancreati-
tis. Am J Surg 1988; 155: 457–66.
45. Jeffrey RB, Jr, Laing FC, Wing VW. Extrapancreatic spread of acute pan-
creatitis: new observations with real-time US. Radiology 1986; 159(3):
707–11.
46. Donovan PJ, Sanders RC, Siegelman SS. Collections of fluid after pancre-
atitis: evaluation by computed tomography and ultrasonography. Radiol
Clin North Am 1982; 20(4): 653–65.
47. Atri M, Finnegan PW. The pancreas. Ultrasound. St. Louis, MO: Mosby,
1998: 241–56.
48. Catalano MF, Lahoti S, Geenen JE, et al. Prospective evaluation of endo-
scopic ultrasonography, endoscopic retrograde pancreatography, and
secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc
1998; 48(1): 11–17.
49. Yassa NA, Yang J, Stein S, et al. Gray-scale and color flow sonography
of pancreatic ductal adenocarcinoma. J Clin Ultrasound 1997; 25(9):
473–80.
50. DeWitt J, Devereaux B, Chriswell M, et al. Comparison of endoscopic
ultrasonography and multidetector computed tomography for detecting
and staging pancreatic cancer. Ann Intern Med 2004; 141(10): 753–63.
51. Gress F, Gottlieb K, Sherman S, et al. Endoscopic ultrasonography—
Guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann
Int Med 2001; 134(6): 459–64.
52. Fendrich V, Bartsch DK, Langer P, et al. Diagnosis and surgical treatment
of insulinoma—experiences in 40 cases. Dtsch Med Wochenschr 2004;
129(17): 941–6.
53. Gorman B, Charboneau JW. Benign pancreatic insulinoma: preoperative
and intraoperative sonographics localization. AJR Am J Roentgenol 2003;
181: 787–92.
54. Buck JL, Hayes WS. From the archives of the AFIP. Microcystic adenoma
of the pancreas. Radiographics 1990; 10(2): 313–22.
55. Fugazzola C, Procacci C, Bergamo Andreis IA, et al. Cystic tumors of the
pancreas: evaluation by ultrasonography and computed tomography.
Gastrointest Radiol 1991; 16(1): 53–61.
56. Johnson CD, Stephens DH, Charboneau JW, et al. . Cystic pancreatic
tumors: CT and sonographic assessment. AJR Am J Roentgenol 1988; 151:
1133–8.
57. Friedman AC, Lichenstein JE, Dachman AH Cystic neoplasms of the pan-
creas. Radiology 1983; 149: 45–50.
58. Allen PJ, D’Angelica M, Gonen M, et al. A selective approach to the resec-
tion of cystic lesions of the pancreas: results from 539 consecutive
patients. Ann Surg 2006; 244(4): 572–82.
 ULTRASOUND FOR HPB DISORDERS
59. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of
pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst
study. Gastroenterology 2004; 126(5): 1330–6.
60. Torzilli G, Makuuchi M. Intraoperative ultrasonography in liver cancer.
Surg Oncol Clin N Am 2003; 12(1): 91–103.
61. Torzilli G, Montorsi M, Donadon M, et al. “Radical but conservative” is
the main goal for ultrasonography-guided liver resection: prospective
validation of this approach. J Am Coll Surg 2005; 201(4): 517–28.
62. Berber E, Garland AM, Engle KL, et al. Laparoscopic ultrasonography
and biopsy of hepatic tumors in 310 patients. Am J Surg 2004; 187(2):
213–8.
63. Kleemann M, Hildebrand P, Birth M, et al. Laparoscopic ultrasound navi-
gation in liver surgery: technical aspects and accuracy. Surg Endosc 2006;
20(5): 726–9.
64. Zacherl J, Scheuba C, Imhof M, et al. Current value of intraoperative sonog-
raphy during surgery for hepatic neoplasms. World J Surg 2002; 26(5):
550–4.
65. Jakimowicz JJ. Intraoperative ultrasonography in open and laparoscopic
abdominal surgery: an overview. Surg Endosc 2006; 20 Suppl 2: S425–35.
66. Kane RA. Intraoperative ultrasonography: history, current state of the art,
and future directions. J Ultrasound Med 2004; 23(11): 1407–20.
67. Minagawa M, Makuuchi M, Kubota K, et al. Intraoperative three-dimen-
sional visualization of liver vasculature by ultrasonography. Hepatogas-
troenterology 2004; 51(59): 1448–50.
68. Sahani DV, Kalva SP, Tanabe KK, et al. Intraoperative US in patients
undergoing surgery for liver neoplasms: comparison with MR imaging.
Radiology 2004; 232(3): 810–4.
69. Santambrogio R, Opocher E, Ceretti AP, et al. Impact of intraoperative
ultrasonography in laparoscopic liver surgery. Surg Endosc 2007; 21(2):
181–8.
70. Shukla PJ, Pandey D, Rao PP, et al. Impact of intra-operative ultrasonog-
raphy in liver surgery. Indian J Gastroenterol 2005; 24(2): 62–5.
71. Silberhumer GR, Steininger R, Laengle F, et al. Intraoperative ultrasonog-
raphy in patients who undergo liver resection or transplantation for hepa-
tocellular carcinoma. Surg Technol Int 2004; 12: 145–51.
72. Thaler K, Kanneganti S, Khajanchee Y, et al. The evolving role of staging
laparoscopy in the treatment of colorectal hepatic metastasis. Arch Surg
2005; 140(8): 727–34.
73. Cerwenka H. Intraoperative ultrasonography during planned liver resec-
tions remains an important surgical tool. Surg Endosc 2008; 22(4): 1137–8.
74. Ellsmere J, Kane R, Grinbaum R, et al.. Intraoperative ultrasonography
during planned liver resections: why are we still performing it? Surg
Endosc 2007; 21(8): 1280–3.
75. Long EE, Van Dam J, Weinstein S, et al. Computed tomography, endo-
scopic, laparoscopic, and intra-operative sonography for assessing resect-
ability of pancreatic cancer. Surg Oncol 2005; 14(2): 105–13.
76. Ravi K, Britton BJ. Surgical approach to insulinomas: are pre-operative
localization tests necessary? Ann R Coll Surg Engl 2007; 89(3): 212–7.
77. Kruskal JB, Kane RA. Intraoperative US of the liver: techniques and clini-
cal applications. Radiographics 2006; 26(4): 1067–84.
78. Machi J, Oishi AJ, Furumoto NL, et al.. Intraoperative ultrasound. Surg
Clin North Am 2004; 84(4): 1085–111.
79. Solbiati L, Ierace T, Tonolini M, et al. Guidance and monitoring of radio-
frequency liver tumor ablation with contrast-enhanced ultrasound. Eur J
Radiol 2004; 51 Suppl: S19–23.
80. Guimaraes CM, Correia MM, Baldisserotto M, et al. Intraoperative ultra-
sonography of the liver in patients with abdominal tumors: a new
approach. J Ultrasound Med 2004; 23(12): 1549–55.
81. Fan RF, Chai FL, He GX, et al. Laparoscopic radiofrequency ablation of
hepatic cavernous hemangioma. A preliminary experience with
27 patients. Surg Endosc 2006; 20(2): 281–5.
82. Wood BJ, Zhang H, Durrani A, et al. Navigation with electromagnetic
tracking for interventional radiology procedures: a feasibility study. J Vasc
Interv Radiol 2005; 16(4): 493–505.
83. Wood BJ, Locklin JK, Viswanathan A, et al. Technologies for guidance of
radiofrequency ablation in the multimodality interventional suite of the
future. J Vasc Interv Radiol 2007; 18(1 Pt 1): 9–24.
84. Krucker J, Xu S, Glossop N, et al. Electromagnetic tracking for thermal
ablation and biopsy guidance: clinical evaluation of spatial accuracy. J
Vasc Interv Radiol 2007; 18(9): 1141–50.
45
5 Liver surgery in elderly patients
Gerardo Sarno and Graeme J. Poston
introduction
The recent increase in the geriatric population in society and
increased life span have raised the expectation from surgeons
to expand their operative indications to include geriatric
patients. In liver surgery, the indications for hepatectomy have
been expanded to include patients aged 70 and older, and sev-
eral studies have demonstrated acceptable long-term survival
of elderly patients after such surgery (1,2). In 1937, Brooks
reported the results of surgery for 287 patients aged 70 and
older. The operative mortality rate was high (19%), and one-
third of patients who had abdominal operations died in hospi-
tal. Nevertheless, the author emphasized that with the rapid
growth of the elderly population, and prolonged life expec-
tancy, surgeons will increasingly be confronted with surgical
problems among the elderly and must therefore strive to
improve their results by studying physiologic processes in the
aged (2,3). In the seven decades since Brooks’ paper, advance-
ments in anesthesiology and intensive care, an increased
knowledge of liver physiology, surgical hepatic anatomy, and
resection techniques have encouraged hepatic resection in
elderly patients, achieving improved surgical outcomes.
Because of the high prevalence of liver cancers and aging of
the world population, the elderly population considered for
liver resection has increased (4,5). Also an effective multidisci-
plinary approach and better selection of elderly patients leads
to reduced age-related perioperative morbidity and mortality
(6). Moreover, the definition of “elderly patients” has been bet-
ter defined so avoiding unnecessary confusion that has gener-
ated over the past years.
Although advances in minimally invasive ablative techniques
have increased the treatment options for patients with malig-
nant hepatobiliary disease, liver resection remains the only
treatment demonstrated to offer long-term survival (7–9). Also
the past three decades have seen a dramatic decline in the mor-
tality rate after liver resection in selected elderly patients, which
is less than 5% in tertiary cancer care referral centers (2,6,10).
Colorectal cancer has become a major public health prob-
lem that increasingly affects older people (11), and because the
liver is the most common site of metastases, the number of
elderly so affected is increasing (12). Liver resection is also suc-
cessfully performed in aged patient suffering primary malig-
nancies such as hepatocellular carcinoma (HCC) with results
comparable to those seen in younger people.
In this chapter, we highlight the main advances performed
in liver surgery, taking into account all the issues that are still a
matter of debate for elderly patients with primary or meta-
static liver disease.
definition of “elderly patients”
The age at which persons become “elderly” depends on social,
environmental, and individual factors. Nowadays, after years
46
of arbitrary definition of “elderly,” in liver surgery the com-
mon practice is to identify as elderly a patient older than
70 years (6,13–18). This is due to the evidence of a rapid
decrease of liver mass and portal blood flow from 70 years
onward (17), which may affect liver function.
A limited life expectancy in the elderly might argue against
extending the indications for hepatectomy in these patients.
However, life expectancy for people aged between 80 and
85 years is still 8 years, and 6 years for those over 85 years old.
Moreover, the risk of cancer-related death diminishes with
increasing age; it is estimated to be 40% for those aged between
50 and 70 years, falling to 10% for those over 90 years old (19).
Recently, several studies reported comparable early and
long-term results between young and aged patients undergo-
ing liver resection. These studies highlighted that an age limit
does not exist to contraindicate liver resection. After a careful
evaluation of the operative risk, a similar chance of long-term
survival can be offered also to well-selected elderly patients.
age-related liver changes
The effects of aging on the human liver have not been clearly
determined (20). In general, aging is characterized by a pro-
gressive decline of cellular functions and also the liver under-
goes physiological changes. Although some recent studies have
shown that aging itself does not affect liver function, the
amount of hepatic tissue that can be safely removed, and the
consequent capacity of liver regeneration are often difficult to
be precisely assessed (14).
Aging has been shown to be associated with multiple changes
in hepatic function, however the clinically relevant biochemi-
cal parameters of liver function remain generally normal in
the elderly. Thus abnormalities of these parameters should be
evaluated for the presence of liver disease (21). As a matter of
fact, the liver function seems to be quite well maintained in old
age, but numerous age-related changes in hepatic structure
have been described (22).
However, there have been few comprehensive studies of liver
morphology during aging, and most of these have been per-
formed in rodents (20). The most frequently cited morpho-
logical change in the human liver is a decrease in size. In elderly
men, liver weight declines by about 6.5% and in women it
decreases by 14.3% (23), which may be attributable to decreased
hepatic blood flow (24–26). The decrease in blood flow is about
45% in subjects over 75 years when compared to those under
40 years (26,27). The classic gross appearance of the liver in
older persons is known as “brown atrophy.” The brown color is
due to accumulation of lipofuscin (ceroid) within hepatocyte
and also associated with major degree of steatosis (21). Altera-
tion in the hepatocyte morphology has been also described
(28). It has been reported that the liver in elderly humans has
histologically fewer, but larger hepatocytes (29).
 LIVER SURGERY IN ELDERLY PATIENTS
In addition, hepatic clearance of many drugs is reduced in
elderly persons (20,22). Traditional theories have attempted to
attribute this observation to age-related reduction in liver
mass and blood flow (24–26). More recently, it has been con-
sidered attributable to age-related changes in the sinusoidal
endothelium and space of Disse, which may restrict the avail-
ability of oxygen and other substrates (30). Several other
mechanisms have been described, among them the impaired
enzymatic activities (31,32) due to oxidative protein damage
sustained by free radicals (21).
The rate of hepatic steatosis allowing safe liver surgery is not
yet clearly defined, although a moderate to severe steatosis
(involving more than 30% of the hepatocytes) seems to affect
both postoperative morbidity and mortality (33,34). However,
although it is impossible to exactly predict this feature before
surgery without a liver biopsy specimen, this diagnostic tool
should be considered when the presence of steatosis is sug-
gested by imaging and a major resection is planned (14).
All of these factors may reduce the functional reserve of the
organ and therefore predisposing to postoperative liver failure
(35). Thus in preoperative risk estimation prior to hepatic
resection, it may be important to take into account the effect
of aging upon liver function and structure, in addition to car-
rying out a qualitative and quantitative evaluation of liver
parenchyma.
evaluation of the surgical risk
The stress of liver resection may not be well-tolerated in the
elderly (4). Liver surgery is not without complication and,
before considering liver resection in elderly patients, the
increased risks and costs of such surgery must be balanced
against the potential improvement of life expectancy. Elderly
patients are more likely to have decreased life expectancy with
comorbidity, so the decision to perform major hepatectomy
has to be carefully balanced against the likelihood of benefit
before undertaking such resections. However, most studies
record small numbers of cases or have not distinguished
between major and minor resections, making interpretation of
results difficult (32).
Factors other than age should be considered in evaluating
surgical risk in the elderly.
It is well known that in elderly patients, a preoperative
decline in cardiac and pulmonary functions, also combined
with cerebrovascular disease can be frequently seen (2,36). To
achieve better results in the elderly population, proper patient
selection in terms of liver functional reserve and comorbidities
conditions is mandatory. This necessitates a close collabora-
tion between surgeons, anesthesiologists, cardiologists, pul-
monary physicians, and geriatric physicians (6). A clear
preoperative selection process should be undertaken to mini-
mize perioperative risks (37).
The majority of elderly may suffer from more than one
comorbid disease or for many reasons do not have a good per-
formance status. Cardiovascular and pulmonary disease have a
prevalence among the elderly of 20% to 27% and 14%, respec-
tively (38). Moreover, cardiovascular disease and diabetes mel-
litus were reported to be significant risk factors especially
when associated with cirrhosis (39–41).
The most frequently reported causes of death in elderly
patients with no underlying liver disease undergoing liver
resection are hepatic insufficiency, myocardial infarction,
pneumonia, and gastrointestinal bleeding (4,42,43).
The evaluation of associated medical disease has been widely
investigated focusing in particular on American Society of
Anesthesiology (ASA) scores. Advanced ASA grading is known
as one of the most reliable predictors of postoperative compli-
cations and mortality (4). ASA scores measure major comor-
bid diseases easily and with minimal expense and are able to
predict outcomes after major surgical procedures (4,44).
Some authors have considered an ASA score higher than II
(i.e., a patient with mild to moderate systemic disease) as a
contraindication for surgery for HCC or for major hepatecto-
mies (42,45). In such patients procedures other than surgery
(radiofrequency ablation or transarterial chemoembolization)
could be considered (16).
The exact determination of the ASA score is highly operator-
dependent and the reported experiences of postoperative deaths
for causes unrelated to surgery (i.e., myocardial infarc-
tion) (42,46) in subjects with an unremarkable history of cardiac
or pulmonary disease suggest that this score should be applied
more selectively during the evaluation of elderly patients with
underlying liver disease (14). Also in the elderly, the perfor-
mance status, especially if they were physically active before sur-
gery, has to be taken into account since a significant lower risk of
postoperative complications have been recorded (47).
Finally, the morphologic characteristics of the underlying
liver pathology and number and size of malignancies have to
be carefully evaluated prior to performing hepatectomy, aim-
ing to avoid overextensive resections and to minimize intraop-
erative haemorrhage (6). One other factor having deleterious
effects on early and late outcome is intraoperative blood loss.
It is well known that hemorrhage and the need for transfusion
are closely associated with worse prognoses (48), and this may
be even worse in an aged liver.
colorectal liver metastases
Colorectal cancer is a major public health problem. In western
society, it is expected to increase in incidence by over 30% over
the next 20 years because of ever-growing elderly (>70 years of
age) population (49,50). The liver is the most common site of
metastases and is involved approximately in half of patients
(12). By the time of initial diagnosis of colorectal cancer, nearly
a quarter of patients will have clinically detectable liver metas-
tases (CRLM), despite increasing patient and clinician aware-
ness of the disease. Of those who undergo apparently successful
resection of the primary tumor, nearly half will develop liver
metastases, usually within the first three years after colec-
tomy (49,51,52).
Currently, over half of all cancers are diagnosed in elderly
patients, and 76% of all colorectal cancer patients are diag-
nosed between 65 and 85 years old (53,54). Encouraging
results of surgery for CRLM in the elderly have been reported
with 5-year survival rates between 21% and 44% (2,4,55–58).
In elderly patients, liver resection for CRLM provides, as
with younger patients, the only chance of cure, compared with
untreated patients who have a median survival of 4.5 to
47
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
6.5 months (59,60), or patients treated by chemotherapy alone
who have a median survival of 9.2 to 16.5 months (60,61). The
only true contraindication for liver resection is the technical
nonfeasibility of hepatectomy, independent of the presence of
other poor prognostic factors (8,62).
In 2005, the reported percentage of patients over 70 years of
age undergoing liver resection for CRLM was 26.5%, which was
dramatically higher when compared to 6% in the early 1990s
(6). This improvement is mostly related to developments in
liver surgery since resection for CRLM can be performed with
a mortality rate below 5% (6,13), with 5-year survival rates
ranging from 28% to 39% (4,7,63,64). Better results can now
also be achieved because of the extensive use of chemotherapy
in the elderly. Elderly patients can receive protocols similar to
younger ones (65). In general, since the introduction of oxali-
platin into chemotherapy regimens, a prolonged survival and a
delay of progression of disease has been reported (13,66,67).
The main issue of the use of oxaliplatin is hepatotoxicity (sinu-
soidal congestion and thrombosis), which could also prove to
be a problem, especially in case of impaired liver function
(13,68). However, no significant postoperative complications
have been reported in elderly patients who did or did not
receive chemotherapeutic treatment (13).
Further evidence for offering hepatic resection to well-selected
older patients is the evidence of similar benefit provided by
repeat hepatectomy to elderly and younger patients (6).
Liver failure is a worrying but thankfully rare complication
after liver resection. Some authors have found elderly patients
to be more at risk of developing this complication than younger
ones, resulting in a more conservative surgical selection policy
(69,70). Severe postoperative liver dysfunction may be present
in fewer than 10% of elderly patients who have undergone
major liver resection for malignancy (71). Postoperative liver
failure due to large resections or sepsis is the most frequent
cause of death (71). In general, liver resection should be avoided
in the presence of bilobar or need for extended resections, espe-
cially when associated to concomitant extrahepatic disease and
in medically compromised patients. In those cases, the indica-
tion for surgery should therefore be very carefully considered
only in selected cases (6,72). In view of these findings, it is
advisable to consider limited resection whenever possible from
the oncologic perspective rather than extended surgery.
The existing surgical literature on surgery for CRLM in
elderly patients (2,4,55–58) should be interpreted with cau-
tion because of the small patient numbers treated at single
centers. Often these series describe less than 50 patients. Only
recently a large cohort study, collecting data from more than
100 centers, has been published (6). This study highlighted the
evidence that hepatic resection for CRLM can be performed
safely in elderly patients provided they are fit for such a proce-
dure. The difference in survival between elderly and younger
patients could in part be explained by the more limited sur-
vival expectancy of the elderly population, also reflecting the
higher prevalence of comorbidity.
hepatocellular carcinoma
Primary tumors of the liver are among the most common
solid tumours worldwide (4).
48
The incidence of HCC is the fourth highest among all
tumors (18), the number of patients affected has been increas-
ing (73), and the age for detection of HCC is increasing in
both men and women (17). Clarification of the optimal treat-
ment strategy for extremely elderly patients with HCC has
thus become an urgent necessity. Management of HCC with
other modalities, such as percutaneous ethanol injection ther-
apy (74), microwave therapy (75), and percutaneous radiofre-
quency ablation (RFA), may be an acceptable alternative to
hepatic resection in the elderly, but the best treatment for
patients in this age group remains controversial.
Liver transplantation is theoretically the optimal treatment
for HCC because it is the only method of treating both the
tumor and the underlying liver cirrhosis. Replacement of the
diseased liver is not only the best oncological treatment, but
also the best method for preventing the development of new
tumors and avoiding the life-threatening complications of cir-
rhosis. In patients with HCC and cirrhosis, transplantation
based on the Milan criteria achieves a better outcome than
hepatic resection with respect to both survival and disease
recurrence (76–79). However, the limited availability of donor
organs makes liver transplantation problematic (80,81) and as
a consequence patients older than 70 years are excluded from
transplantation programs (82).
With advances in surgical treatment for HCC, hepatectomy
for elderly HCC patients has become safer. There have been
many reports of hepatectomies for elderly HCC patients
(83–85). But because of the unclear data on long-term survival
after local ablation of HCC, especially for large tumors, liver
resection remains the preferred treatment, with 5-year survival
rates ranging from 40% to 50% (86,87).
Resection is considered to be a reasonable first-line treat-
ment for patients with small tumors and underlying chronic
liver disease, which may offer potential cure (80).
Recent studies have shown the safety and feasibility of hepa-
tectomy for HCC patients older than 70 years of age (88,89). It
has been demonstrated that long-term outcome after resection
of HCC is similar in older and younger patients (1,10,83,85).
No operative mortality has been reported in a series of care-
fully selected octogenarians who underwent liver resection for
HCC (45).
Recent studies have identified some differences in the clinical
pathological features of HCC between elderly and younger
patients. Risk factors for HCC seem to be different in elderly
people. A significant lower positive rate for HBsAg has been
described among the elderly (88,90). Most HBV-related HCCs
develop in patients in their early fifties. This may be the reason
why there are few elderly HCC patients with HBV infection. On
the other hand, HCV infection constitutes a major part of the
etiology in elderly patients with HCC (17,91). Factors other
than viral hepatitis infection, such as alcohol or genetic muta-
tions, may contribute to the development of HCC in some
elderly patients (88). Several studies have shown that elderly
patients with HCC had good liver function and that only a
small percentage of elderly patients with HCC had liver cirrho-
sis (90,92). It is possible that a large proportion of patients with
cirrhosis and HCC die before reaching the age of 70 years, and
those who survive have well-preserved hepatic function (93).
 LIVER SURGERY IN ELDERLY PATIENTS
Some studies have demonstrated a close relation between
HCC and alcohol abuse, that is, individuals who abuse alcohol
have a significantly higher relative risk of developing HCC
than those who do not. Although data about the role of alco-
hol in the development of HCC are inconsistent, the mecha-
nisms that have been proposed include the induction of
tumorigenesis secondary to alcoholic cirrhosis, a direct tumor-
initiating and promoting effect of ethanol through induction
of various enzymes, alterations of DNA repair, dietary defi-
ciencies, immune suppression, and depletion of hepatic anti-
tumor factors (17).
There is no general agreement about the relation between
alcohol abuse and postoperative recurrence of HCC or sur-
vival, but there have been a few reports of an interaction
between alcohol abuse and postoperative recurrence (94). The
mechanism by which alcohol abuse is related to HCC recur-
rence and a lower survival rate remains to be elucidated. How-
ever, at least two possible reasons can be suggested for the
higher postoperative recurrence rate in patients with alcohol
abuse. First, these patients may be more susceptible to devel-
oping new primary tumors after hepatectomy because chronic
alcohol abuse enhances hepatocarcinogenesis. Second, they
might have a higher incidence of unrecognized intrahepatic
metastases at the time of initial hepatectomy because chronic
alcohol abuse seems to be related to the aggressiveness of HCC,
including the rate of metastasis (17).
Heavy alcohol abuse and HCV infection are two leading
causes of cirrhosis (91). Preoperative severe liver dysfunction
carried a high risk for postoperative hepatic failure, and cir-
rhosis is associated with increased postoperative mortality in
general (71).
Advanced age is still related to poor early outcome (42), with
operative mortality rates of up to 42%, attributable to liver
failure in patients with cirrhosis (95). The significance of AFP
has still not been well-defined. Some authors found a lower
frequency of raised AFP level, compared with younger
patients (17).
Various other predictors have been reported to be risk fac-
tors for poor prognosis of postoperative HCC patients, such as
liver cirrhosis, Child–Pugh grading, tumor size, satellite nod-
ules, and vascular invasion (18).
Some authors found a significantly higher frequency of
tumor encapsulation in elderly HCC patients when compar-
ing the histological characteristics of the resected tumors.
Tumor encapsulation has been reported as a favorable prog-
nostic factor for HCC (96). Also a higher frequency of tumor
encapsulation might be an indicator for less malignant degree
of the elderly patients with HCC (18).
Tumor diameter should not be considered a prognostic fac-
tor. Patients over 70 years of age with large tumors should be
scheduled for surgery with expected favorable results (85).
For the elderly patients with HCC, predictors of postopera-
tive survival are not well known. So far, only a few papers
revealed differing findings by multivariate analysis. Hanazaki
et al. (83) reported that liver cirrhosis and vascular invasion
were independent prognostic factors for the survival of postre-
sectional elderly HCC patients. Zhou et al. (97) found that
Child–Pugh grading, portal vein tumor thrombus, and
Edmondson–Steiner grading were prognostic factors.
However, other authors failed to yield similar results.
Postoperative recurrence of HCC is the most important fac-
tor affecting the survival of patients who underwent radical
resection. Poor results in some series can be explained by a
high proportion of patients with cirrhosis. If the amount of
resected nontumors liver parenchyma is reduced, resection of
the primary liver tumor is justified despite narrow surgical
resection margins. A significant reduction in postoperative
mortality, as well as morbidity can be achieved by this
approach. When postoperative complications occur, they do
not correlate with the amount of liver resected but with preop-
erative liver function and intraoperative haemorrhage (71).
However, the prognosis following resection for HCC remains
unsatisfactory because of the high incidence of recurrence in
the liver remnant; the cumulative 5-year recurrence rates after
curative hepatectomy are <70% (98). Therefore appropriate
management of recurrent HCC is important to improve long-
term outcomes after hepatectomy.
Many studies have supported favorable results after repeat
hepatectomy for recurrent HCC (89). Repeat hepatectomy is
the first choice for patients with preserved liver function (18).
Even for the elderly patients with recurrent HCC, repeated
hepatectomy has been recommended to achieve better survival
if these tumors were resectable (83).
Patients with recurrent HCC are older than those with pri-
mary HCC. Repeat hepatectomy for recurrent HCC is safe
even for patients aged more than 75 years, especially when
they underwent limited hepatectomies (89).
Recently, an alternative strategy of primary hepatectomy fol-
lowed by liver transplantation for recurrent HCC (salvage liver
transplantation) has been proposed (29). Percutaneous abla-
tion therapy may also be a preferable therapeutic modality for
small-sized or small-volume HCC; however, there have been
only a few studies on ablation therapies for recurrent HCC,
and the overall 3-year survival rate after ablation therapy was
43% to 48%, which is less than the survival rates obtained after
repeat hepatectomies (>70%) in certain centers (89). Not only
younger patients but also elderly patients with early-stage
HCC might benefit from this modality, which is less invasive
than hepatectomy. Selection criteria for elderly patients with
recurrent HCC who are good candidates for repeat hepatec-
tomy remain to be determined, and the age limitations for
such an aggressive operative approach are not clear at present.
Nevertheless, advanced age by itself does not have an adverse
effect on operative outcomes, including postoperative compli-
cations and long-term prognosis, after repeat hepatectomies
on patients with recurrent HCC. Repeat hepatectomy may
therefore be justified for treating recurrent HCC in selected
elderly patients.
In conclusion, both the short-term and long-term outcome
of resection of HCC seems similar to the younger in carefully
selected elderly patients, even though elderly have a higher inci-
dence of associated diseases. HCC in the elderly is less HBV-
associated, less advanced, and less aggressive. Elderly patients
with preoperative alcohol abuse should be followed up very
closely, even after R0 surgery, since alcohol abuse is strongly
correlated with postoperative recurrence and poor survival.
49
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Hepatectomy is safe for the elderly HCC patients without
preoperative comorbidities or with well-controlled preopera-
tive comorbidities.
financial cost
In the current climate of scarce health care resources, treat-
ment for elderly patients has been under close scrutiny. Several
studies have shown that elderly patients have benefited from
liver resection for malignancy with results comparable to those
younger than 70 years of age. The use of health care resources
in terms of intensive care unit and in-hospital stays is no dif-
ferent than in the younger population, and some of this cost-
saving can be attributed to better support in terms of
anesthesia and community nursing (32). Therefore careful
selection of patients using the ASA grade and meticulous sur-
gical technique are essential to achieve better outcomes after
hepatic resection in patients over the age of 70 years.
conclusions
Age alone should not be considered a contraindication for
liver resection: hepatectomy is safe, effective, and a curative
therapy in the elderly. Major hepatectomies are the feasible
procedure in patients older than 70 years who have preserved
liver function and controllable medical conditions, yielding
close to 0% operative mortality and low morbidity rates in
specialized tertiary centers.
references
1. Takenaka K, Shimada M, Higashi H, et al. Liver resection for hepatocel-
lular carcinoma in the elderly. Arch Surg. 1994; 129(8): 846–50.
2. Fong Y, Blumgart LH, Fortner JG, Brennan MF. Pancreatic or liver resec-
tion for malignancy is safe and effective for the elderly. Ann Surg 1995;
222(4): 426–34; discussion 34–7.
3. Brooks B. Surgery in patients of advanced age. Ann Surg 1937; 105(4):
481–95.
4. Fong Y, Brennan MF, Cohen AM, et al. Liver resection in the elderly. Br J
Surg 1997; 84(10): 1386–90.
5. WHO. Ageing—Exploding the Myths. Ageing and Health Program
(AHE). WHO. 1999.
6. Adam R, Frilling A, Elias D, et al. Liver resection of colorectal metastases
in elderly patients. Br J Surg 2010; 97(3): 366–76.
7. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal
liver metastases. World J Surg 1995; 19(1): 59–71.
8. Jaeck D, Bachellier P, Guiguet M, et al. Long-term survival following
resection of colorectal hepatic metastases. Association Francaise de
Chirurgie. Br J Surg 1997; 84(7): 977–80.
9. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for
predicting recurrence after hepatic resection for metastatic colorectal can-
cer: analysis of 1001 consecutive cases. Ann Surg 1999; 230(3): 309–18;
discussion 18–21.
10. Poon RT, Fan ST, Lo CM, et al. Hepatocellular carcinoma in the elderly:
results of surgical and nonsurgical management. Am J Gastroenterol
1999; 94(9): 2460–6.
11. Cooper GS, Yuan Z, Landefeld CS, Johanson JF, Rimm AA. A national
population-based study of incidence of colorectal cancer and age. Impli-
cations for screening in older Americans. Cancer 1995; 75(3): 775–81.
12. Steele G, Jr., Ravikumar TS. Resection of hepatic metastases from colorec-
tal cancer. Biologic perspective. Ann Surg 1989; 210(2): 127–38.
13. de Liguori Carino N, van Leeuwen BL, Ghaneh P, et al. Liver resection for
colorectal liver metastases in older patients. Crit Rev Oncol Hematol
2008; 67(3): 273–8.
14. Cescon M, Grazi GL, Del Gaudio M, et al. Outcome of right hepatecto-
mies in patients older than 70 years. Arch Surg 2003; 138(5): 547–52.
50
15. Nagasue N, Chang YC, Takemoto Y, et al. Liver resection in the aged (seventy
years or older) with hepatocellular carcinoma. Surgery 1993; 113(2): 148–54.
16. Mazzoni G, Tocchi A, Miccini M, et al. Surgical treatment of liver metas-
tases from colorectal cancer in elderly patients. Int J Colorectal Dis 2007;
22(1): 77–83.
17. Kaibori M, Matsui K, Ishizaki M, et al. Hepatic resection for hepatocellu-
lar carcinoma in the elderly. J Surg Oncol 2009; 99(3): 154–60.
18. Huang J, Li BK, Chen GH, et al. Long-term outcomes and prognostic fac-
tors of elderly patients with hepatocellular carcinoma undergoing hepa-
tectomy. J Gastrointest Surg 2009; 13(9): 1627–35.
19. Ganz PA. Does (or should) chronologic age influence the choice of cancer
treatment? Oncology (Williston Park). 1992; 6(2 Suppl): 45–9.
20. Schmucker DL. Aging and the liver: an update. J Gerontol A Biol Sci Med
Sci 1998; 53(5): B315–20.
21. Anantharaju A, Feller A, Chedid A. Aging liver. A review. Gerontology
2002 ; 48(6): 343–53.
22. Zeeh J, Platt D. The aging liver: structural and functional changes and
their consequences for drug treatment in old age. Gerontology 2002;
48(3): 121–7.
23. Popper H. Aging and the liver. Prog Liver Dis 1986; 8: 659–83.
24. Woodhouse KW, Wynne HA. Age-related changes in liver size and hepatic
blood flow. The influence on drug metabolism in the elderly. Clin Phar-
macokinet 1988; 15(5): 287–94.
25. Marchesini G, Bua V, Brunori A, et al. Galactose elimination capacity and
liver volume in aging man. Hepatology 1988; 8(5): 1079–83.
26. Wynne HA, Cope LH, Mutch E, et al. The effect of age upon liver volume
and apparent liver blood flow in healthy man. Hepatology 1989; 9(2):
297–301.
27. Zoli M, Magalotti D, Bianchi G, et al. Total and functional hepatic blood
flow decrease in parallel with ageing. Age Ageing 1999; 28(1): 29–33.
28. James OF. Gastrointestinal and liver function of old age. Clin Gastroen-
terol 1983; 12(3): 671–91.
29. Watanabe T, Tanaka Y. Age-related alterations in the size of human hepa-
tocytes. A study of mononuclear and binucleate cells. Virchows Arch B
Cell Pathol Incl Mol Pathol 1982; 39(1): 9–20.
30. Le Couteur DG, Cogger VC, Markus AM, et al. Pseudocapillarization and
associated energy limitation in the aged rat liver. Hepatology 2001; 33(3):
537–43.
31. Kitani K. Aging of the liver: facts and theories. Arch Gerontol Geriatr
1991; 12(2–3): 133–54.
32. Menon KV, Al-Mukhtar A, Aldouri A, et al. Outcomes after major hepa-
tectomy in elderly patients. J Am Coll Surg 2006; 203(5): 677–83.
33. Behrns KE, Tsiotos GG, DeSouza NF, et al. Hepatic steatosis as a potential
risk factor for major hepatic resection. J Gastrointest Surg 1998; 2(3): 292–8.
34. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts
steatohepatitis and an increase in 90-day mortality after surgery for
hepatic colorectal metastases. J Clin Oncol 2006; 24(13): 2065–72.
35. Mentha G, Huber O, Robert J, et al. Elective hepatic resection in the
elderly. Br J Surg 1992; 79(6): 557–9.
36. Kahng KU, Roslyn JJ. Surgical issues for the elderly patient with hepatobi-
liary disease. Surg Clin North Am 1994; 74(2): 345–73.
37. Ashkanani F, Heys SD, Eremin O. The management of cancer in the
elderly. J R Coll Surg Edinb 1999; 44(1): 2–10.
38. Repetto L, Granetto C, Venturino A. Comorbidity and cancer in the aged:
the oncologists point of view. Rays 1997; 22(1 Suppl): 17–19.
39. Miyagawa S, Makuuchi M, Kawasaki S, Kakazu T. Criteria for safe hepatic
resection. Am J Surg 1995; 169(6): 589–94.
40. Shimada M, Takenaka K, Fujiwara Y, et al. Risk factors linked to postop-
erative morbidity in patients with hepatocellular carcinoma. Br J Surg
1998 ; 85(2): 195–8.
41. Little SA, Jarnagin WR, DeMatteo RP, Blumgart LH, Fong Y. Diabetes is
associated with increased perioperative mortality but equivalent long-
term outcome after hepatic resection for colorectal cancer. J Gastrointest
Surg 2002; 6(1): 88–94.
42. Ettorre GM, Sommacale D, Farges O, et al. Postoperative liver function after
elective right hepatectomy in elderly patients. Br J Surg 2001; 88(1): 73–6.
43. Fortner JG, Lincer RM. Hepatic resection in the elderly. Ann Surg 1990;
211(2): 141–5.
 LIVER SURGERY IN ELDERLY PATIENTS
44. Cullen DJ, Apolone G, Greenfield S, Guadagnoli E, Cleary P. ASA Physical
Status and age predict morbidity after three surgical procedures. Ann
Surg 1994; 220(1): 3–9.
45. Wu CC, Chen JT, Ho WL, et al. Liver resection for hepatocellular carci-
noma in octogenarians. Surgery 1999; 125(3): 332–8.
46. Yanaga K, Kanematsu T, Takenaka K, et al. Hepatic resection for hepato-
cellular carcinoma in elderly patients. Am J Surg 1988; 155(2): 238–41.
47. Seymour DG, Pringle R. Post-operative complications in the elderly sur-
gical patient. Gerontology 1983; 29(4): 262–70.
48. Poon RT, Fan ST, Lo CM, et al. Improving perioperative outcome expands
the role of hepatectomy in management of benign and malignant hepato-
biliary diseases: analysis of 1222 consecutive patients from a prospective
database. Ann Surg 2004; 240(4): 698–708; discussion 709–10.
49. Poston GJ. Surgical strategies for colorectal liver metastases. Surg Oncol
2004; 13(2–3): 125–36.
50. Primrose JN. Treatment of colorectal metastases: surgery, cryotherapy, or
radiofrequency ablation. Gut 2002; 50(1): 1–5.
51. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influ-
encing the natural history of colorectal liver metastases. Lancet 1994;
343(8910): 1405–10.
52. Sugarbaker PH. Surgical decision making for large bowel cancer meta-
static to the liver. Radiology 1990; 174(3 Pt 1): 621–6.
53. Quaglia A, Capocaccia R, Micheli A, Carrani E, Vercelli M. A wide differ-
ence in cancer survival between middle aged and elderly patients in
Europe. Int J Cancer 2007; 120(10): 2196–201.
54. Petrowsky H, Clavien PA. Should we deny surgery for malignant hepato-
pancreatico-biliary tumors to elderly patients? World J Surg 2005; 29(9):
1093–100.
55. Zacharias T, Jaeck D, Oussoultzoglou E, Bachellier P, Weber JC. First and
repeat resection of colorectal liver metastases in elderly patients. Ann Surg
2004; 240(5): 85 8–65.
56. Brunken C, Rogiers X, Malago M, et al. [Is resection of colorectal liver metas-
tases still justified in very elderly patients?]. Chirurg. 1998; 69(12): 1334–9.
57. Zieren HU, Muller JM, Zieren J. Resection of colorectal liver metastases in
old patients. Hepatogastroenterology 1994; 41(1): 34–7.
58. Figueras J, Ramos E, Lopez-Ben S, et al. Surgical treatment of liver metas-
tases from colorectal carcinoma in elderly patients. When is it worth-
while? Clin Transl Oncol 2007; 9(6): 392–400.
59. Moreaux J. [Hepatic metastases of colorectal cancer. Natural history and
surgical treatment by excision]. Chirurgie 1985; 111(7): 528–37.
60. Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan
plus supportive care versus supportive care alone after fluorouracil failure
for patients with metastatic colorectal cancer. Lancet 1998; 352(9138):
1413–8.
61. Scheithauer W, Kornek GV, Raderer M, et al. Randomized multicenter
phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-
line treatment in advanced colorectal cancer. J Clin Oncol 2002; 20(1):
165–72.
62. Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers of
surgical indications in the treatment of liver metastases from colorectal
cancer: long-term results. Ann Surg 2000; 231(4): 487–99.
63. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal
carcinoma metastases to the liver. A prognostic scoring system to improve
case selection, based on 1568 patients. Association Francaise de Chirurgie.
Cancer 1996; 77(7): 1254–62.
64. Iwatsuki S, Dvorchik I, Madariaga JR, et al. Hepatic resection for meta-
static colorectal adenocarcinoma: a proposal of a prognostic scoring sys-
tem. J Am Coll Surg 1999; 189(3): 291–9.
65. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety
and efficacy of oxaliplatin plus fluorouracil/leucovorin administered
bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006;
24(25): 4085–91.
66. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial
of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations
in patients with previously untreated metastatic colorectal cancer. J Clin
Oncol 2004; 22(1): 23–30.
67. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil
with or without oxaliplatin as first-line treatment in advanced colorectal
cancer. J Clin Oncol 2000; 18(16): 2938–47.
68. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the
liver. J Gastrointest Surg 2007; 11(8): 1057–77.
69. Kimura F, Miyazaki M, Suwa T, Kakizaki S. Reduction of hepatic acute
phase response after partial hepatectomy in elderly patients. Res Exp Med
(Berl) 1996; 196(5): 281–90.
70. Aalami OO, Fang TD, Song HM, Nacamuli RP. Physiological features of
aging persons. Arch Surg 2003; 138(10): 1068–76.
71. Koperna T, Kisser M, Schulz F. Hepatic resection in the elderly. World J
Surg 1998; 22(4): 406–12.
72. Wanebo HJ, Chu QD, Vezeridis MP, Soderberg C. Patient selection for
hepatic resection of colorectal metastases. Arch Surg 1996; 131(3): 322–9.
73. El-Serag HB. Hepatocellular carcinoma: recent trends in the United
States. Gastroenterology 2004; 127(5 Suppl 1): S27–34.
74. Kotoh K, Sakai H, Sakamoto S, et al. The effect of percutaneous ethanol
injection therapy on small solitary hepatocellular carcinoma is compara-
ble to that of hepatectomy. Am J Gastroenterol. 1994; 89(2): 194–8.
75. Seki T, Wakabayashi M, Nakagawa T, et al. Ultrasonically guided percuta-
neous microwave coagulation therapy for small hepatocellular carcinoma.
Cancer 1994; 74(3): 817–25.
76. Figueras J, Jaurrieta E, Valls C, et al. Resection or transplantation for hepa-
tocellular carcinoma in cirrhotic patients: outcomes based on indicated
treatment strategy. J Am Coll Surg 2000; 190(5): 580–7.
77. Michel J, Suc B, Montpeyroux F, et al. Liver resection or transplantation
for hepatocellular carcinoma? Retrospective analysis of 215 patients with
cirrhosis. J Hepatol 1997; 26(6): 1274–80.
78. Sarasin FP, Giostra E, Mentha G, Hadengue A. Partial hepatectomy or
orthotopic liver transplantation for the treatment of resectable hepatocel-
lular carcinoma? A cost-effectiveness perspective. Hepatology 1998;
28(2): 436–42.
79. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treat-
ment of small hepatocellular carcinomas in patients with cirrhosis. N
Engl J Med 1996; 334(11): 693–9.
80. Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: diagnosis and
treatment. Gastroenterology 2002; 122(6): 1609–19.
81. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular
carcinoma. Semin Liver Dis 1999; 19(3): 311–22.
82. Figueras J, Ibanez L, Ramos E, et al. Selection criteria for liver transplanta-
tion in early-stage hepatocellular carcinoma with cirrhosis: results of a
multicenter study. Liver Transpl 2001; 7(10): 877–83.
83. Hanazaki K, Kajikawa S, Shimozawa N, et al. Hepatic resection for
hepatocellular carcinoma in the elderly. J Am Coll Surg 2001; 192(1):
38–46.
84. Yeh CN, Lee WC, Jeng LB, Chen MF. Hepatic resection for hepatocellular
carcinoma in elderly patients. Hepatogastroenterology 2004; 51(55): 219–23.
85. Ferrero A, Vigano L, Polastri R, et al. Hepatectomy as treatment of choice
for hepatocellular carcinoma in elderly cirrhotic patients. World J Surg
2005; 29(9): 1101–5.
86. Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical
treatment for small-sized hepatocellular carcinomas: a retrospective and
nationwide survey in Japan. The Liver Cancer Study Group of Japan.
Hepatology 2000; 32(6): 1224–9.
87. Vivarelli M, Guglielmi A, Ruzzenente A, et al. Surgical resection versus
percutaneous radiofrequency ablation in the treatment of hepatocellular
carcinoma on cirrhotic liver. Ann Surg 2004; 240(1): 102–7.
88. Oishi K, Itamoto T, Kobayashi T, et al. Hepatectomy for hepatocellular
carcinoma in elderly patients aged 75 years or more. J Gastrointest Surg
2009; 13(4): 695–701.
89. Tsujita E, Utsunomiya T, Ohta M, et al. Outcome of repeat hepatectomy in
patients with hepatocellular carcinoma aged 75 years and older. Surgery
2009; 147: 696–703.
90. Tsukioka G, Kakizaki S, Sohara N, et al. Hepatocellular carcinoma in
extremely elderly patients: an analysis of clinical characteristics, prognosis
and patient survival. World J Gastroenterol 2006; 12(1): 48–53.
91. Dohmen K, Shirahama M, Shigematsu H, Irie K, Ishibashi H. Optimal
treatment strategy for elderly patients with hepatocellular carcinoma. J
Gastroenterol Hepatol 2004; 19(8): 859–65.
92. Nakamuta M, Morizono S, Kohjima M, Kotoh K, Enjoji M. Baseline
characterization of patients aged 70 years and above with hepatocellular
carcinoma. World J Gastroenterol 2005; 11(47): 7512–4.
51
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
93. Namieno T, Kawata A, Sato N, Kondo Y, Uchino J. Age-related, different
clinicopathologic features of hepatocellular carcinoma patients. Ann Surg
1995; 221(3): 308–14.
94. Kubo S, Tamori A, Nishiguchi S, et al. Effect of alcohol abuse on poly-
amine metabolism in hepatocellular carcinoma and noncancerous
hepatic tissue. Surgery 1998; 123(2): 205–11.
95. Yamamoto K, Takenaka K, Matsumata T, et al. Right hepatic lobectomy in
elderly patients with hepatocellular carcinoma. Hepatogastroenterology.
1997; 44(14): 514–8.
52
96. Nagao T, Inoue S, Goto S, et al. Hepatic resection for hepatocellular
carcinoma. Clinical features and long-term prognosis. Ann Surg 1987;
205(1): 33–40.
97. Zhou L, Rui JA, Wang SB, et al. Clinicopathological features, post-surgical
survival and prognostic indicators of elderly patients with hepatocellular
carcinoma. Eur J Surg Oncol 2006; 32(7): 767–72.
98. Sugimachi K, Maehara S, Tanaka S, Shimada M. Repeat hepatectomy
is the most useful treatment for recurrent hepatocellular carcinoma.
J Hepatobiliary Pancreat Surg 2001; 8(5): 410–6.
6 Small solitary hepatic metastases: when and how?
David L. Bartlett and Yuman Fong
introduction
The management of patients with small hepatic metastases
from colorectal cancer and other histologies requires the con-
sideration of many diverse patient- and tumor-related factors.
These factors include the natural history of the tumor type, the
expected cure rate after surgical treatment, effectiveness of
alternative treatments, and the morbidity of surgical resection.
In general, the indications for any major surgical procedure
include the potential for cure, prolongation of survival, and
palliation of symptoms. For metastatic tumors to the liver in
selected cases, the cure rate may be over 50% for colorectal
cancer (1), but will be exceedingly rare for other histologies
such as gastric cases, and melanoma and sarcoma. Small
metastases to the liver generally do not cause symptoms
(except for hormone secreting neuroendocrine tumors) and,
therefore, palliation of symptoms is not a common indication
for management of these lesions. Nevertheless, many issues
remain unresolved. Does resection of a small solitary hepatic
metastasis prolong survival in cases where the patient is likely
to develop widespread metastases in the future? Is there any
harm in allowing a tumor to go untreated for a period of time,
knowing that with close follow-up the resection option may
still be possible in the future? Do metastases metastasize such
that a delay in management may obviate the curative option?
Unfortunately, all of these difficult issues are only addressed by
sparse data in the literature.
The risk and extent of the surgical procedure plays a sig-
nificant role in the decision making for management of small
hepatic metastases. It is more reasonable to excise an enlarged
subcutaneous lymph node for metastatic cancer than it is to
perform a hepatic lobectomy when the chance of benefit is
low in both cases. As other less invasive ablative options
become routine therapy, it may be reasonable to consider
these options in cases where surgical resection is unreason-
able. These alternative options include percutaneous
approaches at ablation such as radiofrequency ablation and
percutaneous alcohol injection (2). Laparoscopic procedures
may also be an alternative for the management of small
hepatic metastases, including laparoscopic resection of
tumors and laparoscopically directed ablation such as cryo-
therapy. If the risks, discomfort, and hospital stay are truly
minimal, then it becomes reasonable to consider local treat-
ment of these lesions, even with a small chance of overall
benefit to the patient.
This chapter will provide an overview of the data on survival
benefit after resection of hepatic metastases and the techniques
of surgical management. A brief discussion of minimally inva-
sive and percutaneous procedures for management of small
solitary hepatic metastases will follow. In addition, a discus-
sion of the role for adjuvant therapy after resection or ablation
of the hepatic metastases will be included.
survival results for hepatic
metastasectomy
While the purpose of this chapter is not to provide an in-depth
review of the results of hepatic metastasectomy, a general sense
of expected cure rate and prolongation of survival after hepatic
metastasectomy for various histologies is required in order to
make an informed decision regarding resection of small
hepatic metastases.
Colorectal Metastases
Colorectal cancer, compared to other histologies, is more likely
to present as disease isolated to the liver. The natural history of
unresected solitary hepatic metastases from colorectal cancer
was described by Wagner et al. where 39 patients with solitary
metastases did not undergo therapy and the median survival
was 24 months (3). Wood et al. described 15 patients with sol-
itary hepatic metastases left untreated with a mean survival of
17 months (4).
There is a considerable body of literature on the results of
hepatic metastasectomy for colorectal cancer. The overall
5-year survival ranges from 22% to 39% (5). In many studies,
low number and small size are associated with improved prog-
nosis such that a small solitary metastasis from colorectal can-
cer has a greater than 50% of 5-year survival. Nuzzo et al.
report 56% actuarial 5-year survival in patients with solitary
metachronous hepatic metastases from colorectal cancer less
than 4 cm in size (1). Table 6.1 reviews the results of the largest
series for solitary metastasectomy. After resection of solitary
metastases from colorectal cancer, 5-year survival ranges from
30% to 47% (6–10). These reports do not consider the small
solitary metastases separately from the entire group of solitary
metastases. The size of the lesion is expected to affect progno-
sis and, therefore, the actual results for small solitary hepatic
metastases may be even better than the numbers reported in
Table 6.1. Liver resection for hepatic colorectal metastases is,
therefore, safe and effective, and may be curative.
Neuroendocrine Metastases
For cancers of other than colorectal origin, patients with
hepatic metastases from neuroendocrine tumors have been
thought to be the most likely to benefit from surgical resection.
Certainly, if the tumor were symptomatic for either hormonal
or physical reasons, resection should be considered even though
cure is unlikely. Because of the indolent nature of these tumors,
durable palliation can be achieved with cytoreduction. Five-
year survival rates for untreated hepatic metastases from neu-
roendocrine tumors have ranged from 13% to 54% (11–15).
In patients with no symptoms, the case for surgical resec-
tion, or any treatment for that matter, is less clear. We and
others (16) have adopted a very aggressive approach even
for asymptomatic tumors based only on retrospective data.
53
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Chen et al. compared liver resection for neuroendocrine tumors Table 6.2 reviews the largest series for hepatic metastasectomy
with a retrospectively matched cohort who did not undergo with a variety of histologies.
resection, demonstrating improved survival after resection (17).
The general recommendation is for aggressive surgical man-
Breast cancer
agement of neuroendocrine metastasis (18). We acknowledge
Many reviews have been published on hepatic metastasec-
that the variable growth rate and sometimes indolent nature of
tomy for breast cancer. Due to the high incidence of breast
these tumors make firm conclusions based on retrospective
cancer and the frequency of liver metastases for this histol-
data without a nontreated control group suspect. The rarity of
ogy, the first site of metastases is frequently observed to be
these tumors, however, does not allow for random assignment
hepatic. In highly selected patients, favorable results of sec-
trials. Certainly for small hepatic metastases, aggressive surgical
tion of such liver metastases have been reported. Raab et al.
resection is indicated, while it is acknowledged that definitive
reported a 5-year survival of 18.4% in 34 patients after
proof of its benefit may never be achieved.
hepatic metastasectomy for breast cancer (19). Elias et al.
reported 9% 5-year survival after resection in 21 patients
Noncolorectal, Nonneuroendocrine Metastases
(20). The relatively few patients in these reports compared
For histologies other than colorectal or neuroendocrine can-
to the total number of breast cancer patients in each institu-
cer, the utility of hepatic metastasectomy is not as obvious. For
tion during the study period reflect the degree of patient
these tumors, the liver is rarely the sole site of disease; liver
selection for surgery. The survival rates reported are actu-
metastases are rarely the ultimate cause of death, nor does it
arial survival rates and the actual cure rate is much lower. At
contribute significantly to symptoms prior to death. Neverthe-
most, hepatic metastasectomy for breast cancer should be
less, selected cases of disease isolated to the liver after a long
considered cytoreductive. It may delay the development of
disease-free interval raise the possibility of a single site of met-
symptoms and prolong survival, but it has very little chance
astatic disease that could be cured with surgical therapy.
of curing the disease.

Sarcoma
Table 6.1 Survival After Hepatic Resection for a Solitary Similarly, hepatic resection for sarcoma metastases may be
Colorectal Metastasis associated with long-term survival in highly selected patients,
Actuarial but it is unlikely to result in cure. In a series of 14 hepatic
5-year Median resections for metastatic sarcoma, recurrence was found in all
survival survival
patients during follow-up, and 11 of 14 failed in the liver (21).
Author Date N (%) (months)
The median survival in that series was 30 months.
Hughes et al. (6) 1988 509 37 –
Rosen et al. (7) 1992 185 30 – Melanoma
Scheele et al. (8) 1995 180 36a 45
Metastatic cutaneous melanoma to the liver has been resected
Taylor et al. (9) 1997 A077 47 54
Fong et al. (10) 1997 240 47 –
with long-term survival, but these tumors also ultimately
a
recur (22). The erratic behavior of melanoma makes conclu-
Actual 5-year survival.
sions regarding the benefit of hepatic metastasectomy difficult.

Table 6.2 Survival Following Hepatic Metastasectomy for Noncolorectal Histologies

Actuarial 5-year Median survival
Author Histology N survival (%) (months)
Chen et al. (17) Neuroendocrine 15 73 NR
Que et al. (57) Neuroendocrine 74 73a NR
Harrison et al. (26) Genitourinaryb 34 60 NR
Jaques et al. (21) Sarcoma 14 A00 30
Harrison et al.26 Breast/melanoma/sarcoma 41 26 32
Elias et al. (20) Breast 21 A09 26
Raab et al.19 Breast 34 18 27
Ochiai et al. (24) Gastric 21 19c 18
Bines et al. (25) Gastric A07 14d 15
Harrison et al. (26) Gastrointestinale A07 A00 25
a
4-year survival.
b
Includes renal (5), testicular (9), adrenal (7), ovary (7), uterine (4), cervix (2).
c
4 of 21 actual 5-year survivors.
d
1 of 7 actual 5-year survivors.
e
Includes gastric (5), pancreatic (2).
NR: not reached.

54
 SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW?
Only in highly selected cases is it appropriate to consider resec-
tion of cutaneous melanoma. Ocular melanoma, on the other
hand, has a unique natural history. Ocular melanoma preferen-
tially metastasizes to the liver and the majority of patients die of
liver failure as a direct result of tumor progression. Anecdotal
reports exist of long-term survival after metastasectomy for
ocular melanoma (23), although these tumors are also almost
always multifocal and resection of what appears to be a solitary
metastasis is most often associated with liver recurrence. These
hepatic metastases may show up many years after the treatment
of the primary tumor. A long disease-free interval reflects a slow
tumor doubling time, and suggests resection may achieve dura-
ble palliation. Usually in this disease, however, the appearance of
a solitary liver metastasis is merely a precursor of the later
appearance of multiple metastases.
Other gastrointestinal cancers
In general, hepatic metastasectomy for gastrointestinal
primaries other than colorectal is not associated with pro-
longed survival. For tumors such as esophageal, gastric,
small bowel, and pancreatic cancer, the pattern of spread
includes regional lymph nodes, the peritoneal cavity, and
lung metastases in addition to liver metastases. It is unlikely
that these patients will die of liver failure as a result of pro-
gression of hepatic metastases, but instead, suffer other gas-
trointestinal sequelae from extrahepatic tumor progression.
A major operative procedure can be of significant detri-
ment to these patients with aggressive cancers where sur-
vival is expected to be of the order of weeks to months.
Nevertheless, even for these tumors, selected cases exist
where one might consider resection, and the literature con-
tains anecdotal reports of long-term survivors after liver
resection (24,25).
Genitourinary tumors
For noncolorectal, nonneuroendocrine tumors, metastases
from genitourinary primaries seem to have the best prognosis
following hepatic metastasectomy. In a recent review by
Harrison et al., 34 patients underwent hepatic resections for
genitourinary primaries (including testicular, adrenal, ovary,
renal, uterine, and cervix) with a 5-year actuarial survival of
60% (26). Other investigators have reported prolonged sur-
vival after resection for renal cell cancer (27) and adrenal can-
cer (28). While the natural history of genitourinary tumors
contributes to these remarkable results, it does suggest a sur-
vival benefit to resection in selective cases.
do metastases metastasize?
For small solitary hepatic metastases, where many months
of growth would still not preclude resection, the question is
whether a waiting period would allow for further spread of
the tumor from the metastatic deposit itself. If metastatic
tumors were unable to further metastasize, waiting for the
first sign of progression prior to initiating treatment and
allowing other metastatic disease to declare itself would
seem a reasonable approach. If, however, metastases are able
to spread during that waiting period, then the chance of
potential cure may be adversely affected by the delay in
definitive treatment. Unfortunately, it is clear that meta-
static tumors do have the potential to metastasize them-
selves, and this must be considered when recommending
observation alone.
Experimental evidence suggests that cells from spontaneous
metastases are more likely to metastasize than cells populating
the parent neoplasm (29). Clinically, the most obvious exam-
ples of metastases from metastatic colorectal cancer deposits
are in the cases of perihepatic lymph node metastases (30) and
satellite-tumor formation (31).
Published data would indicate that metastases to periportal
lymph nodes occur in 10% to 20% of cases of hepatic colorectal
metastases (30). The presence of lymph node metastases por-
tends a poor prognosis. Therefore, excision of liver tumors before
they spread to regional lymph nodes would be advantageous.
A recent paper examined the incidence of satellite micro-
metastasis in colorectal liver metastases by careful histologic
examination of resection specimens and found that 56% of
specimens had micrometastases as far as 3.8 cm away from
the tumor being resected (31). In some cases, these satellites
could be traced to the original metastasis by a trail of cells,
suggesting spread from the original metastasis. As discussed
previously, the presence of satellitosis is an important inde-
pendent poor prognostic factor. It may be that a delay in
resection allows for the development of satellitosis, which
negatively impacts on prognosis. On the other hand, the
presence of satellitosis may be an indicator of biologic aggres-
siveness, which portends a poor prognosis regardless of when
the tumor is resected.
patient selection
Colorectal Metastases
In order to decide when surgical resection is reasonable for
small solitary hepatic metastases, it is important to review
prognostic factors that are independent of size and number,
which may influence the decision regarding management of
these tumors. Many studies have examined data on prognostic
factors for outcome after hepatic resection for colorectal
metastases. The time to development of liver tumor after
resection of the primary, pathologic margin, stage of the pri-
mary tumor, tumor number, carcinoembryonic antigen levels,
satellitosis, extrahepatic disease, and positive surgical margin
have all been shown to predict survival after hepatic resection
for colorectal metastases independent of size (7,8,10,32).
Extrahepatic disease is considered a contraindication to
hepatic resection. Even the presence of perihepatic lymph
nodes portends a poor prognosis and generally is felt to be a
contraindication to resection. Particularly in the cases of small
solitary hepatic metastases with extrahepatic disease, there
would be no advantage to resection or ablation of the liver
tumor because systemic disease will likely be the ultimate
cause of death regardless of what is done with the liver
metastases. Of the other various factors that are prognostic for
outcome, surgical margin, and satellitosis are the least useful in
patient selection. No one would subject a patient to surgical
resection expecting a positive margin. Satellitosis cannot be
easily assessed preoperatively and therefore is a poor selection
criterion for surgery.
55
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
We analyzed our recent data on factors prognostic for out-
come after resection of hepatic metastases from colorectal
cancer (33). In data derived from our last 1001 liver resections
for this disease, the seven factors found to be independent
predictors of poor long-term outcome were
1. node positive outcome,
2. presentation of liver disease within 12 months of the
primary cancer,
3. CEA > 200 ng/dl,
4. number of liver tumors > 1,
5. size > 5 cm,
6. positive margin, and
7. extrahepatic disease.
From this, we formulated a clinical risk score (CRS) based on
the first five of these factors for use in patient selection for sur-
gery and for stratification of patients for clinical studies. Using
one point for each criterion, a summed score of 0–2 puts patients
in a low-risk group and is a strong indication for hepatectomy.
In the patients with small tumors, a maximum score of 4 is pos-
sible. The 5-year survival of patients with small tumors and 0–2
points on the CRS is 47% and the median survival is 56 months
(33). Patients with a score of 3–4 are in a high-risk group, with a
median survival of 32 months and 5-year survival of 24% (Fig.
6.1). In these high-risk patients, a period of observation with no
therapy or systemic chemotherapy allowing for the extent of
metastases to declare themselves is reasonable. Improved imag-
ing techniques such as fluorodeoxyglucose positron emission
tomography (FDG PET) scanning should be considered and
may help discover extrahepatic disease noninvasively in these
patients at high risk for additional cancer (34). Finally, these
patients should be considered for clinical studies of aggressive
adjuvant chemotherapy after liver resection.
1.0
0.8
0.6
Survival
0.4
0.2
0.0
0 12 24 36 48 60
Months
Figure 6.1 Prediction of long-term outcome for small (<3 cm) (N = 293)
metastatic deposits based on clinical risk score (CRS). CRS is based on the
following five criteria: (1) node positive primary cancer, (2) disease-free inter-
val <12 months, (3) number of liver tumors >1, (4) size of liver tumor >5 cm
and (5) CEA > 200 ng/dl. For score = 0–2 (N = 236) (open box), the median
survival was 56 months and the 5-year survival 47%. For score = 3–4 (N = 57)
(filled triangles), the median survival was 32 months and the 5-year
survival 24%.
56
Neuroendocrine Tumors
Patients with symptomatic neuroendocrine tumors should be
considered for resection or ablation. For the small tumor,
symptoms are most likely derived from hormonal secretion by
the tumors, and such hormone levels will also provide a
marker for effectiveness of the ablation or resection. For
asymptomatic tumors, a period of observation to allow assess-
ment of the pace and aggressiveness of the tumors is reason-
able when the tumors are small. At the first signs of progression,
resection or ablation should be considered.
Noncolorectal, Nonneuroendocrine Tumors
Harrison et al. defined prognostic factors involved in the resec-
tion of noncolorectal, nonneuroendocrine hepatic metastases
(26). In this study, 96 patients underwent liver resection. The
prognostic factors of significance on multivariate analysis
included the disease-free interval (>36 months), curative
resection (versus palliative incomplete resection), and primary
tumor type. Their conclusions would suggest that regardless of
histology, with a long disease-free interval patients may benefit
from surgical resection.
resection techniques
For small solitary metastases to the liver, the goal of resection
is to completely excise the tumor while preserving the maxi-
mum normal hepatic parenchyma. Preserving parenchyma
facilitates postoperative recovery and also provides flexibility
for further resections should intrahepatic recurrences
occur (35). Small surface-oriented metastases can be excised
using a nonanatomic wedge resection, whereas deeper lesions
require formal segmentectomies or sectorectomies. A goal of
at least a 1 cm margin is reasonable (36). The use of intraop-
erative ultrasound is important to rule out other small hepatic
metastases, which may not be evident on preoperative scans
and in defining the intersegmental planes for designing the
approach to segmentectomy. Even for wedge resections, ultra-
sound is beneficial in defining the vascular anatomy around
the lesion, which may help minimize blood loss.
Wedge Resections
Wedge resections must be performed meticulously to avoid
inadvertently leaving a positive margin. Large chromic liver
sutures can be placed and used for retraction during dissec-
tion. The parenchymal dissection should be performed
along the lines used for other forms of liver resection. We
prefer the Kelly clamp technique where the clamp is used to
crush the normal parenchyma, exposing vessels that are then
clipped, tied, suture ligated, or stapled using a vascular sta-
pling device (37). The Pringle maneuver is used intermit-
tently for 5 minutes at a time followed by reperfusion of the
parenchyma, during which time the argon beam coagulator
is used to coagulate small bleeding vessels on the surface.
This technique is superior to the simple use of electrocau-
tery for the dissection, which is often attempted for what
seems to be routine wedge resections. The char effect of the
electrocautery prevents adequate visualization of the anat-
omy, making it quite easy to stray into large vessels or into
the tumor.
 SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW?
The most difficult margin in performing a wedge resection
is the deep margin of dissection. Using intraoperative ultra-
sound, the depth of dissection should be measured prior to the
initiation of parenchymal dissection, including at least a 1-cm
margin deep to the tumor. The dissection should be carried
down perpendicular to the liver surface to the predetermined
depth. At this point, the tumor can be lifted up and dissection
can proceed horizontally across the base of the wedge. The
tendency to resect with a “V-shaped approach” is more likely
to be complicated by a positive deep margin. At the end of the
dissection, the Pringle maneuver is removed and the argon
beam coagulator is used to control bleeding vessels. Careful
examination is made for any evidence of a bile leak, which is
controlled with suture ligature.
For larger lesions where it is especially difficult to achieve
the deep margin safely, a cryoassisted wedge resection can be
performed (38). The cryotherapy probe is inserted into the
tumor and freezing is begun with real time ultrasound imag-
ing. When the zone of freezing is confirmed by ultrasound to
be at least 1 cm beyond the tumor, wedge resection is per-
formed using the freeze margin as the margin of resection.
The cryotherapy probe makes a ready retracting device and
the parenchyma is usually easy to dissect at the margin of the
ice-ball. Freezing must continue intermittently during dis-
section to ensure that the ice-ball does not retract and expose
the tumor.
Segmental Resections
For all but the most superficial lesions, we prefer a segmental
approach for the resection of tumor (39). Segmental resec-
tions have a significantly lower rate of pathologic positive
margins, and this translates into improved long-term
survival (40). Small, deep solitary metastases and surface
lesions adjacent to major vascular structures lend themselves
particularly well to segmentectomies or sectorectomies. The
intersegmental planes can be identified intraoperatively using
vascular landmarks with the aid of intraoperative ultrasound.
Using these planes for parenchymal dissection will minimize
blood loss and help ensure a safe margin.
Inflow occlusion for the segment can almost always be per-
formed first, thereby producing demarcation of the segmental
planes to further enhance the dissection. The portal triad to
segments II, III, and IV can be identified and controlled within
the umbilical fissure with little parenchymal dissection (37).
The right posterior sectoral pedicle can be found by dividing
the parenchyma along a horizontal cleft (fissure of Gans) pres-
ent on the inferior surface of the right lobe of the liver. The
pedicle can be traced to its bifurcation to segments VI and VII
for control of the individual segmental portal triads. The ante-
rior sectoral pedicle can be dissected from an inferior or ante-
rior approach.
The major hepatic veins lie within the intersegmental planes
and can be a source of significant blood loss during the
parenchymal transection phase of a segmentectomy. The use
of low central venous pressure (0–5 mmHg) during parenchy-
mal dissection can decrease back bleeding in these veins (41).
Extrahepatic control of the left, middle, and right hepatic veins
can also be achieved and the vein of concern temporarily
clamped at its junction with the vena cava during parenchymal
transection to further minimize blood loss.
When the solitary metastases lie near an intersegmental
plane, two segments can be removed. This is most easily done
as a formal sector such as the left lateral sectorectomy (seg-
ments II and III) and right posterior sectorectomy (segments
VI and VII). The caudate lobe (segment I) can be resected as
an isolated segmentectomy when the tumor is confined to this
lobe (42). This requires a more extensive dissection, including
complete division of all the perforating caudate veins draining
directly into the vena cava as well as the numerous small portal
triads extending off the main left pedicle at the base of the
umbilical fissure.
Figure 6.2 demonstrates a case of a small, solitary segment of
hepatic metastasis for colorectal cancer, which was detected on
an MRI scan used for screening because of a rising CEA.
Although this was a surface lesion, intraoperative ultrasound
revealed the segment VI triad immediately adjacent to the
tumor. The segment VI triad was located by ultrasound and
ligated at its origin with minimal parenchymal dissection. The
intersegmental planes were then marked by electrocautery and
a formal segmentectomy was performed with negative mar-
gins. While an aggressive resection was indicated and per-
formed, the patient can still undergo a formal left or right
hepatic lobectomy in the future if indicated. No dissection of
the vena cava or porta hepatis was required.
Morbidity and Mortality
The mortality rates for major hepatic resection have decreased
significantly over time to a common reporting of mortality in
the 1% to 4% range (43). These values are even lower for
wedge resections and segmentectomies. In a recent report of
270 wedge or segmental resections, the operative mortality
was 0.5% (40). This low mortality is not surprising consider-
ing that the main cause of death in studies of liver resection is
liver failure secondary to inadequate residual normal paren-
chyma, an unlikely event for resection of small solitary hepatic
metastases where minimal normal parenchyma is sacrificed.
While mortality rates are low, the complication rate for major
hepatic resection is still relatively high, ranging from 20% to
50% (5). Bile leaks, perihepatic abscess, hemorrhage, cardio-
pulmonary complications, pleural effusions, pneumonia, and
pulmonary embolism are among the most common complica-
tions (43). Many of these could be expected after segmentec-
tomy and wedge resections as well as major hepatic resections.
Even though these complications do not translate into a high
mortality rate, they may affect recovery time and quality of life.
While this is not a significant issue for patients expected to
undergo a long-term disease-free interval or cure, it may be sig-
nificant for patients whose survival is expected to be of the
order of months. For those patients with aggressive tumors
who are likely to fail outside the liver in the near future, less
invasive techniques which are associated with a lower compli-
cation rate and quicker recovery time are more appealing.
Ablative Techniques
Other minimally invasive techniques include local ablative
therapies such as laparoscopically directed cryotherapy (44) or
57
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
(A)
(C)
Figure 6.2 An example of a small, solitary colorectal metastasis to segment VI. (A) MRI reveals subtle abnormality not seen on CT scan. (B) Intraoperative ultra-
sound reveals the tumor and adjacent segment VI portal vein. (C) Intersegmental planes have been marked on the liver capsule with electrocautery and parenchy-
mal dissection begun. (D) Resected segment with tumor (microscopic negative margins). (Special thanks to Dr Peter Choyke for MRI scan.)
radiofrequency ablation (45). These techniques will be dis-
cussed further in chapter 8. They provide ideal alternatives to
laparotomy and major liver resection for the treatment of
small solitary hepatic metastases, since the small tumor is
the most likely to be completely treated by ablation tech-
niques. Furthermore, treatment by ablative techniques does
not preclude future resection.
Percutaneous approaches to tumor ablation are even more
attractive than laparoscopic procedures. Local injection of
toxic agents such as ethanol has been shown to be effective
for hepatocellular cancers, however these agents have not
been proven for other histologies and are known to be
poorly effective for colorectal cancer (2). Radiofrequency
ablation can be performed percutaneously under ultrasound
guidance with local anesthesia. Figure 6.3 demonstrates a
case of a metastatic pancreatic cancer 2 years after a dra-
matic primary response to gemcitabine and radiation ther-
apy. Because the patient will likely begin to fail in multiple
sites in the near future with limited survival potential, a lap-
arotomy and hepatic resection was not considered reason-
able. She was treated with percutaneous radiofrequency
ablation, achieving a good zone of necrosis encompassing
the mass, and she spent only one day in the hospital with
very minimal discomfort. How such procedures, which have
low morbidity and which maintain quality of life, will factor
58
(B)
(D)
in the treatment of patients with small hepatic metastases
must be addressed by studies with sufficient follow-up to
define the local recurrence rate.
adjuvant chemotherapy
The role for adjuvant systemic chemotherapy after the
removal of small solitary hepatic metastases is not well
defined. Even for hepatic colorectal metastases, which are
commonly treated with surgery, data on adjuvant chemother-
apy after liver resection is sparse. Two retrospective studies
have suggested a benefit of adjuvant systemic chemotherapy
after metastasectomy, but others have not supported this
(6,46–48). Use of systemic chemotherapy after resection of
hepatic colorectal metastases is based mainly on data demon-
strating adjuvant 5-fluorouracil (5-FU) and levamisol or
5-FU and leucovorin to decrease recurrence rate and improve
survival when used after resection of the primary tumor (49).
It is hoped that a similar benefit will be seen when 5-FU-
based chemotherapy is used after metastasectomy. Current
practice is to offer adjuvant 5-FU-based chemotherapy after
hepatic resection to patients who have had no previous che-
motherapy. There are currently no data to support the use of
irinotecan and oxaliplatin in an adjuvant setting, although
studies are in progress.
 SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW?

(A) (B)

(C)
Figure 6.3 An example of a small, solitary pancreatic cancer metastasis treated with percutaneous radiofrequency ablation. (A) Pretreatment CT scan reveals
hypodense 3 cm right lobe liver metastasis. (B) Ultrasound hoto with radiofrequency probe inserted into tumor. (C) Post-treatment scan (3 weeks) reveals large
zone of necrosis replacing prior tumor. (Special thanks to Dr Thomas Shawker for ultrasound photo.)

For patients with hepatic colorectal metastases, the most
common site of tumor recurrence after liver resection is the
remnant liver (50). In the treatment of patients with small
hepatic metastases, there is particular concern that even
smaller undetected metastases may subsequently present as
a liver tumor recurrence. Regional chemotherapy to treat
the liver site is therefore a theoretically attractive option for
adjuvant care. Data addressing the utility for such hepatic
arterial infusional (HAI) chemotherapy had been sparse,
consisting only of four small single-arm studies (51–53) and
a single, small, randomized trial consisting of 36 patients
(54). These preliminary studies demonstrated safety of such
an approach, but efficacy data were insufficient to support
the routine use of adjuvant intraarterial chemotherapy. Two
large randomized trials examining adjuvant HAI have been
completed. In the first trial (55), 224 patients from 25 centers
were randomized to either no adjuvant therapy or adjuvant
HAI 5-FU + systemic folinic acid. Although no difference
was found between the groups, technical factors compro-
mised this study such that only 34 of the 114 patients
randomized to chemotherapy completed the adjuvant
treatments. In another study, Kemeny et al. randomized
156 patients to either systemic 5-FU + leucovorin or HAI
floxuridine (FUDR) + systemic 5-FU after complete resec-
tion of tumor (56). There was a significant survival advan-
tage to HAI that is most likely related to local liver tumor
control. We believe HAI chemotherapy is effective and
should be considered as an adjuvant to resection of hepatic
colorectal metastases.
For noncolorectal, nonneuroendocrine histologies meta-
static to the liver, the most likely cause of death will be related
to the disease outside the liver, regardless of how the liver is
managed. For patients who are likely to develop systemic
metastases in the near future, it may be reasonable to offer
chemotherapy prior to resection. If the tumor responds, then
a resection will be performed with confidence that other
micrometastatic disease may be effectively treated with che-
motherapy. If the tumor does not respond and the liver
remains the only site of metastatic disease, resection is per-
formed with increased confidence conferred by the longer
period of observation. If the patient advances systemically
during chemotherapy, then it is very unlikely that a resection
would have been of benefit and the patient will have avoided
the potential morbidity, pain, discomfort, and recovery time
of an hepatic resection. That patient can go on to obtain
second-line chemotherapy, investigational chemotherapy, or
have no additional treatment.
conclusions
Algorithms for the management of small solitary hepatic
metastases are shown in Figure 6.4. Both patient and tumor
characteristics must be considered in making management
decisions. The most important tumor-related characteristic is

59
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Colorectal
metastases

Low CRS High CRS

(0–2) (3–4)

Observation
Resection or Ablation Resection
chemotherapy

No Adjuvant Adjuvant
Extrahepatic
extrahepatic therapy therapy
progression
progression protocol protocol

Resection
Chemotherapy
or ablation
(A)

Neuroendocrine
metastases Non-colorectal
non-neuroendocrine

Symptomatic Asymptomatic
Long disease-free Short disease-free
interval interval

Resection Ablation Observation

Effective
No effective
Resection chemotherapy
chemotherapy
No (>20% response)
Progression
progression

Resection Trial of Ablation vs

Observation chemotherapy observation
or ablation

(B) (C)
Figure 6.4 Algorithms for the management of small hepatic metastases. (A) Algorithm for colorectal metastases (CRS, clinical risk score). (B) Algorithm for
neuroendocrine metastases. (C) Algorithm for non-colorectal, non-neuroendocrine metastases.

histology. For patients with colorectal cancer (Fig. 6.4A), the
prognostic factors for tumor recurrence after resection are well
defined. Using the clinical risk score (CRS) as selection crite-
rion, patients with CRS = 0–2 are ideal candidates for resec-
tion. Those with CRS = 3–4 should consider observation or
chemotherapy prior to a definitive hepatic procedure. Imme-
diate ablation or resection should be performed in the setting
of a clinical trial, and most appropriately a trial examining
adjuvant therapy.
For neuroendocrine cancers (Fig. 6.4B), symptomatic
tumors should be treated with resection and/or ablation when
possible. When the cancer is found in an asymptomatic patient,
a period of observation is not unreasonable because of the
often indolent nature of these tumors. At resection, the prin-
ciple should be to leave as much normal liver behind in order
to minimize the risk of liver failure and in order to allow for
repeat anatomic liver resections in the future for recurrent dis-
ease. Enucleation with positive margins is acceptable for treat-
ment of this histology because resection is almost never
curative, and such cytoreduction can provide significant and
durable palliation with minimum risk.
For patients with small, solitary, noncolorectal nonneuro-
endocrine tumors, the most significant factor in terms of
prognosis seems to be the disease-free interval (Fig. 6.4C).
For patients with a long disease-free interval from primary
resection a curative surgical resection is indicated as the
most effective means of therapy. While it may be still unlikely
that these patients can be cured, they must be given the ben-
efit of the doubt and the most optimal procedure performed.
The definition of “long” has been arbitrarily set at 36 months
by Harrison et al. (26), but in reality it must vary according
to histology. For gastric cancer, 12–24 months would be

60
 SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW?
considered long, whereas for ocular melanoma, 3–5 years
would be more reasonable.
Patients with a short disease-free interval from a tumor
with a poor prognosis should undergo a trial of chemother-
apy if there is a known effective agent. If no effective agent
exists (as is the case for most solid malignancies), then these
patients are ideal for an experimental, minimally invasive,
local ablative therapy. This provides an advantage to observa-
tion alone, given the low but definite risk of the metastases
spreading during the observation period. It will be psycho-
logically more comforting to the patient to know that the
lesion has been ablated, and risk, pain, and recovery duration
are minimal. Observation alone is also quite reasonable, but it
is often not accepted by patients. Patient-related factors must
also be taken into consideration. Patients who have concomi-
tant illnesses that make them poor operative candidates may
be better served with a minimally invasive or percutaneous
technique, even in the case of potentially curable metastases
from colorectal cancer.
Because of improvements in diagnostic techniques and the
routine use of serum tumor markers, the detection of small
solitary hepatic metastases from various tumors will likely
increase in the future. A uniform approach to these patients
such as that which is outlined in the treatment algorithm
should be considered.
key points
Factors that determine management
● Natural history of tumor type
● Expected cure rate after surgical treatment
● Effectiveness of alternative treatment strategies
● Morbidity of surgical resection
Survival rates following hepatic resection
● Good evidence for long-term survival
Colorectal metastases
Neuroendocrine metastases
● Survival possible in highly selected cases
Breast cancer
Sarcoma (especially gastrointestinal stromal
tumors)
Melanoma
Patient selection factors in colorectal metastases
● Contraindications
Extrahepatic disease (except solitary pulmonary
metastases)
Positive hilar lymph nodes
● Relative contraindications
Presentation within 12 months of resection of
primary tumor
CEA >200 ng/dl
>1 liver tumor
Tumor >5 cm in size
Positive resection margin
references
1. Nuzzo G, Giuliante F, Giovannini I, Tebala GD, Clemente G, Vellone M.
Resection of hepatic metastases from colorectal cancer. Hepato-gastroen-
terology 1997; 44: 751–9.
2. Alexander HR, Bartlett DL, Fraker DL, Libutti SK. Regional treatment
strategies for unresectable primary or metastatic cancer confined to the
liver. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles
and Practice of Oncology. Philadelphia, PA: JB Lippincott, 1996: 1–19.
3. Wagner JS, Adson MA, van Heerden JA, Adson MD, Ilstrup DM. The
natural history of hepatic metastases from colorectal cancer. A compari-
son with resective treatment. Ann Surg 1984; 199: 502–8.
4. Wood CB, Gillis CR, Blumgart LH. A retrospective study of the natural
history of patients with liver metastases from colorectal cancer. Clin
Oncol 1976; 2: 285–8.
5. Fong Y, Blumgart LH, Cohen AM. Surgical treatment of colorectal metas-
tases to the liver. CA Cancer J Clin 1995; 45: 50–62.
6. Hughes KS, Simon R, Songhorabodi S. Resection of the liver for colorectal
carcinoma metastases: a multi-institutional study of indications for resec-
tion. Surgery 1988; 103: 278–88.
7. Rosen CB, Nagorney DM, Taswell HF et al. Perioperative blood transfu-
sion and determinants of survival after liver resection for metastatic
colorectal carcinoma. Ann Surg 1992; 216: 493–505.
8. Scheele J, Stang R, Altendort-Hofmann A, Paul M. Resection of colorectal
liver metastases. World J Surg 1995; 19: 59–71.
9. Taylor M, Forster J, Langer B, Taylor BR, Greig PD, Mahut C. A study of
prognostic factors for hepatic resection for colorectal metastases. Am J
Surg 1997; 173: 467–71.
10. Fong Y, Cohen AM, Fortner JG et al. Liver resection for colorectal metas-
tases. J Clin Oncol 1997; 15: 938–46.
11. Moertel CG. An odyssey in the land of small tumors. J Clin Oncol 1987;
5: 1503–22.
12. Thompson GB, van Heerden JA, Grant CS, Carney JA, Ilstrup DM. Islet
cell carcinomas of the pancreas: a twenty-year experience. Surgery 1988;
104: 1011–7.
13. Declore R, Friesen SR. Gastrointestinal neuroendocrine tumors. J Am
Coll Surg 1994; 178: 188–211.
14. Godwin JD. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975;
36: 560–9.
15. Sjoblom SM. Clinical presentation and prognosis of gastrointestinal
carcinoid tumours. Scand J Gastroenterol 1988; 23: 779–87.
16. McEntee GP, Nagourney DMN, Kvols LK, Moertel CG, Grant CS.
Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990;
108: 1091.
17. Chen H, Hardacre JM, Uzra A, Cameron JL, Choti MA. Isolated liver
metastases from neuroendocrine tumors: does resection prolong sur-
vival? J Am Coll Surg 1998; 187: 88–92.
18. Ihse I, Persson B, Tibblin S. Neuroendocrine metastases of the liver. World
J Surg 1995; 19: 76–82.
19. Raab R, Nussbaum KT, Behrend M, Weimann A. Liver metastases of
breast cancer: results of liver resection. Anticancer Res 1998; 18: 2231–3.
20. Elias D, Lasser PH, Montrucolli D, Bonvallot S, Spielmann M.
Hepatectomy for liver metastases from breast cancer. Eur J Surg Oncol
1995; 21: 510–3.
21. Jaques DP, Coit DG, Casper ES, Brennan MF. Hepatic metastases from
soft-tissue sarcoma. Ann Surg 1995; 221: 392–7.
22. Schwartz SI. Hepatic resection for noncolorectal nonneuroendocrine
metastases. World J Surg 1995; 19: 72–5.
23. Salmon RJ, Levy C, Plancer C, et al. Treatment of liver metastases from
uveal melanoma by combined surgery-chemotherapy. Eur J Surg Oncol
1998; 24: 127–30.
24. Ochiai T, Sasako M, Mizuno S. Hepatic resection for metastatic tumours
from gastric cancer: analysis of prognostic factors. Br J Surg 1994; 81:
1175–8.
25. Bines SD, England G, Deziel DJ, Witt TR, Doolas A, Roseman DL. Syn-
chronous, metachronous and multiple hepatic resections of liver tumors
originating from primary gastric tumors. Surgery 1993; 114: 799–805.
26. Harrison LE, Brennan MF, Newman E et al. Hepatic resection for non-
colorectal, nonneuroendocrine metastases: a fifteen-year experience with
ninety-six patients. Surgery 1997; 121: 625–32.
61
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
27. Fujisaki S, Takayama T, Shimada K, et al. Hepatectomy for metastatic
renal cell carcinoma. Hepato-gastroenterology 1997; 44: 817–9.
28. Iwatsuki S, Shaw BW, Starzl TE. Experience with 150 liver resections. Ann
Surg 1983; 197: 247.
29. Talmadge JE, Fidler IJ. Enhanced metastatic potential of tumor cells har-
vested from spontaneous metastases of heterogeneous murine tumors. J
Natl Cancer Inst 1982; 69: 975–80.
30. Elias D, Saric J, Jaeck D et al. Prospective study of microscopic lymph
node involvement of the hepatic pedicle during curative hepatectomy for
colorectal metastases. Br J Surg 1996; 83: 942–5.
31. Nanko M, Shimada H, Yamaoka H et al. Micrometastatic colorectal cancer
lesions in the liver. Jpn J Surg 1998; 28: 707–13.
32. Hughes KS, Simon R, Songhorabodi S, Adson MA. Resection of the liver
for colorectal carcinoma metastases: a multi-institutional study of pat-
terns of recurrence. Surgery 1986; 100: 278–84.
33. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for
predicting recurrence after hepatic resection for metastatic colorectal can-
cer: analysis of 1001 consecutive cases. Ann Surg 1999; 230(3): 309–18.
34. Delbeke D, Vitola JV, Sandler MP et al. Staging recurrent metastatic
colorectal carcinoma with PET. J Nucl Med 1997; 38: 1196–201.
35. FernE1ndez-Trigo V, Shamsa F, Sugarbaker PH. Repeat liver resections
from colorectal metastasis. Surgery 1995; 117: 296–304.
36. Shirabe K, Takenaka K, Gion T et al. Analysis of prognostic risk factors in
hepatic resection for metastatic colorectal carcinoma with special refer-
ence to the surgical margin. Br J Surg 1997; 84: 1077–80.
37. Blumgart LH. Liver resection—liver and biliary tumours. In: Blumgart,
LH ed. Surgery of the Liver and Biliary Tract. New York: Churchill
Livingstone, 1994: 1495–538.
38. Polk W, Fong Y, Karpeh M, Blumgart LH. A technique for the use of cryo-
surgery to assist hepatic resection. J Am Coll Surg 1995; 180: 171–6.
39. Billingsley KG, Jarnagin WR, Fong Y, Blumgart LH. Segment-oriented
hepatic resection in the management of malignant neoplasms of the liver.
J Am Coll Surg 1999; 187: 471–81.
40. DeMatteo RP, Palese C, Jarnagin WJ, Sun RL, Blumgart LH, Fong Y. Ana-
tomic segmental hepatic resection is superior to wedge resection as an
oncologic operation for colorectal liver metastases. J Gastrointest Surg
2000; 4(2): 178–84.
41. Cunningham JD, Fong Y, Shriver C. One hundred consecutive hepatic
resections: blood loss, transfusion and operative technique. Arch Surg
1994; 129: 1050–6.
42. Bartlett D, Fong Y, Blumgart LH. Complete resection of the caudate lobe
of the liver: technique and results. Br J Surg 1996; 83: 1076–81.
62
43. Fong Y, Blumgart LH. Hepatic colorectal metastasis: current status of sur-
gical therapy. Oncology 1998; 12: 1489–94.
44. Lezoche E, Paganini AM, Feliciotti F, et al. Ultrasound-guided laparo-
scopic cryoablation of hepatic tumors: preliminary report. World J Surg
1998; 22: 829–36.
45. Siperstein AE, Rogers SJ, Hansen PD, Gitomersky A. Laparoscopic ther-
mal ablation of hepatic neuroendocrine tumor metastases. Surgery 1997;
122: 1147–55.
46. Fortner JG, Silva JS, Golbey RB. Multivariate analysis of a personal series
of 247 consecutive patients with liver metastases from colorectal cancer: I.
Treatment by hepatic resection. Ann Surg 1984; 196: 306–16.
47. Butler J, Attiyeh FF, Daly JM. Hepatic resection for metastases of the colon
and rectum. Surg Gynecol Obstet 1986; 162: 109–13.
48. Pagana TJ. A new technique for hepatic infusional chemotherapy. Semin
Surg Oncol 1986; 2: 99–102.
49. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole and fluorouracil
for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;
322: 352–8.
50. Blumbart LH, Fong Y. Surgical management of colorectal metastases to
the liver. Curr Prob Surg 1995; 5: 333–428.
51. Goodie DB, Horton MD, Morris RW, Nagy LS, Morris DL. Anaesthetic
experience with cryotherapy for treatment of hepatic malignancy. Anaes
Int Care 1992; 20: 491–6.
52. Moriya Y, Sugihara K, Hojo K, Makuuchi M. Adjuvant hepatic intra-arterial
chemotherapy after potentially curative hepatectomy for liver metastases
from colorectal cancer: a pilot study. Eur J Surg Oncol 1991; 17: 519–25.
53. Curley SA, Roh MS, Chase JL, Hohn DC. Adjuvant hepatic artery infusion
chemotherapy after curative resection of colorectal liver metastases. Am J
Surg 1993; 166: 743–8.
54. Kemeny MM, Goldberg D, Beatty D et al. Results of a prospective ran-
domized trial of continuous regional chemotherapy and hepatic resection
as treatment of hepatic metastases from colorectal primaries. Cancer
1986; 57: 492–8.
55. Lorenz M, Muller HH, Schramm H et al. Randomized trial of surgery
versus surgery followed by adjuvant hepatic arterial infusion with 5-fluo-
rouracil and folinic acid for liver metastases of colorectal cancer. Ann Surg
1998; 228: 756–62.
56. Kemeny N, Huang Y, Cohen AM et al. Hepatic arterial infusion of chemo-
therapy after resection of hepatic metastases from colorectal cancer. N
Engl Med 1999; 341(27): 2039–48.
57. Que FG, Nagorney DM, Batts KP, Linz LJ, Kvols LK. Hepatic resection for
metastatic neuroendocrine carcinomas. Am J Surg 1995; 169: 36–43.
7 Managing complications of hepatectomy
Fenella K. S.Welsh, Timothy G. John, and Myrddin Rees
introduction
The safety of elective liver surgery has improved dramatically
in the past 30 years. A multicenter American series comprising
621 liver resections published in the late 1970s reported a 13%
mortality (1). By contrast, recent large published series
describe posthepatectomy mortality rates of 0% to 4.4%, with
19.6% to 45% morbidity (2–8) (Table 7.1). Furthermore, indi-
vidual units have demonstrated a significant reduction in
morbidity and mortality over time, despite ever-widening the
indications for hepatectomy (6,8). This dramatic improve-
ment in immediate postoperative outcome can be explained
by increased specialization of liver surgery in high-volume
centers (9), better selection of patients in terms of hepatic
functional reserve and comorbid conditions, advances in sur-
gical technique, including greater understanding of hepatic
segmental anatomy and improved instrumentation for the
parenchymal transection. Furthermore, anesthesia and critical
care has improved enormously, the routine use of low central
venous pressure (CVP) anesthesia being a particular advance.
However, even a 20% complication rate remains significant,
particularly if the indication for hepatectomy is for living-
donor transplantation. Furthermore, postoperative morbidity
can also adversely affect disease-specific and disease-free sur-
vival (10–12). Thus the short- and long-term consequences of
postoperative morbidity, coupled with increasing litigation,
and limited health care resources, has renewed the drive to fur-
ther improve the immediate outcome from liver resection,
with emphasis on prevention of and improved management of
complications, when they occur. The precise definitions of the
specific complications such as bleeding, bile leak, and hepatic
insufficiency are still without consensus. Moreover, the strati-
fication of the severity of each complication is still unclear.
Standardized definitions, grading, and reporting of the com-
plications of hepatectomy are needed to allow an objective,
quality assessment of outcome data from different units and
further improve results. The system proposed and validated by
Clavien, focusing on the therapeutic consequences of compli-
cations in order to rank their severity, is currently the best
available (13). However, it is still not universally adopted
within the surgical community.
A number of studies have attempted to identify the risk fac-
tors associated with complications and death from hepatec-
tomy, three of which are detailed in Table 7.2. From these
studies, there is consensus that the estimated blood loss or
blood transfusion rate, the extent of hepatic resection, and an
additional extrahepatic procedure are all independent predic-
tors of morbidity and mortality. In addition, medical comor-
bidity, an elevated preoperative creatinine, preoperative
thrombocytopenia, or hypoalbuminemia also appear to
increase the operative risk. However, in the Hong Kong
study (8), while cirrhosis per se was associated with increased
postoperative morbidity and mortality on an initial univariate
analysis, it failed to independently predict outcome on subse-
quent multivariate analysis. Similarly, Belghiti’s group found
that the in-hospital mortality rate was significantly higher in
those patients with cirrhosis (8.7%) compared to those with-
out underlying liver disease (1%, p < 0.001), but this was not
subjected to multivariate analysis (7). Thus while liver resec-
tion in cirrhotic patients is technically more challenging than
resecting normal liver, with a higher incidence of bleeding,
septic complications, and postoperative liver failure (14), these
two studies would suggest that in experienced high-volume
centers, liver resection can be safely performed in patients with
early cirrhosis.
The common complications of hepatectomy may be classi-
fied as specific to the procedure or of a more general nature
(Table 7.3). This chapter will deal with these complications in
turn, focusing on their definition, incidence, predisposing fac-
tors, prevention, presentation, investigation, and treatment.
bleeding
Incidence
Bleeding is the most feared complication of hepatectomy, both
on the operating table and in the immediate aftermath of sur-
gery. In the 1960s and 1970s, it was the cause of major morbid-
ity and mortality. The 1974 Liver Tumor Survey was a
multicenter series of 621 hepatic resections performed in 98
U.S. centers, published in 1977. It reported a 13% mortality,
with 15 of the 82 deaths (18%) due to exsanguinating hemor-
rhage in the operating room and bleeding being the docu-
mented primary cause of death in 26 of the 76 patients (34%),
where the cause of death could be determined (1). However,
bleeding is now relatively rare, with the median estimated
blood loss for an elective hepatectomy being 345 to 600 ml
(3,6) and the need for perioperative blood transfusion now
being the exception rather than the rule. Indeed, the incidence
of major hemorrhagic complications is rare, 0.7% (7/1005) in
our own series (3). Of these seven cases, there were no on-table
deaths, five patients were treated nonoperatively and two
underwent reexploration for bleeding from a hepaticojejunal
anastomosis and a left caudate branch of the portal vein
respectively. In the Sloan-Kettering series of 1803 patients, the
incidence is similar (1%) (6).
Prevention
Prevention remains the key to the management of bleeding. In
the preoperative assessment, a careful drug history should be
taken. If the patient is on drugs such as aspirin, clopidogrel, or
warfarin, the indication for the treatment should be reviewed,
and the drugs stopped where possible. Patients on warfarin as
prophylaxis for thromboembolic events can be managed with
an inferior vena cava (IVC) filter, placed preoperatively. It is
63
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 7.1 Morbidity and Mortality from Hepatic Resection in Recent Large Case-Series
Reference Years of study No of centers No of resections Case-mix Mortality Morbidity
Imamura 1994–2002 1 1056 50% HCC 0% 39%
et al. 29% cirrhotic
Rees et al. 1987–2005 1 1005 100% CRLM 1.5% 25.9%
Wei et al. 1992–2002 2 423 100% CRLM 1.7% 19.6%
Malik et al. 1993–2006 1 687 100% CRLM 3.0% 29.5%
Jarnagin et al. 1991–2001 1 1803 62% CRLM 3.1% 45.0%
10% HCC
Belghiti et al. 1990–1997 1 747 Elective & emergency. 4.4% all 22.0%
35% benign 28% HCC 3.9% elective
17% CRLM 8.7% cirrhotic
32% cirrhotic 25.0% emergency
Poon et al. 1989–2003 1 1222 60% HCC 4.9% 32.4%
33% cirrhotic
Abbreviations: CRLM, colorectal liver metastases; HCC, hepatocellular carcinoma.

Table 7.2 Three Studies Reporting the Independent Predictors of Morbidity and Mortality after Hepatic Resection
Reference Years of study No of resections Predictors of morbidity Predictors of mortality
Jarnagin et al. 1991–2001 1803 Estimated blood loss Estimated blood loss
Extent of resection Extent of resection
+ EH procedure + EH procedure
↑ preoperative creatinine ↑ preoperative bilirubin
Hypoalbuminemia Thrombocyt openia
Medical comorbidity
Male gender Age
Belghiti et al. 1990–1997 478 elective resections, ASA score + EH procedure (in patients with
no cirrhotics Extent of resection malignancy)
Steatosis
Blood transfusion
+ EH procedure
Poon et al. 1989–2003 1222 Thrombocytopenia Hypoalbuminemia
Blood transfusion Thrombocytopenia
+ EH procedure ↑ preoperative creatinine
Major resection
Blood transfusion
Abbreviation:+EH Procedure, additional extra-hepatic procedure.

important to identify patients with tricuspid regurgitation or
right heart disease, where the anesthetist may encounter diffi-
culties in lowering the CVP, as this may influence the extent of
resection. Careful evaluation and correction of coagulation
abnormalities should be performed pre- and perioperatively,
particularly in the cirrhotic patient.
Two key maneuvers are used to prevent bleeding during
hepatic transection: portal triad clamping and low CVP
anesthesia. Portal triad clamping, first described by Pringle
in 1908, reduces hepatic arterial and portal venous bleeding
(15,16). Although a European survey demonstrated that the
use of inflow occlusion is not universal, it did confirm that
most hepatic surgeons resort to it in difficult cases and that
experienced surgeons are more likely to use it routinely (17).
However, a recent systematic review and meta-analysis of the
effect of inflow occlusion on postoperative morbidity and
mortality failed to demonstrate any significant outcome
benefit (18). This is confirmed by another systematic review
published in 2009, which compared 166 patients with vascu-
lar occlusion to 165 patients with no vascular occlusion (19).
However, despite the small numbers involved, this later study
showed that blood loss was significantly lower in those
patients who had vascular occlusion. A low CVP reduces
back bleeding from hepatic veins during the transection
(20–22) and is now accepted practice during liver resection
worldwide. Indeed, following the introduction of low CVP
anesthesia in our own unit, the mean blood loss was signifi-
cantly reduced from 2116 to 426 ml (3). However, these
techniques can test the patients’ cardiovascular reserve.
Obstructing the portal blood flow causes venous congestion
of bowel and in combination with warm ischemic liver
injury, releasing a flush of anerobic metabolites and cyto-
kines back into the circulation on release of the clamp (23).
Low CVP anesthesia relies on patients being maintained in a

64
 MANAGING COMPLICATIONS OF HEPATECTOMY
Table 7.3 Complications of Hepatectomy
General complications Specific complications
Immediate • Hypothermia • Bleeding
(on table)
Early (days) • Respiratory— • Bleeding
atelectasis, pleural • Bile leak
effusion, pneumonia • Hepatic insufficiency
• Cardiovascular— • Intra-abdominal
DVT, PE, MI, abscess
arrhythmias, CVA
• Renal failure
• Wound infection
• Pain
Late (weeks/ • Incisional hernia • Biliary stricture
months)
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolus; MI,
myocardial infarction; CVA, cerebrovascular accident.
hypovolemic state until liver resection has been completed
(20,21). This is in contrast to most other major surgical pro-
cedures, where patients have large volumes of crystalloid and
colloid perioperatively.
While a recent meta-analysis has confirmed that the use of
the antifibrinolytic agent aprotinin can significantly reduce
transfusion requirements during liver transplantation (24),
there is no evidence for its routine use during liver resection
(25). In contrast, a prospective double-blind randomized
trial of tranexamic acid, another antifibrinolytic agent, has
shown that its use perioperatively significantly reduced the
blood loss and transfusion requirements in elective liver
resection (26). Two prospective randomized controlled trials
have failed to show any benefit of using recombinant factor
VIIa in either noncirrhotic (27) or cirrhotic (28) patients
undergoing hepatectomy.
Since the early 1990s, the use of fibrin sealants has become a
popular aid hemostasis at the hepatic parenchymal transection
site. Two early randomized trials suggested some benefit in
achieving hemostasis (29) and reducing postoperative blood
loss (30), although the numbers involved were small. A more
recent trial of a carrier-bound fibrin sealant (TachoSil®) sug-
gested it was quicker and more effective hemostasis compared
to argon beam coagulation (31). However, the numbers
involved were again small (<65 patients in each group). A
larger prospective randomized trial of fibrin glue versus con-
trol involving 300 patients undergoing hepatic resection was
published in 2007 (32). This showed no difference in blood
loss, blood transfusion, or overall morbidity between those
who received the fibrin glue and those who did not. This study
provides the best evidence to date that the routine use of such
topical hemostats is not justified, although it is our own per-
sonal bias that fibrin glue needs to be combined with a colla-
gen matrix to be effective.
Presentation
Postoperatively, patients who are bleeding may present with
classical signs of shock, persistent blood loss in an abdominal
drain, a drop in hemoglobin, or gastrointestinal bleeding.
Investigation and Treatment
The hemoglobin concentration and clotting screen should be
performed urgently, ensuring that the patient has an up-to-
date cross match. Any coagulopathy should be corrected. If the
patient remains shocked, appropriate investigations may
include endoscopy and mesenteric arteriography. Ultimately,
as in our own series, small number of patients may need to
return to the operating theatre for surgical control of
hemorrhage.
biliary complications
Incidence and Definition of a Bile Leak
Bile leak remains a persistent problem after hepatectomy, with
a reported incidence of 1% to 12% (3,33). In addition, it
appears to be the most common complication after living
donor hepatectomy, with an incidence of 7.5% in the 731
donors in one Japanese series (34) and 9% in 381 donors in an
American series (35). The variable incidence may be explained
by the different patient populations analyzed and the lack of
consensus regarding the definition. The Amsterdam group has
defined bile leakage as one or more of the following criteria:
the presence of persisting bile-stained effluent from an abdom-
inal drain, leakage detected on radiological imaging, and
occurrence of a bile collection drained percutaneously or
found during relaparotomy (36). This definition of a bile leak,
used in conjunction with Clavien’s severity grading (13), could
be widely applied in clinical practice.
Prevention
Meticulous technique during the parenchymal transection,
ensuring that both small and large bile ducts are adequately
secured with clips, ties, or sutures, is vital for the prevention of
bile leakage. Inspection of the cut surface and application of a
clean white-gauze swab is usually enough to reveal a bile leak,
which must then be sutured. Methods for testing for bile leak-
age have previously been advocated and include injection of
the biliary system (usually via the cystic duct stump) with
saline solution or methylene blue, or formal direct cholangiog-
raphy after the transection has been completed. However, the
only prospective randomized study has shown no evidence
that such maneuvers reduce the bile-leak rate (37) and thus
this technique cannot be recommended as a routine. While
one study has show that topical fibrin glue significantly reduces
the bile-leak rate following hepatectomy (38), other studies
have failed to show any benefit (29,39). Thus there is no clear
evidence that topical hemostatic agents used after the liver
resection on the parenchymal surface reduce the bile-leak
rate (33).
Risk Factors for a Bile Leak
There is consensus in the literature that extended hepatic
resections are associated with an increased risk of bile leak
(36). An Italian series of 610 liver resections without a concur-
rent hepaticojejunostomy reported a 3.6% incidence of post-
operative bile leakage (38). On multivariate analysis, they
found that resection of a peripheral cholangiocarcinoma (rel-
ative risk 5.5) and hepatectomies including segment 4 (relative
risk 3.1) were the only independent risk factors for a bile leak.
65
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Other risk factors reported include a large transection area and
operations, which expose the major Glissonian sheath around
the hepatic hilum (major central resections including seg-
ments 4b, 5, or the caudate), with subsequent unrecognized
injury to the bile duct (40). Gertsch and coworkers showed
that patients who had postoperative ischemia of part of the
remnant liver had a higher incidence of bile leakage (18.4%)
compared to those with no ischemia (2.7%) (41). In addition,
any hepatic resection, which includes resection of the extrahe-
patic biliary tree with concomitant hepaticojejunostomy has a
significantly higher bile leak rate (36,40,42). The presence of
cirrhosis appears to be associated with a lower risk of a bile
leak, possibly because of a less aggressive surgical approach in
these patients (38).
Presentation of a Postoperative Bile Leak
A bile leak can present as bile-stained effluent from an abdom-
inal drain. Other patients will show signs of intra-abdominal
sepsis, with a fever, abdominal pain, or right-sided chest signs,
and leak bile into a secondarily placed drain.
Management of a Postoperative Bile Leak
Minor bile leaks may often resolve with no requirement for
further intervention. In their case series, Vigano and cowork-
ers found that 77% of bile leaks settled spontaneously. How-
ever, a drainage output greater than 100 ml on postoperative
day 10 was the only independent risk factor for failure of con-
servative management (43). Percutaneous tube drainage
should then be the intervention of choice. If percutaneous
drainage fails because of persistent or recurrent bile leakage,
endobiliary stenting should be undertaken, to reduce the
intrabiliary pressure and promote rapid resolution of the bile
leak (44,45). Clearly this can only be successful if there is
communication between the leaking bile duct and the main
biliary tree.
In the face of failure of percutaneous and endoscopic
approaches, relaparotomy should be undertaken, with a view
to optimizing drainage, a further hepatic resection, or forma-
tion of a biliary enteric anastomosis. The precise intraopera-
tive decision will depend on the volume of the liver remnant
and functional liver reserve as well as the extent of local sepsis.
We have had to perform a biliary enteric anastomosis for a
persistent bile leak in one patient out of our entire cohort of
liver resections (1/1600). The patient had undergone an
extended left hepatectomy. Following an initially uncompli-
cated postoperative course with discharge home on day 4, she
was readmitted three weeks later with intra-abdominal sepsis.
After initial percutaneous drainage of a large bile collection,
the leak failed to resolve with endoscopic biliary drainage. A
laparotomy was therefore performed and the area of bile leak-
age identified at the resection edge, but no actual bile duct
seen. A Roux-en-Y jejunal loop was therefore anastomosed to
the resection edge with a successful outcome.
Consequences of a Bile Leak
The direct consequences of a postoperative bile leak include
prolonged hospital stay and increased morbidity and mortal-
ity (39). Patients with persistent bile leakage are at risk of
66
developing intra-abdominal sepsis, with the attendant risk of
liver failure and death (46).
Incidence of Biliary Stricture after Hepatectomy
A biliary stricture is an uncommon, late complication of hepa-
tectomy, with an incidence of 0.2% (4/1803) in the Sloan-
Kettering series (6). It is caused by unrecognized intrahepatic
injury to the bile ducts, either directly or due to isolated devas-
cularization of the biliary tree. A distal biliary stricture may be
responsible for a persistent proximal bile leak.
Management of Biliary Stricture After Hepatectomy
A biliary stricture after hepatectomy should be managed in the
same way as any iatrogenic biliary stricture. This will include
radiological and/or endoscopic assessment of the level of the
stricture and its relationship to the remaining biliary tree,
together with an estimate of the volume and function of the
hepatic remnant. Avoidance of sepsis or cholangitis is para-
mount, as is attention to the nutritional status of the patient.
Potential treatments include endobiliary stenting, biliary
reconstruction, or a further hepatic resection tailored to the
individual circumstances.
hepatic insufficiency
Definition and Incidence
There is currently no internationally accepted definition of
postoperative liver failure or hepatic insufficiency. Belghiti’s
group have proposed the “50-50 criteria,” which are a pro-
thrombin index <50% of normal (corresponding to an Inter-
national Normalized Ratio (INR) of 1.7 or more) and a
serum bilirubin > 50 µmol/L on postoperative day 5, as a
simple, accurate predictor of liver failure and death (47). On
the fifth postoperative day, both prothrombin time and bili-
rubin should have returned to normal values. They found
that the persistence of the “50-50 criteria” at this time indi-
cated a significant impairment of liver function and was
associated with a 59% risk of early postoperative mortality,
compared with a 1.2% risk if the criteria were not met. They
recently prospectively evaluated these criteria in a cohort of
436 elective hepatectomies and found that the “50-50 crite-
ria” on postoperative days 3 and 5 were accurate predictors of
death on multivariate analysis (48). The MD Anderson group
reviewed data from 1059 noncirrhotic patients who under-
went a major hepatectomy and found that a peak bilirubin of
more than 120 µmol/L (7.0 mg/d/L), accurately predicted
liver-related death and suggested that this be used as a defini-
tion (49). By this definition, the incidence of postoperative
liver failure with or without multiorgan failure resulting in
death in their series was 2.8%. In the French multicenter
series of 1568 hepatectomies, the incidence of liver failure
was 43/1568 (2.7%), however this was responsible for death
in 7/43 (16%) of those patients (50). In the Hong Kong series
(8), postoperative liver failure occurred in 47 out of the
1222 hepatic resections (3.8%), but again, it is not defined.
This series had a higher incidence of patients (59.2%) with
cirrhosis or chronic hepatitis compared to most Western case
series. Overall, the reported incidence in the literature ranges
from 0.7% to 9.1% (51).
 MANAGING COMPLICATIONS OF HEPATECTOMY
Prevention
The incidence of postoperative liver failure is related to the
volume and quality of the remnant liver, the amount of blood
lost during surgery (52,53), and the presence of comorbid
conditions such as diabetes mellitus (51,52). As treatments are
limited and the consequences life-threatening, preoperative
assessment of the individual patient’s risk is vital and will
affect the operative approach (54). Assessment of liver func-
tion can be achieved using liver biochemistry, coagulation
studies, and the Child–Pugh classification (55). However,
because of the limits of the Child–Pugh scoring system, sur-
geons have looked for other tests of hepatic function to help
identify patients at risk of postoperative liver failure. The indo-
cyanine green (ICG) retention test is the most widely used in
clinical practice. ICG is a dye that is removed from plasma by
the liver and rapidly excreted unchanged into bile. The ICG
retention rate at 15 minutes (ICGR-15) provides a measure of
hepatic function, with clearance said to be impaired when
15% or more of the ICG remains within the plasma at 15 min-
utes (56). Makuuchi’s group has successfully incorporated the
ICGR-15 in their preoperative work-up of Child–Pugh class A
patients to guide the extent of resection (54). The Hong Kong
group also uses it in their preoperative assessment of patients
with HCC, because of their high incidence of chronic liver dis-
ease. They use an ICGR of <20% as a cut-off for a major resec-
tion in cirrhotic patients (57).
There is a close relationship between liver function and vol-
ume. The volume of the future liver remnant (FLR) may be
assessed by computed tomography (CT) volumetry. Vauthey
and colleagues reported the value of residual liver volume using
CT as a predictor of hepatic dysfunction, noting a critical value
of 25% below which they found a significant risk of hepatic
dysfunction in patients with no underlying liver disease (58).
These data have been confirmed by two other groups, who
defined a critical FLR of 26.6% (53) and 26.5% (59), respec-
tively. In patients with underlying liver disease, such as chemo-
therapy-associated steatohepatitis or cirrhosis, the FLR should
be greater (59), with Vauthey’s group suggesting it should be at
least 30% if the patient has received extensive preoperative che-
motherapy and 40% if they have cirrhosis (60). A recent sys-
tematic review (61) looked at the association between
chemotherapy type, liver injury, and the impact of liver injury
on outcome following liver resection. This study found a sig-
nificant association of irinotecan with steatohepatitis, espe-
cially in obese patients. These patients had a higher 90-day
mortality rate compared to patients who did not have steato-
hepatitis (15% vs. 2%, p = 0.001) and a significantly higher risk
of death from postoperative liver failure (6% vs. 1%, p = 0.01),
highlighting that irinotecan appears to impair the functional
reserve and regenerative capacity of the liver (60). Chemother-
apy-associated hepatotoxicity and its impact on outcome after
hepatectomy are covered in more detail in chapter 17.
The use of portal vein embolization (PVE) to improve
volume of the FLR and as a functional test of hepatic reserve
PVE can be used to induce hypertrophy of the FLR and reduce
the incidence of postoperative complications, including liver
failure, in patients with a marginal FLR (62–65). PVE may also
provide an important functional test of hepatic reserve in
patients with a borderline FLR, with the degree of hypertrophy
predicting outcome from hepatectomy (63). Certainly, if
patients with borderline FLR remnants do not exhibit hyper-
trophy following PVE, they should not undergo hepatic resec-
tion because of the risk of postoperative liver failure—the
so-called “trial of PVE.” A recent consensus statement suggests
that PVE is indicated when the FLR is <20% in patients with
normal liver, <30% in patients who have had chemotherapy,
and <40% in patients with well-compensated cirrhosis (66).
Optimization of Venous Drainage
A key aspect of maximizing the function of the remnant liver
and prevention of hepatic insufficiency is to preserve and opti-
mize its venous drainage. Belghiti showed that following a
right hepatectomy, left hepatic venous outflow was impaired if
the left liver was not fixed in the anatomical position (defined
as the position where the falciform ligament was in its strict
medial position) (67). The consequent venous congestion
could result in bleeding from the resection surface in the
short-term and impaired function and regeneration of the
liver remnant in the ensuing few days or weeks.
The venous drainage on preoperative imaging should be
carefully evaluated when planning any resection, therefore
allowing optimization of the venous drainage of the future
liver remnant. For example, preserving the umbilical vein
when performing a right hepatectomy extended to segment 4a
will allow adequate drainage of segment 4b. Belghiti’s group
has demonstrated the importance of this, using the living
donor hepatectomy as a model (68). They showed that 84% of
donors who underwent right liver harvesting to include the
middle hepatic vein, developed venous congestion of segment
4 postoperatively, compared to none of the donors who had
right liver harvesting without including the middle hepatic
vein. Furthermore, this was associated with impaired postop-
erative liver function and regeneration.
Treatment of Postoperative Hepatic Insufficiency
As emphasized above, the mainstay of management of opera-
tive hepatic insufficiency is prevention. However, should it
occur, there are a number of important strategies to employ.
Patients should be receiving best supportive care, to optimize
other organ functions, in a minimum level 1 environment,
with intensive escalation of care as required. It is important to
avoid secondary septic insults such as pneumonia or intra-
abdominal sepsis, as any second “hit” will increase the risk of
death. Liver failure and sepsis appear to be closely linked.
Schindl and coworkers have reported a direct correlation
between the extent of liver resection and the incidence of
infective complications (53). This risk is further increased in
the presence of cirrhosis or liver failure (53). Thus in a patient
developing liver failure, infectious complications should be
actively excluded by clinical assessment and radiological
and bacteriological investigations. Infectious complications
should be aggressively treated with appropriate antibiotics
and drainage or reoperation as required.
Other management strategies to combat posthepatectomy
liver failure include dietary sodium restriction (<90 mmol
67
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
sodium per day), to reduce the sodium retention that can occur
as a result of decreased renal excretion and enhanced sodium
resorption (69). Some patients will develop hyponatremia and
worsening ascites due to water retention. It is our practice to
moderately restrict fluid for such patients to 1.5 to 2 L per day.
If the serum sodium is > 126 mmol/L, patients should be com-
menced on spironolactone, an aldosterone antagonist, which
acts on the distal tubules to increase natriuesis and conserve
potassium. The initial dose should be 50 to 100 mg per day,
increased up to 400 mg per day and limited by the development
of hyperkalemia. The additional use of frusemide, a loop
diuretic, at a dose of 40 mg per day, can enhance its natriuretic
effect. In patients with a serum sodium 121 to 125 mmol/L, cli-
nicians should consider stopping diuretics, particularly if there
is evidence of renal impairment. In this scenario, patients
should be given volume expansion, ideally with 20% salt-poor
albumin. Other volume expanders such as Gelofusine® and
4.5% albumin solutions contain high concentrations of sodium
(154 mmol/L) and their use will potentially worsen patients’
sodium retention. The management of patients with a serum
sodium < 120 mmol/L is difficult and controversial. In this sce-
nario, all diuretics should be stopped and patients should
undergo volume expansion with colloid or saline. It is impor-
tant that these patients are not taking nonsteroidal antiinflam-
matory drugs (NSAIDs), as these can also inhibit salt and water
excretion and compound the problem (70,71). Hypoglycemia
and hypophosphatemia should be aggressively corrected. These
recommendations from the evolution of our own practice are
reinforced by the current U.K. guidelines on the management
of ascites in cirrhosis (69).
A few small case series suggest that artificial liver support
systems such as the molecular-adsorbent recirculating system
(MARS) may be of value in treating posthepatectomy liver
failure (72). However, a recent systematic review showed that
there is currently insufficient evidence to support their use in
these patients (73).
intra-abdominal infection
Importance and Incidence
Posthepatectomy infections are important as they can precipi-
tate liver failure and death, as discussed earlier. The incidence
of infected perihepatic collections ranges from 2.7% to 6.1% in
modern case series (6,8), but is higher (12.8%) in older series
(74). The incidence of infected ascites is less than 1% (8).
Factors Affecting the Incidence of Intra-abdominal Infection
The decreasing incidence of intra-abdominal infections over
time is a reflection of the evolution of liver surgery in the past
30 years. In Yanaga’s series of 149 liver resections performed
between 1973 and 1984, 19 patients (12.8%) developed intra-
peritoneal septic complications, of whom 13 patients died of
liver failure (74). They identified five risk factors for this,
which were: (1) right or extended right hepatectomy, (2) age >
65 years, (3) operation time > 5 hours, (4) blood loss > 3L, and
(5) postoperative bleeding, which required a laparotomy to
achieve hemostasis. A further Japanese case series of 535 hepa-
tectomies performed between 1992 and 2005 reported that
advanced age, diabetes mellitus, the use of silk sutures, and bile
68
leakage were all associated with postoperative infective com-
plications (75). They show a reduction in their postoperative
infection rate from 44.7% at the start of the study to 9.2% by
the end, with improvements in clinical practice such as early
enteral nutrition and aggressive management of bile leaks.
There is no evidence that the use of postoperative systemic
antibiotics reduces postoperative infective complications. In a
prospective randomized trial, Wu and coworkers showed that
postoperative systemic antibiotics after liver resection did not
influence the incidence of infective complications, which was
23% in each group (76). Another prospective randomized trial
investigated whether omentoplasty to the hepatic parenchy-
mal transection surface reduced the incidence of deep abdom-
inal complications (bleeding, hematoma, infection with or
without purulent discharge through drains, or bile leakage).
The authors found that while deep abdominal complications
were significantly associated with major hepatic resections,
omentoplasty did not reduce their incidence (77).
Abdominal Drainage
The use of routine drainage after liver resection and its role
in preventing complications remains controversial. A pro-
spective randomized trial involving 186 patients compared
closed suction drainage with open drainage after elective
hepatectomy. The trial showed that the incidence of infected
subphrenic collections, postoperative ascites, and pleural
effusion was significantly lower in the closed suction drain-
age group. However, both groups showed similar rates of
subphrenic hematoma and biloma formation (78). In con-
trast, another trial prospectively randomized 120 patients
undergoing elective hepatectomy to closed suction drainage
or no drainage (79). This showed no difference in overall
complication rate between the two groups. However, 18% of
patients in the no drainage group subsequently required a
percutaneous drain, compared to 8% in the drained group,
but this was not statistically significant. The authors con-
cluded that routine drainage was unnecessary after elective
hepatectomy and adopted a selective drainage policy. A trial
from Hong Kong, which randomized 104 patients with
chronic liver disease to closed suction drainage or no
drainage, showed that there was significantly higher morbid-
ity in the drainage group (73%) compared to the no drainage
group (38%) (80). Further, specifically there was a higher
incidence of wound complications in the drainage group and
a trend towards more septic complications.
In conclusion, elective closed suction drainage in patients
with chronic liver disease is not recommended. For all other
patients, there is no evidence that routine abdominal drainage
prevents postoperative abdominal septic complications. How-
ever, for patients at high risk of bile leakage (as outlined earlier
in this chapter), routine drainage is recommended.
respiratory complications and pain relief
Incidence
Respiratory complications such as pleural effusion and bron-
chopneumonia are common after hepatectomy. In the Hong
Kong series, 7% of patients developed a postoperative pneu-
monia and 5% of patients had a pleural effusion requiring
 MANAGING COMPLICATIONS OF HEPATECTOMY
aspiration (8). In the Sloan-Kettering series of 1803 resections,
the corresponding incidence was 3% pneumonia and 8.5%
symptomatic pleural effusion; 2.5% of patients had basal atel-
ectasis, with a further 2.5% developing respiratory failure
requiring support. In addition, 1% of patients suffered a pul-
monary embolus postoperatively (6).
Prevention and Management
As with any abdominal operation, a patient’s risk for respira-
tory complications should be assessed preoperatively. Smokers
should be encouraged to stop. Patients with chronic lung dis-
ease should have aggressive preoperative physiotherapy. Good
postoperative pain relief to facilitate early mobilization, deep
breathing, and coughing is paramount. Epidural analgesia is
one of the best methods for provision of postoperative pain
relief in patients recovering from major upper abdominal
operations (81,82). However, the procedure itself is associated
with complications such as hypotension, bradycardia, imme-
diate or delayed respiratory depression, urinary retention,
dural puncture and hematoma, and/or infection within the
spinal cord. Furthermore, patients undergoing hepatectomy
are at risk of a prolonged prothrombin time postoperatively
and this may affect the timing of removal of the epidural cath-
eter (83). A retrospective review of 367 patients who under-
went elective hepatectomy showed that patients who had
epidural analgesia had a significantly lower mean arterial
blood pressure in the theater recovery area and were more
likely to have a blood transfusion during their hospital
course (84). Thus in our unit, for the past five years, we have
moved away from epidural anesthesia to using a continuous
intermuscular bupivacaine infusion combined with patient-
controlled analgesia (85). This is a safe, simple, and efficacious
method of providing postoperative pain relief in patients after
liver resection and is associated with a low incidence of pul-
monary complications (85).
To prevent the small but potentially fatal risk of thromboem-
bolic complications, all our patients wear graduated compres-
sion stockings. Pneumatic foot pumps are worn in the operating
theatre and continued until the patient is fully mobile. Low-
dose subcutaneous low-molecular-weight heparin is given
daily postoperatively, once the prothrombin time has returned
to within three seconds of normal.
When respiratory complications do occur, they should be
managed aggressively and proactively to minimize the risk of
sepsis precipitating hepatic insufficiency.
cardiac complications
In our own series, the Sloan-Kettering and the Hong-Kong
series, the most common cardiac complication of hepatectomy
is arrhythmia, with an incidence of 2% to 5% (6,8). Myocardial
infarction and heart failure will also occur in about 1% of
patients. At-risk patients should be identified preoperatively
and undergo a cardiac assessment with exercise or pharmaco-
logical stress echocardiography and coronary angiography. Car-
diac function should be optimized preoperatively with medical
therapy, coronary stenting, and coronary artery bypass grafting
as required. We have also used a perioperative intra-aortic
balloon pump (86).
Patients who develop cardiac complications following
hepatectomy should be managed in conjunction with the local
cardiologists. If required, aspirin, clopidogrel, and formal anti-
coagulation with heparin can be given within days of a hepa-
tectomy, although it is advisable to avoid the administration of
a large loading dose of warfarin, to minimize the risk of early
secondary hemorrhage.
renal failure
Definition and Incidence
Renal failure is defined as the need for renal replacement ther-
apy. Studies have shown that 3% to 7% of patients require
renal replacement therapy after liver resection (21,87). In our
own case series, the incidence is 0.9% (unpublished data).
Etiology of Renal Failure After Hepatic Resection
There are three main factors which may contribute to the
development of renal failure following liver resection. Elderly
patients and those with conditions such as hypertension,
atherosclerosis, or chronic kidney disease are at risk (88).
These patients have a reduced capacity for neurohumoral
autoregulation of glomerular blood flow during surgery and
thus an increased risk of acute tubular necrosis (ATN) (88).
Perioperative use of NSAIDs may also impair normal auto-
regulation of glomerular perfusion through inhibition of
arteriolar dilatory prostaglandins (88) and should be avoided
in patients with preoperative renal impairment. The second
factor relates to the “hit” of surgery. Two key factors in the
pathogenesis of ATN are hypovolemia and renal damage by
inflammatory mediators (87). Both these events are predict-
able in every hepatic resection that employs low CVP anes-
thesia and portal inflow occlusion. Obstruction of the portal
blood flow with the Pringle maneuver causes splanchnic
venous congestion and, in combination with warm ischemic
liver injury, results in a flush of anerobic metabolites and
cytokines into the systemic circulation on release of the
hepatic inflow clamp (23). Low CVP anesthesia relies on
patients being maintained in a hypovolemic state until liver
resection has been completed (20,21). This is in contrast to
most other major surgical procedures, where patients are
given significant volumes of crystalloid and colloid in the
perioperative period. Moreover, vasodilators are often used
to further reduce the CVP, leading to distributive changes in
blood flow (20). Certainly, low CVP anesthesia with or with-
out hepatic inflow occlusion can produce major circulatory
changes, potentially resulting in ATN and subsequent renal
impairment or failure (87). Another factor, which contrib-
utes to the etiology of renal failure following liver resection is
a low perfusion state either secondary to cardiac dysfunction
or distributive circulatory changes, such as sepsis or hepa-
torenal failure (87,88). Postoperative renal dysfunction is
often multifactorial.
Consequences of Postoperative Renal Failure
The potential consequences of acute kidney injury include
increased risk of mortality and may contribute to the
development of chronic kidney disease (89).
69
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Hepatectomy in Patients with Preoperative
Renal Impairment
Patients with preoperative renal impairment, as defined by a
raised preoperative serum creatinine, are at increased risk of
both renal and non-renal complications (6). These patients
require careful monitoring in the early postoperative period in
order to optimize fluid balance and cardiac output and in
some instances may require hemofiltration.
wound complications
The incidence of wound infection was 5.2% in the Sloan-
Kettering series, with a further 10 patients (0.5%) having a
wound dehiscence (6). The Hong Kong series of 1222 liver resec-
tions reports double these complication rates—with 115 patients
(9.4%) developing a wound infection and 16 patients (1.3%)
suffering wound dehiscence (8). An explanation of the higher
incidence of wound complications in the Hong Kong series may
be their higher percentage of cirrhotic patients (33% vs. 9%).
A study from Japan of 626 liver resections, with a 7.7% inci-
dence of incisional hernias, examined the risk factors for this
(90). Risk factors included the type of incision, with a reversed
T incision having a significantly higher incidence of an inci-
sional hernia (21.7%) compared to midline (6.3%), J-shaped
(4.7%), or a right transverse incision with long midline exten-
sion (5.4%). Furthermore, postoperative ascites, body mass
index, repeat hepatectomy, and steroid use were also signifi-
cant risk factors. The incidence of reported incisional hernia
was 0.2% in our own series, with the two known patients who
developed incisional hernias undergoing repair of these at the
time of repeat liver resection. We believe this low incidence is
related to the method of closure of the J-shaped wound, with
a tension-free, 2-layer closure, using a 6:1 suture (looped
0-nylon) to wound–length ratio, as opposed to the traditional
4:1 ratio (85).
conclusions
The safety of elective liver surgery has improved dramatically
in the past 30 years, despite ever-widening indications for
hepatectomy. However, complications still happen and pre-
vention is the key to minimizing their incidence. When com-
plications do occur, they should be aggressively managed, in a
high-dependency environment, by a multidisciplinary team.
International consensus regarding definitions of complica-
tions and a severity classification is still required.
references
1. Foster JH and Berman MM. Solid liver tumours. Major Problems in
Clinical Surgery, Vol. 22. Philadelphia, PA: WB Saunders, 1977: 1–342.
2. Imamura H, Seyama Y, Kokudo N, et al. One thousand fifty-six hepatec-
tomies without mortality in 8 years. Arch Surg 2003; 138:1198–206.
3. Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long-term survival after
hepatic resection for metastatic colorectal cancer: a Multifactorial model
of 929 patients. Ann Surg 2008; 247: 125–35.
4. Wei AC, Greig PD, Grant D, et al. Survival after hepatic resection for
colorectal metastases: a 10-year experience. Ann Surg Oncol 2006;
13: 668–76.
5. Malik HZ, Prasad KR, Halazun KJ, et al. Preoperative prognostic scoring
for predicting survival after hepatic resection for colorectal liver metastases.
Ann Surg 2007; 246: 806–14.
70
6. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative out-
come after hepatic resection. Analysis of 1803 consecutive cases over the
past decade. Ann Surg 2002; 4: 397–407.
7. Belghiti J, Hiramatsu K, Benoist S, et al. Seven hundred and forty-seven
hepatectomies in the 1990s: an update to evaluate the actual risk of liver
resection. J Am Coll Surg 2000; 191: 38–46.
8. Poon RT, Fan ST, Lo CM, et al. Improving perioperative outcome expands
the role of hepatectomy in management of benign and malignant hepato-
biliary disease: analysis of 1222 consecutive patients from a prospective
database. Ann Surg 2004; 240: 698–708.
9. Dimick JB, Cowan JA Jr, Knol JA, et al. Hepatic resection in the United
States: indications, outcomes and hospital procedural volumes from a
nationally representative database. Arch Surg 2003; 138: 185–91.
10. Laurent C, Sa Cunha A, Couderc P, et al. Influence of postoperative mor-
bidity on long-term survival following liver resection for colorectal
metastases. Br J Surg 2003; 90: 1131–6.
11. Ito H, Are C, Gonen M, et al. Effect of postoperative morbidity on long-
term survival after hepatic resection for metastatic colorectal cancer. Ann
Surg 2008; 247: 994–1002.
12. Chok KS, Ng KK, Poon RT, et al. Impact of postoperative complications
on long-term outcome of curative resection for hepatocellular carcinoma.
Br J Surg 2009; 96: 81–87.
13. Dindo D, Demartines N, Clavien PA. Classification of surgical complica-
tions. A new proposal with evaluation in a cohort of 6336 patients and
results of a survey. Ann Surg 2004; 240: 205–13.
14. Fan ST. Problems of hepatectomy in cirrhosis. Hepatogastroenterology
1998; 45: 1288–90.
15. Pringle JH. Notes on the arrest of hepatic haemorrhage due to trauma.
Ann Surg 1908; 48: 541.
16. Man K, Fan ST, Ng IO, et al. Prospective evaluation of Pringle maneuver
in hepatectomy for liver tumors by a randomised study. Ann Surg 1997;
226: 704–11.
17. van der Bilt JD, Livestro DP, Borren A, et al. European survey on the appli-
cation of vascular clamping in liver surgery. Dig Surg 2007; 24: 423–35.
18. Rahbari NN, Wente MN, Schemmer P, et al. Systematic review and meta-
analysis of the effect of portal triad clamping on outcome after hepatic
resection. Br J Surg 2008; 95: 424–32.
19. Gurusamy KS, Kumar Y, Ramamoorthy R, et al. Vascular occlusion for
elective liver resections. Cochrane Database of Systematic Reviews 2009;
Issue 1. Art No: CD007530. DOI: 10.1002/14651858.CD007530.
20. Rees M, Plant G, Wells J, et al. One hundred and fifty hepatic resections:
evolution of technique towards bloodless surgery. Br J Surg 1996;
83: 1526–9.
21. Melendez JA, Arslan V, Fischer ME, et al. Perioperative outcomes of major
hepatic resections under low central venous pressure anesthesia: blood
loss, blood transfusion, and the risk of postoperative renal dysfunction. J
Am Coll Surg 1998; 187: 620–5.
22. Smyrniotis V, Kostopanagiotou G, Theodoraki K, et al. The role of central
venous pressure and type of vascular control in blood loss during major
liver resections. Am J Surg 2004; 187: 398–402.
23. Choukèr A, Schachtner T, Schauer R, et al. Effects of Pringle manoeuvre
and ischaemic preconditioning on haemodynamic stability in patients
undergoing elective hepatectomy: a randomized trial. Br J Anaesth 2004;
93:204–11.
24. Liu CM, Chen J, Wang XH. Requirements for transfusion and postopera-
tive outcomes in orthotopic liver transplantation: a meta-analysis on
aprotinin. World J Gastro 2008; 14: 1425–9.
25. Pereboom IT, de Boer MT, Porte RJ, et al. Aprotinin and nafamostat mesi-
late in liver surgery: effects on blood loss. Dig Surg 2007; 24: 282–7.
26. Wu CC, Ho WM, Cheng SB, et al. Perioperative parenteral tranexamic
acid in liver tumour transection: a prospective randomised trial toward a
“blood-transfusion”-free hepatectomy. Ann Surg 2006; 243: 173–80.
27. Lodge JP, Jonas S, Oussoultzoglou E, et al. Recombinant coagulation fac-
tor VIIa in major liver resection: a randomised placebo-controlled dou-
ble-blind clinical trial. Anesthesiology 2005; 102:269–75.
28. Shao YF, Yang JM, Chau GY, et al. Safety and hemostatic effect of recom-
binant activated factor VII in cirrhotic patients undergoing partial hepa-
tectomy: a multicentre randomised double-blind placebo-controlled
trial. Am J Surg 2006; 191: 245–9.
 MANAGING COMPLICATIONS OF HEPATECTOMY
29. Noun R, Elias D, Balladur P, et al. Fibrin glue effectiveness and tolerance
after elective liver resection: a randomised trial. Hepatogastroenterology
1996; 43: 221–4.
30. Liu M, Lui WY. The use of fibrin adhesive for haemostasis after liver resec-
tion. Chinese Medical Journal 1993; 51:19–22.
31. Frilling A, Stavrou GA, Mischinger HJ, et al. Effectiveness of a new carrier-
bound sealant versus argon beamer as haemostatic agent during liver
resection: a randomised prospective trial. Langenbecks Arch Surg 2005;
390: 114–20.
32. Figueras J, Llado L, Miro M, et al. Application of fibrin glue sealant after
hepatectomy does not seem justified: results of a randomised study in
300 patients. Ann Surg 2007; 245: 536–42.
33. Erdogan D, Busch ORC, Gouma DJ, et al. Prevention of biliary leakage
after partial liver resection using topical haemostatic agents. Dig Surg
2007; 24: 294–9.
34. Shio S, Yazumi S, Ogawa K, et al. Biliary complications in donors for living
donor liver transplantation. Am J Gastro 2008; 103:1393–8.
35. Ghobrial RM, Freise CE, Trotter JF, et al. Donor morbidity after living
donation for liver transplantation. Gastroenterology 2008; 135: 468–76.
36. Erdogan D, Busch ORC, van Delden OM, et al. Incidence and manage-
ment of bile leakage after partial liver resection. Dig Surg 2008; 25: 60–6.
37. Ijichi M, Takayama T, Toyoda H, et al. Randomised trial of the useful-
ness of a bile leakage test during hepatic resection. Arch Surg 2000; 135:
1395–1400.
38. Capussotti L, Ferrero A, Vigano L, et al. Bile leakage and liver resection:
where is the risk? Arch Surg 2006; 141:690–4.
39. Lam CM, Lo CM, Liu CL, et al. Biliary complications during liver resec-
tion. World J Surg 2001; 25: 1273–6.
40. Yamashita Y, Hamatsu T, Rikimaru T, et al. Bile leakage after hepatic resec-
tion. Ann Surg 2001; 233: 45–50.
41. Gertsch P, Vandoni RE, Pelloni A, et al. Localised hepatic ischaemia after
liver resection: a prospective evaluation. Ann Surg 2007; 246:958–65.
42. Vauthey JN, Baer HU, Guastella T, et al. Comparison of outcome between
extended and nonextended liver resections for neoplasms. Surgery 1993;
114:968–75.
43. Vigano L, Ferrero A, Sgotto E, et al. Bile leak after hepatectomy: predictive
factors of spontaneous healing. Am J Surg 2008; 196: 195–200.
44. Bhattacharjya S, Puleston J, Davidson B et al. Outcome of early endo-
scopic biliary drainage in the management of bile leaks after hepatic
resection. Gastrointest Endosc 2003; 57:526–30.
45. Binmoeller KF, Katon RM, Shneidman R. Endoscopic management of
postoperative biliary leaks: review of 77 cases and report of two cases with
biloma formation. Am J Gastroenterol 1991; 86:227–31.
46. Yanaga K, Kanematsu T, Takenaka K, et al. Intraperitoneal septic compli-
cations after hepatectomy. Ann Surg 1986; 203: 148–52.
47. Balzan S, Belghiti J, Farges O, et al. The “50-50 criteria” on postoperative
day 5: an accurate predictor of liver failure and death after hepatectomy.
Ann Surg 2005; 242: 824–8.
48. Paugam-Burtz C, Janny S, Delefosse D, et al. Prospective validation of the
“fifty-fifty” criteria as an early and accurate predictor of death after liver
resection in intensive care unit patients. Ann Surg 2009; 249: 124–8.
49. Mullen JT, Ribero D, Reddy SK, et al. Hepatic insufficiency and mortality
in 1059 noncirrhotic patients undergoing major hepatectomy. J Am Coll
Surg 2007; 204: 854–62.
50. Nordlinger B, Guiguet M, Vailiant JC, et al. Surgical resection of colorectal
carcinoma metastases to the liver: a prognostic scoring system to improve
case selection based on 1568 patients. Cancer 1996; 77: 1254–62.
51. Van den Broek MA, Damink SW, Dejong CH, et al. Liver failure after par-
tial hepatectomy: definition, pathophysiology, risk factors and treatment.
Liver Int 2008; 28: 767–80.
52. Shirabe K, Shimada M, Gion T, et al. Postoperative liver failure after major
hepatic resection for hepatocellular carcinoma in the modern era with spe-
cial reference to remnant liver volume. J Am Coll Surg 1999; 188: 304–9.
53. Schindl MJ, Redhead DN, Fearon KC, et al. The value of residual liver
volume as a predictor of hepatic dysfunction and infection after major
liver resection. Gut 2005; 54: 289–96.
54. Imamura H, Sano K, Sugawara Y, et al. Assessment of hepatic reserve for
indication of hepatic resection: decision tree incorporating indocyanine
green test. J Hepatobiliary Pancreat Surg 2005; 12:16–22.
55. Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transection of the esoph-
agus for bleeding oesophageal varices. Br J Surg 1973; 60: 646–9.
56. Schneider PD. Preoperative assessment of liver function. Surg Clin N Am
2004; 84: 355–73.
57. Poon RT, Fan ST, Lo CM, et al. Extended hepatic resection for hepatocel-
lular carcinoma in patients with cirrhosis: is it justified? Ann Surg 2002;
236: 602–11.
58. Vauthey JN, Chaoui A, Do KA, et al. Standardised measurement of the
future liver remnant prior to extended resection: methodology and clini-
cal associations. Surgery 2000; 127: 512–9.
59. Ferrero A, Vigano L, Polastri R, et al. Postoperative liver dysfunction and
future remnant liver: where is the limit? Results of a prospective study.
World J Surg 2007; 31:1643–51.
60. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotox-
icity and surgery for colorectal liver metastases. Br J Surg 2007; 94: 274–86.
61. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts
steatohepatitis and an increase in 90-day mortality after surgery for
hepatic colorectal metastases. J Clin Oncol 2006; 24: 2065–72.
62. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale,
technique and future prospects. Br J Surg 2001; 88: 165–75.
63. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before
right hepatectomy: prospective clinical trial. Ann Surg 2003; 237: 208–17.
64. Kokudo N, Makuuchi M. Current role of portal vein embolization/
hepatic artery chemoembolization. Surg Clin N Am 2004; 84: 643–57.
65. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embo-
lization for major liver resection: a meta-analysis. Ann Surg 2008;
247: 49–57.
66. Abdalla EK, Adam R, Bilchik AJ, et al. Improving resectability of hepatic
colorectal metastases; expert consensus statement. Ann Surg Oncol 2006;
13: 1271–80.
67. Ogata S, Kianmanesh R, Belghiti J. Doppler assessment after right hepa-
tectomy confirms the need to fix the remnant left liver in the anatomical
position. Br J Surg 2005; 92: 592–5.
68. Scatton O, Plasse M, Dondero F, et al. Impact of localised congestion
related to venous deprivation after hepatectomy. Surgery 2008; 143:483–9.
69. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrho-
sis. Gut 2006; 55 Suppl 6: 1–12.
70. Mirouze D, Zipser RD, Reynolds TB. Effect of inhibitors of prostaglandin
synthesis on induced diuresis in cirrhosis. Hepatology 1983; 3:50–5.
71. Planas R, Arroyo V, Rimola A, et al. Acetylsalicylic acid suppresses the
renal haemodynamic effect and reduces the diuretic action of furosemide
in cirrhosis with ascites. Gastroenterology 1983; 84: 247–52.
72. Van de Kerkhove MP, de Jong KP, Rijken AM, et al. MARS treatment in
post hepatectomy liver failure. Liver Int 2003; 23 Suppl 3: 44–51.
73. Liu JP, Gluud LL, Als-Nielsen D, et al. Artificial and bioartificial support
systems for liver failure. Cochrane Database of Systematic Reviews 2004;
Issue 1. Art No.: CD003628. DOI: 10.1002/14651858.CD003628.
74. Yanaga K, Kanematsu T, Takenaka K, et al. Intraperitoneal septic compli-
cations after hepatectomy. Ann Surg 1986; 203: 148–52.
75. Togo S, Matsuo K, Tanaka K, et al. Perioperative infection control and its
effectiveness in hepatectomy patients. J Gastroent Hep 2007; 22: 1942–8.
76. Wu CC, Yeh DC, Lin MC, et al. Prospective randomised trial of systemic
antibiotics in patients undergoing liver resection. Br J Surg 1998; 85:
489–93.
77. Paquet JC, Dziri C, Hay JM, et al. Prevention of deep abdominal compli-
cations with omentoplasty on the raw surface after hepatic resection. The
French Association for Surgical Research. Am J Surg 2000; 179: 103–9.
78. Uetsuji S, Kwon AH, Komada H, et al. Clinical evaluation of closed suc-
tion drainage following hepatectomy. Surgery Today 1997; 27: 298–301.
79. Fong Y, Brennan MF, Brown K, et al. Drainage is unnecessary after elective
hepatic resection. Am J Surg 1996; 171: 158–62.
80. Liu CL, Fan ST, Lo CM, et al. Abdominal drainage after hepatic resection
is contraindicated in patients with chronic liver diseases. Ann Surg 2004;
239: 194–201.
81. Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality
and morbidity with epidural or spinal anaesthesia: results from overview
of randomised trials. Br Med J 2000; 321: 1493.
82. Lui S, Carpenter RL, Neal JM. Epidural anaesthesia and analgesia. Their
role in postoperative outcome. Anaesthesiology 1995; 82: 1474–506.
71
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
83. Matot I, Scheinin O, Eid A, et al. Epidural anesthesia and analgesia in liver
resection. Anesth Analg 2002; 95:1179–81.
84. Page A, Rostad B, Staley CA, et al. Epidural analgesia in hepatic resection.
J Am Coll Surg 2008; 206: 1184–92.
85. Basu S, Taamijmarane A, Bulters D, et al. An alternative method of wound
pain control following hepatic resection: a preliminary study. HPB 2004;
6: 186–9.
86. Oliver JC, Welsh FKS, Bell J, et al. Elective intra-aortic balloon counter-
pulsation during a high-risk liver resection. Anaesth 2008; 63: 1365–8.
72
87. Saner F. Kidney failure following liver resection. Transplant Proc 2008;
40: 1221–4.
88. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med 2007;
357: 797–805.
89. Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network: report
of an initiative to improve outcomes in acute kidney injury. Crit Care
2007; 11: R31.
90. Togo S, Nagano Y, Masumoto C, et al. Outcome of and risk factors for inci-
sional hernia after partial hepatectomy. J Gastrointest Surg 2008; 12: 1115–20.
8 Pancreatic resection
Thilo Hackert, Moritz Wente, and Markus W. Büchler
background
Pancreatic cancer remains—with an overall long-term sur-
vival rate of less than 1%—one of the most difficult cancers to
treat. It is the fourth leading cause of cancer-related mortality
in the Western world and is responsible for around 30,000
deaths per year in the United States and 65,000 per year in
Europe (1,2). In only 10% to 20% of pancreatic cancer patients
potentially curative surgery is possible, and even in these
patients, the median survival is only 10 to 18 months with
5-year survival rates of approximately 20% to 25% (3,4).
Nonetheless, surgery remains the only treatment option with
the chance of cure. Pancreatic surgery has significantly changed
during the past few years. Irrespectively, pancreas resections
remain an intervention of particular significance, often techni-
cally challenging and with high logistic demands for preopera-
tive diagnostics and perioperative management. Recently, the
value of centralization of pancreatic surgery in “high volume
institutions” has been demonstrated. The current mortality
rates following pancreatic resections are well below 5% in spe-
cialized surgical centers (5,6).
standard resections
Whipple Resection
Partial Pancreaticoduodenectomy (Whipple resection) with or
without distal stomach resection is the surgical option for
tumors of the pancreatic head, which account for the majority
of pancreatic cancers (Fig. 8.1). Pylorus-preserving pancreati-
coduodenectomy has been proven to be equal to the classical
pancreaticoduodenectomy in terms of tumor recurrence or
long-term survival, and should therefore be considered the stan-
dard procedure for tumors of the pancreatic head (7). Key steps
of the surgical procedure are the postpyloric division of the duo-
denum, which is usually carried out by use of a stapling device
and—meanwhile common in many centers—the supracolic
division of the ascending duodenum as soon as this portion is
reached during resection. This modification facilitates the resec-
tion procedure and allows manual control of the pancreatic head
without switching positions between the supra- and infracolic
department. Division of the pancreas is done sharply above the
superior mesenteric vein after this has been tunneled to make
sure that the vein is not injured during resection and that the dis-
section can be done without vein replacement (see below).
After removing the specimen, tumor-free resection margins
should be confirmed intraoperatively by frozen sections of the
cut end of the bile duct and the cut end of the pancreatic rem-
nant. Bleeding control along the pancreatic dissection margin
is achieves by carefully stitching single bleeding sites with
monofilament and nonabsorbable sutures. The pancreatic
duct must be seen and protected during this procedure. Dur-
ing pancreaticoduodenectomy, a standardized lymphadenec-
tomy needs to be carried out. This includes the complete
dissection of the hepatoduodenal ligament, the lymph nodes
along the common hepatic artery, portal vein, and the cranial
portion of superior mesenteric vein as well as dissection of the
right-sided lymph nodes of the celiac trunk and along the
right side of the superior mesenteric artery (Fig. 8.2). Today,
we have good evidence that there is no benefit for a more
extended approach of lymphadenectomy. Meta-analysis from
four randomized controlled clinical trials has shown no sur-
vival benefit after extended lymph node dissection but has
demonstrated a significant increase in surgical morbidity (8).
Completion of the dissection can then be done from the infra-
colic aspect by removing the first jejunal loop (20–25 cm) to
ensure tensionless mobility of the next loop that is used for the
following reconstruction and is transposed into the right
upper quadrant transmesocolically.
One of the most important operative steps to prevent severe
postoperative complications is the pancreaticojejunostomy.
We prefer to perform this anastomosis end-to-side in a two-
layer fashion stitching the pancreatic duct separately (Fig. 8.3).
Using this technique, insufficiency rates of less than 3.5% can
be achieved (9,10). Bile duct reconstruction should be stan-
dardized as well to avoid leakage or postoperative bile collec-
tions. Although this complication is less frequent than
pancreatic fistula, it may cause severe and long-lasting compli-
cations. An approach that can be performed even in techni-
cally challenging situations with small and deep ducts is the
single-stitch distant suture of the posterior wall by a one-layer
technique completed by single stitches of the anterior wall.
Finally, an end-to-side duodenojejunostomy completes the
reconstruction. Recent studies have shown that an antecolic
reconstruction is much more favorable in terms of delayed
gastric emptying (1,12).
Drain placement seems to be another essential step at the
end of the operation as there has been growing evidence that
pancreatic leakage can be recognized and severe complications
caused by intra-abdominal pancreatic fluid collections can be
prevented by adequate drain positions. As there may be need
for a long-lasting maintenance of intra-abdominal drains in
case of fistulas, soft silicon drains should favorably be used.
Drain removal—which can usually be done 48 hours postop-
eratively—should be preceded by analysis of pancreatic
enzyme levels in the drain fluid. Amylase levels of more than
5000 iU/ml seem to represent a cutoff value for the recogni-
tion of pancreatic fistulas and should therefore be respected
carefully (13–17).
Distal Pancreatectomy
Distal pancreatectomy is performed for tumors in the body or
tail of the pancreas and includes—depending on the dignity of
the underlying tumor—total splenectomy. From the surgical
point of view, tumors above or on the left side of the superior
73
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 8.1 Partial pancreaticoduodenectomy. Classical Whipple resection (left) and pylorus-preserving modification (right).
Figure 8.2 Intraoperative situs after partial pancreaticoduodenectomy. Pan-
creatic remnant with probe introduced, dissected portal vein and hepatic
artery. A jejunal loop is prepared for the pancreaticojejunostomy.
mesenteric vein are suitably located for this procedure. Dis-
section of the pancreas is performed above the vein after tun-
neling and lifting up the body of the gland. The dissection
itself can be done sharply or by using a stapling device, prefer-
ably with a thickness-adopted adjustment of the stapler. To
date, there are no high-power studies to support either proce-
dure. In case of sharp dissection, we prefer a V-shaped transec-
tion line. As in other resections, tumor-free resection margins
should be examined by intraoperative frozen section. The pan-
creatic duct is separately closed by a monofilament Z-shaped
nonabsorbable suture and the transection line can afterward
be closed by single stitches covering the complete margin by
pancreatic capsular tissue. There is no need or evidence for any
further covering of the resection margin by sealants or
patches (18). This procedure implies a certain limitation con-
cerning the extent of distal resection toward the head of the
74
pancreas. The larger the tissue area of the transected paren-
chyma gets, the more difficult it gets to close the parenchyma,
which is associated with increased fistula rates. Therefore, the
right margin of the superior mesenteric vein represents the
limit to which a safe surgical closure of the pancreatic remnant
can be performed. In case of transection by a stapling device,
this limitation is technically implied by the length of the sta-
pler line. No additional sutures are necessary after stapler dis-
section. Despite all approaches, fistula development after distal
pancreatectomy remains an unsolved problem. Fistula rates
range from 12% to 40% (8,19). To address this clinical prob-
lem, remnant closure by sutures after sharp dissection is cur-
rently compared to stapler dissection in a randomized
controlled study (DISPACT trial) in a multicenter approach
including 21 European centers and 360 patients by February
2009 (20). A spleen-preserving distal pancreatectomy can be
performed in benign lesions or intraductal papillary muci-
nous neoplasias (IPMNs), if the splenic vessels are not involved
in the tumor or cystic process. However, there are no clear
advantages in preserving the spleen in adult patients (21). Pos-
sible advantages could be infection prophylaxis, less operative
blood loss, fistula rates as well as fewer thromboembolic com-
plications (22,23). By contrast, the risk of splenic infarction
and portal hypertension has to be regarded whenever the
spleen is preserved. From the currently available literature—
mainly retrospective studies—none of these parameters is
clearly proven, further studies have to address this topic in the
future. By contrast, there is growing evidence that distal pan-
createctomy can be performed with good results laparoscopi-
cally. This approach is usually performed using 5 trocars and
stapler dissection of the pancreas. It is routinely performed in
several centers with results comparable to the open approach
in terms of operative morbidity and outcome (23). The possi-
ble advantages of laparoscopic operations, with faster patient
recovery, less pain medication, and better cosmetic results are
currently evaluated in larger series.
Total Pancreatectomy
The concept of total pancreatectomy has to be divided into the
rescue procedure in not conservatively managed postoperative
 PANCREATIC RESECTION
Figure 8.3 Pancreatico-jejunostomy. Preparation of duct sutures (upper left), position of the jejunal loop (upper right), anterior wall sutures (lower left), and
completed anastomosis (lower right).
complications caused by the pancreatic remnant after head
resections and the primarily performed total removal of the
gland with or without the spleen (24). Completion pancre-
atectomy may be necessary in case of severe complication like
insufficiency of the pancreaticojejunostomy with septic or
bleeding complications. In this situation, an early completion
operation can be life-saving for the patient and is technically
similar to a distal pancreatectomy after disconnection of the
pancreas anastomosis (25,26). Primary total pancreatectomy
can be required in patients with a nonaltered pancreatic rem-
nant due to the soft tissue texture, e.g., in distal bile dust cancer
or duodenal tumors without congestion of the pancreatic
duct, which can make the pancreatic anastomosis a dangerous
reconstruction. The surgeon has to evaluate the cost–benefit
relation carefully; in doubtful situations a risky anastomosis
should rather be avoided. From the oncological point of view,
extensive main-duct IPMNs, IPMNs with progression to
carcinoma, familial or multifocal pancreatic cancer are indica-
tions for a primary total pancreatectomy. Furthermore, this
procedure may be necessary if a tumor-free resection margin
and R0 situation cannot be achieved otherwise (24–29). The
resection can be performed as a two-part procedure with an
initial head resection similar to a Whipple procedure followed
by the distal resection, which facilitates the surgical prepara-
tion, or with a removal of the gland as a complete specimen,
if a pancreatic transection implies the risk of tumor cell spill-
ing. Whenever possible, a pylorus-preserving reconstruction
should be preferred.
Duodenum-Preserving Pancreatic Head Resection
The best technique for the surgical treatment of pancreatic
head lesions in chronic pancreatitis is still under debate. Par-
tial pancreatoduodenectomy with or without preservation of
the pylorus have served for many years as the primary surgi-
cal procedure. However, these resections are unsatisfactory in
terms of late morbidity with an incidence of up to 48% of
postoperative diabetes mellitus (30). Today, duodenum-
preserving pancreatic head resection duodenum-preserving
pancreatic head resection (DPPHR), which was introduced
by Beger in 1972 (31), has undergone several modifications
and is considered the standard procedure for nonmalignant
head lesions in chronic calcified pancreatitis (32). Whenever
possible, depending on the extent of the calcified and fibrotic
lesions, the Berne modification as the most tissue-sparing
75
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
approach should be performed (Fig. 8.4). The surgical
procedure starts with an extensive Kocher maneuver of the
pancreatic head to palpate the head of the pancreas and
achieve bleeding control by compression during the resec-
tion phase. The anterior aspect of the head should be pre-
pared under dissection of the right gastroepiploic vessels and
ligation of the gastroduodenal artery to minimize blood loss
during excision of the head. It is not necessary to tunnel the
pancreas above the mesenteric vein, especially as this is often
difficult due to the chronic inflammatory adherence of the
parenchyma. The resection margin should be defined by cir-
cular sutures around the altered tissue area. Afterward, the
head is sharply excised manually to control bleeding and per-
foration of the posterior parenchyma layer. All fibrotic and
calcified tissue should be removed and the pancreatic duct
has to be opened and inspected to extract stones and ensure
free drainage into the resection cavity. Special attention has
to be paid to the bile duct. In case of preoperative cholestasis
and/or preceding stents, the bile duct needs to be opened by
a T-shaped incision and the orifice should be fixed in the
Figure 8.4 Pylorus-preserving pancreatic head resection (Berne modifica-
tion). Note the incision and fixation of the bile duct in the resection cavity.
Figure 8.5 Pylorus-preserving pancreatic head resection (Berne modification). Resection cavity with first layer of the posterior wall of the pancreaticojejunostomy
(left), completed anastomosis (right).
76
resection cavity to avoid postoperative recurrence of bile
duct stenosis (33). Hemostasis in the resection cavity is
achieved by selective single stitches with nonabsorbable
sutures. The operation is completed by an anastomosis with
a Roux-Y-transected jejunal loop in a side-to-side fashion by
a two-layer running suture (Fig. 8.5). As in all other resec-
tions, drainage placement is important to monitor postop-
erative secretion and recognize possible fistula development
soon. the DPPHR procedure is widely accepted nowadays
and has proven to be equally efficient as the Whipple proce-
dure in terms of long-term pain relief, overall morbidity and
mortality combined with significantly less intraoperative
blood replacement, shorter hospital stay, more postoperative
weight gain, less exocrine insufficiency, better occupational
rehabilitation, and quality of life in randomized controlled
trials and a recent meta-analysis (32–37).
Segmental Resection
Segmental resections of the pancreas can be performed in
benign lesions located in the body of the gland (38). Surgical
technique includes a careful mobilization of the pancreatic seg-
ment under clipping of vessels followed by sharp dissection of
the defined segment. Afterward, reconstruction was done by
two-layer sutured anastomosis toward the tail of the pancreas
similar to the Whipple anastomosis and V-shaped closure of the
dissected margin toward the pancreatic head comparable to the
left resection technique. In case of extended resections toward
the head leading to a large resection margin, this can addition-
ally be sealed with a seromuscular patch using the jejunal loop
that has been anastomosed onto the pancreatic tail before. No
fibrin glue or other sealants are required. At present, fistula rates
between 8% and 63% are reported, which shows the heteroge-
neity of the present studies (38–41). However, a surgical mortal-
ity of 2% shows that segmental resections can be performed
safely and offers a useful tissue-sparing tool in selected patients.
Enucleation
Especially benign tumors, cystic lesions or IPMNs do not
necessarily require extensive pancreatic resections to
 PANCREATIC RESECTION
achieve surgical cure. Limited resections represent a tissue-
sparing treatment option to minimize the risk of exocrine
or endocrine pancreatic insufficiency postoperatively (42)
and to reduce surgical morbidity and mortality by reduced
operative trauma. One of the most important aspects to
perform an enucleation successfully is the accurate localiza-
tion of the tumor or cystic lesion. Besides preoperative
localization by CT or MRI scan, the most important tool
for tumor location is the experience of the surgeon per-
forming the exploration (43–46). Mobilization of the pan-
creas is essential when tumors or cystic lesions have to be
located to enable a careful digital examination of the sus-
pected lesion. This should be supplemented by intraopera-
tive ultrasound to exclude multifocal tumorous lesions
especially in endocrine tumors or IPMNs. In addition, a
possible relation to the pancreatic duct can only be clarified
by ultrasound examination, if there is any doubt about it
intraoperatively (47).
A tumor size of 2.5 cm in diameter can be regarded as the
limit for a safely performed enucleation. Tumors measuring
more than 2.5 cm in size show malignant histological changes
significantly more frequently, making a local surgical approach
impossible. Besides, tissue trauma and wound surface follow-
ing an enucleation reach a critical size for development of fistu-
las or other complications including bleeding or postoperative
pancreatitis (47). Enucleation itself is performed by careful
dissection along the tumor under clip ligation or stitching of
vessels supplying the lesion (Fig. 8.6). There is no evidence for
Figure 8.6 Tumor enucleation in the body of the pancreas.
Figure 8.7 Examples of portal vein resections. Direct end-to-end anastomosis (left) and graft implantation (right).
any sealant or glue application after completing of the enucle-
ation. Drain placement is essential as currently fistula rates of
approximately 20% are reported (48), most of them, however,
clinically uncomplicated.
exceptional indications
Vessel Resections
A common problem in pancreatic head resections is tumor
adherence to the superior mesenteric or portal vein. Today,
portal vein resection has become an established procedure and
can be carried out with morbidity rates of that are comparable
to standard Whipple procedures (49–56). Portal vein resection
can be performed as a tangential resection with a direct suture
or a patch reconstruction. In cases where a segmental resection
is required due to a more extensive tumor adherence, either a
direct anastomosis or the interposition of an autologous venous
graft such as the saphenous vein or an allograft, e.g., a gore-tex
tube. In case of a primary anastomosis, it is essential to mobi-
lize the mesenteric root completely, which implies the complete
mobilization of the right hemicolon. After this preparation, a
tension-free reconstruction of defects up to 3 cm length is usu-
ally possible. The anastomosis is performed as a running suture
of the posterior and anterior vessel wall with two 5-0 or 6-0
nonabsorbable sutures. When defects cannot be reconstructed
by the patient’s vein alone, a size-adopted graft should be
inserted in a similar end-to-end manner (52). Kinking of any
venous anastomosis must be avoided to prevent intra- and
postoperative vein or graft thrombosis with consecutive failure
of the bowel circulation. In certain situations, it may be helpful
not only to minimize the time of intraoperative occlusion of
the mesenteric/portal vein but also to clamp the superior mes-
enteric artery for this period to avoid venous congestion and
swelling of the small bowel and the right hemicolon (Fig. 8.7).
Arterial resection is a rather uncommon surgical proce-
dure during pancreatic cancer resection. If the superior mes-
enteric artery is involved in the tumor process, this is a
general exclusion criterion for resection and has only been
reported in few patients (56). By contrast, tumor adherence
or infiltration along the celiac axis must not be considered as
generally irresectable (43,53). In selected patients, the celiac
trunk might be resected down to its aortic orifice in Whipple
as well as in left resection or total pancreatectomies (54–56).
As long as the proper hepatic artery can be preserved, a
reconstruction is possible. The left gastric and splenic artery
can usually be cut without reconstruction, a consecutive
77
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
splenectomy may be necessary in some patients. Restoration
of the hepatic perfusion must be ensured by re-anastomosing
the proper or common hepatic artery. This reconstruction
can be done with an interposition of any arterial vessel of the
celiac axis or a venous interposition graft. However, the arte-
rial perfusion of the liver should be controlled by regular
duplex examinations and restored aggressively in case of a
vessel occlusion. Arterial hepatic perfusion failure may oth-
erwise cause acute problems postoperatively in terms of liver
ischemia, necrosis, and infection and is a risk factor for bile
duct-associated complications in the long-term follow-up
(54,55). Yet, it needs to be mentioned that there are no larger
patient series on arterial resections in pancreatic surgery.
Therefore, this procedure can be carried out safely in experi-
enced hands but is not based on high-quality scientific data
and outcome studies so far.
Multivisceral Resections
There are several studies (57–60) on the outcome after multi-
visceral resection for pancreatic cancer. In general, resection of
adjacent organs, most commonly the stomach or left hemico-
lon in left resections and the right hemicolon in Whipple pro-
cedures as well as either adrenal gland or kidney in both types
of resection can be performed safely to achieve a R0 situation.
Technically, an en bloc resection should be performed without
preparation along or injuring the tumor surface. This may
result in “typical” resections such as right or left colectomies as
well as individual segmental- or wedge-type resections. Multi-
visceral approaches can also be combined with vessel resec-
tions of the portal vein or the celiac axis. From the limited
number of available studies, this approach is associated with
an increased intraoperative blood loss and overall surgical
morbidity as well as ICU and hospital stay (58,60). However,
there seems to be a survival advantage in these patients and
overall mortality is not increased compared to standard resec-
tions (59,60). Due to the limited number of patients reported
so far, it is not possible to give valid data on long-term
Figure 8.8 Pancreatic cancer recurrence resection. Intraoperative finding of the recurrence located in the interaortocaval space (left), situs after resection (right)
prior to intraoperative radiation.
78
oncological outcome, making multivisceral resections an indi-
vidually tailored approach that requires careful patient selec-
tion and surgical experience.
Recurrence Resections
Localized recurrence in pancreatic cancer may be an indica-
tion for relaparotomy and resection in selected patients.
Although a large number of recurrences are located close to
the arterial vessels, and therefore not resectable, recent studies
support the concept of surgical exploration and resection
whenever possible (61–63). This approach can be combined
with intraoperative radiotherapy and radiation of the tumor
bed to reduce the risk of another recurrence at the site of resec-
tion (Fig. 8.8). In case of local irresectability, intraoperative
radiation can be performed with a palliative intention in terms
of tumor reduction and pain control. An extended resection of
the recurrent tumor with arterial vessels does not seem to be
justified as the chance for a radical tumor removal is poor and
patients do not seem to benefit from R1 or R2 resections. The
available studies report successful resection rates of approxi-
mately 50% with acceptable surgical morbidity and suggest a
survival benefit for those patients, especially in situations with
a long time interval (>9–12 months) between the initial tumor
diagnosis and the recurrence manifestation (63). As these are
observational studies, there is no proven evidence for this
approach today and larger controlled trials are required to
evaluate long-term oncological value.
Metastasis Resections
Resection for metastatic pancreatic cancer is clearly restricted
to exceptional indication and has only been reported anecdot-
ally so far (64,65). Most commonly, the indication for metas-
tasis resection arises in young patients with the accidental
finding of a synchronous single liver lesion intraoperatively,
which can be removed without increasing operative
morbidity (64). Apart from this individual indication, metas-
tasis resection can be performed in long-term survivors with
 PANCREATIC RESECTION
localized metastastic disease, indicating favorable tumor biol-
ogy and justifying the aggressive operative approach. This has
to be embedded in a global oncological concept, must be
decided highly individually and cannot be regarded as a
standard procedure (65).
conclusion
Pancreatic surgery has undergone a remarkable development
during the last decades. Appropriate surgical approaches have
been established and can be used in differential indications
today. In pancreatic cancer, standard resections include the
classical Whipple operation and the pylorus-preserving modi-
fication, which should be preferred whenever possible as well
as a distal or total pancreatectomy in extended tumors of the
gland. All of these procedures can be carried out safely with
surgical mortality rates well below 5% in specialized centers
due to a high grade of standardization and experience. Modern
tissue-sparing procedures such as the duodenum-preserving
pancreatic head resection in chronic pancreatitis or tumor
enucleations offer limited approaches for circumscribed non-
malignant pancreatic pathologies. Furthermore, extended
resections for the treatment of pancreatic malignancies—
including multivisceral and recurrence resections—are tech-
nically feasible although the oncological outcome of these
procedures has to be further evaluated and pancreatic cancer
treatment must always be embedded in an interdisciplinary
concept of surgery and adjuvant therapy to ensure best
possible outcome.
references
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin 2007;
57(1): 43–66.
2. Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for pancre-
atic cancer across the world. HPB (Oxford) 2008; 10(1): 58–62.
3. Wagner M, Redaelli C, Lietz M, et al. Curative resection is the single most
important factor determining outcome in patients with pancreatic ade-
nocarcinoma. Br J Surg 2005; 91: 586–94.
4. Schnelldorfer T, Ware AL, Sarr MG, et al. Long-term survival after pancre-
atoduodenectomy for pancreatic adenocarcinoma: Is cure possible? Ann
Surg 2008; 247(3): 456–62.
5. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgi-
cal mortality in the United States. N Engl J Med 2002; 346(15): 1128–37.
6. McPhee JT, Hill JS, Whalen GF, et al. Perioperative mortality for pancre-
atectomy: A national perspective. Ann Surg 2007; 246(2): 246–53.
7. Diener MK, Knaebel HP, Heukaufer C, et al. A systematic review and
meta-analysis of pylorus-preserving versus classical pancreaticoduode-
nectomy for surgical treatment of periampullary and pancreatic carci-
noma. Ann Surg 2007; 245(2): 187–200.
8. Michalski CW, Kleeff J, Wente MN, et al. Systematic review and meta-
analysis of standard and extended lymphadenectomy in pancreaticoduo-
denectomy for pancreatic cancer. Br J Surg 2007; 94(3): 265–73.
9. Büchler MW, Wagner M, Schmied BM, et al. Changes in morbidity after
pancreatic resection: Toward the end of completion pancreatectomy. Arch
Surg 2003; 138(12): 1310–4; discussion 1315.
10. Wente MN, Shrikhande SV, Kleeff J, et al. Management of early hemor-
rhage from pancreatic anastomoses after pancreaticoduodenectomy. Dig
Surg 2006; 23(4): 203–8. Epub 2006 Jul 26.
11. Hartel M, Wente MN, Hinz U, et al. Effect of antecolic reconstruction on
delayed gastric emptying after the pylorus-preserving Whipple proce-
dure. Arch Surg 2005; 140(11): 1094–9.
12. Tani M, Terasawa H, Kawai M, et al. Improvement of delayed gastric
emptying in pylorus-preserving pancreaticoduodenectomy: Results of a
prospective, randomized, controlled trial. Ann Surg 2006; 243(3): 316–20.
13. Pedrazzoli S, Liessi G, Pasquali C, et al. Postoperative pancreatic fistulas:
Preventing severe complications and reducing reoperation and mortality
rate. Ann Surg 2009; 249(1): 97–104.
14. Veillette G, Dominguez I, Ferrone C, et al. Implications and management
of pancreatic fistulas following pancreaticoduodenectomy: The Massa-
chusetts General Hospital experience. Arch Surg 2008; 143(5): 476–81.
15. Reid-Lombardo KM, Farnell MB, Crippa S, et al. Pancreatic anastomotic
leakage after pancreaticoduodenectomy in 1,507 patients: A report from
the Pancreatic Anastomotic Leak Study Group. J Gastrointest Surg 2007;
11(11): 1451–8; discussion 1459. Epub 2007 Aug 21.
16. Molinari E, Bassi C, Salvia R, et al. Amylase value in drains after pancreatic
resection as predictive factor of postoperative pancreatic fistula: Results of
a prospective study in 137 patients. Ann Surg 2007; 246(2): 281–7.
17. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula:
An international study group (ISGPF) definition. Surgery 2005; 138(1):
8–13.
18. Knaebel HP, Diener MK, Wente MN, et al. Systematic review and meta-
analysis of technique for closure of the pancreatic remnant after distal
pancreatectomy. Br J Surg 2005; 92(5): 539–46.
19. Andrén-Sandberg A, Wagner M, Tihanyi T, et al. Technical aspects of left-
sided pancreatic resection for cancer. Dig Surg 1999; 16(4): 305–12.
20. Diener MK, Knaebel HP, Witte ST, et al. DISPACT trial: A randomized
controlled trial to compare two different surgical techniques of DIStal
PAnCreaTectomy—study rationale and design. Clin Trials 2008; 5(5):
534–45.
21. Fernández-Cruz L, Orduña D, Cesar-Borges G, Angel López-Boado M.
Distal pancreatectomy: En-bloc splenectomy vs spleen-preserving pan-
createctomy. HPB (Oxford) 2005; 7(2): 93–8.
22. Kimura W, Moriya T, Ma J, et al. Spleen-preserving distal pancreatectomy
with conservation of the splenic artery and vein. World J Gastroenterol
2007; 13(10): 1493–9.
23. Distal pancreatectomy: radical or spleen-preserving? Chromik AM, Janot
M, Sülberg D, Seelig MH, Uhl W. Chirurg 2008; 79(12): 1123–33.
24. Keck T, Hopt UT. Total pancreatectomy: Renaissance of a surgical proce-
dure. Chirurg 2008; 79(12): 1134–40.
25. Wente MN, Shrikhande SV, Kleeff J, et al. Management of early hemor-
rhage from pancreatic anastomoses after pancreaticoduodenectomy. Dig
Surg 2006; 23(4): 203–8. Epub 2006 Jul 26.
26. Büchler MW, Wagner M, Schmied BM, et al. Changes in morbidity after
pancreatic resection: toward the end of completion pancreatectomy. Arch
Surg 2003; 138(12): 1310–4; discussion 1315.
27. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neo-
plasms of the pancreas: an updated experience. Ann Surg 2004; 239(6):
788–97; discussion 797–9.
28. Inagaki M, Obara M, Kino S, et al. Pylorus-preserving total pancreatec-
tomy for an intraductal papillary-mucinous neoplasm of the pancreas. J
Hepatobiliary Pancreat Surg 2007; 14(3): 264–9. Epub 2007 May 29.
29. Müller MW, Friess H, Kleeff J, Dahmen R, Wagner M, Hinz U, Breisch-
Girbig D, Ceyhan GO, Büchler MW. Is there still a role for total pancre-
atectomy? Ann Surg 2007; 246(6): 966–74; discussion 974–5.
30. Sakorafas GH, Farnell MB, Nagorney DM, et al. Pancreatoduodenectomy
for chronic pancreatitis: long-term results in 105 patients. Arch Surg
2000; 135: 517–23.
31. Beger HG, Buchler M, Bittner RR, et al. Duodenum-preserving resection
of the head of the pancreas in severe chronic pancreatitis. Early and late
results. Ann Surg 1989; 209: 273–78.
32. Diener MK, Rahbari NN, Fischer L, et al. Duodenum-preserving pancre-
atic head resection versus pancreatoduodenectomy for surgical treatment
of chronic pancreatitis: A systematic review and meta-analysis. Ann Surg
2008; 247(6): 950–61.
33. Cataldegirmen G, Bogoevski D, Mann O, et al. Late morbidity after duo-
denum-preserving pancreatic head resection with bile duct reinsertion
into the resection cavity. Br J Surg 2008; 95(4): 447–52.
34. Büchler MW, Friess H, Muller MW, et al. Randomized trial of duodenum-
preserving pancreatic head resection versus pylorus-preserving Whipple
in chronic pancreatitis. Am J Surg 1995; 169: 65–9.
35. Farkas G, Leindler L, Daroczi M, et al. Prospective randomised comparison
of organ-preserving pancreatic head resection with pylorus-preserving
pancreaticoduodenectomy. Langenbecks Arch Surg 2006; 391: 338–42.
79
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
36. Klempa I, Spatny M, Menzel J, et al. Pancreatic function and quality of life
after resection of the head of the pancreas in chronic pancreatitis. A pro-
spective, randomized comparative study after duodenum preserving
resection of the head of the pancreas versus Whipple’s operation. Chirurg
1995; 66: 350–9.
37. Izbicki JR, Bloechle C, Knoefel WT, et al. Duodenum-preserving resection
of the head of the pancreas in chronic pancreatitis. A prospective, ran-
domized trial. Ann Surg 1995; 221: 350–8.
38. Müller MW, Friess H, Kleeff J, et al. Middle segmental pancreatic resec-
tion: An option to treat benign pancreatic body lesions. Ann Surg 2006;
244: 909–18; discussion 918–20.
39. Bassi C. Middle segment pancreatectomy: A useful tool in the manage-
ment of pancreatic neoplasms. J Gastrointest Surg 2007; 11: 726–9.
40. Adham M, Giunippero A, Hervieu V, Courbière M, Partensky C. Central
pancreatectomy: Single-center experience of 50 cases. Arch Surg 2008;
143: 175–180; discussion 180–1.
41. Christein JD, Smoot RL, Farnell MB. Central pancreatectomy: A technique
for the resection of pancreatic neck lesions. Arch Surg 2006; 141: 293–9.
42. Fang WL, Su CH, Shyr YM, et al. Functional and morphological changes
in pancreatic remnant after pancreaticoduodenectomy. Pancreas 2007;
35: 361–5.
43. Chung JC, Choi SH, Jo SH, et al. Localization and surgical treatment of
the pancreatic insulinomas. ANZ J Surg 2006; 76: 1051–5.
44. Ritzel RA, Isermann B, Schilling T, et al. Diagnosis and localization of insuli-
noma after negative laparotomy by hyperinsulinemic, hypoglycaemic clamp
and intra-arterial calcium stimulation. Rev Diabet Stud 2004; 1: 42–6.
45. Kisker O, Bastian D, Bartsch D, Nies C, Rothmund M. Localization, malig-
nant potential, and surgical management of gastrinomas. World J Surg
1998; 22: 651–7; discussion 657–8.
46. Schmitz-Winnenthal FH, Z’graggen K, Volk C, Schmied BM, Büchler
MW. Intraductal papillary mucinous tumors of the pancreas. Curr Gas-
troenterol Rep 2003; 5: 133–40.
47. Lee CJ, Scheiman J, Anderson MA, et al. Risk of malignancy in resected
cystic tumors of the pancreas < or =3 cm in size: Is it safe to observe
asymptomatic patients? A multi-institutional report. J Gastrointest Surg
2008; 12: 234–42.
48. Crippa S, Bassi C, Salvia R, et al. Enucleation of pancreatic neoplasms. Br
J Surg 2007; 94: 1254–9.
49. Fuhrman GM, Leach SD, Staley CA, et al. Rationale for en bloc vein resec-
tion in the treatment of pancreatic adenocarcinoma adherent to the supe-
rior mesenteric-portal vein confluence. Pancreatic Tumor Study Group.
Ann Surg 1996; 223(2): 154–62.
50. Hartel M, Niedergethmann M, Farag-Soliman M, et al. Benefit of venous
resection for ductal adenocarcinoma of the pancreatic head. Eur J Surg
2002; 168(12): 707–12.
80
51. Harrison LE, Klimstra DS, Brennan MF. Isolated portal vein involvement
in pancreatic adenocarcinoma. A contraindication for resection? Ann
Surg 1996; 224(3): 342–7; discussion 347–9.
52. Weitz J, Kienle P, Schmidt J, Friess H, Büchler MW. Portal vein resection
for advanced pancreatic head cancer. J Am Coll Surg 2007; 204(4): 712–6.
Epub 2007 Feb 26.
53. Hartel M, Wente MN, Di Sebastiano P, Friess H, Büchler MW. The role of
extended resection in pancreatic adenocarcinoma: is there good evi-
dence-based justification? Pancreatology 2004; 4(6): 561–6. Epub 2004
Nov 15.
54. Martin RC 2nd, Scoggins CR, Egnatashvili V, et al. Arterial and venous
resection for pancreatic adenocarcinoma: operative and long-term out-
comes. Arch Surg 2009; 144(2): 154–9.
55. Nakao A, Takeda S, Inoue S, et al. Indications and techniques of extended
resection for pancreatic cancer.World J Surg 2006; 30(6): 976–82; discus-
sion 983–4.
56. Yekebas EF, Bogoevski D, Cataldegirmen G, et al. En bloc vascular resec-
tion for locally advanced pancreatic malignancies infiltrating major blood
vessels: Perioperative outcome and long-term survival in 136 patients.
Ann Surg 2008; 247(2): 300–9.
57. Sasson AR, Hoffman JP, Ross EA, et al. En bloc resection for locally
advanced cancer of the pancreas: is it worthwhile? J Gastrointest Surg
2002; 6(2): 147–57; discussion 157–8.
58. Shoup M, Conlon KC, Klimstra D, Brennan MF. Is extended resection for
adenocarcinoma of the body or tail of the pancreas justified? J Gastroin-
test Surg 2003; 7(8): 946–52; discussion 952.
59. Imamura M, Doi R. Treatment of locally advanced pancreatic cancer:
Should we resect when resectable? Pancreas 2004; 28(3): 293–5.
60. Kleeff J, Diener MK, Z’graggen K, et al. Distal pancreatectomy: risk factors
for surgical failure in 302 consecutive cases. Ann Surg 2007; 245(4):
573–82.
61. Meyers MO, Meszoely IM, Hoffman JP, et al. Is reporting of recurrence
data important in pancreatic cancer? Ann Surg Oncol 2004; 11(3):
304–9.
62. Shibata K, Matsumoto T, Yada K, et al. Factors predicting recurrence
after resection of pancreatic ductal carcinoma. Pancreas 2005; 31(1):
69–73.
63. Kleeff J, Reiser C, Hinz U, et al. Surgery for recurrent pancreatic ductal
adenocarcinoma. Ann Surg 2007; 245(4): 566–72.
64. Shrikhande SV, Kleeff J, Reiser C, et al. Pancreatic resection for M1 pan-
creatic ductal adenocarcinoma. Ann Surg Oncol 2007; 14(1): 118–27.
Epub 2006 Oct 25.
65. Gleisner AL, Assumpcao L, Cameron JL, et al. Is resection of periampul-
lary or pancreatic adenocarcinoma with synchronous hepatic metastasis
justified? Cancer 2007; 110(11): 2484–92.
9 Surgical complications of pancreatectomy
Steven C. Katz and Murray F. Brennan
Pancreatic resection and the associated complications remain
challenging problems for patients and surgeons. Since the ear-
liest reports describing the technique of pancreaticoduode-
nectomy (PD) by Kausch and Whipple, significant reductions
in operative mortality and morbidity have been achieved (1,2).
Postoperative mortality rates have been reduced from greater
than 25% in the 1960s to less than 5% in specialized centers (3).
The lower risk of death following pancreatic resection is due
to advances in operative technique, improvements in peri-
operative care, percutaneous and endoscopic management
of complications, and refinements in patient selection (4).
Unfortunately, morbidity rates for PD continue to exceed 30%
to 40% in large series (5–9).
We discuss the prevalence, nature, predisposing factors, and
management for major surgical complications that occur fol-
lowing pancreatic resection. While there are many nonsurgical
complications that occur following pancreatic resection, these
are not addressed. Right, left, central, and total pancreatecto-
mies are discussed separately where appropriate. The most
common individual complications are considered, followed by
factors affecting morbidity rates. Throughout, we outline
operative strategies and postoperative interventions that
impact the risk and severity of surgical complications follow-
ing pancreatectomy.
specific complications
Pancreatic Anastomotic Leak and Pancreatic Fistula
Pancreatic leak occurs in 7% to 29% of patients following pan-
creatic resection (Tables 9.1 and 9.2) (5,7,10–14). The wide
range in incidence is due in part to variability in defining the
manifestations of pancreatic leaks and several classification
systems have been proposed (9,15,16). Given similarity in
management and clinical manifestations, pancreatic leak,
fistula, fluid collection, and abscess will be considered
together (12).
Parenchymal consistency and the extent of operation are
associated with pancreatic leak following right or left pancre-
atectomy (Table 9.3) (17). Small pancreatic duct diameter is a
predictor of leak following PD (7,18). Management of fluid
collections resulting from a pancreatic leak may involve opera-
tive drains, placement of postoperative drains, or reoperation
(Fig. 9.1). Vin et al. reported that prolonged drainage was pre-
dicted by volume collected during the first 48 hours, fluid
amylase >1000, or distal pancreatectomy (12). The magnitude
of the pancreatic leak may also depend on whether the source
is the main duct or parenchyma (19). Those patients who do
develop pancreatic leaks are more likely to suffer from other
complications or death, and this risk is exacerbated by super-
imposed infection (12). Numerous strategies have been
attempted to minimize the chances of pancreatic leakage and
these are discussed below.
Delayed Gastric Emptying
The incidence of delayed gastric emptying (DGE) following
PD ranges from 4% to 29% (5,11,13) and is associated with
other intraabdominal complications (Table 9.1). While DGE is
not associated with an increased risk of death, it does prolong
hospitalization time (5,20). Parameters used to define DGE
include the volume of nasogastric tube output, the length of
time before tolerance of oral feeding, and results of scinti-
graphic studies. At our institution, DGE is defined as failure to
achieve oral intake sufficient to maintain adequate hydration
by postoperative day 10 (9).
DGE is thought to be due to numerous factors, including
management of the pylorus, extent of retroperitoneal dissec-
tion, intraabdominal fluid collections, and decreased motilin
activity (21). Early reports indicated that pylorus-preserving
pancreaticoduodenectomy (PPPD) increased the risk of DGE
(22,23) but subsequent studies have failed to confirm this
(Table 9.4) (24,25). Radical resection or extended retroperito-
neal dissection may also be associated with DGE (26). It is
unclear if more extensive dissection has a direct effect or if
higher rates of pancreatic leak, sepsis, or hemorrhage predis-
pose to DGE (25). Expeditious management of fluid collec-
tions, infection, or bleeding may limit gastric dysmotility.
An additional contributing factor to DGE may be reduced
levels of circulating motilin following PD (27). In a random-
ized control trial (RCT) including 118 patients undergoing
PD, erythromycin, the motilin analogue, reduced the DGE rate
from 30% to 19% compared to placebo (21). By contrast, rou-
tine nasogastric decompression or withholding of oral feeding
has not been shown to affect the rate of DGE. Based upon data
from RCTs involving patients subjected to gastrectomy, rou-
tine nasogastric tube placement following pancreatic surgery
is unnecessary (28,29). Furthermore, early oral feeding should
be considered following major abdominal procedures (30,31).
Postpancreatectomy Hemorrhage
Postpancreatectomy hemorrhage (PPH) occurs in 2% to 9%
of cases and the consequences may be severe (8,32–37). The
initial evidence of hemorrhage may be the “sentinel bleed,”
which is present in 30% to 100% of patients prior to massive
PPH (38–41). Risk of PPH is related to inadequate intraopera-
tive hemostasis, bile leak, pancreatic leak, intraabdominal
infection, and sepsis (39,40,42–44). The presence of jaundice
at the time of pancreatic resection may increase the risk of
PPH, but this is not lessened by preoperative biliary
drainage (37). The implications and management of PPH vary
depending on the time of onset and source (4).
Postoperative bleeding within the first 24 hours is most
often due to a technical failure and requires reoperation if
severe (35). The most appropriate course of action for PPH
occurring beyond the immediate postoperative period will
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Table 9.1 Complications Following Pancreaticoduodenectomy

Pancreatic Delayed Gastric Overall
Author N Fistula or Leak Emptying Hemorrhage Bile Leak Complications Death
Balladur (42) 223 13% NR 9% NR 41% 9%
Bottger (10) 228 8% NR NR <1% 26% 6.1%
Gouma (11) 300 7% 29% 5% 2% 48% 10.1%
Balcom (5) 489 13% 12% NR 2% 39%
Muscari (7) 300 17% NR 6% <1% 39% 11%
Winter (13) 1423 9% 15% NR 2% 38% 2%
Vin (12) 680 18% NR NR NR NR 2.0%*
House (49) 356 15% 4% NR NR 38% 1.7%
Baker (47) 440 16% 7% 2% 2% 36% 1.6%
*Includes pancreaticoduodenectomy, central pancreatectomy, and distal pancreatectomy.

Table 9.2 Complications Following Distal Pancreatectomy

Author N Fistula or Leak Hemorrhage Overall Complications Death
Bottger (10) 72 13% NR 27% 1.7%
Balcom (5) 190 13% NR 26% 1.5%
Pannegeon (103) 175 23% 2% 42% 0
Siergaza (104) 132 14% 4% 57% 5.0%
Ridolfini (105) 64 22% 3% 37% 1.5%
Kleeff (50) 302 12% 3% 35% 2.0%
Ferrone (14) 462 29% NR NR 0.8%
Vin (12) 220 13% NR NR 2.0%*
*Includes pancreaticoduodenectomy, central pancreatectomy, and distal pancreatectomy.

Table 9.3 Predictors of Pancreatic Leak or Fistula
Following Pancreaticoduodenectomy
Small duct diameter (7,10)
Friable parenchyma (7,10)
Extended resection (7)
Placement of intraoperative drains (59)
Blood loss (10)
Obesity (49)
Following Distal Pancreatectomy
Multivisceral resection (14,104,105)
Proximal (body) transaction (103)
Friable parenchyma (105)
Malnutrition (104)
Obesity (14)
depend on its location. Extraluminal PPH may arise from the
gastroduodenal artery (GDA), splenic artery, or tributaries of
the superior mesenteric vessels. Intraperitoneal hemorrhage
is often associated with a pancreatic leak and options include
reoperation or angioembolization. When reoperation is
selected, completion pancreatectomy and suture ligation of
the bleeding vessel have been advocated (45). Operative
intervention more than 1 week following pancreatic resec-
tion may be particularly challenging due to adhesions and
tissue friability (46). Arterial embolization is valuable under
these circumstances, with a success rate of approximately
80% (Fig. 9.2) (41). We advocate distal ligation of the GDA to
ensure the technical feasibility of angioembolization as it
may not be possible when the bleeding point is in close prox-
imity to the common hepatic or superior mesenteric artery.
Intraluminal PPH should be initially addressed endoscopi-
cally and may originate from anastomoses, mucosal ulcer-
ation, or the cut pancreatic surface. When bleeding is found
to originate from the cut pancreatic surface, hemostasis may
be achieved during reoperation through a jejunotomy or gas-
trotomy (32).
In summary, PPH may occur in up to 9% of patients. The
timing and location of the bleeding in patients suffering from
PPH are important factors in predicting outcome and deter-
mining appropriate management. The overall mortality of
PPH is as high as 16% and delayed PPH is associated with a
47% chance of death (41,43). Appreciation of the clinical
factors associated with PPH, including sentinel bleeding, sep-
sis, and pancreatic leak, facilitates prompt recognition.
Bile Leak
The incidence of choledochoenteric leak following PD is
notably lower than pancreatic leak or fistula (Table 9.1). The
larger size of the bile duct and more reliable tissue integrity
may account for the relative infrequency of biliary leak when
compared to pancreatic leak. Similar to pancreatic leak, bile
leak is associated with both sterile and infected intraabdomi-
nal fluid collections (47). The vast majority of biliary leaks or
fistulae can be managed by percutaneous, transhepatic, or
transabdominal drainage (48).

82
 SURGICAL COMPLICATIONS OF PANCREATECTOMY

Table 9.4 Pylorus Preservation

OR TIME
DGE % Morbidity % Mortality % LOS (days) EBL (minutes)
Author N PD PPPD PD PPPD PD PPPD PD PPPD PD PPPD PD PPPD
Van Berge 200 34 37 48 44 6 1 20 18* 1580 1247* 360 288*
Henegouwen (25)
Lin (23) 31 6 38 50 56 0 6 – – 687 451 237 215
Jimenez (106) 62 12 33 45 44 0 3 12 15* 723 707 – –
Seiler (24) 114 45 32 72 57* 5 3 24 25 2096 1453* 476 404*
*p < 0.05, DGE = delayed gastric emptying, PD = standard pancreaticoduodenectomy, PPPD = pylorus-preserving pancreaticoduodenectomy,
LOS = length of stay, EBL = estimated blood loss.

Figure 9.1 The patient presented with fever and abdominal pain 2 weeks after a pancreaticoduodenectomy. A CT scan revealed a fluid collection in the RUQ (long
arrow), which was managed with CT-guided percutaneous drainage (catheter indicated by short arrow). The amylase level in the aspirated fluid was consistent with
a pancreatic leak (11,320 U/L).

Death
Long-term survival following pancreatic resection is a func-
tion of the underlying disease, while perioperative mortality is
related to the occurrence of complications, in addition to
patient, institutional, and technical factors. Fortunately, the
perioperative mortality rate following pancreatic resection has
been reported to be less than 2% in the most recent large series
(12–14,47,49,50). Pancreatic leak (11) and PPH (40,51,52) are
the complications most frequently associated with periopera-
tive mortality. As noted above, the improved mortality rates
following pancreatic resection are due in large part to better
management of complications. The vast majority of complica-
tions can be managed percutaneously, thereby reducing their
severity and the risk of death (47).

factors affecting complication rates

following pancreatectomy
Pancreatic Duct Management Following Resection
Pancreatic leaks prolong hospitalization, and are associated with
other complications including DGE, intraabdominal abscess,
and cholangitis (3,53). Numerous strategies for management of
the pancreatic duct following PD have been advocated, includ-
ing pancreaticojejunostomy (PJ), pancreaticogastrostomy (PG),
and duct ligation (DL). In addition, several technical modifi-
cations to distal pancreatectomy (DP) have been tested to
reduce the leak rate.
Figure 9.2 Following a pancreaticoduodenectomy and hemodynamic insta-
bility, metallic coils were placed in the gastroduodenal artery stump (long
arrow) to treat a suspected pseudoaneurysm. The catheter is positioned within
the common hepatic artery (short arrow).
Investigators at Johns Hopkins compared PG and PJ in
145 patients who underwent PD and found that the two
methods were associated with similar leak rates (53). Several

83
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
variations of PJ have been reported including invagination,
end-to-side anastomosis, and side-to-side anastomosis. When
compared to end-to-side (duct to mucosa) PJ, end-to end
(invaginating) PJ was associated with a trend toward a higher
pancreatic fistula rate (15% vs. 4%, p > 0.05). (54) Pancreatic
duct ligation following PD as opposed to PG or PJ posed a
greater risk of adverse outcomes (55). Marcus et al. also
reported that duct ligation following PD was an independent
risk factor for pancreatic leakage (18). Whether PG or PJ is
employed, ensuring robust perfusion to the cut pancreatic
surface prior to anastomosis is essential (56).
Various techniques have been applied to both right and left
pancreatic resections. Suc et al. (57) conducted an RCT with
182 patients undergoing DP or PD and determined that the
use of fibrin glue did not affect the overall complication rate or
incidence of pancreatic fistula. Thaker et al. reported that the
use of absorbable mesh with a stapler reduced the leak rate
significantly among 40 patients undergoing DP compared to
the 40 control cases (58). Ferrone et al. did not confirm the
efficacy of reinforcing pancreatic transection margins (14).
Peritoneal Drainage
The only randomized trial addressing the value of routine
intraperitoneal drainage following pancreatic resection did
not show a benefit (59). Patients who underwent pancreatic
resection at the Memorial Sloan-Kettering Cancer Center were
randomized to placement of closed suction drains (n = 88) or
to no drain placement (n = 91). Those patients who had drains
placed were significantly more likely to develop intraperito-
neal sepsis, fluid collections, or fistulae (22% vs. 9%, p < 0.02).
Thus, placement of drains following pancreatic resection
should be considered on a selective basis.
Octreotide
The pathogenesis of pancreatic leaks has been thought to
involve the enzymatic activity of the exocrine secretions. Thus,
investigators have tested the ability of octreotide, a synthetic
somatostatin analogue, to reduce the risk of postpancreatec-
tomy complications (Table 9.5) (60). The majority of trials
demonstrated that octreotide was associated with a significant
reduction in perioperative morbidity (61–64). Two trials
showed a significant reduction in the incidence of pancreatic
fistula in patients receiving octreotide (62,63). The overall fre-
quency of pancreatic fistula was particularly low in two of the
trials in which octreotide and placebo were similar (65,66).
Table 9.5 Prophylactic Octreotide
Pancreatic Fistula %
Author N Placebo
Buchler (61) 246 38
Pederzoli (64) 252 19
Montorsi (63) 218 20
Friess (62) 247 22
Lowy (65) 110 6 12
Yeo (66) 211 11
*p < 0.05 versus the control group, ^statistical significance not indicated.
84
The trials differ with respect to the proportion of patients
undergoing right or left pancreatic resection, frequencies of
various diagnoses, the dose of octreotide, and the definitions
of pancreatic leak. Given the discrepant results among avail-
able trials, the routine use of octreotide for the prevention of
pancreatic fistulas cannot be recommended. Individuals at
high risk for pancreatic leak (61), such as those with ampullary
cancer or soft, friable glands may benefit from exocrine
inhibition. The cost of the drug must be balanced against its
impact on length of stay and potential avoidance of additional
procedures.
Pylorus-Preserving Pancreaticoduodenectomy
In a RCT comparing classic PD and pylorus-preserving PD
(PPPD), the incidence of pancreatic fistula was not signifi-
cantly different but PPPD was associated with more instances
of DGE (23). This study was limited by small sample size and
the difference in incidence of DGE between the two groups
was not statistically significant. A subsequent RCT demon-
strated that cumulative morbidity was significantly more fre-
quent following classic PD when compared to PPPD (72% vs.
57%, p = 0.05) (24). Other trials failed to show significant dif-
ferences in the rates of DGE or overall surgical complications
when comparing classic PD to PPPD (Table 9.4). The decision
to perform a PPPD or classic PD is a matter of surgeon prefer-
ence as the two procedures do not result in markedly different
perioperative outcomes.
Extended Lymphadenectomy and Resection
of Contiguous Structures
Several investigators have studied the impact of extended
retroperitoneal lymphadenectomy in patients with adeno-
carcinoma of the pancreas. In a multicenter prospective
randomized trial involving 81 patients, extended lymphad-
enectomy did not significantly affect operative time, blood
loss, morbidity, or mortality when compared to the standard
dissection (67). The number of lymph nodes removed was
similar among the two groups and the extent of resection
did not correlate with locoregional control. Yeo et al.
reported that radical PD increased operative times (68), as
well as the rates of pancreatic fistula, delayed gastric empty-
ing, and overall morbidity (26). Radical or extended PD
does not appear to confer an oncologic benefit in patients
with adenocarcinoma and may be associated with higher
morbidity rates.
Morbidity % Mortality %
Octreotide Placebo Octreotide Placebo Octreotide
18^ 55 32* 5.8 3.2
9 29 16* 3.8 1.6
9* 36 22* 5.6 8.1
10* 30 16* 0.8 1.6
25 30 0 2
9 34 40 0 1
 SURGICAL COMPLICATIONS OF PANCREATECTOMY
Among the 10% to 20% of patients with adenocarcinoma of
the pancreas who are potentially curable, resection of contigu-
ous structures, including the portal vein or spleen, may be nec-
essary in up to 39% (69). While those undergoing resection of
contiguous structures may experience higher degrees of intra-
operative blood loss and longer hospital stays, perioperative
and long-term outcomes are not significantly different (70).
When portal vein involvement is the only factor precluding a
potentially curative pancreatectomy, resection of the vessel
with appropriate reconstruction may be performed without a
significant change in operative mortality (71). In a separate
study, splenectomy did not lead to increased perioperative
morbidity but was associated with decreased survival in
patients with pancreatic adenocarcinoma (72). Whether these
findings are the result of direct immunologic effects of sple-
nectomy or reflections of more aggressive tumor biology
remains uncertain.
Total and Central Pancreatectomy
The incidence of multifocal pancreas adenocarcinoma is suf-
ficiently low to render total pancreatectomy (TP) unnecessary
in the vast majority of cases (73,74). The perioperative (75)
and long-term outcomes (76) following TP for adenocarci-
noma are even less favorable than those obtained following
partial pancreatectomy. The lack of an incremental benefit of
TP, along with the endocrine and exocrine sequelae, has lim-
ited the use of TP (77). However, increased recognition of
intraductal papillary mucinous neoplasms (IPMNs) has led to
increased interest in TP (78). Quality of life following TP may
not be significantly different from patients with diabetes mel-
litus not undergoing pancreatic resection (79). Intermittent
hypoglycemia is the most common endocrine complication,
but fewer than 3% die following TP due to metabolic derange-
ments (80,81). Although islet cell transplantation may delay or
prevent the diabetic complications of total pancreatectomy,
the role of the procedure is not fully defined (82).
As the use of cross-sectional imaging has increased, the fre-
quency of cystic and neuroendocrine lesions of the pancreas is
growing. Given that cystic and neuroendocrine pancreatic
tumors are often noninvasive, parenchyma-sparing pancreatic
resections, such as central pancreatectomy (CP), may be
appropriate (83). CP may pose a lower risk of diabetes mellitus
than extended DP (84,85) and the rate of exocrine insuffi-
ciency is reported to be between 0% and 20% (84–87). The
range of pancreatic fistula formation following CP is 14–62%
(83–88), which is somewhat higher than what has been associ-
ated with right or left pancreatic resection. However, in a
recent series, the overall rate of major complications was
similar following CP when compared to extended DP (84).
Laparoscopic Pancreatectomy
Since initially reported (89), laparoscopic distal pancreatec-
tomy is being performed with increasing frequency due to
growing interest among patients and physicians. There are no
RCTs from which to draw definitive conclusions about compli-
cations. Two series including a total of 286 laparoscopic left
pancreatectomies indicate a pancreatic fistula rate of 16%
to 17% (90,91). The oncologic equivalence of laparoscopic
pancreatic resection to conventional approaches remains to be
proven. One advantage of laparoscopic pancreatectomy appears
to be a decreased length of stay (90). Laparoscopic right and
central pancreatectomies are not widely performed and the lit-
erature is limited to case reports and small series. In properly
selected patients, laparoscopic pancreatectomy may offer short-
term benefits when performed by experienced surgeons.
Institutional Factors
Hospital or surgeon volume and practice paradigms influence
outcome and cost following pancreatic resection. Short-term
mortality rates following PD are lower in high-volume com-
pared to low-volume centers (92,93). Improved outcomes in
high-volume centers are more likely a reflection of systematic
factors rather than an independent effect of more experienced
surgeons (93). Utilization of clinical pathways following pan-
creatic resection has been demonstrated to lower overall cost
and decrease the average length of stay by 3 to 6 days (94,95).
Clinical pathways have not been associated with significant
reductions in morbidity or mortality in patients undergoing
pancreatic resection (96).
Patient Factors
Numerous patient-related factors have been purported to
increase the risks of complications and death following pan-
creatic resection. As noted elsewhere in this chapter, large duct
diameter and firm pancreatic parenchymal texture may be
associated with a lower risk of pancreatic leak (Table 9.3).
Other patient variables that have been reported to increase
morbidity rates include coagulopathy, severe jaundice, acute
renal failure, obesity, and protein-calorie malnutrition
(97–99). Age has not been shown to be an independent risk
factor for morbidity and mortality following pancreatectomy
(10). The impact of morbid obesity on the risk for postpancre-
atectomy complications deserves special attention given the
scope of this problem in the U.S. population. House et al.
determined that retrorenal visceral fat thickness was an inde-
pendent predictor of overall morbidity, wound infection, and
pancreatic fistula (49).
Whether jaundice increases the risks of pancreatic resection
and the impact of preoperative biliary drainage on periopera-
tive outcomes remain an area of considerable controversy.
Povoski et al. (100) demonstrated that in patients undergoing
PD, preoperative biliary drainage was an independent predic-
tor of postoperative infection, overall complications, and
death. In contrast, Pisters et al. (101) reviewed their experi-
ence with preoperative biliary decompression in patients sub-
jected to PD and determined that drainage did not increase
the overall morbidity or mortality rates, but did increase the
rate of wound infections. A recent meta-analysis of RCTs and
comparative cohort studies concluded that there is no benefit
to routine preoperative biliary drainage (102). Routine pre-
operative biliary drainage in jaundiced patients with pancre-
atic head tumors does not appear to be warranted, but may
be appropriate in properly selected patients. Biliary decom-
pression should be considered to address acute cholangitis,
intractable pruritis, or to facilitate participation in studies
investigating neoadjuvant therapy.
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 9.6 Recommendations for Prevention or Management of Pancreatectomy Complications

Recommendation
Evidence Category Strength Category
Radical pancreatectomy or extended retroperitoneal lymphadenectomy may be associated Ib A
with a higher rate of certain complications and does not confer a significant benefit in
oncologic outcome.
Restoration of pancreaticoenteric continuity as opposed to ductal ligation is associated Ib A
with significantly lower rates of pancreatic fistula and endocrine insufficiency.
Pancreaticojejunostomy and pancreatogastrostomy following PD have similar Ib A
complication rates.
Pylorus preservation and PD with distal gastrectomy lead to similar perioperative Ib A
outcomes.
Utilization of absorbable mesh when transecting the distal pancreas with a stapling device III C
has not been definitively shown to decrease the risk of pancreatic leak.
Routine use of octreotide following pancreatic resection is not indicated but may be useful Ib A
in selected, high-risk patients.
Routine preoperative biliary drainage prior to pancreaticoduodenectomy is not indicated Ia A
and should be performed in selected patients based upon the presence of symptoms,
infection, or severe hyperbilirubinemia.
Recommended grading of categories of evidence: Ia, evidence from meta-analysis of randomised controlled trials; Ib, evidence from at least one randomised
controlled trial; IIa, evidence from at least one controlled study without randomisation; IIb, evidence from at least one other type of quasi-experimental study;
III, evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies and case-control studies; IV, evidence from expert
committee reports or opinions and/or clinical experience of respected authorities. Recommended strengths of management recommendation: A, directly based
on category I evidence; B, directly based on category II evidence or extrapolated recommendation from category I evidence; C, directly based on category III
evidence or extrapolated recommendation from category I or II evidence; D, directly based on category IV evidence or extrapolated recommendation from
category I, II, or III evidence.

summary
While the mortality rates following pancreatic resection
have improved dramatically, the incidence of complica-
tions remains high. Based upon the available literature,
several recommendations have been proposed ( Table 9.6).
Refinements in our abilities to detect and manage compli-
cations following pancreatectomy account, in large part,
for improved perioperative mortality statistics. Further
progress in enhancing the safety of pancreatic resection
will depend upon the development of more effective mea-
sures to prevent and treat postpancreatectomy complica-
tions. Better understanding of the biology of the diseases
we subject to pancreatic resection will allow for more pre-
cise patient selection and improve both perioperative and
long-term outcomes.
references
1. Kausch W. Das carcinoma der papilla duodeni und seine radikale ent-
fernung. Beitr Klin Chir 1912; 78: 439–51.
2. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the
ampulla of vater. Ann Surg 1935; 102(4): 763–79.
3. Stojadinovic A, Brooks A, Hoos A, et al. An evidence-based approach to
the surgical management of resectable pancreatic adenocarcinoma. J
Am Coll Surg 2003; 196(6): 954–64.
4. Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage
(PPH): an International Study Group of Pancreatic Surgery (ISGPS)
definition. Surgery 2007;142(1): 20–5.
5. Balcom JH, Rattner DW, Warshaw AL, et al. Ten-year experience with
733 pancreatic resections: changing indications, older patients, and
decreasing length of hospitalization. Arch Surg 2001; 136(4): 391–8.
6. Buchler MW, Wagner M, Schmied BM, et al. Changes in morbidity after
pancreatic resection: toward the end of completion pancreatectomy.
Arch Surg 2003; 138(12): 1310–4; discussion 1315.
7. Muscari F, Suc B, Kirzin S, et al. Risk factors for mortality and intra-
abdominal complications after pancreatoduodenectomy: multivariate
analysis in 300 patients. Surgery 2006; 139(5): 591–8.
8. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pan-
creaticoduodenectomies in the 1990s: pathology, complications, and
outcomes. Ann Surg 1997; 226(3): 248–57; discussion 257.
9. Grobmyer SR, Pieracci FM, Allen PJ, et al. Defining morbidity after pan-
creaticoduodenectomy: use of a prospective complication grading sys-
tem. J Am Coll Surg 2007; 204(3): 356–64.
10. Bottger TC, Engelmann R, Junginger T. Is age a risk factor for major
pancreatic surgery? An analysis of 300 resections. Hepatogastroenterol-
ogy 1999; 46(28): 2589–98.
11. Gouma DJ, van Geenen RC, van Gulik TM, et al. Rates of complications
and death after pancreaticoduodenectomy: risk factors and the impact
of hospital volume. Ann Surg 2000; 232(6): 786–95.
12. Vin Y, Sima CS, Gertrajdmen GI, et al. Management and outcomes of
postpancreatectomy fistula, leak, and abscess: results of 908 patients
resected at a single institution between 2000 and 2005. J Am Coll Surg
2008; 207(4): 490.
13. Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduode-
nectomies for pancreatic cancer: A single-institution experience. J Gas-
trointest Surg 2006; 10(9): 1199–210; discussion 1210–1.
14. Ferrone CR, Warshaw AL, Rattner DW, et al. Pancreatic fistula rates after
462 distal pancreatectomies: staplers do not decrease fistula rates. J Gas-
trointest Surg 2008; 12(10): 1691–7; discussion 1697–8.
15. Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of com-
plications of surgery with examples of utility in cholecystectomy. Sur-
gery 1992; 111(5): 518–26.
16. DeOliveira ML, Winter JM, Schafer M, et al. Assessment of complica-
tions after pancreatic surgery: A novel grading system applied to
633 patients undergoing pancreaticoduodenectomy. Ann Surg 2006;
244(6): 931–7; discussion 937–9.
17. Bartoli FG, Arnone GB, Ravera G, Bachi V. Pancreatic fistula and relative
mortality in malignant disease after pancreaticoduodenectomy. Review
and statistical meta-analysis regarding 15 years of literature. Anticancer
Res 1991; 11(5): 1831–48.

86
 SURGICAL COMPLICATIONS OF PANCREATECTOMY
18. Marcus SG, Cohen H, Ranson JH. Optimal management of the pancre-
atic remnant after pancreaticoduodenectomy. Ann Surg 1995; 221(6):
635–45; discussion 645–8.
19. Nguyen JH. Distinguishing between parenchymal and anastomotic
leakage at duct-to-mucosa pancreatic reconstruction in pancreatico-
duodenectomy. World J Gastroenterol 2008; 14(43): 6648–54.
20. Berberat PO, Friess H, Kleeff J, et al. Prevention and treatment of com-
plications in pancreatic cancer surgery. Dig Surg 1999; 16(4): 327–36.
21. Yeo CJ, Barry MK, Sauter PK, et al. Erythromycin accelerates gastric emp-
tying after pancreaticoduodenectomy. A prospective, randomized, pla-
cebo-controlled trial. Ann Surg 1993; 218(3): 229–37; discussion 237–8.
22. Warshaw AL, Torchiana DL. Delayed gastric emptying after pylorus-
preserving pancreaticoduodenectomy. Surg Gynecol Obstet 1985;
160(1): 1–4.
23. Lin PW, Lin YJ. Prospective randomized comparison between pylorus-
preserving and standard pancreaticoduodenectomy. Br J Surg 1999;
86(5): 603–7.
24. Seiler CA, Wagner M, Sadowski C, et al. Randomized prospective trial of
pylorus-preserving vs. classic duodenopancreatectomy (Whipple pro-
cedure): initial clinical results. J Gastrointest Surg 2000; 4(5): 443–52.
25. van Berge Henegouwen MI, van Gulik TM, DeWit LT, et al. Delayed
gastric emptying after standard pancreaticoduodenectomy versus pylo-
rus-preserving pancreaticoduodenectomy: an analysis of 200 consecu-
tive patients. J Am Coll Surg 1997; 185(4): 373–9.
26. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with
or without distal gastrectomy and extended retroperitoneal lymphade-
nectomy for periampullary adenocarcinoma, part 2: randomized con-
trolled trial evaluating survival, morbidity, and mortality. Ann Surg
2002; 236(3): 355–66; discussion 366–8.
27. Tanaka M, Sarr MG. Role of the duodenum in the control of canine
gastrointestinal motility. Gastroenterology 1988; 94(3): 622–9.
28. Carrère N, Seulin P, Julio CH, et al. Is nasogastric or nasojejunal decom-
pression necessary after gastrectomy? A prospective randomized trial.
World J Surg 2007; 31(1): 122–7.
29. Doglietto GB, Papa V, Tortorelli AP, et al. Nasojejunal tube placement
after total gastrectomy: a multicenter prospective randomized trial.
Arch Surg 2004; 139(12): 1309–13; discussion 1313.
30. Brennan MF. Is nil per os still appropriate for patients undergoing
upper gastrointestinal surgery? Nat Clin Pract Gastroenterol Hepatol
2008; 5(12): 660–1.
31. Han-Geurts IJ, Hop WC, Kok NF, et al. Randomized clinical trial of the
impact of early enteral feeding on postoperative ileus and recovery. Br J
Surg 2007; 94(5): 555–61.
32. Balladur P, Christophe M, Tiret E, Parc R. Bleeding of the pancreatic
stump following pancreatoduodenectomy for cancer. Hepatogastroen-
terology 1996; 43(7): 268–70.
33. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula:
an international study group (ISGPF) definition. Surgery 2005; 138(1):
8–13.
34. Cunningham JD, Weyant MT, Levitt M, et al. Complications requiring
reoperation following pancreatectomy. Int J Pancreatol 1998; 24(1): 23–9.
35. de Castro SMM, Kuhlmann KFD, Busch ORC, et al. Delayed massive
hemorrhage after pancreatic and biliary surgery: embolization or sur-
gery? Ann Surg 2005; 241(1): 85–91.
36. Miedema BW, Sarr MG, van Heerden JA, et al. Complications following
pancreaticoduodenectomy. Current management. Arch Surg 1992;
127(8): 945–9; discussion 949.
37. Rumstadt B, Schwab M, Korth P, et al. Hemorrhage after pancreatoduo-
denectomy. Ann Surg 1998; 227(2): 236–41.
38. Brodsky JT, Turnbull AD. Arterial hemorrhage after pancreatoduode-
nectomy. The ‘sentinel bleed’. Arch Surg 1991; 126(8): 1037–40.
39. Shankar S, Russell RC. Haemorrhage in pancreatic disease. Br J Surg
1989; 76(8): 863–6.
40. Tien YW, Lee PH, Yang CY, et al. Risk factors of massive bleeding related
to pancreatic leak after pancreaticoduodenectomy. J Am Coll Surg 2005;
201(4): 554–9.
41. Yekebas EF, Wolfram L, Cataldegirmen G, et al. Postpancreatectomy
hemorrhage: diagnosis and treatment: an analysis in 1669 consecutive
pancreatic resections. Ann Surg 2007; 246(2): 269–80.
42. Balladur P, Christophe M, Tiret E, Parc R. Bleeding of the pancreatic
stump following pancreatoduodenectomy for cancer. Hepatogastroen-
terology 1996; 43(7): 268–70.
43. Choi SH, Moon HJ, Heo JS, et al. Delayed hemorrhage after pancreati-
coduodenectomy. J Am Coll Surg 2004; 199(2): 186–91.
44. Koukoutsis I, Bellagamba R, Morris-Stiff G, et al. Haemorrhage follow-
ing pancreaticoduodenectomy: risk factors and the importance of sen-
tinel bleed. Dig Surg 2006; 23(4): 224–8.
45. Farley DR, Schwall G, Trede M. Completion pancreatectomy for surgi-
cal complications after pancreaticoduodenectomy. Br J Surg 1996;
83(2): 176–9.
46. Otah E, Cushin BJ, Rozenblit GN, et al. Visceral artery pseudoaneurysms
following pancreatoduodenectomy. Arch Surg 2002; 137(1): 55–9.
47. Baker TA, Aaron JM, Borge M, et al. Role of interventional radiology in
the management of complications after pancreaticoduodenectomy. Am
J Surg 2008; 195(3): 386–90; discussion 390.
48. Sohn TA, Yeo CJ, Cameron JL, et al. Pancreaticoduodenectomy: role of
interventional radiologists in managing patients and complications. J
Gastrointest Surg 2003; 7(2): 209–19.
49. House MG, Fong Y, Arnaoutakis DJ, et al. Preoperative predictors for
complications after pancreaticoduodenectomy: impact of BMI and
body fat distribution. J Gastrointest Surg 2008; 12(2): 270–8.
50. Kleeff J, Diener MK, Z’Graggen K, et al. Distal pancreatectomy: risk fac-
tors for surgical failure in 302 consecutive cases. Ann Surg 2007; 245(4):
573–82.
51. Trede M. The surgical treatment of pancreatic carcinoma. Surgery 1985;
97(1): 28–35.
52. van Berge Henegouwen MI, Allema JH, van Gulik TM, et al. Delayed
massive haemorrhage after pancreatic and biliary surgery. Br J Surg
1995; 82(11): 1527–31.
53. Yeo CJ, Cameron JL, Maher MM, et al. A prospective randomized trial
of pancreaticogastrostomy versus pancreaticojejunostomy after pan-
creaticoduodenectomy. Ann Surg 1995; 222(4): 580–8; discussion
588–92.
54. Chou FF, Sheen-Chen SM, Chen YS, et al. Postoperative morbidity and
mortality of pancreaticoduodenectomy for periampullary cancer. Euro-
pean J Surg 1996; 162(6): 477–81.
55. Tran K, Van Eijck C, Di Carlo V, et al. Occlusion of the pancreatic duct
versus pancreaticojejunostomy: a prospective randomized trial. Ann
Surg 2002; 236(4): 422–8; discussion 428.
56. Strasberg SM, Drebin JA, Mokadam NA, et al. Prospective trial of a
blood supply-based technique of pancreaticojejunostomy: effect on
anastomotic failure in the Whipple procedure. J Am Coll Surg 2002;
194(6): 746–58; discussion 759–60.
57. Suc B, Msika S, Fingerhut A, et al. Temporary fibrin glue occlusion of
the main pancreatic duct in the prevention of intra-abdominal compli-
cations after pancreatic resection: prospective randomized trial. Ann
Surg 2003; 237(1): 57–65.
58. Thaker RI, Matthews BD, Linehan DC, et al. Absorbable mesh reinforce-
ment of a stapled pancreatic transection line reduces the leak rate with
distal pancreatectomy. J Gastrointest Surg 2007; 11(1): 59–65.
59. Conlon KC, Labow D, Leung D, et al. Prospective randomized clinical
trial of the value of intraperitoneal drainage after pancreatic resection.
Ann Surg 2001; 234(4): 487–93; discussion 493.
60. Klempa I, Schwedes U, Usadel KH. [Prevention of postoperative pan-
creatic complications following duodenopancreatectomy using soma-
tostatin]. Chirurg 1979; 50(7): 427–31.
61. Büchler M, Friess H, Klempa I, et al. Role of octreotide in the prevention
of postoperative complications following pancreatic resection. Amer J
Surg 1992; 163(1): 125–30; discussion 130.
62. Friess H, Beger HG, Sulkowski U, et al. Randomized controlled multicen-
tre study of the prevention of complications by octreotide in patients
undergoing surgery for chronic pancreatitis. Br J Surg 1995; 82(9): 1270–3.
63. Montorsi M, Zago M, Mosca F, et al. Efficacy of octreotide in the preven-
tion of pancreatic fistula after elective pancreatic resections: a prospec-
tive, controlled, randomized clinical trial. Surgery 1995; 117(1): 26–31.
64. Pederzoli P, Bassi C, Falconi M, Camboni MG. Efficacy of octreotide in
the prevention of complications of elective pancreatic surgery. Italian
Study Group. Br J Surg 1994; 81(2): 265–9.
87
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
65. Lowy AM, Lee JE, Pisters PW, et al. Prospective, randomized trial of
octreotide to prevent pancreatic fistula after pancreaticoduodenectomy
for malignant disease. Ann Surg 1997; 226(5): 632–41.
66. Yeo CJ, Cameron JL, Lillemoe KD, et al. Does prophylactic octreotide
decrease the rates of pancreatic fistula and other complications after
pancreaticoduodenectomy? Results of a prospective randomized pla-
cebo-controlled trial. Ann Surg 2000; 232(3): 419–29.
67. Pedrazzoli S, DiCarlo V, Dionigi R, et al. Standard versus extended
lymphadenectomy associated with pancreatoduodenectomy in the sur-
gical treatment of adenocarcinoma of the head of the pancreas: a mul-
ticenter, prospective, randomized study. Lymphadenectomy Study
Group. Ann Surg 1998; 228(4): 508–17.
68. Yeo CJ, Cameron JL, Sohn TA, et al. Pancreaticoduodenectomy with
or without extended retroperitoneal lymphadenectomy for periam-
pullary adenocarcinoma: comparison of morbidity and mortality
and short-term outcome. Ann Surg 1999; 229(5): 613–22; discussion
622–4.
69. Brennan MF, Moccia RD, Klimstra D. Management of adenocarcinoma
of the body and tail of the pancreas. Ann Surg 1996; 223(5): 506–11;
discussion 511–2.
70. Shoup M, Conlon KC, Klimstra D, Brennan MF. Is extended resection
for adenocarcinoma of the body or tail of the pancreas justified? J Gas-
trointest Surg 2003; 7(8): 946–52; discussion 952.
71. Harrison LE, Klimstra DS, Brennan MF. Isolated portal vein involve-
ment in pancreatic adenocarcinoma. A contraindication for resection?
Ann Surg 1996; 224(3): 342–7; discussion 347–9.
72. Schwarz RE, Harrison LE, Conlon KC, et al. The impact of splenectomy
on outcomes after resection of pancreatic adenocarcinoma. J Am Coll
Surg 1999; 188(5): 516–21.
73. Cooperman AM, Herter FP, Marboe CA, et al. Pancreatoduodenal
resection and total pnacreatectomy—an institutional review. Surgery
1981; 90(4): 707–12.
74. Edis AJ, Kiernan PD, Taylor WF. Attempted curative resection of ductal
carcinoma of the pancreas: review of Mayo Clinic experience, 1951–
1975. Mayo Clin Proc 1980; 55(9): 531–6.
75. Ihse I, Anderson H, Andren S. Total pancreatectomy for cancer of
the pancreas: is it appropriate? World J Surg 1996; 20(3): 288–93;
discussion 294.
76. Karpoff HM, Klimstra DS, Brennan MF, Conlon KC. Results of total
pancreatectomy for adenocarcinoma of the pancreas. Arch Surg 2001;
136(1): 44–7; discussion 48.
77. Grace PA, Pitt HA, Tompkins RK, et al. Decreased morbidity and mor-
tality after pancreatoduodenectomy. Am J Surg 1986; 151(1): 141–9.
78. Cuillerier E, Cellier C, Palazzo L, et al. Outcome after surgical resection
of intraductal papillary and mucinous tumors of the pancreas. Am J
Gastroenterol 2000; 95(2): 441–5.
79. Billings BJ, Christein JD, Harmsen WS, et al. Quality-of-life after total
pancreatectomy: is it really that bad on long-term follow-up? J Gastro-
intest Surg 2005; 9(8): 1059–66; discussion 1066–7.
80. Assan R, Alexandre JH, Tiengo A, et al. Survival and rehabilitation after
total pancreatectomy. A follow-up of 36 patients. Diabete Metab 1985;
11(5): 303–9.
81. Dresler CM, Fortner JG, McDermott K, Bajorunas DR. Metabolic con-
sequences of (regional) total pancreatectomy. Ann Surg 1991; 214(2):
131–40.
82. Webb MA, Illouz SC, Pollard CA, et al. Islet auto transplantation follow-
ing total pancreatectomy: a long-term assessment of graft function.
Pancreas 2008; 37(3): 282–7.
83. Warshaw AL, Rattner DW, Fernandez-del Castillo C, Z’Graggen K. Mid-
dle segment pancreatectomy: a novel technique for conserving pancre-
atic tissue. Arch Surg 1998; 133(3): 327–31.
84. Ocuin LM, Sarmiento JM, Staley CA, et al. Comparison of central and
extended left pancreatectomy for lesions of the pancreatic neck. Ann
Surg Oncol 2008; 15(8): 2096–103.
88
85. Adham M, Giunippero A, Hervieu V, et al. Central pancreatectomy:
single-center experience of 50 cases. Arch Surg 2008; 143(2): 175–80;
discussion 180–1.
86. Iacono C, Bortolasi L, Serio G. Is there a place for central pancreatec-
tomy in pancreatic surgery? J Gastrointest Surg 1998; 2(6): 509–16; dis-
cussion 516–7.
87. Rotman N, Sastre B, Fagniez PL. Medial pancreatectomy for tumors of
the neck of the pancreas. Surgery 1993; 113(5): 532–5.
88. Celis J, Berrospi F, Ruiz E, et al. Central pancreatectomy for tumors of
the neck and body of the pancreas. J Surg Oncol 2001; 77(2): 132–5.
89. Gagner M, Pomp A, Herrera MF. Early experience with laparoscopic
resections of islet cell tumors. Surgery 1996; 120(6): 1051–4.
90. Kooby DA, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a
multicenter comparison of laparoscopic and open approaches. Ann
Surg 2008; 248(3): 438–46.
91. Mabrut JY, Fernandez-Cruz L, Azagra JS, et al. Laparoscopic pancreatic
resection: results of a multicenter European study of 127 patients. Sur-
gery 2005; 137(6): 597–605.
92. Birkmeyer JD, Finlayson SR, Tosteson AN, et al. Effect of hospital vol-
ume on in-hospital mortality with pancreaticoduodenectomy. Surgery
1999; 125(3): 250–6.
93. Lieberman MD, Kilburn H, Lindsey M, Brennan MF. Relation of peri-
operative deaths to hospital volume among patients undergoing pan-
creatic resection for malignancy. Ann Surg 1995; 222(5): 638–45.
94. Kennedy EP, Rosato EL, Sauter PK, et al. Initiation of a critical pathway
for pancreaticoduodenectomy at an academic institution—the first step
in multidisciplinary team building. J Am Coll Surg 2007; 204(5): 917–
23; discussion 923–4.
95. Porter GA, Pisters PW, Mansyur C, et al. Cost and utilization impact of
a clinical pathway for patients undergoing pancreaticoduodenectomy.
Ann Surg Oncol 2000; 7(7): 484–9.
96. Vanounou T, Pratt W, Fischer JE, et al. Deviation-based cost modeling:
a novel model to evaluate the clinical and economic impact of clinical
pathways. J Am Coll Surg 2007; 204(4): 570–9.
97. Gilsdorf RB, Spanos P. Factors influencing morbidity and mortality in
pancreaticoduodenectomy. Ann Surg 1973; 177(3): 332–7.
98. Warren KW, Cattell RB, Blackburn JP, Nora PF. A long-term appraisal of
pancreaticoduodenal resection for peri-ampullary carcinoma. Ann Surg
1962; 155: 653–62.
99. Winter JM, Cameron JL, Yeo CJ, et al. Biochemical markers predict
morbidity and mortality after pancreaticoduodenectomy. J Am Coll
Surg 2007; 204(5): 1029–36; discussion 1037–8.
100. Povoski SP, Karpeh MS, Jr., Conlon KC, et al. Association of preopera-
tive biliary drainage with postoperative outcome following pancreatico-
duodenectomy. Ann Surg 1999; 230(2): 131–42.
101. Pisters PW, Hudec WA, Hess KR, et al. Effect of preoperative biliary
decompression on pancreaticoduodenectomy-associated morbidity in
300 consecutive patients. Ann Surg 2001; 234(1): 47–55.
102. Sewnath ME, Karsten TM, Prins MH, et al. A meta-analysis on the effi-
cacy of preoperative biliary drainage for tumors causing obstructive
jaundice. Ann Surg 2002; 236(1): 17–27.
103. Pannegeon V, Pessaux P, Sauvanet A, et al. Pancreatic fistula after
distal pancreatectomy: predictive risk factors and value of conser-
vative treatment. Arch Surg 2006; 141(11): 1071–6; discussion 1076.
104. Sierzega M, Niekowal B, Kulig J, Popiela T. Nutritional status affects the
rate of pancreatic fistula after distal pancreatectomy: a multivariate
analysis of 132 patients. J Am Coll Surg 2007; 205(1): 52–9.
105. Ridolfini MP, Alfieri S, Gourgiotis S, et al. Risk factors associated with
pancreatic fistula after distal pancreatectomy, which technique of pan-
creatic stump closure is more beneficial? World J Gastroenterol 2007;
13(38): 5096–100.
106. Jimenez RE, Fernandez-del Castillo C, Rattner DW, et al. Outcome of
pancreaticoduodenectomy with pylorus preservation or with antrectomy
in the treatment of chronic pancreatitis. Ann Surg 2000; 231(3): 293–300.
10 Laparoscopy in HPB surgery
Nicholas O’Rourke and Richard Bryant
introduction
Laparoscopy offers great advantages to the patient with HPB
disease. Although described in the early part of the 20th cen-
tury, crude instrumentation limited its use. Progress seemed
slow until the 1960s saw widespread uptake in the gynecologic
community, with the Hopkins rod lens system greatly improv-
ing the optics.
Sporadic reports of laparoscopic staging for HPB cancer
soon followed, but it was not until the handheld camera devel-
opment in the 1980s that the minimal access explosion began.
Now surgeons could view the image on a monitor, and use two
hands to operate instruments, while an assistant held the cam-
era. Even the gall bladder could be removed using tiny inci-
sions. The next 10 years saw almost every abdominal operation
attempted, such that the interest now is not in what can be
done, but in what should be done, and how best to do it.
laparoscopic cholecystectomy
Cholecystectomy was the first general surgical procedure to be
widely performed laparoscopically. Following the first reports
in 1985 and 1988 (1), the technique was rapidly popularized
(2–5). Despite a possible increase in the incidence of severe
bile duct injuries, the benefits of the laparoscopic approach
have subsequently been confirmed by meta-analysis (6), dem-
onstrating shorter hospital stay and faster convalescence with
no difference in operating time or complications.
There are various techniques in common usage, with the
surgeon standing either on the patient’s right or left or between
the legs, with the choice of technique depending on local
teaching and personal preference. There are, however, funda-
mental principles to safely performing a laparoscopic chole-
cystectomy.
Correct identification of the anatomy is fundamental. Most
bile duct injuries are due to misperception rather than techni-
cal errors (7). It is important to understand the normal varia-
tions in biliary anatomy and how pathological changes may
alter the relationships between the structures. The 30º tele-
scope permits better visualization of Calot’s triangle.
Hartmann’s pouch is retracted laterally and inferiorly so that
the angle between the cystic and common hepatic ducts is
increased rather than closed. Calot’s triangle is dissected high,
just beneath the edge of the gall bladder, on both its anterior
and posterior surfaces, to clearly identify the cystic duct and
cystic artery as the only structures passing to the gall bladder
(the “critical view” (8)). Dissection is never carried below the
plane of Rouvière’s sulcus (9).
Routine intraoperative cholangiography is recommended.
This has been shown to decrease the risk and severity of biliary
injury (10). It is essential that the full complement of upper
duct anatomy is visualized to be certain that the common bile
duct or an aberrant right hepatic duct is not being excised. It
also enables the identification of choledocholithiasis, which in
most cases can then be successfully managed during the same
laparoscopic procedure (11).
In the setting of acute cholecystitis, early laparoscopic chole-
cystectomy is preferred (12,13). The problem with a policy of
delayed laparoscopic cholecystectomy is that a significant pro-
portion of patients require an emergency cholecystectomy for
recurrent or nonresolving acute cholecystitis in the difficult
intermediate period with a higher rate of conversion. How-
ever, if symptoms have been present for more than a week or
there is a mass present without generalized peritonism then it
may be more prudent to manage the patient conservatively
with a view to a delayed cholecystectomy.
For mild gall stone pancreatitis, laparoscopic cholecystec-
tomy with intraoperative cholangiogram should be performed
during the same admission (14). A policy of interval cholecys-
tectomy incurs a real risk of recurrent pancreatitis (15–21).
Laparoscopic cholecystectomy has traditionally been per-
formed with an overnight stay, but appropriately selected
patients can be safely managed as a day case (22).
laparoscopic common bile duct exploration
Most common duct stones can be managed laparoscopically
(11,23–36). This allows treatment in one operation, rather
than endoscopic retrograde cholangiopancreatography
(ERCP) and sphincterotomy done as a separate procedure,
either before or after laparoscopic cholecystectomy. Obviously,
operative cholangiography, with fluoroscopy, and accurate
interpretation is mandatory. Techniques used, in order of
increasing complexity, are as follows:
● Transcystic flushing
● Transcystic stone extraction
● Choledochotomy
● Transampullary stenting
● Choledochoduodenostomy
Flushing
Small filling defects in the bile duct may be air bubbles, and
only the dynamic image of fluoroscopy may allow visible dis-
tortion or coalescence of these bubbles. Small stones low in the
bile duct may be flushed or pushed into the duodenum using
the cholangiogram catheter, with intravenous glucagon occa-
sionally helping by relaxing the sphincter.
Transcystic Stone Extraction
Formal duct exploration is performed, where possible (in
about two-thirds of cases), via a transcystic approach. We pre-
fer to use a purpose-built Nathanson CBD exploration cathe-
ter (Cook). This allows manipulation of a basket under
contrast-assisted fluoroscopy. The cystic duct is dissected
lower, close to the common bile duct. Balloon dilatation of the
89
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
cystic duct may occasionally be required. The stone to be
extracted must not be larger than this diameter. If so, the stone
may become stuck in the junction and require fragmentation
or, worse, incision to remove. Choledochotomy as a primary
procedure may be preferred for large or numerous stones.
When inserting the Nathanson transcystic catheter, one
must be careful that the basket is 1 to 2 cm inside the flexible
tip of the catheter, to avoid turning the device into a spear,
which can perforate the posterior aspect of the common duct.
Under fluoroscopic guidance, the wire basket is deployed in
the distal common bile duct, without traversing the ampulla.
Gentle “jiggling” of the basket entraps the stone, which can
then be retrieved by withdrawing the open basket. The stone
can “flip” out of the duct and land anywhere in the right abdo-
men, often too quickly to be seen (Figs. 10.1 and 10.2). The
characteristics of the basket employed are important. A four-
wire steel basket will spring open in the bile duct such that
with “jiggling” the stone is able to enter between the wires to
then be trapped in the apex as the open basket is withdrawn. A
softer nitonol basket will not tend to spring open in the same
fashion and it is therefore often difficult to ensnare the stone
under fluoroscopic guidance.
An alternative transcystic approach is with a flexible cho-
ledochoscope. A 3-mm scope is normally required, as a 5-mm
scope will only rarely pass trans-cystically. A grasper in the epi-
gastric port provides traction to the right. A long 5-mm trocar
in the right subcostal position is positioned against the cystic
duct incision to prevent bowing of the choledochoscope
within the abdomen. The choledochoscope is advanced into
the common bile duct and the stone retrieved under direct
vision. In these circumstances, a nitonol basket with a para-
chute arrangement at the apex is usually more effective as the
stone entrapment is performed under direct vision. Clearance
of the common bile duct can be confirmed by transcystic flex-
ible choledochoscopy; however it is often difficult transcysti-
cally to introduce the choledochoscope to the common hepatic
duct to confirm that there are no calculi above the cystic
duct junction.
Figure 10.1 Laparoscopic transcystic cholangiography demonstrating calcu-
lus in the distal common bile duct.
90
If the transcystic approach fails, then a decision must be
made between postoperative ERCP versus laparoscopic cho-
ledochotomy. A randomized controlled trial between these
two options, after failure of transycstic CBDE, did not demon-
strate any differences (27), and therefore the choice depends
on individual patient factors and local expertise. If the com-
mon bile duct is narrow (<7 mm) then a choledochotomy
should be avoided due to the risk of stricturing. Postoperative
ERCP can be facilitated by the passage of an antegrade biliary
stent (37).
Choledochotomy
In certain circumstances, a transcystic approach is unlikely to
be successful, and if the CBD is of sufficient diameter, then it is
reasonable to proceed straight to a laparoscopic choledochot-
omy. These circumstances include large stones (>10mm),
multiple stones (>3) or stones above the cystic duct
confluence.
To perform laparoscopic choledochotomy, the anterior sur-
face of the common bile duct is dissected just sufficiently to
confidently identify the anatomy. A 1.5-cm vertical incision is
made in the common bile duct below the cystic duct conflu-
ence. Filling of the duct system with saline via the transcystic
catheter distends the collapsed duct and helps prevent injury
to the posterior duct wall when the anterior wall is incised.
Another method is to gently lift up the anterior wall with a
suitable small atraumatic grasper (such as a “dolphin-nose”)
introduced via the right subcostal port. This will create a small
transverse ridge of the anterior duct wall, which can then be
cut using scissors introduced via the epigastric port, thus cre-
ating a vertical incision that can then be extended with the
scissors. A similar effect can also be created using stay sutures.
Initial flushing via the choledochotomy with the sucker-
aspirator and massaging of the duct may remove the stones. A
choledochoscope can be introduced, this time from the epi-
gastric port. A 3 or 5 mm flexible scope may be employed, or
even a rigid ureteroscope if the orientation is suitable. (On the
rare occasions that a rigid ureteroscope is required, it can
Figure 10.2 The calculus from Figure 10.1 after transcystic extraction utilizing
the Nathanson basket. Inset: completion cholangiography.
 LAPAROSCOPY IN HPB SURGERY
sometimes be introduced transcystically via the epigastric port
if the orientation is suitable.) With the choledochoscope, the
stones can be removed under direct vision, and the flexible
choledochoscope can be maneuvered into both the upper
ducts and lower CBD to confirm clearance of all calculi. On
rare occasions, hydraulic lithotripsy may be required to break
up impacted stones (27).
Where there is confidence about stone clearance and biliary
drainage, choledochotomy can be simply closed by
suturing (25). If there is any doubt about biliary drainage or
duct clearance, then choledochotomy should be closed after
passage of an antegrade biliary stent, or a T-tube inserted.
Choledochoduodenostomy
For the elderly patient with a suspected benign stricture, and a
reasonable stone load, laparoscopic choledochoduodenostomy
is a good option (23). As in open surgery, a common duct
diameter of greater than 10 mm is preferable. A continuous
absorbable suture is used, and the operation mimics the open
procedure with anastamosis of the choledochotomy to a longi-
tudinal opening in the duodenum.
pancreatic pseudocyst
Pancreatic pseudocysts can be managed endoscopically with
gastrotomy and stenting (perhaps the only current valid indi-
cation for NOTES [Natural Orifice Transabdominal Endo-
scopic Surgery]). Pancreatic pseudocysts can also be drained
internally via a laparoscopic approach (38–46). Most com-
monly the pseudocyst is located in the lesser sac and the appro-
priate procedure is a cyst-gastrostomy. An anterior gastrotomy
is made. The cyst can be seen bulging forward, adherent to the
posterior stomach wall, which is incised with diathermy or the
harmonic scalpel to enter the cyst. Cyst fluid will come flowing
out under pressure at this point, and is important to have an
instrument ready to pass into the cyst so that the point of
communication is not lost. The cyst fluid is aspirated with the
sucker and the cyst emptied. A linear stapler is then intro-
duced into the small cyst-gastrotomy to create a wide cyst-
gastrostomy, and the residual unstapled edges are sutured
together. The pseudocyst can be entered with the laparoscope
and inspected, and any debris removed. The anterior gastro-
tomy is then closed with sutures or a stapling device. In some
cases, the position of the pseudocyst will require a side-to-side
cyst-gastrostomy or Roux-en-Y cyst-enterostomy.
Published reports suggest that laparoscopic cyst-gastrostomy
has a higher initial success rate and lower recurrence rate than
endoscopic cyst-gastrostomy (42,47). As the cyst-gastrostomy
created via the endoscopic approach is only small, any large
debris is unable to exit the cyst. However, endoscopic
approaches can be improved with using balloon dilatation and
multiple stents to maintain better drainage, endoscopic ultra-
sound to guide the procedure and avoid vessels (48,49), and
with the development of stapling instrumentation for natural
orifice surgery (50).
laparoscopic staging
A proportion of patients with hepatobiliary and pancreatic
malignancies will appear to be resectable on noninvasive
imaging studies, but be found to have locally advanced disease
or small liver or peritoneal metastases (imaging-occult metas-
tases) that render the disease inoperable (Fig. 10.3). Staging
laparoscopy can identify these patients and therefore spare the
patient a laparotomy. Staging laparoscopy in its simplest form
involves visual inspection of the peritoneal and liver surfaces,
but may also include laparoscopic ultrasound, trial dissection,
or peritoneal washing for cytology.
Staging laparoscopy is preferable to a nontherapeutic lapa-
rotomy to identify unresectability. The hospital stay is shorter
(51,52), and the patient is able to start chemotherapy
sooner (53). The risks of a staging laparoscopy are low, with
morbidity reported at 0% to 4% and mortality 0% to
0.15% (54). Port-site recurrences are uncommon, between 0%
and 2% (54), and usually occur in patients with extensive peri-
toneal carcinomatosis. Staging laparoscopy may be performed
as a prelude to resection in the same procedure or as a separate
procedure prior to planned resection—there can be significant
scheduling issues depending on the institution if an aborted
procedure means allocated theater time is unable to be utilized.
The yield of staging laparoscopy depends on many factors.
The type and stage of the malignancy affects the likely pres-
ence of imaging-occult metastases, as does the quality and
type of the imaging performed. The extent of the staging pro-
cedure is also important—whether laparoscopic ultrasound,
peritoneal washings or trial dissection is included. It is also
obviously influenced by what findings are considered to con-
traindicate resection; for example, localized peritoneal disease
or porta hepatis nodes for colorectal liver metastases, or
involvement of the portal vein requiring vein resection and
grafting in pancreas cancer may not be considered contraindi-
cations to resection. The value of a positive staging laparos-
copy also depends on whether any required palliative
procedures, such as biliary or gastric bypass in carcinoma of
the head of the pancreas, can be performed laparoscopically.
In adenocarcinoma of the pancreas, after high-quality CT
scanning, staging laparoscopy has been shown to identify
Figure 10.3 Peritoneal metastases at staging laparoscopy and carcinoma of the
head of the pancreas.
91
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
unresectability in 15% to 51% of patients, and spare 10% to
31% of patients an unnecessary laparotomy (51,55–61). Lapa-
roscopic ultrasound has been shown to add information in
12% to 14% of patients (62–64). Patients with tumors larger
than 3 cm are more likely to have unsuspected metastases at
exploration (65), as are patients with a Ca 19.9 level greater
than 150 kU/L (66,67). Positive peritoneal lavage has been
found in 3% to 51% of patients (57,68–76), and is more likely
in locally advanced or metastatic tumors (77), larger tumors,
and tumors of the body or tail (70,78). Positive peritoneal
cytology, which has the same prognosis as metastatic
disease (79), is the only marker of unresectability in 1% to
14% of patients (57,69,70,76). Tumors of the body and tail of
the pancreas are twice as likely as pancreatic head lesions to
have imaging-occult metastases (57,69). Imaging-occult
metastases are uncommon in nonpancreatic periampullary
tumors (60,80,81) and routine laparoscopy in these patients is
probably not indicated. Patients who on imaging have locally
advanced, unresectable pancreatic cancer should also be con-
sidered for staging laparoscopy, as those without metastatic
disease can be considered for chemoradiotherapy regimens
aimed at local control or even downstaging followed by resec-
tion, regimens which would incur unnecessary treatment-
related morbidity for those with metastatic disease (69,77,82).
In colorectal liver metastases, laparoscopy will identify unre-
sectable disease in 10% to 38% of patients, with a sensitivity of
39% to 75% (83–90). Laparoscopy is more likely to be positive
in patients with a higher clinical risk score (83,86,91). In non-
colorectal, nonneuroendocrine liver metastases, laparoscopy
has been reported to identify unresectable disease in 25% of
patients, with a sensitivity of 66% (92).
Staging laparoscopy is useful for patients with primary bili-
ary malignancies. For patients with suspected resectable gall
bladder carcinoma on imaging, the yield for detecting unre-
sectable disease is 56% to 62% (93,94), though the yield is less
for intrahepatic cholangiocarcinoma (93) at 36% and hilar
cholangiocarcinoma (93–95) at 25%. The yield for hilar chol-
angiocarcinomas is higher for T2 or T3 lesions than for T1
lesions (94) (36% vs. 9%).
In hepatocellular carcinoma that is considered suitable for
curative resection, peritoneal dissemination is uncommon,
and standard laparoscopy is unlikely to add much informa-
tion. Laparoscopy with laparoscopic ultrasound, however, can
identify the extent of the primary tumor, additional imaging-
occult tumors, portal or hepatic venous tumor thrombus or an
inadequate hepatic remnant, with a yield for unresectability of
10% to 36% and a sensitivity of 63% to 96% (96–100). The
results obtained will depend on the type and quality of preop-
erative imaging and the level of experience with laparoscopic
ultrasound.
laparoscopic palliative bypass
In patients with inoperable periampullary tumors, there is
often biliary and/or gastric obstruction that requires relief.
The traditional teaching in open surgery was to perform both
a biliary and gastric bypass whether or not the patient was
symptomatic. If at laparoscopy the tumor is found to be unre-
sectable, in the absence of actual or impending biliary or
92
gastric outlet obstruction, it is not necessary to perform a pal-
liative biliary or gastric bypass (101). In many instances, the
endoscopic approach is effective to relieve obstruction. Duo-
denal stenting is safer and provides a better quality of life than
laparoscopic gastrojejunostomy in the short term (102),
although laparoscopic gastrojejunostomy may provide a more
durable result for patients with a longer life expectancy (103).
ERCP with placement of a plastic biliary stent has a lower
morbidity than traditional open surgical bypass, although
plastic biliary stents have a tendency to occlude, resulting in
recurrent biliary obstruction requiring a repeat procedure
(104). Metallic stents, however, have a much higher patency
rate in the longer term, and can serve many patients for the
remainder of their survival (104–106).
In some cases, however, stenting fails for technical reasons or
due to inability to access the ampulla. In these cases, a laparo-
scopic bypass is a useful option (107–116), with the potential
for lower morbidity and shorter hospital stay than an open sur-
gical procedure (113,115). A laparoscopic biliary bypass is most
easily performed as a stapled or sutured side-to-side cholecys-
tojejunostomy. The main limitation of this approach is that the
confluence of the cystic and common hepatic ducts must
be well above the tumor to prevent recurrent biliary
obstruction (117). This can be confirmed at the procedure by
cholangiography via the fundus of the Gall bladder—a Verres
needle with large syringe attached is used to empty the gall
bladder of bile, which is then filled with contrast to confirm
that the cystic duct confluence is more than 1 cm above the
level of the tumor. If this is not the case, an hepaticojejunos-
tomy is constructed. A gastrojejunostomy is typically fashioned
in an antecolic, isoperistaltic stapled side-to-side manner.
laparoscopic pancreatectomy
Distal pancreatectomy is well suited to a laparoscopic approach.
The usual indication is a solid or cystic tumor of the tail of the
pancreas that is not clearly benign on preoperative imaging.
The procedure may involve en-bloc resection of the spleen and
splenic vessels; preservation of the spleen with preservation of
the splenic vessels; or preservation of the spleen without pres-
ervation of the splenic vessels with the spleen supplied from
the short gastric and gastroepiploic vessels (the Warshaw tech-
nique (118)).
For lesions close to the spleen, when splenectomy is neces-
sary, the approach can be similar to laparoscopic splenectomy,
with the patient left side up, and the spleen and distal pancreas
mobilized from lateral to medial. After division of the short
gastric vessels and the gastrocolic omentum, the pancreas
can be divided en bloc with the splenic vessels using a
linear stapler.
For a medial to lateral approach, the pancreatic neck is
divided, either with a stapling device or with the harmonic
scalpel with subsequent suture closure of the pancreatic
stump. Where the splenic vessels are being resected, the
splenic vein is divided with a stapling device and the splenic
artery divided with a stapling device or locking clips. If the
splenic vessels are to be preserved, then the tail of the pan-
creas is dissected carefully from them with control of the
small vessels with clips and/or the harmonic scalpel or
 LAPAROSCOPY IN HPB SURGERY
electrosurgical sealing device. Otherwise the dissection con-
tinues in the relatively avascular plane behind the splenic
vein. At this point, if the spleen is to be preserved with the
Warshaw technique, then the splenic hilum is divided with a
stapling device taking care to preserve the short gastric ves-
sels, and the gastroepiploic arcade. Otherwise if the spleen is
to be resected, the dissection continues in this plane behind
the splenic vein to complete the mobilization of the spleen
and complete the resection. The specimen is retrieved in a bag
and a closed suction drain is placed.
Laparoscopic distal pancreatectomy has been shown to be a
safe procedure, with a shorter hospital stay and overall mor-
bidity that is less than the open procedure (119–124). The
main complication is a pancreatic fistula occurring in about
15% of patients, though this occurs at no greater rate than
with an open resection (120,124). The application of fibrin
glue to the stump (125) and the use of staple line mesh rein-
forcement (126) have both shown some benefit in small stud-
ies in reducing this rate, and in open surgery the placement of
a transampullary stent (127) has shown some benefit, as has
identification and direct suture of the main pancreatic
duct (128), although the optimal management of the pancre-
atic stump is still to be determined. Preservation of the spleen
by the Warshaw technique can be complicated by infarction of
the lower pole of the spleen (129,130).
Laparoscopic central pancreatectomy has been reported in
the literature (131) and successfully been performed twice by
one of the authors. The indication of a central tumor where
diabetes is a risk postoperatively is not common.
Laparoscopic enucleation of insulinomas has been reported
in small series but is associated with a significant rate of pan-
creatic fistula (129,132,133). Intraoperative ultrasound is
essential to ensure that the main pancreatic duct is not close to
the resection line.
Laparoscopic pancreaticoduodenectomy has been reported
in small numbers (134–137). The procedure is feasible but
prolonged and difficult, and the potential role for this proce-
dure remains to be determined.
laparoscopic liver resection
The laparoscopic approach to liver resections presents certain
technical challenges. It is a heavy solid organ that can be cum-
bersome to mobilize and manipulate, parenchymal transec-
tion requires the identification and control of large vessels
with the potential for significant bleeding, and the paucity of
external anatomical markers can make the maintenance of
surgical orientation to ensure a satisfactory oncologic clear-
ance difficult.
Laparoscopic liver resection was initially reported in 1995 by
Rau (138), Cuesta (139), and Hashizume (140). Anatomic
resections in the form of left lateral sectionectomy were
reported in 1996 by Azagra (141) and Kaneko (142), formal
hemihepatectomies were reported in 1998 by Huscher (143),
and Cherqui (144) reported the first significant series of
30 patients in 2000. The largest series were recently reported
by Koffron (145) and Buell (146).
Dr. Joe Buell organized the first international consensus
meeting on laparoscopic liver resection, held in Louisville,
Kentucky in November 2008. Agreed definitions of laparo-
scopic liver surgery include the following:
● Pure laparoscopic: where the liver resection is com-
pleted laparoscopically and the specimen removed
via a remote incision;
● Hand assisted: where the surgeon operates with his
nondominant hand inside the abdomen, placed via
an airtight device, through which the specimen is
removed;
● Hybrid liver resection (145): where the liver is mobi-
lized laparoscopically and most of the resection is
done through a smaller than usual right upper quad-
rant incision;
● Conversion: where the surgeon changes to an open
operation from one of the above. One can also con-
vert from pure laparoscopic to hand assist or hybrid.
The most suitable cases for a laparoscopic approach are soli-
tary small (<5 cm) lesions located in the peripheral segments
(2–6) of the liver. Larger lesions are acceptable if they are
pedunculated or located in the left lateral section. Multiple
lesions may be suitable if they can be resected with a single ana-
tomic hepatectomy with a clear margin, but not where multiple
complicated or bilobar procedures are required. Hemihepatec-
tomies can be considered for a laparoscopic approach where
the plane of transection and major structures (pedicles, hepatic
veins and inferior vena cava) are well clear of any lesions.
Lesions located in segments 7 and 8 are difficult to approach
laparoscopically for a tumorectomy as the costal margin limits
the approach angles of the instruments, and there is a real risk
of compromising the deep margin for fear of causing difficult-
to-control bleeding—they should only be considered for a
laparoscopic tumorectomy if they are particularly small and
superficial, otherwise they need to be considered for an open
procedure or a laparoscopic right hemihepatectomy.
The procedures are usually performed in the supine posi-
tion, often with the surgeon standing between the legs. The
left lateral decubitus position is useful for lesions in segments
6 and 7, which enables better exposure of the right posterior
section of the liver. Hand ports may be used. These are most
useful in right sided resections where mobilization is diffi-
cult, either in nonanatomical resections with a posterior
tumor in the right lobe, or right hemihepatectomies with a
bulky right lobe. Good quality laparoscopic equipment is
vital. A good 10-mm laparoscopic right angle is also a very
important tool.
An initial laparoscopy is performed, and laparoscopic ultra-
sound is used to identify the lesions and their relationships to
the appropriate anatomy (Fig. 10.4). A tape can be placed
around the hepatic pedicle in readiness for a Pringle maneuver
if required; this is usually reserved for situations where bleed-
ing is encountered rather than used routinely, and uses an
intermittent protocol (as the time of transection tends to be
longer than in open surgery). The gall bladder is resected
where indicated, but after division of the cystic duct and artery,
it may be left attached to the liver until later in the procedure
to help maneuver the liver, such that the gall bladder and
round ligament become the two “handles of the liver.” It is a
93
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 10.4 Laparoscopic ultrasound used to mark out resection line for a
tumor in segment 6.
useful point to divide the round ligament flush with the ante-
rior abdominal wall such that there is not dangling tissue
irritatingly obstructing the view and dirtying the camera
through the whole procedure.
There are many methods of parenchymal transection: har-
monic scalpel (Ethicon), Ligasure device (Covidien), Gyrus
(Gyrus ACMI), CUSA (Integra), TissueLink (Salient Surgical
Technologies), stapling devices, water jet, and metal clips. Each
have their advantages and disadvantages, and used appropri-
ately each can have their place. Personal preference and experi-
ence as well as local teaching and availability determine the
choice. The various energy-delivery devices will not control
the large venous structures; these must be identified intrapa-
renchymally and controlled with clips or stapling devices. It is
also prudent to individually control the large pedicular
branches. Stapling devices can be used en-masse across por-
tions of the parenchyma to control the larger structures within,
but a degree of finesse is lost and unexpected bleeding can be
encountered. The combination of the harmonic scalpel for the
superficial 2 cm of dissection with the CUSA for the deeper
dissection is a good technique (147). A good alternative is the
Ligasure device, which when used with a modified technique
(closing while activating, using the cutting blade sparingly,
with gentle saline irrigation to prevent charring) can be used
to dissect out the larger intraparenchymal structures (148).
Left lateral sectionectomy begins with mobilization of the
falciform ligament, left coronary ligament, and lesser omen-
tum to mobilize the left lobe. The parenchyma is divided so as
to expose the upper surface of the segments 2 and 3 pedicles
intrahepatically. The pedicles are then divided with a stapler.
The parenchymal transection is then completed to expose the
left hepatic vein intrahepatically, which is divided with a sta-
pler. An alternative to this technique is mass stapling of the left
lateral section (149,150). Left lateral sectionectomy is particu-
larly suitable to a laparoscopic approach and arguments have
been made that the laparoscopic approach should be used rou-
tinely for this resection (149,151).
94
Figure 10.5 Laparoscopic dissection of the right portal vein. The right hepatic
artery has been divided. The cystic duct has been divided and is used to retract
the bile duct. The right portal vein has been looped. The left portal vein is
clearly demonstrated and the right portal vein can be seen dividing into its
anterior and posterior branches.
For a left hepatectomy, the left liver is mobilized as above.
The left hepatic artery and left portal vein are dissected extra-
hepatically, demonstrating the line of demarcation. The paren-
chymal transection is then begun, opening the liver to allow a
good exposure of the left pedicle and sufficient space to intro-
duce a stapling device to divide the left bile duct. The paren-
chymal transection is then continued, exposing the left hepatic
vein intrahepatically, which is divided with a stapling device to
complete the transection.
A right hepatectomy can be performed either with an ante-
rior or a traditional approach. An anterior approach begins
with an extrahepatic dissection and division of the right
hepatic artery and right portal vein (Fig. 10.5). The parenchy-
mal transection is then begun, opening the liver to allow an
intrahepatic division of the right bile duct. The parenchymal
transection is then completed down to the anterior surface of
the inferior vena cava. The minor hepatic veins are then
divided between clips, followed by the right hepatic vein and
hepatocaval ligament with stapling devices. The final step is
mobilization of the liver and division of the right coronary
ligament. In the traditional approach, there is the same extra-
hepatic division of the right hepatic artery and right portal
vein, with full mobilization of the liver and division of the
hepatocaval ligament and right hepatic vein before transection
of the parenchyma (Fig. 10.6). Laparoscopic right hepatec-
tomy is a difficult procedure that requires expertise in both
laparoscopic and hepatic surgery.
The specimen is removed intact in a bag, either through the
hand port incision, a previous appendicectomy scar, or a
Pfannenstiel incision. After this period of desufflation, the
extraction incision is closed to allow re-establishment of the
pneumoperitoneum to confirm hemostasis, as bleeding may
have been tamponaded by the pressure of the pneumoperito-
neum. In any type of laparoscopic liver resection, significant
 LAPAROSCOPY IN HPB SURGERY
Figure 10.6 Mobilization of the right liver from the inferior vena cava.
bleeding can be encountered, and the surgeon must have the
requisite laparoscopic skills to be able to control this situation.
Good skills in laparoscopic suturing are essential. Conversion
to laparotomy may certainly be required, but immediate con-
version is not always the best response. Venous bleeding is
often partly tamponaded by the pneumoperitoneum. The
bleeding source is identified and controlled with a grasper, and
hemostasis is achieved with suturing or a clip as appropriate. If
initial maneuvers are not successful then conversion is required
without persisting for too long or worsening the bleeding.
These are potentially dangerous situations that require both
skill and judgment.
Assessment of laparoscopic liver resection has been based
on series (144,147–149,151–173) and retrospective compara-
tive studies (145,174–185). These reports from expert centers
demonstrate that laparoscopic liver resection can be per-
formed safely, and that despite a longer operating time there
is the potential for reduced hospital stay and reduced bleed-
ing. Despite initial concerns, CO2 embolus occurs uncom-
monly. The oncologic results in nonrandomized studies have
been good (145,158,174–177,180), but care must be taken in
interpreting these series, as those patients undergoing laparo-
scopic resection have been selected with smaller and fewer
tumors that would normally also infer a better prognosis.
There is a potential benefit in cirrhotic patients, with a lower
incidence of ascites postoperatively (147,176), as well as fewer
adhesions that facilitate subsequent transplantation (186).
conclusion
Laparoscopic approaches for the simplest of HPB procedures,
cholecystectomy, have literally exploded around the world.
More complex operations have been reported in small series,
but have not been taken up with the same enthusiasm. As tech-
nology improves, and the skill set of surgeons increases, it
seems inevitable to us that more and more will be done. As
long as basic oncologic principles are adhered to, and the sur-
gical maxim of conversion if concerned is followed, patients
will continue to benefit from this exciting surgery.
references
1. Reynolds W. The first laparoscopic cholecystectomy. J Soc Laparoen-
dosc Surgeons 2001; 5(1): 89–94.
2. Dubois F, Berthelot G, Levard H. Laparoscopic cholecystectomy: his-
toric perspective and personal experience. Surgical Laparosc Endosc
1991; 1(1): 52–7.
3. Schirmer BD, Edge SB, Dix J, et al. Laparoscopic cholecystectomy. Treat-
ment of choice for symptomatic cholelithiasis. Ann Surg 1991; 213(6):
665–76; discussion 677.
4. Bailey RW, Zucker KA, Flowers JL, et al. Laparoscopic cholecystectomy.
Experience with 375 consecutive patients. Ann Surg 1991; 214(4): 531–
40; discussion 540–1.
5. Fielding GA. Laparoscopic cholecystectomy. Aust NZ J Surg 1992; 62(3):
181–7.
6. Keus F, de Jong JAF, Gooszen HG, van Laarhoven CJHM. Laparoscopic
versus open cholecystectomy for patients with symptomatic cholecysto-
lithiasis. Cochrane Database of Systematic Reviews (Online). 2006; (4):
CD006231.
7. Way LW, Stewart L, Gantert W, et al. Causes and prevention of laparo-
scopic bile duct injuries: analysis of 252 cases from a human factors and
cognitive psychology perspective. Ann Surg 2003; 237(4): 460–9.
8. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary
injury during laparoscopic cholecystectomy. J Am Coll Surg 1995;
180(1): 101–25.
9. Hugh TB, Kelly MD, Mekisic A. Rouvière’s sulcus: a useful landmark in
laparoscopic cholecystectomy. Br J Surg 1997; 84(9): 1253–4.
10. Fletcher DR, Hobbs MS, Tan P, et al. Complications of cholecystectomy:
risks of the laparoscopic approach and protective effects of operative
cholangiography: a population-based study. Ann Surg 1999; 229(4):
449–57.
11. Rhodes M, Nathanson L, O’Rourke N, Fielding G. Laparoscopic explo-
ration of the common bile duct: lessons learned from 129 consecutive
cases. Br J Surg 1995; 82(5): 666–8.
12. O’Rourke NA, Fielding GA. Laparoscopic cholecystectomy for acute
cholecystitis. Aust NZ J Surg 1992; 62(12): 944–6.
13. Gurusamy KS, Samraj K. Early versus delayed laparoscopic cholecystec-
tomy for acute cholecystitis. Cochrane Database of Systematic Reviews
(Online). 2006; (4): CD005440.
14. UK guidelines for the management of acute pancreatitis. Gut 2005; 54
Suppl 3: iii1–9.
15. Cameron DR, Goodman AJ. Delayed cholecystectomy for gallstone
pancreatitis: re-admissions and outcomes. Ann Royal Coll Surgeons
Engl 2004; 86(5): 358–62.
16. Cheruvu CVN, Eyre-Brook IA. Consequences of prolonged wait before
gallbladder surgery. Ann Royal Coll Surgeons Engl 2002; 84(1): 20–2.
17. DeIorio AV, Vitale GC, Reynolds M, Larson GM. Acute biliary pancre-
atitis. The roles of laparoscopic cholecystectomy and endoscopic retro-
grade cholangiopancreatography. Surg Endosc 1995; 9(4): 392–6.
18. Frei GJ, Frei VT, Thirlby RC, McClelland RN. Biliary pancreatitis:
clinical presentation and surgical management. Am J Surg 1986;
151(1): 170–5.
19. Ong S, Christie PM, Windsor JA. Management of gallstone pancreatitis
in Auckland: progress and compliance. ANZ J Surg 2003; 73(4): 194–9.
20. Ranson JH. The timing of biliary surgery in acute pancreatitis. Ann Surg
1979; 189(5): 654–63.
21. Sargen K, Kingsnorth AN. Management of gallstone pancreatitis: effects
of deviation from clinical guidelines. J Pancreas 2001; 2(5): 317–22.
22. Gurusamy K, Junnarkar S, Farouk M, Davidson BR. Meta-analysis of
randomized controlled trials on the safety and effectiveness of day-case
laparoscopic cholecystectomy. Br J Surg 2008; 95(2): 161–8.
23. Campbell-Lloyd AJM, Martin DJ, Martin IJ. Long-term outcomes after
laparoscopic bile duct exploration: a 5-year follow up of 150 consecu-
tive patients. ANZ J Surg 2008; 78(6): 492–4.
24. Fielding GA, O’Rourke NA. Laparoscopic common bile duct explora-
tion. Aust NZ J Surg 1993; 63(2): 113–5.
25. Martin IJ, Bailey IS, Rhodes M, et al. Towards T-tube free laparoscopic
bile duct exploration: a methodologic evolution during 300 consecutive
procedures. Ann Surg 1998; 228(1): 29–34.
95
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
26. Millat B, Atger J, Deleuze A, et al. Laparoscopic treatment for choledo-
cholithiasis: a prospective evaluation in 247 consecutive unselected
patients. Hepato-Gastroenterology 1997; 44(13): 28–34.
27. Nathanson LK, O’Rourke NA, Martin IJ, et al. Postoperative ERCP ver-
sus laparoscopic choledochotomy for clearance of selected bile duct
calculi: a randomized trial. Ann Surg 2005; 242(2): 188–92.
28. Paganini AM, Lezoche E. Follow-up of 161 unselected consecutive
patients treated laparoscopically for common bile duct stones. Surg
Endosc 1998; 12(1): 23–9.
29. Paganini AM, Guerrieri M, Sarnari J, et al. Thirteen years’ experience
with laparoscopic transcystic common bile duct exploration for stones.
Effectiveness and long-term results. Surg Endosc 2007; 21(1): 34–40.
30. Petelin JB. Laparoscopic common bile duct exploration. Surg Endosc
2003; 17(11): 1705–15.
31. Rhodes M, Sussman L, Cohen L, Lewis MP. Randomised trial of laparo-
scopic exploration of common bile duct versus postoperative endo-
scopic retrograde cholangiography for common bile duct stones. Lancet
1998; 351(9097): 159–61.
32. Rojas-Ortega S, Arizpe-Bravo D, Marín López ER, et al. Transcystic
common bile duct exploration in the management of patients with cho-
ledocholithiasis. J Gastrointest Surg 2003; 7(4): 492–6.
33. Taylor CJ, Kong J, Ghusn M, et al. Laparoscopic bile duct exploration:
results of 160 consecutive cases with 2-year follow up. ANZ J Surg 2007;
77(6): 440–5.
34. Tokumura H, Umezawa A, Cao H, et al. Laparoscopic management of
common bile duct stones: transcystic approach and choledochotomy. J
Hepat Biliary Pancreatic Surg 2002; 9(2): 206–12.
35. Topal B, Aerts R, Penninckx F. Laparoscopic common bile duct stone
clearance with flexible choledochoscopy. Surg Endosc 2007; 21(12):
2317–21.
36. Tranter SE, Thompson MH. Comparison of endoscopic sphincterot-
omy and laparoscopic exploration of the common bile duct. Br J Surg
2002; 89(12): 1495–504.
37. Martin CJ, Cox MR, Vaccaro L. Laparoscopic transcystic bile duct stent-
ing in the management of common bile duct stones. ANZ J Surg 2002;
72(4): 258–64.
38. Barragan B, Love L, Wachtel M, Griswold JA, Frezza EE. A comparison
of anterior and posterior approaches for the surgical treatment of pan-
creatic pseudocyst using laparoscopic cystogastrostomy. J Laparoendosc
Adv Surg Tech Part A 2005; 15(6): 596–600.
39. Dávila-Cervantes A, Gómez F, Chan C, et al. Laparoscopic drainage of
pancreatic pseudocysts. Surg Endosc 2004; 18(10): 1420–6.
40. Hindmarsh A, Lewis MPN, Rhodes M. Stapled laparoscopic cystgastros-
tomy: a series with 15 cases. Surg Endosc 2005; 19(1): 143–7.
41. Makris KI, St Peter SD, Tsao K, Ostlie DJ. Laparoscopic intragastric sta-
pled cystgastrostomy of pancreatic pseudocyst in a child. J Laparoen-
dosc Adv Surg Tech Part A 2008; 18(5): 771–3.
42. Melman L, Azar R, Beddow K, et al. Primary and overall success rates for
clinical outcomes after laparoscopic, endoscopic, and open pancreatic
cystgastrostomy for pancreatic pseudocysts. Surg Endosc [Internet].
2008 November 27 [cited 2009 January 11]. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/19037696
43. Mori T, Abe N, Sugiyama M, Atomi Y. Laparoscopic pancreatic cystgas-
trostomy. J Hepat Biliary Pancreatic Surg 2002; 9(5): 548–54.
44. Obermeyer RJ, Fisher WE, Salameh JR, Jeyapalan M, Sweeney JF,
Brunicardi FC. Laparoscopic pancreatic cystogastrostomy. Surg
Laparosc Endosc Percutaneous Tech 2003; 13(4): 250–3.
45. Palanivelu C, Senthilkumar K, Madhankumar MV, et al. Management
of pancreatic pseudocyst in the era of laparoscopic surgery—experience
from a tertiary centre. Surg Endosc 2007; 21(12): 2262–7.
46. Teixeira J, Gibbs KE, Vaimakis S, Rezayat C. Laparoscopic Roux-en-Y
pancreatic cyst-jejunostomy. Surg Endosc 2003; 17(12): 1910–3.
47. Aljarabah M, Ammori BJ. Laparoscopic and endoscopic approaches for
drainage of pancreatic pseudocysts: a systematic review of published
series. Surg Endosc 2007; 21(11): 1936–44.
48. Fockens P, Johnson TG, van Dullemen HM, Huibregtse K, Tytgat
GN. Endosonographic imaging of pancreatic pseudocysts before
endoscopic transmural drainage. Gastrointest Endosc 1997; 46(5):
412–6.
96
49. Krüger M, Schneider AS, Manns MP, Meier PN. Endoscopic manage-
ment of pancreatic pseudocysts or abscesses after an EUS-guided 1-step
procedure for initial access. Gastrointest Endosc 2006; 63(3): 409–16.
50. Romanelli JR, Desilets DJ, Earle DB. Pancreatic pseudocystgastrostomy
with a peroral, flexible stapler: human natural orifice transluminal
endoscopic surgery anastomoses in 2 patients (with videos). Gastroin-
test Endosc 2008; 68(5): 981–7.
51. Conlon KC, Dougherty E, Klimstra DS, et al. The value of minimal
access surgery in the staging of patients with potentially resectable peri-
pancreatic malignancy. Ann Surg 1996; 223(2): 134–40.
52. Holzman MD, Reintgen KL, Tyler DS, Pappas TN. The role of laparos-
copy in the management of suspected pancreatic and periampullary
malignancies. J Gastrointest Surg 1997; 1(3): 236–43; discussion 243–4.
53. Velanovich V, Wollner I, Ajlouni M. Staging laparoscopy promotes
increased utilization of postoperative therapy for unresectable intra-
abdominal malignancies. J Gastrointest Surg 2000; 4(5): 542–6.
54. Stefanidis D, Grove KD, Schwesinger WH, Thomas CR. The current role
of staging laparoscopy for adenocarcinoma of the pancreas: a review.
Ann Oncol 2006; 17(2): 189–99.
55. Pietrabissa A, Caramella D, Di Candio G, et al. Laparoscopy and laparo-
scopic ultrasonography for staging pancreatic cancer: critical appraisal.
World J Surg 1999; 23(10): 998–1002; discussion 1003.
56. Velasco JM, Rossi H, Hieken TJ, Fernandez M. Laparoscopic ultrasound
enhances diagnostic laparoscopy in the staging of intra-abdominal neo-
plasms. Am Surg 2000; 66(4): 407–11.
57. Jimenez RE, Warshaw AL, Rattner DW, et al. Impact of laparoscopic
staging in the treatment of pancreatic cancer. Arch Surg 2000; 135(4):
409–14; discussion 414–5.
58. Schachter PP, Avni Y, Shimonov M, et al. The impact of laparoscopy and
laparoscopic ultrasonography on the management of pancreatic cancer.
Arch Surg 2000; 135(11): 1303–7.
59. Menack MJ, Spitz JD, Arregui ME. Staging of pancreatic and ampullary
cancers for resectability using laparoscopy with laparoscopic ultra-
sound. Surg Endosc 2001; 15(10): 1129–34.
60. Vollmer CM, Drebin JA, Middleton WD, et al. Utility of staging laparos-
copy in subsets of peripancreatic and biliary malignancies. Ann Surg
2002; 235(1): 1–7.
61. Doran HE, Bosonnet L, Connor S, et al. Laparoscopy and laparoscopic
ultrasound in the evaluation of pancreatic and periampullary tumours.
Dig Surg 2004; 21(4): 305–13.
62. Minnard EA, Conlon KC, Hoos A, et al. Laparoscopic ultrasound
enhances standard laparoscopy in the staging of pancreatic cancer. Ann
Surg 1998; 228(2): 182–7.
63. Hünerbein M, Rau B, Hohenberger P, Schlag PM. [Value of laparoscopic
ultrasound for staging of gastrointestinal tumors]. Der Chirurg;
Zeitschrift Für Alle Gebiete Der Operativen Medizen. 2001; 72(8): 914–9.
64. Durup Scheel-Hincke J, Mortensen MB, Qvist N, Hovendal CP. TNM
staging and assessment of resectability of pancreatic cancer by laparo-
scopic ultrasonography. Surg Endosc 1999; 13(10): 967–71.
65. Morganti AG, Brizi MG, Macchia G, et al. The prognostic effect of
clinical staging in pancreatic adenocarcinoma. Ann Surg Oncol 2005;
12(2): 145–51.
66. Schlieman MG, Ho HS, Bold RJ. Utility of tumor markers in determin-
ing resectability of pancreatic cancer. Arch Surg 2003; 138(9): 951–5;
discussion 955–6.
67. Connor S, Bosonnet L, Alexakis N, et al. Serum CA19-9 measurement
increases the effectiveness of staging laparoscopy in patients with sus-
pected pancreatic malignancy. Dig Surg 2005; 22(1–2): 80–5.
68. Warshaw AL. Implications of peritoneal cytology for staging of early
pancreatic cancer. Am J Surg 1991; 161(1): 26–9; discussion 29–30.
69. Liu RC, Traverso LW. Diagnostic laparoscopy improves staging of pan-
creatic cancer deemed locally unresectable by computed tomography.
Surg Endosc 2005; 19(5): 638–42.
70. Jimenez RE, Warshaw AL, Fernandez-Del Castillo C. Laparoscopy and
peritoneal cytology in the staging of pancreatic cancer. J Hepat Biliary
Pancreatic Surg 2000; 7(1): 15–20.
71. Fernández-del Castillo CL, Warshaw AL. Pancreatic cancer. Laparoscopic
staging and peritoneal cytology. Surg Oncol Clin North Am. 1998; 7(1):
135–42.
 LAPAROSCOPY IN HPB SURGERY
72. Merchant NB, Conlon KC. Laparoscopic evaluation in pancreatic can-
cer. Semin Surg Oncol 1998; 15(3): 155–65.
73. Leach SD, Rose JA, Lowy AM, et al. Significance of peritoneal cytology
in patients with potentially resectable adenocarcinoma of the pancre-
atic head. Surgery 1995; 118(3): 472–8.
74. Makary MA, Warshaw AL, Centeno BA, et al. Implications of peritoneal
cytology for pancreatic cancer management. Arch Surg 1998; 133(4):
361–5.
75. Schmidt J, Fraunhofer S, Fleisch M, Zirngibl H. Is peritoneal cytology a
predictor of unresectability in pancreatic carcinoma? Hepat Gastroen-
terol 2004; 51(60): 1827–31.
76. Nieveen van Dijkum EJ, Sturm PD, de Wit LT, et al. Cytology of perito-
neal lavage performed during staging laparoscopy for gastrointestinal
malignancies: is it useful? Ann Surg 1998; 228(6): 728–33.
77. Liu RC, Traverso LW. Laparoscopic staging should be used routinely for
locally extensive cancer of the pancreatic head. J Gastrointest Surg 2004;
8(8): 923–4.
78. Burdiles P, Rossi RL. Laparoscopy in pancreatic and hepatobiliary can-
cer. Surg Onco Clin North Am 2001; 10(3): 531–55, viii.
79. American Joint Committee on Cancer, American Cancer Society, Amer-
ican College of Surgeons. AJCC Cancer Staging Manual, 5th ed. Phila-
delphia, PA: Lippincott-Raven, 1997: 294.
80. Barreiro CJ, Lillemoe KD, Koniaris LG, et al. Diagnostic laparoscopy for
periampullary and pancreatic cancer: what is the true benefit? J Gastro-
intest Surg 2002; 6(1): 75–81.
81. Brooks AD, Mallis MJ, Brennan MF, Conlon KCP. The value of laparos-
copy in the management of ampullary, duodenal, and distal bile duct
tumors. J Gastrointest Surg 2002; 6(2): 139–45; discussion 145–6.
82. Shoup M, Winston C, Brennan MF, Bassman D, Conlon KC. Is there a role
for staging laparoscopy in patients with locally advanced, unresectable
pancreatic adenocarcinoma? J Gastrointest Surg 2004; 8(8): 1068–71.
83. Grobmyer SR, Fong Y, D’Angelica M, et al. Diagnostic laparoscopy prior
to planned hepatic resection for colorectal metastases. Arch Surg 2004;
139(12): 1326–30.
84. Jarnagin WR, Conlon K, Bodniewicz J, et al. A clinical scoring system
predicts the yield of diagnostic laparoscopy in patients with potentially
resectable hepatic colorectal metastases. Cancer 2001; 91(6): 1121–8.
85. Khan AZ, Karanjia ND. The impact of staging laparoscopy prior to
hepatic resection for colorectal metastases. Eur J Surg Oncol 2007;
33(8): 1010–3.
86. Mann CD, Neal CP, Metcalfe MS, et al. Clinical Risk Score predicts yield
of staging laparoscopy in patients with colorectal liver metastases. Br J
Surg 2007; 94(7): 855–9.
87. Metcalfe MS, Close JS, Iswariah H, et al. The value of laparoscopic staging
for patients with colorectal metastases. Arch Surg 2003; 138(7): 770–2.
88. Pilkington SA, Rees M, Peppercorn D, John TG. Laparoscopic staging in
selected patients with colorectal liver metastases as a prelude to liver
resection. HPB 2007; 9(1): 58–63.
89. Rahusen FD, Cuesta MA, Borgstein PJ, et al. Selection of patients for
resection of colorectal metastases to the liver using diagnostic laparos-
copy and laparoscopic ultrasonography. Ann Surg 1999; 230(1): 31–7.
90. Thaler K, Kanneganti S, Khajanchee Y, et al. The evolving role of staging
laparoscopy in the treatment of colorectal hepatic metastasis. Arch Surg
2005; 140(8): 727–34.
91. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for
predicting recurrence after hepatic resection for metastatic colorectal
cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230(3): 309–
18; discussion 318–21.
92. D’Angelica M, Jarnagin W, Dematteo R, et al. Staging laparoscopy for
potentially resectable noncolorectal, nonneuroendocrine liver metasta-
ses. Ann Surg Oncol 2002; 9(2): 204–9.
93. Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparoscopy
in subsets of biliary cancers : laparoscopy is a powerful diagnostic tool
in patients with intrahepatic and gallbladder carcinoma. Surg Endosc
2006; 20(5): 721–5.
94. Weber SM, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR. Staging
laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of
100 patients. Ann Surg 2002; 235(3): 392–9.
95. Connor S, Barron E, Wigmore SJ, et al. The utility of laparoscopic
assessment in the preoperative staging of suspected hilar cholangiocar-
cinoma. J Gastrointest Surg 2005; 9(4): 476–80.
96. Lai ECH, Tang CN, Ha JPY, Tsui DKK, Li MKW. The evolving influence
of laparoscopy and laparoscopic ultrasonography on patients with
hepatocellular carcinoma. Am J Surg 2008; 196(5): 736–40.
97. Lang BHH, Poon RTP, Fan ST, Wong J. Influence of laparoscopy on post-
operative recurrence and survival in patients with ruptured hepatocellu-
lar carcinoma undergoing hepatic resection. Br J Surg 2004; 91(4): 444–9.
98. Lo CM, Lai EC, Liu CL, Fan ST, Wong J. Laparoscopy and laparoscopic
ultrasonography avoid exploratory laparotomy in patients with hepato-
cellular carcinoma. Ann Surg 1998; 227(4): 527–32.
99. Lo CM, Fan ST, Liu CL, et al. Determining resectability for hepatocel-
lular carcinoma: the role of laparoscopy and laparoscopic ultrasonogra-
phy. J Hepat Biliary Pancreatic Surg 2000; 7(3): 260–4.
100. Weitz J, D’Angelica M, Jarnagin W, et al. Selective use of diagnostic lap-
aroscopy prior to planned hepatectomy for patients with hepatocellular
carcinoma. Surgery 2004; 135(3): 273–81.
101. Espat NJ, Brennan MF, Conlon KC. Patients with laparoscopically
staged unresectable pancreatic adenocarcinoma do not require subse-
quent surgical biliary or gastric bypass. J Am Coll Surg 1999; 188(6):
649–55; discussion 655–7.
102. Mehta S, Hindmarsh A, Cheong E, et al. Prospective randomized trial of
laparoscopic gastrojejunostomy versus duodenal stenting for malignant
gastric outflow obstruction. Surg Endosc 2006; 20(2): 239–42.
103. Jeurnink SM, Steyerberg EW, Hof GV, et al. Gastrojejunostomy versus
stent placement in patients with malignant gastric outlet obstruction: a
comparison in 95 patients. J Surg Oncol 2007; 96(5): 389–96.
104. Moss AC, Morris E, Mac Mathuna P. Palliative biliary stents for obstruct-
ing pancreatic carcinoma. Cochrane Database of Systematic Reviews
(Online) 2006; (2): CD004200.
105. Davids PH, Groen AK, Rauws EA, Tytgat GN, Huibregtse K. Randomised
trial of self-expanding metal stents versus polyethylene stents for distal
malignant biliary obstruction. Lancet 1993; 340(8834–8835): 1488–92.
106. Weber A, Mittermeyer T, Wagenpfeil S, Schmid RM, Prinz C. Self-
expanding metal stents versus polyethylene stents for palliative
treatment in patients with advanced pancreatic cancer. Pancreas 2009;
38(1): e7–e12.
107. Casaccia M, Diviacco P, Molinello P, Danovaro L, Casaccia M. Laparo-
scopic palliation of unresectable pancreatic cancers: preliminary results.
Eur J Surg Acta Chirurg 1999; 165(6): 556–9.
108. Fletcher DR, Jones RM. Laparoscopic cholecystjejunostomy as pallia-
tion for obstructive jaundice in inoperable carcinoma of pancreas. Surg
Endosc 1992; 6(3): 147–9.
109. Kazanjian KK, Reber HA, Hines OJ. Laparoscopic gastrojejunostomy
for gastric outlet obstruction in pancreatic cancer. Am Surg 2004;
70(10): 910–3.
110. Khan AZ, Miles WFA, Singh KK. Initial experience with laparoscopic
bypass for upper gastrointestinal malignancy: a new option for pallia-
tion of patients with advanced upper gastrointestinal tumors. J Laparo-
endosc Adv Surg Techn Part A 2005; 15(4): 374–8.
111. Kuriansky J, Sáenz A, Astudillo E, Cardona V, Fernández-Cruz L. Simul-
taneous laparoscopic biliary and retrocolic gastric bypass in patients
with unresectable carcinoma of the pancreas. Surg Endosc 2000; 14(2):
179–81.
112. Nagy A, Brosseuk D, Hemming A, Scudamore C, Mamazza J. Laparo-
scopic gastroenterostomy for duodenal obstruction. Am J Surg 1995;
169(5): 539–42.
113. Navarra G, Musolino C, Venneri A, De Marco ML, Bartolotta M. Pallia-
tive antecolic isoperistaltic gastrojejunostomy: a randomized controlled
trial comparing open and laparoscopic approaches. Surg Endosc 2006;
20(12): 1831–4.
114. Rhodes M, Nathanson L, Fielding G. Laparoscopic biliary and gastric
bypass: a useful adjunct in the treatment of carcinoma of the pancreas.
Gut 1995; 36(5): 778–80.
115. Röthlin MA, Schöb O, Weber M. Laparoscopic gastro- and hepaticoje-
junostomy for palliation of pancreatic cancer: a case controlled study.
Surg Endosc 1999; 13(11): 1065–9.
97
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
116. Shimi S, Banting S, Cuschieri A. Laparoscopy in the management of
pancreatic cancer: endoscopic cholecystojejunostomy for advanced dis-
ease. Br J Surg 1992; 79(4): 317–9.
117. Tarnasky PR, England RE, Lail LM, Pappas TN, Cotton PB. Cystic duct
patency in malignant obstructive jaundice. An ERCP-based study rele-
vant to the role of laparoscopic cholecystojejunostomy. Ann Surg 1995;
221(3): 265–71.
118. Warshaw AL. Conservation of the spleen with distal pancreatectomy.
Arch Surg 1988; 123(5): 550–3.
119. Eom B, Jang J, Lee S, et al. Clinical outcomes compared between laparo-
scopic and open distal pancreatectomy. Surg Endosc [Internet] 2007
November 20 [cited 2009 January 3]. Available from: http://www.ncbi.
nlm.nih.gov/pubmed/18027035
120. Kooby DA, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a
multicenter comparison of laparoscopic and open approaches. Ann
Surg 2008; 248(3): 438–46.
121. Matsumoto T, Shibata K, Ohta M, et al. Laparoscopic distal pancreatec-
tomy and open distal pancreatectomy: a nonrandomized comparative
study. Surg Laparosc Endosc Percutaneous Techn 2008; 18(4): 340–3.
122. Nakamura Y, Uchida E, Aimoto T, et al. Clinical outcome of laparo-
scopic distal pancreatectomy. J Hepat Biliary Pancreatic Surg [Internet].
2008 December 16 [cited 2009 January 3]. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/19083146
123. Tang CN, Tsui KK, Ha JPY, Wong DCT, Li MKW. Laparoscopic distal
pancreatectomy: a comparative study. Hepat Gastroenterol 2007; 54(73):
265–71.
124. Velanovich V. Case-control comparison of laparoscopic versus open
distal pancreatectomy. J Gastrointest Surg 2006; 10(1): 95–8.
125. Velanovich V. The use of tissue sealant to prevent fistula formation after
laparoscopic distal pancreatectomy. Surg Endosc 2007; 21(7): 1222.
126. Thaker RI, Matthews BD, Linehan DC, et al. Absorbable mesh reinforce-
ment of a stapled pancreatic transection line reduces the leak rate with
distal pancreatectomy. J Gastrointest Surg 2007; 11(1): 59–65.
127. Fischer CP, Bass B, Fahy B, Aloia T. Transampullary pancreatic duct
stenting decreases pancreatic fistula rate following left pancreatectomy.
Hepat Gastroenterol 2008; 55(81): 244–8.
128. Bilimoria MM, Cormier JN, Mun Y, et al. Pancreatic leak after left pan-
createctomy is reduced following main pancreatic duct ligation. Br J
Surg 2003; 90(2): 190–6.
129. Fernández-Cruz L, Martínez I, Cesar-Borges G, et al. Laparoscopic surgery
in patients with sporadic and multiple insulinomas associated with mul-
tiple endocrine neoplasia type 1. J Gastrointest Surg 2005; 9(3): 381–8.
130. Taylor C, O’Rourke N, Nathanson L, et al. Laparoscopic distal pancreatec-
tomy: the Brisbane experience of forty-six cases. HPB 2008; 10(1): 38–42.
131. Sa Cunha A, Rault A, Beau C, Collet D, Masson B. Laparoscopic central
pancreatectomy: single institution experience of 6 patients. Surgery
2007; 142(3): 405–9.
132. Sweet MP, Izumisato Y, Way LW, et al. Laparoscopic enucleation of insu-
linomas. Arch Surg 2007; 142(12): 1202–4; discussion 1205.
133. Toniato A, Meduri F, Foletto M, Avogaro A, Pelizzo M. Laparoscopic
treatment of benign insulinomas localized in the body and tail of the
pancreas: a single-center experience. World J Surg 2006; 30(10): 1916–9;
discussion 1920–1.
134. Cuschieri SA, Jakimowicz JJ. Laparoscopic pancreatic resections. Semin
Laparosc Surg 1998; 5(3): 168–79.
135. Dulucq JL, Wintringer P, Stabilini C, et al. Are major laparoscopic pan-
creatic resections worthwhile? A prospective study of 32 patients in a
single institution. Surg Endosc 2005; 19(8): 1028–34.
136. Mabrut J, Fernandez-Cruz L, Azagra JS, et al. Laparoscopic pancreatic
resection: results of a multicenter European study of 127 patients. Sur-
gery 2005; 137(6): 597–605.
137. Sa Cunha A, Rault A, Beau C, et al. A single-institution prospective
study of laparoscopic pancreatic resection. Arch Surg 2008; 143(3):
289–95; discussion 295.
138. Rau HG, Meyer G, Cohnert TU, et al. Laparoscopic liver resection with
the water-jet dissector. Surg Endosc 1995; 9(9): 1009–12.
139. Cuesta MA, Meijer S, Paul MA, de Brauw LM. Limited laparoscopic liver
resection of benign tumors guided by laparoscopic ultrasonography:
report of two cases. Surg Laparosc Endosc 1995; 5(5): 396–401.
98
140. Hashizume M, Takenaka K, Yanaga K, et al. Laparoscopic hepatic resec-
tion for hepatocellular carcinoma. Surg Endosc 1995; 9(12): 1289–91.
141. Azagra JS, Goergen M, Gilbart E, Jacobs D. Laparoscopic anatomical
(hepatic) left lateral segmentectomy-technical aspects. Surg Endosc
1996; 10(7): 758–61.
142. Kaneko H, Takagi S, Shiba T. Laparoscopic partial hepatectomy and left
lateral segmentectomy: technique and results of a clinical series. Surgery
1996; 120(3): 468–75.
143. Hüscher CG, Lirici MM, Chiodini S. Laparoscopic liver resections.
Semin Laparosc Surg 1998; 5(3): 204–10.
144. Cherqui D, Husson E, Hammoud R, et al. Laparoscopic liver resections:
a feasibility study in 30 patients. Ann Surg 2000; 232(6): 753–62.
145. Koffron AJ, Auffenberg G, Kung R, Abecassis M. Evaluation of 300 min-
imally invasive liver resections at a single institution: less is more. Ann
Sur 2007; 246(3): 385–92; discussion 392–4.
146. Buell JF, Thomas MT, Rudich S, et al. Experience with more than
500 minimally invasive hepatic procedures. Ann Surg 2008; 248(3):
475–86.
147. Cherqui D, Laurent A, Tayar C, et al. Laparoscopic liver resection for
peripheral hepatocellular carcinoma in patients with chronic liver dis-
ease: midterm results and perspectives. Ann Surg 2006; 243(4): 499–506.
148. Dagher I, Proske JM, Carloni A, et al. Laparoscopic liver resection:
results for 70 patients. Surg Endosc 2007; 21(4): 619–24.
149. Belli G, Fantini C, D’Agostino A, et al. Laparoscopic left lateral hepatic
lobectomy: a safer and faster technique. J Hepat Biliary Pancreatic Surg
2006; 13(2): 149–54.
150. O’Rourke N, Shaw I, Nathanson L, Martin I, Fielding G. Laparoscopic
resection of hepatic colorectal metastases. HPB 2004; 6(4): 230–5.
151. Chang S, Laurent A, Tayar C, Karoui M, Cherqui D. Laparoscopy as a
routine approach for left lateral sectionectomy. Br J Surg 2007; 94(1):
58–63.
152. Ardito F, Tayar C, Laurent A, et al. Laparoscopic liver resection for
benign disease. Arch Surg 2007; 142(12): 1188–93; discussion 1193.
153. Bachellier P, Ayav A, Pai M, et al. Laparoscopic liver resection assisted
with radiofrequency. Am J Surg 2007; 193(4): 427–30.
154. Berends FJ, Meijer S, Prevoo W, Bonjer HJ, Cuesta MA. Technical consid-
erations in laparoscopic liver surgery. Surg Endosc 2001; 15(8): 794–8.
155. Champault A, Dagher I, Vons C, Franco D. Laparoscopic hepatic resec-
tion for hepatocellular carcinoma. Retrospective study of 12 patients.
Gastroentérol Clin Biol 2005; 29(10): 969–73.
156. Chen H, Juan C, Ker C. Laparoscopic liver surgery for patients with
hepatocellular carcinoma. Ann Surg Oncol 2008; 15(3): 800–6.
157. Cherqui D, Soubrane O, Husson E, et al. Laparoscopic living donor
hepatectomy for liver transplantation in children. Lancet 2002;
359(9304): 392–6.
158. Dagher I, Lainas P, Carloni A, et al. Laparoscopic liver resection for
hepatocellular carcinoma. Surg Endosc 2008; 22(2): 372–8.
159. Descottes B, Lachachi F, Sodji M, et al. Early experience with laparo-
scopic approach for solid liver tumors: initial 16 cases. Ann Surg 2000;
232(5): 641–5.
160. Descottes B, Glineur D, Lachachi F, et al. Laparoscopic liver resection of
benign liver tumors. Surg Endosc 2003; 17(1): 23–30.
161. Dulucq JL, Wintringer P, Stabilini C, Berticelli J, Mahajna A. Laparoscopic
liver resections: a single center experience. Surg Endosc 2005; 19(7): 886–91.
162. Gayet B, Cavaliere D, Vibert E, et al. Totally laparoscopic right hepatec-
tomy. Am J Surg 2007; 194(5): 685–9.
163. Gigot J, Glineur D, Santiago Azagra J, et al. Laparoscopic liver resection
for malignant liver tumors: preliminary results of a multicenter Euro-
pean study. Ann Surg 2002; 236(1): 90–7.
164. Inagaki H, Kurokawa T, Nonami T, Sakamoto J. Hand-assisted laparo-
scopic left lateral segmentectomy of the liver for hepatocellular carci-
noma with cirrhosis. J Hepato Biliary Pancreatic Surg 2003; 10(4): 295–8.
165. Kaneko H. Laparoscopic hepatectomy: indications and outcomes. J
Hepato Biliary Pancreatic Surg 2005; 12(6): 438–43.
166. Koffron AJ, Kung R, Baker T, et al. Laparoscopic-assisted right lobe
donor hepatectomy. Am J Transplant 2006; 6(10): 2522–5.
167. Mala T, Edwin B, Rosseland AR, et al. Laparoscopic liver resection: expe-
rience of 53 procedures at a single center. Journal of Hepat Biliary
Pancreatic Surg 2005; 12(4): 298–303.
 LAPAROSCOPY IN HPB SURGERY
168. O’Rourke N, Fielding G. Laparoscopic right hepatectomy: surgical tech-
nique. J Gastrointest Surg 2004; 8(2): 213–6.
169. Poultsides G, Brown M, Orlando R. Hand-assisted laparoscopic man-
agement of liver tumors. Surg Endosc 2007; 21(8): 1275–9.
170. Shimada M, Hashizume M, Maehara S, et al. Laparoscopic hepatectomy
for hepatocellular carcinoma. Surg Endosc 2001; 15(6): 541–4.
171. Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic left lateral sectio-
nectomy in living donors: safety and reproducibility of the technique in
a single center. Ann Surg 2006; 244(5): 815–20.
172. Tang CN, Tsui KK, Ha JPY, Yang GPY, Li MKW. A single-centre experi-
ence of 40 laparoscopic liver resections. Hong Kong Med J 2006; 12(6):
419–25.
173. Vibert E, Perniceni T, Levard H, et al. Laparoscopic liver resection. Br J
Surg 2006; 93(1): 67–72.
174. Belli G, Fantini C, D’Agostino A, et al. Laparoscopic versus open liver
resection for hepatocellular carcinoma in patients with histologically
proven cirrhosis: short- and middle-term results. Surg Endosc 2007;
21(11): 2004–11.
175. Kaneko H, Takagi S, Otsuka Y, et al. Laparoscopic liver resection of
hepatocellular carcinoma. Am J Surg 2005; 189(2): 190–4.
176. Laurent A, Cherqui D, Lesurtel M, et al. Laparoscopic liver resection for
subcapsular hepatocellular carcinoma complicating chronic liver dis-
ease. Arch Surg 2003; 138(7): 763–9; discussion 769.
177. Lee KF, Cheung YS, Chong CN, et al. Laparoscopic versus open hepatec-
tomy for liver tumours: a case control study. Hong Kong Med J 2007;
13(6): 442–8.
178. Abu Hilal M, McPhail MJW, Zeidan B, et al. Laparoscopic versus open
left lateral hepatic sectionectomy: A comparative study. Eur J Surg
Oncol 2008; 34(12): 1285–8.
179. Cai X, Wang Y, Yu H, Liang X, Peng S. Laparoscopic hepatectomy for
hepatolithiasis: a feasibility and safety study in 29 patients. Surg Endosc
2007; 21(7): 1074–8.
180. Cai XJ, Yang J, Yu H, et al. Clinical study of laparoscopic versus open
hepatectomy for malignant liver tumors. Surg Endosc 2008; 22(11):
2350–6.
181. Farges O, Jagot P, Kirstetter P, Marty J, Belghiti J. Prospective assessment
of the safety and benefit of laparoscopic liver resections. J Hepat Biliary
Pancreatic Surg 2002; 9(2): 242–8.
182. Lesurtel M, Cherqui D, Laurent A, Tayar C, Fagniez PL. Laparoscopic
versus open left lateral hepatic lobectomy: a case-control study. J Am
Coll Surg 2003; 196(2): 236–42.
183. Mala T, Edwin B, Gladhaug I, et al. A comparative study of the short-
term outcome following open and laparoscopic liver resection of
colorectal metastases. Surg Endosc 2002; 16(7): 1059–63.
184. Morino M, Morra I, Rosso E, Miglietta C, Garrone C. Laparoscopic vs
open hepatic resection: a comparative study. Surg Endosc 2003; 17(12):
1914–8.
185. Troisi R, Montalti R, Smeets P, et al. The value of laparoscopic liver sur-
gery for solid benign hepatic tumors. Surg Endosc 2008; 22(1): 38–44.
186. Laurent A, Tayar C, Andréoletti M, et al. Laparoscopic liver resection
facilitates salvage liver transplantation for hepatocellular carcinoma.
J Hepatobiliary Pancreat Surg 2009; 16(3): 310–14.
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11 Cross-sectional imaging for HPB disorders (MRI and CT)
Lawrence H. Schwartz
overview
The maturation of surgery of the liver, biliary tract, and
pancreas as field unto itself has happened concomitantly
with, and partly as a result of, advances in cross-sectional
imaging. Rather than relying on expected anatomy based on
textbooks, surgeons can now plan operations based on the
precise anatomical details of each individual patient. The
ability to predict anatomical variations, which are present in
nearly one-half of the patients, has taken the element of
surprise out of the operating room and can help reduce
operative morbidity (1).
In this chapter, we briefly discuss the application of com-
puted tomography (CT) and magnetic resonance imaging
(MRI) to the surgical management of disease of the liver, bili-
ary tract, and pancreas. We begin by reviewing the relevant
cross-sectional anatomy of the organs being studied. Next, we
discuss the various techniques used to obtain high-quality
CT and MRI images of the liver, biliary tract, and pancreas.
Finally, we review the cross-sectional imaging characteristics
of important pathological entities commonly encountered by
surgeons caring for patients with diseases of the liver, biliary
tract, and pancreas.
cross-sectional anatomy
The effective use of cross-sectional imaging in the diagnosis
and treatment of disorders of the liver, biliary tract, and
pancreas mandates a strong understanding of anatomy. Devel-
oping this understanding of the complex three-dimensional
structures and being able to extrapolate from two-dimensional
representations requires a structured approach. A more
detailed description of relevant anatomy can be reviewed in
the previous chapters and elsewhere, therefore we will here
focus on the interpretation of cross-sectional anatomy and its
relation to in situ anatomy (2).
Liver and Biliary Tract
Segmental liver anatomy is the basis for modern liver surgery;
therefore, we provide a framework with which to define this
anatomy for each patient based upon cross-sectional imaging.
Cantlie’s plane, also known as the main portal fissure, is an
imaginary plane drawn from the gallbladder fossa toward the
inferior vena cava (IVC) that divides the anatomical right and
left lobes of the liver. The course of the middle hepatic vein
(MHV) is fairly constant and lies in this otherwise potentially
avascular plane; therefore, it can be used to delineate the two
lobes on cross-sectional imaging (3). The right hepatic vein
(RHV) defines the plane separating the anterior (segments 5
and 8) and posterior sectors (segments 6 and 7) of the right
lobe. While the plane of the left hepatic vein (LHV) separates
the anterior and posterior sectors of the left lobe, its anatomy
is highly variable, making it a less useful landmark.
100
In contrast to hepatic veins, which course between liver seg-
ments, portal veins and their accompanying artery and bile-
duct branches define the center of each segment. The main
portal vein (PV) typically branches extrahepatically into the
left and right portal veins (LPV and RPV, respectively); the
RPV divides into the anterior and posterior sectoral branches,
while the LPV enters the umbilical fissure and provides
branches to the left lobe. While this describes standard anat-
omy, approximately one-third of patients have variant portal
venous anatomy (Table 11.1) (4).
In standard arterial anatomy the common hepatic artery
arises from the celiac axis and divides into the gastroduodenal
artery and the proper hepatic artery. The proper hepatic artery
then gives rise to the right and left hepatic arteries. However,
nearly one-half of patients have variations in their hepatic
arterial system. A list of arterial variants demonstrated in a
recent study is shown in Table 11.2 (1).
Pancreas
The pancreas is divided into the head, uncinate process, neck,
body, and tail. These divisions are based upon external land-
marks such as the superior mesenteric vein (SMV), which lies
under the neck of the gland and defines the separation between
the head and the body. The pancreas has a long course through
the retroperitoneum and is intimately associated with multi-
ple organs including the transverse colon, stomach, duode-
num, and spleen. Additionally, it has a close relationship with
the portal venous system that, in part, defines the resectability
of pancreatic masses. The pancreas has a rich arterial supply
that comes from multiple branches of the celiac and superior
mesenteric arteries. As in hepatic surgery, preoperative deter-
mination of variations in peripancreatic vascular anatomy can
greatly aid in operative planning.
technique
Liver and Biliary Tract
CT is commonly used as the primary modality to detect, char-
acterize, and follow hepatic or biliary pathology. Modern
multislice helical CT scanners allow for the rapid acquisition
of large volumes of data in a single patient breath-hold, thereby
allowing for the construction of high-resolution axial, coronal,
sagittal, and three-dimensional images.
Noncontrast CT allows us to make determinations about the
character of the liver parenchyma based on changes in density.
This is useful for detecting global hepatic abnormalities;
however, it does not allow for the precise delineation of hepatic
vascular structures nor the detection and characterization of
subtle hepatic masses. CT examination of the liver, therefore,
relies on iodinated contrast enhancement. Accurate CT imaging
requires achieving maximal differences in attenuation between
tissues, therefore understanding the contrast enhancement
 CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT)

characteristics of the liver and each type of liver tumor is essen- exposing patients to ionizing radiation, a greater measure of
tial. The liver receives approximately 20% of its blood from the safety in patients with renal insufficiency, and an improved
hepatic artery and the remaining 80% from the portal vein. ability to characterize certain types of lesions. However, MRI is
Since intravenously injected contrast reaches the liver via the costly, more time intensive for patients, and contraindicated in
hepatic artery before it does via the portal vein, and takes some patients with certain metal implants.
time to reach a state of equilibrium, a triphasic CT scan based In many centers, magnetic resonance cholangiopancreatogra-
on hepatic arterial, portal venous, and equilibrium phases is phy (MRCP) has nearly replaced diagnostic percutaneous tran-
favored for examination of the liver. shepatic cholangiography (PTC) and endoscopic retrograde
Although CT remains the most commonly used modality cholangiopancreatography (ERCP), thus reserving the latter
for obtaining cross-sectional images of the liver because of its studies for situations in which there is therapeutic intent or in
lower cost and its greater ease of interpretation by clinicians, which there is a need for tissue diagnosis. Using heavily
the indications for liver MRI continue to grow. As compared T2-weighted sequences, MRCP represents stationary water with
with triphasic liver CT, liver MRI has the advantages of not high signal intensity (5). As MRCP does not require the admin-
istration or biliary excretion of contrast, it works well even in
the setting of hepatic dysfunction or obstructive jaundice.
Table 11.1 Anatomic Variations in Portal Vein Anatomy in
200 Patients Pancreas
As for liver and biliary tract imaging, contrast-enhanced CT
Patients remains the primary modality used in the setting of pancreatic
Type Portal vein variant No. % disease; however, MRI again has some advantages. While CT
has higher spatial resolution, MRI may have a better ability to
1 Standard anatomy 130 65
2 Trifurcation 18 9 characterize lesions based on tissue composition.
3(Z) Right posterior portal vein as first 26 13 Optimal CT imaging of the pancreas relies on the ability of
branch of main portal vein multidetector CT scanners to rapidly capture large volumes of
4 Segment VII branch as separate 2 1 information during specific time periods after IV contrast
branch of right portal vein administration. Thin slices and the ability to reformat images
5 Segment VI branch as separate 12 6 in multiple axes are helpful in preoperative preparation. Fur-
branch of right portal vein thermore, water is administered as an oral contrast agent to
Other 12 6 improve differentiation among bowel, pancreas parenchyma,

Table 11.2 Frequency of Different Arterial Variants Seen at CT Angiography in 371 Patients
Type of finding No. of findings (o = 394|) % of patients (n = 371)
Classic celiac arterial anatomy 188 51
Replaced RHA off SMA 54 15
Replaced LHA off LGA 30 8
Artery to segments 2 and 3 off LGA 19 5
Artery to segments 4A and 4B off RHA 17 5
Trifurcation of CHA into GDA, RHA, and LHA 15 4
RHA off celiac axis 13 4
Accessory LHA off LGA 13 4
LGA directly oft abdominal aorta 11 3
CHA off SMA 6 2
CHA directly off the aorta 6 2
RHA off GDA 5 1
Accessory RHA 3 1
Common trunk of celiac axis and SMA 2 <1
Medial and lateral branches separate off CHA 2 <1
LHA off CHA 2 <1
GDA off RHA 2 <1
SMA gives rise to GDA 2 <1
LHA off celiac axis 1 <1
RHA off aorta 1 <1
Segment 4 branch off GDA 1 <1
Extrahepatic branching of RHA into anterior and posterior with 1 <1
artery to segment 4 off anterior division of RHA
Note: Twenty patients had two variants seen at CT and one patient had four variants.
Abbreviations: LHA, left hepatic artery; RHA, right hepatic artery; LGA, left gastric artery; SMA, superior mesenteric artery; CHA, common hepatic artery;
GDA, gastroduodenal artery. Source: Reprinted with permission from Ref. 4.

101
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
and blood vessels. Importantly, modern CT scans may have
even greater ability than endoscopic ultrasound to determine
the involvement of major vascular structures by periampullary
pancreatic cancers (6).
MRI is of particular use in patients with contrast allergies or
renal insufficiency, although optimal imaging with MRI still
requires the administration of gadolinium as a contrast agent.
As for biliary pathology, MRCP is often useful in assessing
biliary and pancreatic ductal obstruction due to pancreatic
masses. In clinical practice, these techniques are often supple-
mented by ERCP and endoscopic ultrasound.
cross-sectional imaging characteristics
of liver and biliary tract lesions
Cysts
Nonparasitic simple hepatic cysts are fluid-filled thin-walled
benign lesions that have no malignant potential, and are found
in 1% to 5% of the population. Although treatment of large
hepatic cysts may be undertaken to relieve compressive symp-
toms, most cysts require no treatment at all. Hepatic cysts are
recognized on CT imaging by their spherical or near-spherical
shape, water-attenuation fluid contents, and barely visible wall
that lacks contrast enhancement. By MRI, simple cysts are
homogeneous and have low-T1 and high-T2 signal intensity.
Multiple hepatic cysts may also be present in the setting of
polycystic kidney disease. Distinguishing simple cysts from
cystadenoma, which is a very rare tumor, is important in
that the latter lesion has the potential to compress the bile
ducts, bleed, or develop into a cystadenocarcinoma. On cross-
sectional imaging, cystadenomas may demonstrate internal
septations and a thick wall that enhances with contrast admin-
istration (Fig. 11.1).
Echinococcal or hydatid cysts are common in certain parts
of the world that are endemic for this echinococcus granulosis,
which is a parasitic disease transmitted from dogs. Hydatid
cysts are recognized as being well-circumscribed cystic lesions
that often contain multiple smaller cysts known as daughter
cysts. As the primary treatment for hydatid disease consists of
administering the anthelmintic agent albendazole, recognition
of this entity based on imaging characteristics is essential.
(A)
Figure 11.1 Biliary cystadenoma. (A) T2- and (B) postcontrast T1-weighted images of a biliary cystadenoma hanging off the inferior portion of the right lobe of
the liver. Arrows indicate solid enhancing component of mass distinguishing this from a simple cyst.
102
Hepatic Hemangioma
Hepatic hemangiomata are common vascular lesions of the
liver that receive their blood supply from the hepatic artery.
Hemangiomata rarely cause symptoms; however, giant ones
can be associated with abdominal pain or other compressive
symptoms (7). Hemangiomata are diagnosed based on their
nodular, clump-like pattern of early arterial enhancement on
CT (Fig. 11.2). Although small ones are fairly homogeneous in
appearance, large hemangiomata may have a heterogeneous
appearance due to areas of thrombosis. MRI is the most accu-
rate imaging modality for diagnosing hepatic hemangiomata.
On T2-weighted imaging, they are hyperintense and have a
lobulated appearance. Administration of gadolinium again
shows early peripheral nodular enhancement.
Focal Nodular Hyperplasia
Focal nodular hyperplasia (FNH) is a common benign liver
tumor made up of all elements of the hepatic parenchyma.
FNH are completely benign and rarely, if ever, lead to symp-
toms. However, the fibrolamellar variant of hepatocellular car-
cinoma may be mistaken for FNH based on similar imaging
characteristics (8). Therefore, accurate identification of FNH
is of paramount importance.
On pathological examination, FNH typically have a central
scar that may be demonstrated on cross-sectional imaging.
Contrast-enhanced CT show rapid homogeneous enhance-
ment during the arterial phase with reduced attenuation dur-
ing the portal venous phase (Fig. 11.3). MRI imaging of FNH
reveals isointensity or slight T1 hypointensity or T2 hyperin-
tensity, with a central scar that has even less T1 intensity or
more T2 intensity (9). Contrast administration shows early
enhancement with delayed enhancement of the central scar.
Hepatocellular Adenoma
Hepatocellular adenomas are benign proliferations of hepato-
cytes with a dramatically increased prevalence in patients with
a history of oral contraceptive use. Although they are benign
lesions, resection of hepatocellular adenomas is recommended
because of their propensity for hemorrhage and, albeit rare,
risk of malignant transformation. Adenomas are recognized
(B)
 CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT)

(A) (B)
Figure 11.2 Hemangioma. (A) T1-weighted postcontrast imaging reveals a nodular peripheral enhancement (black arrow) pattern in the early arterial phase that
is characteristic of hemangiomas. (B) T2-weighted imaging reveals a hyperintense, lobulated lesion.

(A) (B)

(C) (D)
Figure 11.3 Focal Nodular Hyperplasia (A) T1-weighted precontrast image is isointense to hepatic parenchyma (B) T2-weighted image is also isointense to hepatic
parenchyma except the central scar (arrow), which is bright (C) T1-weighted postcontrast image in the arterial phase demonstrates homogenous, hyperintense
enhancement with the central scar enhancing on (D) delayed postcontrast images.

103
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
on CT as hypervascular, heterogeneous lesions during arterial
phase that become isodense or hypodense during the portal
venous phase. MRI also shows hepatocellular adenomas to be
heterogeneous, with T1 hyperintensity due to the presence of
fat or hemorrhage and typically show arterial phase enhance-
ment as with CT.
Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) ranks among the most com-
mon causes of cancer-related mortality worldwide; however,
its incidence is markedly variable based on geography and
prevalence of hepatitis B and C virus infection (10). As it
occurs most commonly in the setting of cirrhosis, its radio-
logical diagnosis can be challenging. This is due to the pres-
ence of fibrosis and regenerative nodules that can be difficult
to distinguish from dysplastic nodules or HCC. Contrast-
enhanced CT helps provide some distinction, as small dysplas-
tic nodules or HCC that can be mistaken for regenerative
nodules typically enhance during the arterial phase and have
contrast washout in the delayed venous phase (11). Larger
HCC are more heterogeneous in their appearance and may
not demonstrate contrast enhancement. MRI adds sensitivity
to the diagnosis by showing differences in signal intensity
between areas of carcinoma and cirrhotic liver (12). Although
HCC are typically hypointense on T1-weighted images, well-
differentiated HCC may be hyperintense. T2-weighted images
typically show HCC as hypointense lesions, however, this is
variable as well. HCC usually enhance with gadolinium
administration (Fig. 11.4).
Fibrolamellar Carcinoma
Fibrolamellar carcinoma (FLC) is a rare malignant tumor of
the liver that typically arises in the absence of cirrhosis in
relatively young patients (13). FLC is thought to be a variant of
HCC, and is therefore also referred to as fibrolamellar HCC.
On CT, FLC are usually large, hypoattenuating tumors with
heterogeneous contrast enhancement and a nonenhancing
central scar. The central fibrous scar usually show low signal
intensity on both T1-weighted and T2-weighted images.
Accurate diagnosis is essential since FLC may mimic FNH on
cross-sectional imaging due to the presence of a fibrous cen-
tral scar on both.
Cholangiocarcinoma
Adenocarcinoma that develops from epithelial cells lining the
intrahepatic and extrahepatic bile ducts is termed cholangio-
carcinoma. Hilar cholangiocarcinomas (Klatskin tumors),
which arise at the confluence of the right and left hepatic ducts,
are the most common type and typically present with jaundice
(14). CT or MRI of patients with hilar cholangiocarcinoma
shows intrahepatic biliary ductal dilatation, often in associa-
tion with unilobar parenchymal atrophy, bile duct crowding,
and portal vein impingement. An associated mass lesion may
or may not be present, while a more prognostically favorable
papillary variant may show a nodular mass within the biliary
system (15). Extrahepatic cholangiocarcinoma, which arises
in the common hepatic or common bile ducts, also presents
with jaundice. Cross-sectional imaging demonstrates both
104
intrahepatic and extrahepatic biliary ductal dilatation. Again, a
mass lesion is rarely present, although papillary lesions are pos-
sible in this location as well. More commonly, the distal bile
duct will show an area of focal thickening that enhances with
contrast administration. Peripheral (intrahepatic) cholangio-
carcinoma has an appearance on cross-sectional imaging that is
more similar to that of more commonly encountered liver
tumors. Biliary ductal dilatation is only focal in association
with a low attenuation mass that shows peripheral enhance-
ment (Fig. 11.5).
Gallbladder Carcinoma
Gallbladder carcinoma is a highly aggressive tumor that is
notable for its highly variable incidence. Early gallbladder car-
cinoma may have few findings on cross-sectional imaging. CT
of early lesions may demonstrate focal gallbladder-wall thick-
ening or a polypoid mass within the lumen of the gallbladder.
More advanced tumors may show a hypoattenuating mass in
or replacing the gallbladder, which may be associated with
hepatic involvement or biliary ductal dilatation. T2-weighted
MRI images show heterogeneous signal intensity with irregu-
lar contrast enhancement (16) (Fig. 11.6).
Metastatic Cancer to the Liver
The most common indication for liver resection in the west-
ern world is metastatic disease, especially from colorectal
cancer. Liver metastases from colorectal cancer, as well as
those from other GI malignancies, are typically characterized
by low attenuation relative to normal liver parenchyma;
however, there is high variability in their appearance.
Colorectal liver metastases are most readily appreciated on
portal venous phase CT (Fig. 11.6), and have variable levels
of rim enhancement. By contrast, neuroendocrine (Fig. 11.7)
and other hypervascular metastases tend to show early
arterial enhancement (17). MRI may help to characterize
liver metastases, which are typically of low signal intensity on
T1-weighted images and high signal intensity on T2-weighted
images.
cross-sectional imaging characteristics
of pancreatic lesions
Cysts
The widespread use of high-quality abdominal cross-sectional
imaging for a variety of indications has lead to an increased
recognition of cystic lesions of the pancreas. Cystic pancreatic
lesions may be non-neoplastic, as in the case of pseudocysts, or
can be neoplasms that are completely benign, premalignant, or
frankly cancerous. Given the broad differential diagnosis of
pancreatic cysts, determining their histological origin, while
challenging, is of paramount importance in deciding on man-
agement, especially for tumors greater than 3 cm in diameter
(18,19).
Pseudocysts, which are common sequelae of acute pancre-
atitis, are the most common cystic lesions of the pancreas.
As such, differentiating pseudocysts from cystic neoplasms of
the pancreas prior to treatment is desirable. Since a clinical
history of prior episodes of acute pancreatitis is not perfectly
correlated with the diagnosis of pseudocyst, radiological
 CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT)

(A) (B)
Figure 11.4 Hepatocellular carcinoma. (A) Arterial phase CT image demonstrating a dominate right-lobe mass. (B) Note the change in enhancement on the portal
venous phase of imaging.

(A) (B)
Figure 11.5 Gallbladder carcinoma. T2-weighted MRI (A) axial and (B) coronal images demonstrate a solid mass in the gallbladder with hyperintense surrounding
liver parenchyma consistent with local extension of the tumor into the liver parenchyma.

differentiation is necessary. The presence on MRI of depen-

dent debris within a cystic pancreatic lesion has been found to
be highly suggestive of the diagnosis of pseudocyst (20).
Serous cystadenoma (SCA) are the most common benign
neoplasm of the pancreas and are typically asymptomatic
findings, however a proportion of patients do present with
symptoms due to mass effect (21). SCA are comprised of mul-
tiple smaller cysts and may have a variable appearance based
on the size of the cysts that comprise them. In fact, microcystic
tumors may have an appearance on CT more consistent with
that of a solid tumor. MRI and ultrasound may be helpful in
defining the cystic nature of such tumors. Since asymptomatic
SCA do not require treatment, differentiating them from other
malignant or premalignant lesions is critical. In the event that
imaging characteristics are nondiagnostic, biopsy or resection
may be indicated.
Intraductal papillary mucinous neoplasms (IPMN) are pre- Figure 11.6 Colorectal cancer metastasis. Irregular hypodense central lesion
malignant tumors arising from the main pancreatic duct or its on contrast-enhanced CT represents a colorectal liver metastasis.

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A) (B)
Figure 11.7 Neuroendocrine metastases. (A) Innumerable hypodense neuroendocrine metastatic nodules with variable levels of rim-enhancement on portal
venous phase contrast-enhanced CT. (B) Coronal slice demonstrates direct extension of tumor into the portal vein (arrow).

(A) (B)
Figure 11.8 Intraductal papillary mucinous neoplasm (IPMN). (A) T1-weighted postcontrast imaging reveals a low-intensity multilocular lesion in the head and
uncinate process of the pancreas suspicious for a side-branch IPMN. (B) T2-weighted images demonstrate high signal intensity.

branches. IPMN contain epithelium ranging from benign ade-
noma to invasive adenocarcinoma. IPMN are differentiated
based on whether they arise from side-branches or from the
main pancreatic duct, with the latter having a higher potential
for progressing to invasive malignancy. Cross-sectional imaging
reveals a cystic region within or adjacent to the pancreatic
parenchyma that may demonstrate continuity with the pancre-
atic ductal system. Factors that influence the decision to per-
form pancreatectomy for IPMN include size, growth, and the
presence of fibrous septations or solid components. Mucinous
cystic neoplasms (MCN) are less common lesions, typically seen
in women, which are characterized by ovarian-type stroma.
MCN are also felt to be premalignant lesions, therefore their
resection is recommended. MCN have imaging characteristics
similar to those of IPMN, with the absence of a definable con-
nection to the main pancreatic ductal system (Fig. 11.8).
Pancreatic Neuroendocrine Tumors
Pancreatic neuroendocrine tumors (PNET), also known as islet
cell tumors, are rare malignant neoplasms that have a relatively
slow growth rate. While most PNET are nonfunctional, they
may secrete hormones that lead to clinical symptoms, espe-
cially in the setting of metastatic disease to the pancreas. PNET
are typically hypervascular lesions that show early arterial
phase enhancement on CT, but may be isodense on portal
venous phase. Small functional tumors may prove difficult to
identify on cross-sectional imaging studies, therefore accurate
timing of imaging to the arterial phase of enhancement is
important. Similarly, MRI imaging of PNET usually demon-
strate high signal intensity on T2-weighted images and low
intensity on T1-weighted images with significant contrast
enhancement (22) (Fig. 11.9).
Solid Pseudopapillary Tumor
Solid pseudopapillary tumor (SPT) of the pancreas is a rare,
indolent tumor that most commonly affects women in the
first three decades of life. Although it has metastatic potential,
malignant behavior is uncommon, therefore resection is con-
sidered curative. CT imaging is varied and may demonstrate a
large lesion with internal hemorrhage or cystic degeneration.
While vascular encasement, pancreatic ductal dilatation, and
hepatic metastases are seen only in the carcinomatous variant

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 CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT)
Figure 11.9 Neuroendocrine pancreatic tumor. A well-preserved fat plane is
seen separating this large hypervascular neuroendocrine tumor in the head of
the pancreas from the superior mesenteric/portal vein. Areas of hypoattenua-
tion towards the middle of the tumor are suggestive of central ischemia.
of this tumor, more typical findings based on size, capsule
thickness, internal composition, and calcification pattern do
not help to differentiate benign and malignant lesions (23).
Acinar Cell Carcinoma
Although acinar cells comprise the bulk of pancreatic tissue,
acinar cell carcinomas (ACC) are very uncommon. ACC are
typically well-circumscribed tumors that may be lobulated
and may be heterogeneous or homogeneous in appearance on
cross-sectional imaging (24). ACC range from being completely
solid to mostly cystic with at least some solid components and
central necrotic areas may be seen. Biliary or pancreatic ductal
dilatation is occasionally seen. Contrast-enhanced CT shows
homogeneous enhancement of solid components, but less
than that of the surrounding pancreas. T2-weighted MRI
images may show hyperintense signal in relation to pancreatic
parenchyma.
Pancreatic Adenocarcinoma
Pancreatic adenocarcinoma, commonly referred to as pancreatic
cancer, is the most common malignant neoplasm of the pancreas.
It is a highly aggressive malignancy that carries with it an extremely
high mortality rate, having an incidence that nearly equals its
mortality rate. Because of the biologically aggressive nature of
pancreatic cancer, the majority of patients present with metastatic
or unresectable disease. Contrast-enhanced CT usually shows a
hypoattenuating poorly defined mass with dilatation of the pan-
creatic duct distally and, in the case of tumors of the pancreatic
head, biliary ductal dilatation as well. Biliary and/or pancreatic
ductal dilatation may also be seen in the absence of an identifiable
mass, and dilatation of both of these ductal systems—the double
duct sign—is a classic sign of adenocarcinoma of the head of the
pancreas. The double duct sign is not, however, pathognomonic
for pancreatic cancer and may be associated with benign pro-
cesses (25). MRI has the advantage of being usable in patients
with diminished renal function and can be combined with MRCP
to provide detail about the biliary and pancreatic ductal systems
in a noninvasive fashion (Fig. 11.10).
The primary determinants of the resectability of pancreatic
lesions inevitably relate to vascular involvement, since the
Figure 11.10 Pancreatic adenocarcinoma. Contrast-enhanced CT reveals a
hypointense solid-appearing mass in the tail of the pancreas. This appearance
on cross-sectional imaging is characteristic of pancreatic adenocarcinoma.
pancreas is intimately associated with the portal venous sys-
tem and in close proximity to the celiac artery and superior
mesenteric artery (SMA). High-quality cross-sectional imag-
ing clearly defines these relationships and predicts the likeli-
hood of successful resection.
Metastatic Cancer to the Pancreas
In contrast to the liver, the pancreas is a rare site of metastatic
disease. Although multiple types of cancer have been reported
to metastasize to the pancreas, renal cell carcinoma, nonsmall
cell lung carcinoma, and lymphoma are the most common
sources of isolated pancreatic metastases. Renal cell carcinoma
metastases to the pancreas are typically well-circumscribed,
arterial-enhancing lesions, while other histologies tend to be
more diffuse and variable in enhancement patterns.
conclusions
CT and MRI have become essential components in the diag-
nosis, perioperative management, and follow-up of hepatic,
biliary, and pancreatic pathology. Therefore, the ability to
appropriately order and interpret these studies, in consulta-
tion with radiologists, is a prerequisite to the surgical manage-
ment of patients with such diseases.
references
1. Winston CB, Lee NA, Jarnagin WR, et al. CT angiography for delineation
of celiac and superior mesenteric artery variants in patients undergoing
hepatobiliary and pancreatic surgery. AJR Am J Roentgenol 2007; 189(1):
W13–19.
2. Blumgart LH. Surgery of the Liver, Biliary Tract, and Pancreas, 4th edn.
Philadelphia, PA: Saunders Elsevier, 2007.
3. Kamel IR, Lawler LP, Fishman EK. Variations in anatomy of the middle
hepatic vein and their impact on formal right hepatectomy. Abdom Imag-
ing 2003; 28(5): 668–74.
4. Covey AM, Brody LA, Getrajdman GI, Sofocleous CT, Brown KT. Inci-
dence, patterns, and clinical relevance of variant portal vein anatomy. AJR
Am J Roentgenol Oct 2004; 183(4): 1055–64.
107
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
5. Adam A, Dixon AK, Allison DJ, Grainger RG. Grainger & Allison’s Diag-
nostic Radiology: a Textbook of Medical Imaging 5th edn. Edinburgh:
Churchill Livingstone, 2008.
6. Mansfield SD, Scott J, Oppong K, et al. Comparison of multislice com-
puted tomography and endoscopic ultrasonography with operative and
histological findings in suspected pancreatic and periampullary malig-
nancy. Br J Surg 2008; 95(12): 1512–20.
7. Yoon SS, Charny CK, Fong Y, et al. Diagnosis, management, and outcomes of
115 patients with hepatic hemangioma. J Am Coll Surg 2003; 197(3): 392–402.
8. Blachar A, Federle MP, Ferris JV, et al. Radiologists’ performance in the
diagnosis of liver tumors with central scars by using specific CT criteria.
Radiology 2002; 223(2): 532–9.
9. Hussain SM, Terkivatan T, Zondervan PE, et al. Focal nodular hyperplasia:
findings at state-of-the-art MR imaging, US, CT, and pathologic analysis.
Radiographics 2004; 24(1): 3–17, discussion 18–19.
10. Pang RW, Joh JW, Johnson PJ, Monden M, Pawlik TM, Poon RT. Biology
of hepatocellular carcinoma. Ann Surg Oncol 2008; 15(4): 962–71.
11. Takayama T, Makuuchi M, Kojiro M, et al. Early hepatocellular carcinoma:
pathology, imaging, and therapy. Ann Surg Oncol 2008; 15(4): 972–8.
12. Coakley FV, Schwartz LH. Imaging of hepatocellular carcinoma: a practi-
cal approach. Semin Oncol 2001; 28(5): 460–73.
13. Stipa F, Yoon SS, Liau KH, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer 15 2006; 106(6): 1331–8.
14. Akoad M, Jenkins R. Proximal biliary malignancy. Surg Clin North Am
2008; 88(6): 1409–28, x–xi.
15. Jarnagin WR, Bowne W, Klimstra DS, et al. Papillary phenotype confers
improved survival after resection of hilar cholangiocarcinoma. Ann Surg
2005; 241(5): 703–12, discussion 712–14.
108
16. Schwartz LH, Black J, Fong Y, et al. Gallbladder carcinoma: findings at MR
imaging with MR cholangiopancreatography. J Comput Assist Tomogr
2002; 26(3): 405–10.
17. Tamm EP, Kim EE, Ng CS. Imaging of neuroendocrine tumors. Hematol
Oncol Clin North Am 2007; 21(3): 409–32, vii.
18. Allen PJ, Brennan MF. The management of cystic lesions of the pancreas.
Adv Surg 2007; 41: 211–28.
19. Allen PJ, D’Angelica M, Gonen M, et al. A selective approach to the resec-
tion of cystic lesions of the pancreas: results from 539 consecutive
patients. Ann Surg 2006; 244(4): 572–82.
20. Macari M, Finn ME, Bennett GL, et al. Differentiating pancreatic cystic
neoplasms from pancreatic pseudocysts at MR imaging: value of per-
ceived internal debris. Radiology 2009; 251(1): 77–84.
21. Tseng JF, Warshaw AL, Sahani DV, et al. Serous cystadenoma of the pan-
creas: tumor growth rates and recommendations for treatment. Ann Surg
2005; 242(3): 413–19, discussion 419–21.
22. Rha SE, Jung SE, Lee KH, et al. CT and MR imaging findings of endocrine
tumor of the pancreas according to WHO classification. Eur J Radiol
2007; 62(3): 371–7.
23. Lee JH, Yu JS, Kim H, et al. Solid pseudopapillary carcinoma of the pan-
creas: differentiation from benign solid pseudopapillary tumour using CT
and MRI. Clin Radiol 2008; 63(9): 1006–14.
24. Tatli S, Mortele KJ, Levy AD, et al. CT and MRI features of pure acinar cell
carcinoma of the pancreas in adults. AJR Am J Roentgenol 2005; 184(2):
511–19.
25. Plumley TF, Rohrmann CA, Freeny PC, Silverstein FE, Ball TJ. Double
duct sign: reassessed significance in ERCP. AJR Am J Roentgenol 1982;
138(1): 31–5.
12 Liver metastases: detection and imaging
Valérie Vilgrain, Ludovic Trinquart, and Bernard Van Beers
The liver is the second most frequent site of metastases, after
lymph nodes, providing a very suitable environment for the
growth of metastases because of its rich blood supply from the
systemic and splanchnic system. The overall extent of liver
involvement in cancer patients is unknown but liver metasta-
ses have been found in 30% to 70% of patients who die because
of cancer, depending on their primary tumor (1).
Liver metastases frequently arise from colorectal cancer
(CRC), with 15% to 20% of patients presenting with synchro-
nous liver metastases and another 15% developing metachro-
nous metastases to the liver within five years (2,3). But unlike
many other types of cancers, the presence of distant metastases
from CRC does not necessarily preclude curative treatment. In
fact, CRC metastases are confined to the liver in 25% of
patients (4). This confinement of metastatic disease to the liver
has allowed progress in the treatment of these patients—via
hepatic resection, regional chemotherapy, and thermoablative
treatments, and the benefits of such approaches are demon-
strated by the fact that survival of up to 25% of patients 10 year
after resection of these metastases is possible.
Isolated liver metastases also often arise from gastric and
pancreatic cancers—because of the portal venous drainage
to the liver—and less frequently from breast or lung cancers.
But most non-CRC liver metastases are associated with dis-
tant metastatic spread to other organs and so require a more
systemic therapeutic approach. However, metastases con-
fined to the liver may also be seen in ocular melanoma, breast
cancer, neuroendocrine tumors, renal cell cancers, and some
sarcomas (5–7).
In this context, the goal of imaging for liver metastases is
twofold: first to establish an early and accurate diagnosis of
liver metastases, second to stage preoperatively those patients
with liver metastases confined to the liver, especially when the
primary tumor is CRC. The diagnostic value of ultrasound
(US), contrast-enhanced US, multidetector computed tomog-
raphy (CT), and magnetic resonance (MR) imaging with non-
specific gadolinium chelates and liver-specific contrast agent is
discussed. Pitfalls and limitations of imaging are shown. Lastly,
the role of imaging in assessing number, localization, and size
of metastases to determine resectability is emphasized.
imaging techniques
Ultrasound
Liver metastases are generally multiple, spherical, and have
well-defined margins. Most lesions are hypoechoic. The most
common hyperechoic metastases are observed in patients with
CRC or neuroendocrine tumors. Large lesions often have
more central hypoechogenicity related to areas of necrosis. A
hypoechoic halo is seen surrounding the lesions in 40% of
cases (8). More rarely, liver metastases may appear as diffuse
infiltration.
The role of Doppler techniques is often limited because flow
signals in liver metastases are usually too low to be detected
except in markedly hypervascular liver metastases.
Because there are no specific features of metastases at con-
ventional US, the differentiation of a single metastasis from
other lesions is usually not possible but on the other hand, US
is helpful to characterize benign lesions such as hepatic cysts
and hemangiomas in oncological patients. While in many
European countries, US was the recommended imaging
follow-up method, CT or MRI is nowadays preferred in onco-
logical patients.
contrast-enhanced ultrasound
The principle of this technique is to increase the lesion-to-liver
contrast, using intravascular microbubble contrast agents,
which allows enhanced detection of smaller liver metastases
not seen on conventional US. Most contrast agents used
nowadays provide strong and persistent signal enhancement
due to harmonic resonance at low mechanical index, where
minimal or no bubble destruction occurs. Examination
includes a continuous evaluation of the lesion enhancement
during the arterial (15–30 seconds delay), portal venous
(30–60 seconds delay), and delayed (2–3 minutes delay)
phases. Most liver metastases are hypovascular and exhibit
no or minimal enhancement on the arterial phase. Interest-
ingly, whatever the lesion enhancement is on the arterial
phase, metastases show nonenhancing defects on the delayed
phase, which seem to be the most useful determinant for
both lesion detection and characterization (Fig. 12.1). This
strong washout sign is caused by the biokinetics of the US
contrast agents that are purely vascular effects; conversely to
nonspecific CT and MR contrast agents that spread into the
interstitium. Indeed, the use of contrast agents improves the
sensitivity of US in detecting individual lesions by about
20% in comparison to baseline, independent of the type of
contrast agent used (9).
Contrast-enhanced US imaging is technically successful in
most patients except those with severe obesity and marked
steatosis in whom penetration of contrast-specific imaging is
limited.
computed tomography
Computed tomography (CT) is the most commonly used
imaging modality for both detection and characterization of
liver metastases. Multidetector helical CT is now the stan-
dard technique. It reduces the scan time, with high coverage
and high-quality 3D reconstructions. The examination
comprises of an unenhanced scan and, after intravenous
administration of nonionic iodine contrast medium, two
acquisitions at the late arterial phase and the portal venous
phase. During the latter, the liver parenchyma enhances
109
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
(A)
(C)
Figure 12.1 (A–C) Portal-phase CT shows a small liver tumor that is not characteristic of liver metastasis. This lesion is homogeneous and hyperechoic on
ultrasound (B). Portal-phase contrast-enhanced ultrasound demonstrates washout, which is highly suggestive of liver malignancy (C).
Figure 12.2 Portal-phase CT demonstrating multiple heterogeneous lesions
suggestive of liver metastases.
and it increases the lesion conspicuity of hypovascular
tumors (10) (Fig. 12.2). Most liver metastases are hypoat-
tenuating and hypovascular on unenhanced scans, meaning
that they are better seen on the portal venous phase than on
110
(B)
the arterial phase. A key finding is the presence of a halo (11),
which has been shown as a quite sensitive and specific find-
ing for liver metastases. However, unenhanced, arterial-phase
and delayed-phase imaging (which is optional) are helpful
for differentiating benign lesions such as cyst, hemangioma,
or hepatocellular tumors from metastases.
magnetic resonance imaging
The routine magnetic resonance (MR) imaging protocol
includes nonenhanced T1- and T2-weighted pulse sequences
and postcontrast sequences. On T1-weighted images, most
liver metastases are hypointense, but isointense lesions are
seen in approximately 10% of patients (12). Hyperintense
liver metastases are very uncommon but may be seen in mel-
anoma. On T2-weighted images, liver metastases are most
commonly moderately hyperintense, whereas the remnants
are isointense or markedly hyperintense (12). The areas of
marked hyperintensity correspond to cystic changes or
necrosis (12). It seems that the signal intensity on T2-weighted
images is not related to metastases from a specific primary
neoplasm.
Contrast agents can improve diagnostic accuracy. Two
groups of MR contrast agents may be used: nonspecific gado-
linium chelates whose biokinetics are similar to iodine
contrast agents, and liver-specific contrast agents, either for
 LIVER METASTASES: DETECTION AND IMAGING
(A)
(C)
Figure 12.3 (A–D) MR imaging of a colorectal metastasis. The tumor is hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note the peripheral
halo on portal-phase T1-weighted imaging and the delayed enhancement due to fibrous stroma (C and D).
reticuloendothelial system (ferumoxides) or hepatobiliary
captation (Mn-DPDP or specific hepatobiliary gadolinium
chelates). Briefly, the nonspecific gadolinium chelates are
used for lesion characterization, while the others have been
proposed for preoperative staging. The principle of the latter
is to increase the lesion-to-liver contrast by decreasing mark-
edly the signal of the liver on T2 sequences (ferumoxides) or
increasing it on T1-weighted sequences (13). Some authors
have also proposed double-contrast MR combining specific
and nonspecific contrast agents.
Similarly to CT, nonspecific gadolinium MR imaging
should include baseline precontrast images and sequen-
tial acquisitions at arterial, portal, and equilibrium
phases. In a large series of 516 liver metastases from var-
ious tumors in 165 consecutive patients, most liver
metastases were hypovascular (64% of all patients and
91% of patients with colon cancer) ( 12 ). A hypervascular
pattern of enhancement was identified in 36% of
patients. During the arterial phase, peripheral ring
enhancement was seen in 72% of patients. On the portal
venous and delayed phase, incomplete central progres-
sion of lesion enhancement was found in two-thirds of
patients ( 12 ) ( Fig. 12.3 ). Peripheral washout in metasta-
ses on delayed-phase images was identified in one-third
(B)
(D)
of patients with hypervascular metastases and almost
never in hypovascular metastases ( 12 ) ( Fig. 12.4 ). After
administration of liver-specific contrast agents, liver
metastases that lack functioning hepatocytes or Kupffer
cells do not enhance postcontrast, resulting in improved
lesion conspicuity ( 14 ).
Diffusion-weighted MR imaging is quite interesting in liver
metastases. Nasu et al. (15) have shown increased detection of
metastatic lesions with a combination of diffusion-weighted
imaging and precontrast T1- and T2-weighted imaging when
compared with liver-specific contrast MR imaging. Parikh
et al. have shown that diffusion-weighted sequences were as
accurate as T2-sequences for characterization of focal liver
lesions including metastases (16) (Fig. 12.5).
positron emission tomography
Conversely to the other imaging modalities, which give more
morphologic than functional information, positron emis-
sion tomography (PET) imaging is essentially functional
imaging and provides a physiological survey for hypermeta-
bolic tumors. PET scanning after administration of [18F]
2-fluoro-2-deoxyglucose (FDG) is based upon higher glyco-
lytic activity of many tumors compared to normal tissue.
[18F]FDG is transported into cells and phosphorylated by
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

the enzyme hexokinase to [18F]FDG-6-phosphate, which
cannot proceed down the glycolytic pathway and is therefore
accumulated in malignant tissue. This technique has
improved markedly over the past decade, and many centers
routinely incorporate PET imaging results in the staging of
patients with liver metastases, especially when consideration
is being given for liver resection.
Most studies have focused on the diagnostic yield of fluoro-
deoxyglucose (FDG)-PET in patients with liver metastases
from colon and rectal cancer. The two main limitations of
PET are the lack of anatomical landmarks and poor spatial
resolution. Development of PET/CT has overcome these
drawbacks; unfortunately, most PET/CT examinations are
performed with unenhanced CT images. Recently, some
authors have investigated the role of IV iodinated contrast
material in the evaluation of liver metastases at [18F]FDG
PET/CT (17). They have shown that more liver metastases
were detected on PET/contrast-enhanced CT compared with
PET/unenhanced CT (83% and 67%, respectively). Similarly,
liver metastases were more accurately characterized at PET/
contrast-enhanced CT compared with PET/unenhanced CT
(73% and 57%, respectively).

(A) (B)

(C) (D)

Figure 12.4 (A–D) MR imaging of endocrine metastases. The tumors are strongly hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note
the strong hypervascularity on arterial-phase T1-weighted imaging and the washout on portal-phase imaging (C and D).

(A) (B)
Figure 12.5 MR imaging of liver metastases. Multiple tumors are seen on T2-weighted imaging (A). Conspicuity of small tumors is more evident on diffusion-
weighted imaging (B).

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 LIVER METASTASES: DETECTION AND IMAGING
perfusion imaging
Liver metastases induce changes in liver perfusion and have
been shown to increase arterial blood flow and the arterial–
portal flow ratio (hepatic perfusion index) compared to nor-
mal liver. Interestingly, animal studies have demonstrated that
those changes may be detected at an early stage when liver
metastases are occult on other imaging modalities (18).
Hepatic perfusion index can be obtained using various tech-
niques: nuclear medicine, US, CT, or MR imaging. Early results
in patients were promising but lack of standardization in utili-
zation, lack of consensus regarding the imaging modality, and
the presence of multiple mathematical models have meant
that perfusion has not been adopted in routine practice.
other imaging findings
Hypervascular Metastases
Liver metastases from colon carcinoma, other gastrointesti-
nal carcinoma, and pulmonary carcinoma are considered
hypovascular, and those from thyroid carcinoma, neuroen-
docrine tumor, and renal cell carcinoma are hypervascular
(12) (Fig. 12.5). Breast carcinoma metastases can be either
hypovascular or hypervascular. Furthermore, in Danet’s
series, patients with metastases that exhibit the nonclassical
type of enhancement according to the primary tumor were
not uncommon. For example, 9% of patients with colon car-
cinoma had hypervascular metastases (12). This observation
emphasizes the role of imaging in characterizing liver lesions
in cancer patients, and the importance of multiple comple-
mentary examinations.
Cystic Metastases
Liver metastases may have a cystic appearance with strong
hyperintensity on heavily T2-weighted MR images. However,
these tumors usually have other findings that are not seen in
typical hepatic cysts such as internal septations, thick walls,
and wall enhancement. Most cystic liver metastases arise from
cystadenocarcinoma, neuroendocrine tumor, and sarcoma.
Calcified Metastases
Up to 11% of patients with colon carcinoma have calcified
liver metastases at presentation. Patients may also develop
(A)
Figure 12.6 (A and B) Liver metastases before and after chemotherapy. Note the significant decrease in size of the tumors. Furthermore, the tumors present diffuse
calcifications after chemotherapy.
calcification during response to chemotherapy (19) (Fig. 12.6).
Whether liver metastatic calcification carries a prognostic
significance in CRC is still questionable.
Intrabiliary Metastases
Intrinsic bile duct involvement by metastases may occur either
by growing from within or invading the lumen of the bile
ducts. The most common intrabiliary metastases arise from
colorectal carcinoma. Most patients present with various
degree of biliary obstruction including jaundice (20). The
presence of macroscopic intrabiliary extension seems to be a
good indicator in patients with CRC showing less aggressive
features (21).
Pitfalls and Limitations
The two most difficult situations in oncological patients are
the changes in the liver such as steatosis that can create pseu-
dolesions or hide true metastases, and the characterization of
small lesions.
Steatosis is not always homogeneous and may have either
focal fatty sparing, or more rarely focal fatty deposit. Further-
more, fatty livers are often observed in cancer patients who
have received chemotherapy. Clearly, in this context, MR is
superior to CT by combining fat-suppressed T1 sequences and
in- and opposed-phase T1-weighted imaging that can diag-
nose both focal and diffuse changes, and help to differentiate
focal fat from metastases (Fig. 12.7).
Another issue is the characterization of small liver lesions in
cancer patients. Those lesions (smaller than 1 or 2 cm) are
often deemed “too small to characterize,” and due to the high
prevalence of benign lesions in the liver, are more frequently
benign than malignant. Schwartz et al. reported in a series of
2978 cancer patients that metastases represented only 11.6%
of patients with small liver lesions (22). Other authors have
shown that the positive predictive value for malignancy
increased notably using a cut-off of 20 mm compared to
10 mm (23). Yet, for an individual patient, we cannot rely only
on lesion size for characterization. While CT is an excellent
imaging modality for detection, it is not as good as US, con-
trast-enhanced US, and MR imaging when characterizing
small liver lesions (24,25).
(B)
113
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
(A)
Figure 12.7 (A–C) Liver metastases developed on a fatty liver. The tumor located in the posterior part of the segment 4 is barely visible on portal-phase CT (A) and
is better seen on pre- and postcontrast T1-weighted imaging (B and C).
detection of liver metastases:
which imaging modality?
Many different noninvasive imaging modalities are available
for the preoperative detection of liver metastases: US and
contrast-enhanced US, multidetector CT, MR imaging, and
PET using FDG. Comparison of these imaging techniques is
challenging and results have evolved over time due to tech-
nological improvements. Multidetector CT has notably
increased the performance of CT in decreasing slice thick-
ness and optimizing lesion enhancement on multiphasic
studies after intravenous contrast. The use of liver-specific
contrast agents in MR imaging has given new horizons for
this imaging modality. Diffusion-weighted MR has markedly
improved the detection of liver metastases. The use of US
contrast agents has completely changed the role of US in
oncology. Integrated PET/CT scanners combining metabolic
and anatomical information has also resulted in an increased
interest in PET studies, and it is likely that the role of IV
iodinated contrast material in PET/CT scanners will be quite
significant. Consequently, many studies have assessed and
compared the diagnostic value of these imaging techniques,
resulting in an extensive body of literature and the absence of
any consensus on the diagnostic algorithm (26). Two system-
atic reviews (27,28) and one narrative review (29) have ana-
lyzed the available evidence (Tables 12.1 and 12.2).
The first systematic review was published by Kinkel et al. in
2002, and aimed at comparing current noninvasive imaging
methods such as US, CT, MR imaging, and FDG PET for the
detection of hepatic metastases from colorectal, gastric, and
esophageal cancers (28). Papers published between December
1985 and December 2000 were studied. Among the 54 studies
included, 9 assessed US (686 patients, 74% with CRC), 25
assessed CT (1747 patients, 78% with CRC), 11 addressed MRI
(401 patients, 100% with CRC), and 9 reported on PET
(423 patients, 100% with CRC). In a “per-patient” meta-anal-
ysis, the authors concluded that [18F]FDG PET was the most
sensitive examination (Level of evidence II): the combined
per-patient sensitivity of [18F]FDG PET (0.90, 95% CI 0.82–
0.96) being significantly superior to that of US (0.66, 95% CI
0.54–0.77), CT (0.70, 95% CI 0.63–0.77), and MRI (0.71, 95%
114
(B) (C)
Table 12.1 Levels of Evidence for Studies of Diagnostic
Test Accuracy
Ia: Systematic review (with homogeneity)* of level-1 studies
Ib: Level 1 studies
II: Level 2 studies or systematic reviews of level-2 studies
III: Level 3 studies or systematic reviews of level-3 studies
IV: Expert committee reports or opinions
Level 1 studies are studies that use a blind comparison of the test
withw a validated reference standard (gold standard)
In a sample of patients that reflects the population to whom the
test would apply
Level 2 studies are studies that have only one of the following:
Narrow population (the sample does not reflect the population to
whom the test would apply)
Use a poor reference standard (defined as that where the “test” is
included in the “reference” or where the “testing” affects the
“reference”)
The comparison between the test and reference is not blind
Case–control studies
Level 3 studies are studies that have at least two or three of the
features listed above
*Homogeneity means there are no or minor variations in the directions and
degrees of results between individual studies that are included in the sys-
tematic review.
Table 12.2 Grading of Recommendations on
Diagnostic Tests
Grade A: Studies with level of evidence Ia or Ib
Grade B: Studies with level of evidence II
Grade C: Studies with level of evidence III
Grade D: Studies with level of evidence IV
CI 0.61–0.80). Moreover, in the 35 studies with specificity
higher than 85%, [18F]FDG PET was still the most sensitive
technique, the combined sensitivity being 55% for US, 72%
for CT, 76% for MR imaging, and 90% for FDG PET.
The second systematic review was published by Bipat et al.
in 2005 and aimed at evaluating CT, MR imaging, and [18F]
 LIVER METASTASES: DETECTION AND IMAGING
FDG PET for the detection of colorectal liver metastases on a
per-patient and per-lesion bases, reviewing articles from
1990 to 2003 (27). Among the 61 selected studies, 28 assessed
nonhelical CT, 15 assessed helical CT, 5 concerned 1.0T MRI,
12 concerned 1.5T MRI, and 21 addressed [18F]FDG PET. On
a “per-patient” basis, the combined sensitivity of PET (0.95,
95% CI 0.93–0.96) was significantly superior to that of non-
helical CT (0.60, 95% CI 0.58–0.65), helical CT (0.65, 95%
CI 0.30–0.89), and 1.5T MRI (0.76, 95% CI 0.56–0.89) (Level
of evidence II). On a “per–lesion” basis, nonhelical CT sensi-
tivity (0.52, 95% CI 0.52–0.53) was significantly lower than
that of helical CT (0.64, 95% CI 0.54–0.72), 1.0T MRI (0.66,
95% CI 0.66–0.66), 1.5T MRI (0.64, 95% CI 0.58–0.71), and
PET (0.76, 95% CI 0.61–0.86). In other words, there was no
evidence that the “per-lesion” sensitivities of PET, helical
CT, and MRI differed significantly. For lesions of 1 cm or
larger, SPIO-enhanced MR imaging was the most accurate
modality.
Therefore, considerable debate continues about which imag-
ing modality offers the best noninvasive examination of the
liver, and so some comments concerning the existing evidence
need to be addressed.
First, the diagnostic value of imaging techniques can be
computed per patient (detection of at least one lesion per
patient) or per lesion (detection of all lesions per patient). But,
in cancer patients, the per-patient analysis is not adequate
because the main question is not: “Does the patient have liver
metastases?” But rather, “How many metastases are in the liver,
and where?” As previously seen in the results of the prior meta-
analyses, the per-lesion comparison of imaging modalities is
still open.
The second point worth considering is the frequent use of a
suboptimal diagnostic reference standard. The most reliable
reference standard is the combination of direct visualization
and bimanual palpation of the liver, intraoperative US, and
histopathological examination of resected liver tissue of each
lesion found in the liver, so allowing for a lesion-by-lesion
analysis. But only a minority of studies used this reference
standard, resulting in underdetection of lesions and overesti-
mation of sensitivity. Studies that analyzed the detection of
liver metastases without this surgical reference standard (that
is using imaging follow-up or a combination of other imaging
modalities) are of limited value because sensitivity of the
methodology will appear higher than the true one. It should
be noted that even with this extensive pre- and intraoperative
workup, lesions may be missed and in two series approxi-
mately 15% of patients were found to have “new” tumors on
follow-up CT scans performed four to six months after hepatic
resection (30,31).
Third, the imaging modalities analyzed in the two meta-
analyses extended for a long period of time from 1985 or
1990 to 2000 and their results are difficult to compare with
up-to-date imaging. Research on hepatic contrast agents
has advanced in two directions: first the development of
US contrast agent, especially the more stable second gen-
eration of contrast media, has prompted a revival of inter-
est in contrast-enhanced US; second tissue-specific MR
contrast agents have been developed to target the main cell
populations of the liver. These advances, as well as those of
multidetector-row CT (32 or 64 slice systems) or PET/CT,
were not integrated in the two available systematic reviews
but were discussed in the Rappeport and Loft narrative
review (29).
Considering the available comparisons of modern MR
imaging, multidetector-row CT and PET in the same group of
patients with surgical reference standards, Rappeport and Loft
questioned the conclusions of the two prior systematic reviews.
The authors concluded that “state-of the-art anatomical imag-
ing, e.g., liver-specific MR imaging and multidetector CT,
must be considered more sensitive than PET in the detection
of individual liver metastases” (Level of evidence II) (29). They
also stated that “a preoperative PET/CT-study for detection of
possible extra-hepatic tumor contraindicating liver surgery is
also recommended.” Moreover, recent articles have pointed
out the limitation of FDG-PET in detecting small liver
metastases, with a significant superiority of CT and MR
imaging (32–34). This is a key result because most lesions
larger than 1 cm are depicted on all imaging techniques, but
the detection of subcentimeter metastases remains disap-
pointing and therefore the comparison of imaging modalities
should focus on these small lesions.
Consequently, the question seems to be which is the better
imaging modality between CT and MR? And should we use
nonspecific MR contrast or liver-specific contrast agents? We
have to take into consideration the following:
● Multidetector-row CT scanning is often the first
choice for a “screening” liver examination at many
institutions. This technique also enables rapid scan-
ning of the chest and abdomen and allows evaluation
of extrahepatic disease.
● MRI enhanced with SPIO is probably a more sensi-
tive method than multidetector-row CT for detect-
ing liver metastases (35,36), but to our knowledge,
no study has evaluated the added value of MR imag-
ing after multidetector-row CT examination and the
consequences in treatment planning.
Based on the existing evidence, it is difficult to provide high-
strength management recommendations. Our policy at our
institution is to perform systematically a multidetector CT in
patients with liver metastases. PET/CT is indicated for the
detection of extrahepatic tumor before liver surgery. MR
imaging is not routinely performed and is reserved for charac-
terization of small liver lesions, in fatty livers, and in difficult
cases after multidetector CT. For lesion characterization, we
use nonspecific contrast MR agents, while for tumor detection
and preoperative staging, we use liver-specific contrast agents.
In both cases, our protocol includes diffusion-weighted MR
sequences. Intraoperative US is routinely performed in our
institution and intraoperative contrast-enhanced US is under
investigation.
preoperative staging
Due to their biological properties, most liver metastases that
are resected are secondary to CRC. Selected isolated liver
metastases from breast cancer, sarcoma, renal cell cancer
115
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
and Wilms’ tumors, melanoma, other GI cancers, and, most
frequently, endocrine tumors, may benefit from liver
resection (5).
Assessment of the number and location of liver metastases is
a major issue of preoperative staging and has been described
previously. Yet, imaging has to answer other questions relevant
to technical success and R0 resection:
● Does the future liver remnant have sufficient volume
for the perioperative and postoperative course? This
question is easily addressed by CT or MR volumetric
measurement.
● Does the future liver remnant have satisfactory vas-
cular inflow, venous outflow, and biliary drainage?
Again CT or MR imaging is adequate to answer this
question.
● Is there any contraindication to performing an R0
resection? This point is more difficult as classical
contraindications such as bilobar metastases are
overcome in most specialized centers either by two-
step resection with preoperative portal embolization
to increase the remaining normal liver parenchyma
or downsizing with chemotherapy, or combination
of resection and thermal ablation (37). However, it is
crucial to evaluate the relationship between the liver
tumors and important anatomical landmarks such
as the inferior vena cava (IVC), hepatic venous con-
fluence, and the main portal pedicles.
● Did the liver metastases respond to preoperative che-
motherapy? Preoperative chemotherapy is currently
performed in resectable patients as it has been shown
to reduce the risk of events of progression-free
survival in eligible and resected patients (38). In
these patients, the role of imaging is to evaluate
the tumor response according to RECIST (Response
Evaluation Criteria in Solid Tumors) criteria.
Association with targeted therapy may render more
complex this assessment.
references
1. Pickren J, Tsukada Y, Lane W. Analysis of autopsy data. In: Weiss L, Gilbert
H, eds. Liver Metastasis. Boston, MA: Hall, 1982: 2–18.
2. Kune GA, Kune S, Field B, et al. Survival in patients with large-bowel can-
cer. A population-based investigation from the Melbourne Colorectal
Cancer Study. Dis Colon Rectum 1990; 33: 938–46.
3. Manfredi S, Lepage C, Hatem C, et al. Epidemiology and management of
liver metastases from colorectal cancer. Ann Surg 2006; 244: 254–9.
4. Ballantyne GH, Quin J. Surgical treatment of liver metastases in patients
with colorectal cancer. Cancer 1993; 71: 4252–66.
5. Elias D, Lasser P, Ducreux M, et al. Liver resection (and associated extrahe-
patic resections) for metastatic well-differentiated endocrine tumors: a
15-year single center prospective study. Surgery 2003; 133: 375–82.
6. Hughes K, Sugarbaker P. Resection of the liver for metastatic solid tumors.
In: SA R, ed. Surgical Treatment of Metastatic Cancer. Philadelphia, PA:
Lippincott, 1987; 125–64.
7. Leyvraz S, Spataro V, Bauer J, et al. Treatment of ocular melanoma meta-
static to the liver by hepatic arterial chemotherapy. J Clin Oncol 1997; 15:
2589–95.
8. Albrecht T. Detection and characterisation of liver metastases. In: Len-
cioni R, ed. Enhancing the Role of Ultrasound with Contrast Agents.
Milan: Springer, 2006; 53–67.
116
9. Albrecht T, Hoffmann CW, Schmitz SA, et al. Phase-inversion sono-
graphy during the liver-specific late phase of contrast enhancement:
improved detection of liver metastases. AJR Am J Roentgenol 2001; 176:
1191–8.
10. van Leeuwen MS, Noordzij J, Feldberg MA, Hennipman AH, Door-
newaard H. Focal liver lesions: characterization with triphasic spiral CT.
Radiology 1996; 201: 327–36.
11. Nino-Murcia M, Olcott EW, Jeffrey RB, Jr., et al. Focal liver lesions: pat-
tern-based classification scheme for enhancement at arterial phase CT.
Radiology 2000; 215: 746–51.
12. Danet IM, Semelka RC, Leonardou P, et al. Spectrum of MRI appear-
ances of untreated metastases of the liver. AJR Am J Roentgenol 2003; 181:
809–17.
13. Kim KW, Kim AY, Kim TK, et al. Small (< or = 2 cm) hepatic lesions in
colorectal cancer patients: detection and characterization on manga-
fodipir trisodium-enhanced MRI. AJR Am J Roentgenol 2004; 182:
1233–40.
14. Schima W, Kulinna C, Langenberger H, Ba-Ssalamah A. Liver metastases
of colorectal cancer: US, CT or MR? Cancer Imaging 2005; 5 Spec No A:
S149–56.
15. Nasu K, Kuroki Y, Nawano S, et al. Hepatic metastases: diffusion-weighted
sensitivity-encoding versus SPIO-enhanced MR imaging. Radiology
2006; 239: 122–30.
16. Parikh T, Drew SJ, Lee VS, et al. Focal liver lesion detection and char-
acterization with diffusion-weighted MR imaging: comparison with
standard breath-hold T2-weighted imaging. Radiology 2008; 246:
812–22.
17. Badiee S, Franc BL, Webb EM, et al. Role of IV iodinated contrast material
in 18F-FDG PET/CT of liver metastases. AJR Am J Roentgenol 2008; 191:
1436–9.
18. Cuenod C, Leconte I, Siauve N, et al. Early changes in liver perfusion
caused by occult metastases in rats: detection with quantitative CT. Radi-
ology 2001; 218: 556–61.
19. Hale HL, Husband JE, Gossios K, Norman AR, Cunningham D. CT of
calcified liver metastases in colorectal carcinoma. Clin Radiol 1998;
53: 735–41.
20. Povoski SP, Klimstra DS, Brown KT, et al. Recognition of intrabiliary
hepatic metastases from colorectal adenocarcinoma. HPB Surg 2000;
11: 383–90, discussion 390–1.
21. Kubo M, Sakamoto M, Fukushima N, et al. Less aggressive features of
colorectal cancer with liver metastases showing macroscopic intrabiliary
extension. Pathol Int 2002; 52: 514–18.
22. Schwartz LH, Gandras EJ, Colangelo SM, Ercolani MC, Panicek DM.
Prevalence and importance of small hepatic lesions found at CT in
patients with cancer. Radiology 1999; 210: 71–4.
23. van Erkel AR, Pijl ME, van den Berg-Huysmans AA, et al. Hepatic metas-
tases in patients with colorectal cancer: relationship between size of
metastases, standard of reference, and detection rates. Radiology 2002;
224: 404–9.
24. Eberhardt SC, Choi PH, Bach AM, et al. Utility of sonography for small
hepatic lesions found on computed tomography in patients with cancer. J
Ultrasound Med 2003; 22: 335–43; quiz 345–46.
25. Mueller GC, Hussain HK, Carlos RC, Nghiem HV, Francis IR. Effective-
ness of MR imaging in characterizing small hepatic lesions: routine versus
expert interpretation. AJR Am J Roentgenol 2003; 180: 673–80.
26. Bipat S, van Leeuwen MS, Ijzermans JN, et al. Imaging and treatment of
patients with colorectal liver metastases in the Netherlands: a survey. Neth
J Med 2006; 64: 147–51.
27. Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal liver metastases:
CT, MR imaging, and PET for diagnosis: meta-analysis. Radiology 2005;
237: 123–31.
28. Kinkel K, Lu Y, Both M, Warren RS, Thoeni RF. Detection of hepatic
metastases from cancers of the gastrointestinal tract by using noninvasive
imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology
2002; 224: 748–56.
29. Rappeport ED, Loft A. Liver metastases from colorectal cancer: imaging
with superparamagnetic iron oxide (SPIO)-enhanced MR imaging, com-
puted tomography and positron emission tomography. Abdom Imaging
2007; 32: 624–34.
 LIVER METASTASES: DETECTION AND IMAGING
30. Ward J, Guthrie JA, Wilson D, et al. Colorectal hepatic metastases: detec-
tion with SPIO-enhanced breath-hold MR imaging: comparison of
optimized sequences. Radiology 2003; 228: 709–18.
31. Ward J, Robinson PJ, Guthrie JA, et al. Liver metastases in candidates for
hepatic resection: comparison of helical CT and gadolinium- and SPIO-
enhanced MR imaging. Radiology 2005; 237: 170–80.
32. Coenegrachts K, De Geeter F, Ter Beek L, et al. Comparison of MRI
(including SS SE-EPI and SPIO-enhanced MRI) and FDG-PET/CT for
the detection of colorectal liver metastases. Eur Radiol 2009; 19: 370–9.
33. Kong G, Jackson C, Koh DM, et al. The use of 18F-FDG PET/CT in
colorectal liver metastases: comparison with CT and liver MRI. Eur J Nucl
Med Mol Imaging 2008; 35: 1323–9.
34. Rappeport ED, Loft A, Berthelsen AK, et al. Contrast-enhanced
FDG-PET/CT vs. SPIO-enhanced MRI vs. FDG-PET vs. CT in patients
with liver metastases from colorectal cancer: a prospective study with
intraoperative confirmation. Acta Radiol 2007; 48: 369–78.
35. Onishi H, Murakami T, Kim T, et al. Hepatic metastases: detection with
multi-detector row CT, SPIO-enhanced MR imaging, and both techniques
combined. Radiology 2006; 239: 131–8.
36. Ward J. New MR techniques for the detection of liver metastases. Cancer
Imaging 2006; 6: 33–42.
37. Gonzalez HD, Figueras J. Practical questions in liver metastases of
colorectal cancer: general principles of treatment. HPB 2007; 9:
251–8.
38. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy
with FOLFOX4 and surgery versus surgery alone for resectable liver
metastases from colorectal cancer (EORTC Intergroup trial 40983): a
randomised controlled trial. Lancet 2008; 371: 1007–16.
117
13 Surgery for metastatic colorectal cancer
René Adam and E. Hoti
introduction
Colorectal cancer (CRC) is a common malignancy with a very
high incidence in Western countries. Approximately 150,000
new cases of CRC occur each year in the United States,
accounting for more than 55,000 cancer-related deaths (1).
Over half the patients diagnosed with CRC will develop liver
metastases (CRLM) during the course of their disease (2), of
which 15% to 25% will have liver metastases at the time of the
diagnosis (3,4). In the absence of surgical treatment, 5-year
survival is exceptional (5) and even with the best chemo- and
bio-therapies, to date, median survival of unresected disease
does not exceed two years (6,7). On the other hand, long-term
survival and potential cure after surgical resection for CRLM
has been demonstrated by numerous studies. Surgery is there-
fore considered as the treatment of choice for patients with
resectable CRLM, yielding a 5-year survival between 35% and
52% (8,9). As a result, hepatic resection has evolved from a
rare procedure associated with considerable mortality to a
routine surgery with an operative mortality risk of around 2%
(10,11). At present, the low operative mortality along with sur-
vival improvement has led to an expansion of more extensive
liver surgery and to a clear change in surgical indications to a
point where virtually no tumor should be considered unre-
sectable provided that resection can be complete. These
advances combined with novel systemic and regional ablative
therapies have modified the course of the disease, transform-
ing it from a uniformly fatal to increasingly curable for a
majority of patients.
natural history of colorectal liver
metastases
The natural history of untreated CRLM has been well studied.
The median survival untreated following diagnosis is 6 to
12 months and 5-year survival is extremely rare. Most studies
indicate that the prognosis is most closely related to tumor
burden. Wood et al. showed that while the 1-year survival was
only 5.7% for patients with widespread disease, 60% of the
patients with solitary liver metastases were alive at 1 year with
a mean survival of 25 months (12). Wagner et al. (5) reported
the 3- and 5-year survival for untreated resectable disease to be
14% and 2%, compared to 4% and 0% for unresectable dis-
ease. Wilson and Adson (13) in their case-controlled study
(60 patients treated with hepatic resection versus 60 compa-
rable patients not subjected to surgery) demonstrated that
hepatic resection was associated with 5-, 10- year survival of
25% and 19% compared to no 5-year survival in the non
resectable group. Two other case-control studies demonstrated
almost identical results (5,14). Scheele et al. (14) reported a
5-year survival rate 40% in patients who underwent tumor
resections compared to 0% in 62 patients who had potentially
resectable tumors but did not undergo resection.
118
Although long-term survival and potential cure after surgi-
cal resection has not been demonstrated by randomized con-
trolled trials, the evidence (uniformly poor results observed in
untreated patients in contrast to extensive data documenting
long-term survival after hepatectomy) supports a significant
survival benefit from resection and has provided the rationale
for increasing indications for liver surgery as the most effective
treatment of CRLM.
patient evaluation
Patient Selection for Surgery
In deciding which patient will tolerate liver resection, a num-
ber of factors will need to be considered, including patient
comorbidities. Age per se is not an independent factor for
increased operative risk (15). This is a very important fact,
considering that an increasing proportion of patients being
evaluated for surgery for malignant disease, are elderly. On the
other hand, scores like the American Society of Anaesthesiol-
ogy (ASA) (16) or the preoperative Acute Physiology and
Chronic Health Evaluation score do significantly influence the
incidence of postoperative complications. Patients with an
ASA score > 1 have been shown to have more than three times
the mortality and twice the morbidity compared to those
patients with an ASA of 1 (16). Therefore, a major goal of the
preoperative evaluation is to identify patients who are at high
operative risk so those who have a prohibitive risk can be
excluded from surgery whereas those with manageable comor-
bidities can have these conditions addressed preoperatively in
an attempt to reduce their operative risk.
Definition of Tumor Resectability
The earlier definition of the resectability (based on factors
such as number of lesions, size, distribution, etc.) has been
progressively challenged resulting on a concept shift, which
now focuses on whether a macroscopic and microscopic com-
plete (R0) resection of the liver lesion as well as complete
resection of any extrahepatic diseases can be performed. At
present, CRLM are defined as resectable if two aspects are ful-
filled: (1) oncological anticipation that the disease can be com-
pletely resected without any residual hepatic or extrahepatic
disease; (2) maintenance of an adequate volume of the future
remnant liver with preserved vascular inflow, outflow, and
biliary drainage. In general, at least 25% of the total liver is the
minimum safe volume that can be left after liver resection in
patients with normal liver parenchyma (17).
Preoperative Imaging
The complex decision to determine resectability requires
detailed anatomic imaging to determine tumor location,
exclude unresectable extrahepatic metastases, and assess the
adequacy of the liver parenchyma after surgery. There are a
 SURGERY FOR METASTATIC COLORECTAL CANCER
myriad of diagnostic capabilities available to date, including
three-dimensional CT scanning, CT angiography, magnetic
resonance angiography (MRI), and CT volumetry. Neverthe-
less, despite the evolution of imaging modalities, difficulties
still exist, especially when trying to differentiate between
metastases and benign liver lesions or to detect small meta-
static lesions. The current approach to address these pitfalls is
to use a multimodality strategy (18). For example, although
helical CT scanning provides information for the entire chest
and abdomen during a single breath hold, up to 25% of the
lesion can still be missed (19). MRI, on the other hand, is cur-
rently the most effective imaging modality in detecting and
characterizing liver lesions and is often ordered prior to liver
resection to characterize indeterminate lesions seen on a CT
scan as it has a higher sensitivity to detect and characterize
small lesions (20). Using liver-specific contrast agents, MRI
has equivalent sensitivity to CT angiography (21) (Level of
evidence: 1). Positron emission tomography (PET) is another
useful modality for detecting liver metastases, especially when
combined with CT scann. However, it is no more sensitive
than MRI in detection, and it lacks the special resolution and
the ability to characterize lesions. Truant et al. (22) correlated
PET and CT findings in 53 patients with final pathologic diag-
noses. They found that PET detected significantly more extra-
hepatic, intraperitoneal metastases than CT, with a sensitivity
of 63% versus 25%. Another meta-analysis study, comparing
helical CT, MRI, and fluorodeoxy-glucose PET (FDG-PET) in
the detection of colorectal liver metastases, showed that the
sensitivities on a per-patient basis were 64.7%, 78.8%, and
94.6%, respectively (23). In contrast, there are other reports
that have questioned the superiority of the FDG-PET and con-
sider MRI and helical CT more sensitive in detecting small
liver metastases (24,25). PET and FDG-PET are, however,
more advantageous in identifying extrahepatic and possible
unresectable metastases, which could be a contraindication to
liver resection (26) (Level of evidence 1). In addition, the abil-
ity of the later investigation to detect occult disease prevents
unnecessary surgery in 21.5% of patients and changes the
overall management in 25% (26). Hence, despite their pitfalls,
the use of image overlays, combining FDG-PET and helical CT
or MRI, can increase the accuracy of preoperative staging
before hepatic resection (27) (Level of evidence: 1).
prognostic factors and clinical risk scores
Prognostic Factors
The importance of prognostic factors lies in two aspects: eval-
uation of the prognosis and selection of candidates for surgery.
With the evolution, some accepted negative prognostic factors
are no more considered, while new ones appear as substitutes.
Factors that have been consistently considered as absolute or
relative contraindications to liver resection are number/loca-
tion of liver metastases, resection margin, presence of extrahe-
patic disease, and tumor involvement of portal lymph nodes.
● The number of metastases (≥4) is no longer considered
a contraindication (28) to liver resection (based on the
fact that long-term survival can be obtained for
patients with four or more metastases treated with
surgery). When resecting ≥4 liver metastases, the lim-
iting factor is not the number of metastases but
whether it is possible to remove all of them (29–32).
Similarly, the distribution (bilobar metastatic disease)
is no longer considered as a prohibitive prognostic
factor. Ercolani et al. (33) reported that the total tumor
volume of liver metastases had a stronger influence on
survival than did number and location. Also, data
from LiverMetSurvey concerning patients with bilo-
bar metastatic disease have demonstrated a 1-, 5-, and
10-year survival of 90%, 44%, and 22%, respectively
(34). In general, if a complete resection of the metasta-
ses can be achieved with safe margins (R0 resection)
while maintaining a sufficient volume of the residual
liver, the number and location should not be consid-
ered as a contraindication to resection.
● Whereas achieving a negative resection margin is well
established, the extent of this margin clearance
remains controversial. Increasingly, studies are dem-
onstrating that there is no significant difference in
survival or recurrence related to the width of margin
achieved. Elias et al. (35) demonstrated that the over-
all survival of patients with resection margins less
than 1 cm was 27.8%, comparable to those with resec-
tion margins of ≥1 cm. Fong et al. (36), in his series of
426 patients undergoing hepatectomy for CRLM,
reported an identical 5-year survival in the group
with a clear margin of <1 cm compared to the group
with a margin of 1 cm or greater. Similarly, Figueras
et al. (37) reported that subcentimeter nonpositive
surgical margin did not influence hepatic recurrence
rates after hepatectomy for CLM. Kokudo et al. (38),
in his study, went further on by demonstrating that a
margin of 2 mm is clinically the minimum acceptable
requirement, which carries approximately a 6% risk of
margin-related recurrence. A recently published study
from our center showed that despite a higher recur-
rence rate in patients with R1 resection (complete mac-
roscopic resection with 0 mm free margin) compared
to patients with R0 resection, the two groups had a
similar overall and disease-free survival (61% vs. 57%
and 28% vs. 17%) and recurrences were intrahepatic
rather than being localized at the surgical margin (39).
Therefore, the absence of “safe” margins of resection should
not be considered as an absolute contraindication to surgery
provided that all tumors can be macroscopically resected.
However, at the present surgeons should continue to plan
hepatic resection with a preserved “safety zone” and avoid rou-
tine use of “minimum margin” surgery.
● The presence of extrahepatic disease reduces the
hope of long-term survival and it has been consid-
ered as a contraindication to liver resection. Lately,
however, resection in patients with extrahepatic
disease with curative intent has been advocated by
some groups. In a French series (40) of 84 patients
who underwent complete resection of extrahepatic
disease concurrently with hepatic resection, the
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

overall 5-year survival was 28% compared to 34% in
the 224 patients undergoing liver resection alone. In
addition, the study demonstrated that the total num-
ber of metastases has a stronger negative prognostic
value after complete resection than their location.
Other reports have suggested that patients with
extrahepatic metastases may survive more than
5 years after a successful liver resection (41) (Level of
evidence: 3). Encouraging results have been reported
even after combined resection of concomitant liver
metastases and peritoneal carcinomatosis, which has
been traditionally considered as an absolute contra-
indication to liver resection (42,43). However, these
results are observed in patients with a limited num-
ber of liver metastases (≤3 lesions).
● Involvement of the portal lymph nodes may be present
in as many as 14% of patients with CRLM (44). Some
authors have suggested that radical excision of involved
portal nodes can produce a survival benefit (45). In a
prospective study conducted by Jaeck et al. (46), the
survival rate in patients with involved portal lymph
nodes was significantly lower than in the control group
(3-year survival 19% vs. 62%). However, patients with
involved lymph nodes limited to the hepatoduodenal
ligament and retropancreatic portion demonstrated a
much better prognosis than those with involved lymph
nodes around the common hepatic artery and celiac
axis (3-year survival 38% vs. 0%). In a more recent
study (47) conducted in patients responding to preop-
erative chemotherapy, we reported that combining
liver resection and pedicular lymphadenopathy was
justified in patients with involved pedicular lymph
nodes (3- and 5-year survival 38% and 18%, respec-
tively). Conversely, in patients with involved celiac or
retroperitoneal lymph nodes, this approach was not
justified (5-year survival 0%). In this group of patients,
even the response to chemotherapy did not seem to
change their usual poor prognosis.
Whereas preoperative factors may be generally instructive,
these should not be used to exclude patients from surgical con-
sideration. Patients with one or multiple negative prognostic
factors can still derive a significant survival advantage from
hepatic resection of their CRLM.
To conclude, it is important to mention that at the present
time the only unchallenged contraindication to liver resection
is the impossibility to remove all metastatic disease, while leav-
ing sufficient functional hepatic parenchyma, regardless of the
location, distribution, number and size of the metastases.
Clinical Risk Scores
Over 10 years ago, Nordlinger (48) introduced the first scoring
system for patients with CRLM, based on a multicenter data
from 1568 patients who accepted potentially curative resec-
tions. In this large series, they identified three groups of
patients with low, intermediate and high risk for poor progno-
sis based on seven high risk factors (see Table 13.1A). Since
then, at least six more scoring systems have been developed
among which the proposal from Fong et al. (49) based on a
single institution series of 1001 patients attracted the most
attention. Seven parameters were found to be independent
predictors of prognosis. These include presence of extrahe-
patic disease; positive resection margin; nodal metastases
from primary cancer; short disease free interval; largest tumor
greater than 5 cm; more than 1 liver metastases; CEA greater
than 200 ng/ml (see Table 13.1A). The data for the first two
parameters are not available preoperatively. However, using
the last five criteria, a preoperative clinical risk score system
was created with each positive criterion counting as 1 point.
The total score out of 5 is highly predictive of a poor outcome
(5-year survival 14%). Patients with a score of 0, 1, and 2 have
a highly favorable outcome (5-year survival 60%, 44%, and
40%, respectively). Table 13.1B demonstrates the survival
rates for each score grade.
Table 13.1A Prognostic Scoring Systems
Fong’s score* Nordlinger’s score*
Node-positive primary tumor Stage of the primary tumor
Disease-free interval Disease free interval (≥2 years vs.
(<12 months between colon <2 years)
resection and appearance of
metastases)
Size of largest lesion >5 cm Size of the largest metastasis
(<5 cm vs. ≥5 cm)
More than 1 tumor Number of liver nodules (1–3 vs.
4 or more)
CEA >200 ng/mL Resection margin (>1cm vs.
<1 cm)
Age (<60 years vs. ≥ 60 years
*One point is assigned for each risk factor

Table 13.1B Survival Rates for Each Score Grade

Survival (%)
Fong’s score Nordlinger’s score
Score 1 year 3 years 5 years Median (mo) Risk groups Risk factors 2 years
0 93 72 60 74
1 91 66 44 51 Low risk 0–2 79
2 89 60 40 47
3 86 42 20 33 Intermediate risk 3–4 60
4 70 38 25 20
5 71 27 14 22 High risk 5–7 43

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 SURGERY FOR METASTATIC COLORECTAL CANCER
The applicability of this score has been evaluated by inde-
pendent investigators from Norway (50), indicating that the
score is applicable to other populations outside of a large
tertiary U.S. center. Recent data from Asia has shown that CRS
is useful for predicting outcome after ablative therapy of liver
metastases. Also the CRS can help to select the extent and
sophistication of preoperative assessment (51) acting as a risk
stratification tool in identifying patients who are most and
least likely to have their management altered by the results of
the test.
In practice, although the scores are simple, easy to use and
highly predictive of long-term outcome their clinical relevance
in terms of indications and contraindications to surgery is low
since even with poor prognostic factors, hepatic resection can
provide a chance of long-term survival. Patients with poor
scores could, however, be selected more appropriately for neo-
adjuvant and adjuvant therapy or for refined preoperative
imaging (routine PET CT) to exclude those with contraindica-
tions to surgery. In addition, scores have proved useful for
comparing results from different centers for surgical and abla-
tive therapies as well as stratification of patients for trials.
management of patients with resectable
colorectal liver metastases
Preoperative management
Neoadjuvant Chemotherapy
Conventional first-line chemotherapeutic regimens for resect-
able colorectal liver metastases (CRLM) contain fluorouracil
(5-FU) in addition to leucovorin. Using a bolus administra-
tion regimen for patients treated with 5-FU and leucovorin
response rates ranging from 20% to 30% and a median sur-
vival of 11.5 months has been reported (52,53). No significant
difference in median survival has been observed when the
5-FU was delivered by continuous infusion, despite improve-
ment of the response rate and reduction of the toxicity.
Combination of 5-FU with newer drugs such as irinotecan
(topoisomerase I inhibitor) resulted in a higher response rate
(39%), longer progression free and overall survival time
(14.8) compared to 5-FU and leucovorin alone (54). In addi-
tion, it has been shown that irinotecan in combination with
continuous infusion of 5-FU/ leucovorin (FOLFIRI) produces
better response rates and longer progression free and overall
survival compared to 5-FU/leucovorin alone (55). More
recently, the combination of infusional 5-FU/leucovorin with
oxaliplatin (cisplatin derivative) has been found to be less
toxic and more efficacious than the bolus irinotecan/5-FU/
leucovorin regimen (56,57). Whether the combination of
infusional 5-FU/leucovorin with oxaliplatin (FOLFOX) or
FOLFIRI is better as first-line chemotherapy remains contro-
versial as they have comparable response rates. What may be
more persuasive is that when these regimens are used sequen-
tially when progression or toxicity occurs, regardless the order,
survival is prolonged.
For patients with up to four liver metastases, a prospective
trial conducted by the European Organization for the Research
and Treatment of Cancer compared surgery alone versus
surgery with perioperative chemotherapy (FOLFOX
4 – oxaliplatin/5-FU/leucovorin), six cycles before and six cycles
after the surgery (58). The preoperative cycles induced a com-
plete response in 3.8% of patients and a partial response in
40.1% with a decrease in the diameter of the nodules of 29.5%.
At 3 years, the disease-free survival was 28.1% in the group
treated with surgery alone and 35.4% in the group that received
perioperative chemotherapy (p = 0.058). The reduction of the
size of the nodules could modify and facilitate the liver resection
with a minor hepatectomy instead of a major liver resection.
In patients presenting with five or more bilobar metastases,
Tanaka et al. (59) showed that the 5-year survival rate was 38.9%
in the group receiving neoadjuvant chemotherapy compared to
20.7% of the group treated with hepatectomy alone. In addi-
tion, multivariate analysis revealed neoadjuvant chemotherapy
to be an independent predictive factor for survival. These results
suggest a survival benefit of neoadjuvant chemotherapy in
patients with resectable metastases. Whether the use of adju-
vant chemotherapy would translate as the “gold standard” prac-
tice is still a matter of debate. Obviously, multinodular
metastases are very likely to benefit from neoadjuvant chemo-
therapy owing to the potential of missing small metastases.
Approaches to Surgery
Assessment of Functional Hepatic Reserve
The functional hepatic reserve can be assessed by Child–Pugh
score and hepatic biological blood tests, however, to date the
only test which has proven to have a good predictive value is
the indocyanine green (ICG) clearance test (60). In candidates
for liver resection with retention of less than 20% of ICG at
15 minutes, up to 60% of the volume of the parenchyma can
be resected. Although liver metastases rarely develop in cir-
rhotic liver, with the ever increasing use of more efficient che-
motherapy regimens and targeted agents, a rising number of
patients are expected to present with damaged livers as a result
of chemotherapy given before resection. Specific pathologic
changes of the liver parenchyma (vascular changes and/or che-
motherapy associated steatohepatitis) influencing the liver
regeneration and function as well as the ability of the patient
to recover have been observed, following administration of
preoperative chemotherapy. Hence in this new context, evalu-
ation of the functional reserve of the liver is becoming critical.
Preoperative Biopsies
Currently routine biopsy of liver lesions as part of the diagnos-
tic process for patients who are thought to have potentially
resectable lesions is not recommended. Although the seeding
along the needle track has been believed to be very rare (inci-
dence 0.003–0.07%) (61,62), it appears that it has been greatly
underestimated. An incidence of needle track metastases rang-
ing from 10% to 19% has recently been reported (63,64).
Therefore, the potential benefits of liver biopsy in suspected
patients are outweighted by the risk of these serious complica-
tions as well as the risk of deriving false reassurance from a
false-negative result.
Role of Laparoscopy and Laparoscopic Ultrasound (LUS)
Evaluation
In the recent years, many surgeons have advocated the use of
laparoscopy for evaluation of CRLM preoperatively in order to
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
reduce the number of unnecessary surgical explorations. This
procedure has been reported to exclude 25% to 48% of patients
from laparotomy with a false-negative rate of less than 15%
(65,66). Grobmyer et al. (67) suggested that patients should be
considered for laparoscopic evaluation if they have two of the
following characteristics: lymph node positive primary tumor,
CEA levels greater than 200 ng/mL, >1 hepatic lesion, disease-
free interval <12 months, and hepatic metastatic lesion >5 cm.
Patients with two or more of these factors have a 30% chance of
having occult extrahepatic disease. However, with increasingly
sensitive preoperative imaging and the increasing use of abla-
tion and resection of extrahepatic sites, fewer patients are sub-
jected to nontherapeutic laparoscopy (Level of evidence: 3).
Role of Intraoperative Ultrasound (IOUS)
IOUS is an essential adjunct to conventional imaging and is
widely used to guide surgery and ablative techniques. In expe-
rienced hands, IOUS has been shown to contribute to acquisi-
tion of precise details regarding tumor size, location, extent of
local invasion, and may alter or guide the surgery in up to 67%
of cases (68). Also, when compared with preoperative radio-
logical findings, IOUS has been found to be able to identify at
least one additional malignant lesion in 10% to 12% of cases
(68–70). As such, the use of IOUS should be considered as
mandatory not only for intraoperative diagnostics but also for
determining the type of surgical procedure (resection).
Types of Liver Resection
Generally liver resection can be divided into two groups: ana-
tomic (resection of one or several segments) and nonanatomic
“wedge” resections (resection of a portion of parenchyma sur-
rounding the metastatic lesion). If more than three segments
are resected, the hepatectomy is defined as major. Different
types of anatomic liver resection are performed: right hepatec-
tomy (segments V–VIII), left lateral lobectomy (segments II,
III), and left hepatectomy (segments II–IV). Other types
include central resection (segments IV, V, VIII) and bisegmen-
tectomies (segments V, VI or segments IV, V). Resections
exceeding the boundaries of a normal right or left are defined
as extended hepatic resections and are divided in six different
types. Right hepatectomies extended to segment IV, segment I,
or both. Similarly, extended left hepatectomies may include
segment I, segments V and VIII, or segments I, V, and VIII.
Selecting the Resection Type
The principles of hepatic resection (including the oncological
goal which is to remove all metastatic sites with tumor free
margins) are no different for colorectal metastases than for
any other hepatic surgery. Rather than dogmatically adhering
to an anatomical versus nonanatomic approach, the hepatobi-
liary surgeons now guide their decisions aiming ultimately at
resecting all metastases with negative histologic margins.
Therefore, the type of resection chosen for a particular patient
is and should be individualized based on the size, number, and
location of the metastases, their relation to main vascular ped-
icles, and the volume of future liver parenchyma. Whereas a
small, superficial metastasis can be best treated with a nonana-
tomic resection, a large metastasis deeply located within the
122
Figure 13.1 Picture showing multiple metastasectomies with maximal preser-
vation of the liver parenchyma.
liver may be treated with an anatomical, segment-oriented
resection. The extent of liver resection (major vs. minor or
anatomic vs. nonanatomic resection) is not by itself a prog-
nostic factor. Therefore, independently of being anatomic or
nonanatomic, resection should spare as much as possible the
nontumoral parenchyma, bearing in mind that new recur-
rences could eventually develop for which surgery could pos-
sibly be indicated again (see Fig. 13.1).
postoperative management
Adjuvant Systemic Chemotherapy
At present, despite several chemotherapy regimens, data would
support the use of 5-FU and leucovorin as adjuvant chemo-
therapy after liver resection if patients have not previously
failed this regimen. Portier et al., in a multicenter trial that ran-
domized 173 patients after hepatectomy for CRLM to surgery
alone or to surgery followed by chemotherapy (5-FU/ Leucovo-
rin), demonstrated that patients who received adjuvant chemo-
therapy had a significantly better disease-free survival compared
to that of patients treated with surgery alone (34% vs. 27%; p =
0.03) (71). A year later, Park et al., in a large two-center study
comparing 518 patients treated with no chemotherapy (379
American, 139 European) to 274 patients treated (240 Ameri-
can, 34 European) with 5-FU-based adjuvant chemotherapy,
demonstrated that systemic adjuvant chemotherapy prolongs
survival after hepatic resection for colorectal metastases (72).
Patients subjected to adjuvant chemotherapy had improved
survival (p = 0.007) even after stratification by clinical risk
score (p = 0.001). In every clinical risk score category, patients
subjected to adjuvant chemotherapy had a higher chance of
survival (range 1.3–2.0 times).
Meanwhile, for those who have previously failed this reg-
imen, an oxaliplatin- or irinotecan-based regimen should
be considered. Despite that there has not been a clear dem-
onstration of efficacy of any regimen, the higher response
rate observed in patients treated with FOLFOX or FOLFIRI
over the 5-FU/leucovorin has resulted in many groups to
preferentially use these regimens in adjuvant settings.
 SURGERY FOR METASTATIC COLORECTAL CANCER

Table 13.2 Reported Survival Outcomes after Resection of Colorectal Liver Metastases with Curative Intent
Operative Patient survival (%)
No. of mortality Postoperative
Author Year patients (%) morbidity (%) 1 year 3 years 5 years 10 years
Nordlinger 1995 1568 2 – – – 28 –
et al.
Fong et al. 1999 1001 2.8 – 89 57 36 22
Minagawa 2000 235 0.8 – – 51 38 38
et al.
Suzuki et al. 2001 26 – – – 62 32 –
Choti et al. 2002 226 1 18.6 93 57 40 26
Adam et al. 2003 615 1 18 91 61 41 –
Kato et al. 2003 585 0 – – – 33 –
Abdalla et al. 2004 190 – – – 73 58 –
Tanaka et al. 2004 193 1 26 69 46 43 –
Fernandez 2005 100 – 1 86 66 58 –
et al.
Pawlik et al. 2005 557 1 – 97 74 58 –
Wei et al. 2006 423 2 19.6 93 – 47 28

Adjuvant Intra-arterial Chemotherapy
A number of studies have reported the safety, efficacy, and
feasibility of adjuvant regional hepatic chemotherapy.
Kusunoki et al. conducted a nonrandomized trial of HAI
versus systemic chemotherapy after radical liver surgery. He
showed that the 5-year survival was significantly better for
the HAI group compared to the 5-year survival of the sys-
temic group (59% vs. 27%, p < 0.001) (73). Kemeny et al., in
an intergroup study of 109 patients randomized to surgery
alone or surgery and HAI-FUDR, demonstrated that the
4-year disease-free survival was significantly better in the
HAI group (67% vs. 43%) (74). In another larger study,
156 patients were randomized to resection and systemic
5-FU or resection and combined systemic 5-FU and HAI-
FUDR. The patients who were treated with regional therapy
had a significantly better 2-year survival (86% vs. 72%) and
markedly improved liver disease control (75).
In conclusion, convincing evidence currently exist to sup-
port the use of adjuvant chemotherapy, either systemic or
regional, to prevent to some extent the risk of recurrence
following liver resection.
Outcomes of Resection for Colorectal Liver Metastases
Morbidity and Mortality
Overall, the perioperative mortality of liver resection for
CRLM does not exceed 2%, ranging between 0% and 5% in
most published series (10,11,76) and is strongly influenced by
perioperative blood loss, liver function, and extent of liver
resection. In experienced units, even major hepatic resections,
constituting around 50% of cases have perioperative mortality
not exceeding 2% (76). The principal causes of death are liver
failure and sepsis.
It has been observed that the mortality has changed little
over the last two decades, however, this does not mean that
there has not been progress made. With improved safety, sur-
geons are increasingly performing more extensive resections,
which explain the fact why the operative mortality and long-
term survival have plateaued.
In contrast, the perioperative morbidity rate is reported to
be greater than 20% (28,77). The major morbidity associ-
ated with liver resection includes hemorrhage (1–3%), bile
leak and/or fistula (4%), pleural effusion/pneumonia
(5–10%/5–20%), and hepatic failure (3–8%). Of the non-
liver-related complications, intra-abdominal sepsis is found
to be the most frequent major complication, and pulmonary
infection is the most frequent minor complication. Among
liver-related complications, liver failure is the most serious
and occurs in 3% to 8% of all major liver resections often
being lethal. Similarly, intraoperative hemorrhage, although
rare, is another major complication with a mortality as high
as 17% (78).
Long-term Survival Results
Large series have reported a 5-year survival after hepatectomy
for CRLM of 35% to 52% with a 33- to 46-month median sur-
vival (8,9,46,79) (see Table 13.2). However, recent data have
shown an improved 5-year survival rate of 58% after complete
resection of CRLM (35). Also, a number of series with suffi-
ciently long-term follow-up indicate that the 10-year survival
after resection can be expected in 20% to 30% of patients
(12,46,80) (see Table 13.2 and Fig. 13.1). Similarly the Interna-
tional Registry of Hepatic Metastases of Colorectal Cancer
(LiverMetSurvey), which to date includes more than
8000 patients, has demonstrated a 5- and 10-year survival of
41% and 26%, respectively.
An important oncologic question is whether the recently
improved systemic therapies can achieve the same results as
resection for CRLM? This seems unlikely considering that long-
term survival beyond 5-years is rare without liver resection (5)
(Fig. 13.2). Indeed, the survival results can be questioned if
considering that the patients who undergo resection are selected
and may have better outcomes due to less aggressive disease.

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
However, there has never been a controlled trial to compare
resection versus nonresection or conservative treatment of
potentially resectable CRLM and this is unlikely to happen in
the near future unless more efficacious systemic therapy regi-
mens are discovered.
Management of Nonresectable Metastatic Disease
Despite the advances made so far in liver surgery, approxi-
mately 80% to 90% of patients with CRC liver metastases are
not candidates for liver resection at the time of diagnosis.
Apart from the fitness of the patients, the unresectability of
liver lesions is due to the following reasons: technically unable
to completely remove the lesions due to the number, size, and
their distribution; or due to ill location of the metastatic lesion
(infiltration of IVC, confluence of hepatic veins). As the most
frequent cause responsible for technical unresectability is mul-
tinodular bilobar metastatic disease, different approaches used
alone or in tailored combinations have been developed to
improve the resectability rate by either reducing the tumor
burden (in turn the extent of the hepatic resection) or by
increasing the volume of remnant liver parenchyma. Instead,
ill-located metastases are being increasingly treated by radical
surgery such as liver resection combined with total vascular
exclusion (TVE).
Chemotherapy to Downstage Nonresectable
Metastatic Disease
Systemic Chemotherapy
The improved efficacy of chemotherapy agents has not only
allowed increased patient survival in the noncurative setting,
but has allowed a subset of previously unresectable patients to
undergo liver surgery after “tumor downstaging,” a concept
first introduced by our team (81). By reconsidering the initial
unresectability of patients who strongly respond to chemo-
therapy, several investigators have shown that survival can be
achieved by liver resection in a significant proportion of
patients who otherwise would have had a poor outcome
Patient survival after a 1st liver operation for colorectal metastases: 8179 patients
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3
Resected
Figure 13.2 Five- and ten-year survival following hepatectomy for colorectal liver metastases. Source: www.livermetsurvey.org.
124
(Level of evidence: 3). A study conducted by our group (81)
demonstrated that an additional 16% of patients who had ini-
tially unresectable liver metastases became candidates for
hepatic surgery after receiving systemic chemotherapy. The 3-
and 5-year survival rates were 54% and 40%, respectively,
close to those observed after resection of initially resectable
nodules. These results were confirmed by other studies
including ours (82,83). In 2004, we reported that subsequent
rescue surgery for unresectable CRLM downsized by chemo-
therapy resulted in a 5- and 10-year survival rate of 33% and
23%, respectively, with a disease-free survival of 17% at
10 years (82) (Figs. 13.3 and 13.4). In contrast, patients with
tumor progression during preoperative chemotherapy have a
significantly worse outcome, with a 5-year survival of 8%
versus 37% and 30% for patients with objective tumor
response or tumor stabilization (84). Patients with tumor
progression still had a poor prognosis even when a poten-
tially curative hepatic resection was performed. Another
aspect worth mentioning about is the combination of che-
motherapy with new molecular-targeted drugs (bevaci-
zumab, cetuximab). These agents have had a significant
impact on the survival of patients with advanced CRC dis-
ease when integrated with chemotherapy in trials. Using
them in combination with oxaliplatin- or irinotecan-based
regimens, these agents have produced tumor response rates
greater than 50% to 60% (85). Disease control rates (com-
plete response; partial response or stabilization of disease)
exceeded 90% in the report of a phase II study of FOLFOX
combined with cetuximab in nonoperable patients with epi-
dermal growth factor receptor-expressing metastatic CRC
(86). The objective response rate was 79% according to inde-
pendent expert review (87).
Data from the Paul Brousse series showed that the use of
targeted agents in second line therapy also increases the num-
ber of patients eligible for resection. A total of 131 patients
with epidermal growth factor receptor-positive CRLM who
had progressed following two or more lines of FOLFOX or
Log rank p = <0.0001
41%
7737 resected patients
26%
7% 442 nonresected patients
4 5 6 7 8 9 10
Resected Nonresected
 SURGERY FOR METASTATIC COLORECTAL CANCER

FOLFIRI regimens were treated with cetuximab, resulting in
conversion of 7% unresectable patients to resectable.
Certainly, recent results form the randomized trials
(FOLFIRI vs. FOLFIRI/Cetuximab – CRYSTAL trial; and
FOLFOX vs. FOLFOX/Cetuximab – OPUS trial) (88,89)
add further evidence to the benefit conferred by cetuximab
on the response and resection rates in patients with
advanced CRLM treated with standard first-line therapies.
As a result of using combined chemotherapy regimens, the
Paul Brousse Hospital – 473 patients (Apr. 88–Jul. 99)
100 91%
Resectable: 335
Initially non-resectable: 138
80 No surgery
66%
Survival (%)
resection rates have significantly increased compared to
regimens of FOLFOX or FOLFIRI alone. Furthermore, in
two other studies, cetuximab conferred an increase in
response rate and resection rate over standard chemother-
apy alone, with the benefits being the greatest for patients
with KRAS wild-type tumors; CRYSTAL 59% versus 43%
and OPUS 61% versus 37% (90,91).
Intra-arterial Chemotherapy
The interest in using intra-arterial chemotherapy in neoadju-
vant setting has also progressively increased as it has been
demonstrated to have a high response rate in both the first-
and second-line settings. Clavien et al., using HAI-FUDR
with or without leucovorin, induced resectability in 6 (26%)
of 23 previously treated patients. The actuarial survival rates
at 3 years were 84% for responders to neoadjuvant therapy
compared with 40% for nonresponders (92). In a Memorial

60 p = 0.01
48% Sloan-Kettering study (93), 44 patients with extensive liver
metastases received HAI-FUDR and dexamethasone plus
40 52% 30% oxaliplatin-based systemic chemotherapy as part of two Phase
I trials. The study population in this trial had a high number
33%
20 23% of patients with more than 4 metastases, metastases greater
No surgery
than 5 cm, more than 25% liver involvement with tumor, a
0 CEA level greater than 10 ng/dl and previously chemotherapy
0 1 2 3 4 5 6 7 8 9 10
Years exposure. Despite these negative parameters, the objective
Figure 13.3 Curves demonstrating 5- and 10-year survival for initially resect-
response rate was 82%, resulting in complete gross resection
able patients and for patients who underwent rescue surgery. Source : From of tumor in 9 (20%) of the 44 patients and a median survival
Ref. (82). for all patients of 26 months. Recently, preliminary data from

(A) (B)

(C) (D)
Figure 13.4 Unresectable colorectal liver metastases downsized by chemotherapy.

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
several clinical trials using the oxaliplatin or irinotecan via
HAI have been promising.
In summary, regardless the type of chemotherapy used in
unresectable patients, a significant proportion (15–30%) is
switched to resectability. This proportion of patients will
probably expand with the increasing efficacy of chemotherapy
and biological agents, justifying a close collaboration of oncol-
ogists and surgeons in the multidisciplinary treatment of
these patients.
Techniques to Improve Resectability
In addition to preoperative chemotherapy, a number of inter-
ventional/surgical techniques are available to achieve a situa-
tion of resectability include tumor ablation techniques, portal
vein embolization, two-stage liver resection, and extended
liver surgery (total vascular exclusion and cooling).
Tumor Ablation Techniques
Locally ablative modalities such as radiofrequency ablation
(RFA) and cryotherapy are both techniques used either inde-
pendently or as adjunctive to surgery. These techniques are
regarded as complementary to hepatectomy when complete
resection cannot be achieved. The strategy of using them can
result in an increased number of initially unresectable patients
in whom the curative treatment can be accomplished.
● RFA is currently the most commonly applied abla-
tion method. RFA involves localized application of
conductive thermal energy to destroy tumor cells.
Specifically alternating electric current in the range
of radiofrequency waves (460 kHz) is applied from a
generator through a needle electrode placed directly
into the tumor.
Limitations of RFA are related to the lesion size (suitable for
lesions ≤3 cm) or when a maximum of three tumors are pres-
ent as well as the anatomical location of the tumor. In the
vicinity of large hepatic vessels, the heat sink effect signifi-
cantly increases the risk of incomplete ablation. Also, the risk
of thermal injury is increased when nodules are close to main
biliary structures or to extrahepatic organs.
RFA procedure, when performed in combination with sur-
gery, increases the resectability and curability for patients in
whom hepatic resection alone is not curative. Adding RFA to
hepatic resection has been reported to be well tolerated with a
perioperative morbidity and mortality comparable to those
seen after resection alone (94). For metastases considered as
unresectable, RFA combined with hepatic resection can
achieve a median survival as high 37 months (95).
● Cryotherapy involves freezing and thawing of liver
tumors by means of a cryoprobe. Tumor necrosis
occurs by direct cellular freezing and indirectly
through vascular thrombosis and tissue anoxia.
Results of such treatment combined with hepatic
resection for patients not eligible for hepatic resec-
tion alone have shown a 5-year survival rate of 24%,
better than those obtained by palliative chemother-
apy (96,97). Local recurrence at the site of cryother-
apy occurs in 5% to 44% of patients and it has been
126
found that the rate increases when treating multiple
lesions (>8), large lesions (>3 cm), or tumors located
to major blood vessels (blood warmth may impair
the freezing process).
Portal Vein Embolization
Portal vein embolization (PVE), which was first described
by Makuuchi (98), is used to trigger a compensatory hyper-
trophy of the future remnant liver. In patients with an oth-
erwise normal liver, current guidelines recommend
preoperative PVE when the ratio of the remnant liver vol-
ume is <30%. Patients submitted to prolonged chemother-
apy with a high risk of induced hepatic lesions should
benefit from this method when this ratio is less than 40%.
PVE can be performed percutaneously or using the ilocolic
vein approach via a limited laparotomy. After PVE, hepatic
volume is routinely evaluated using CT scanner volumetry,
which gives information about the degree of the compensa-
tory hypertrophy as well as the status of the metastatic dis-
ease. The optimal time interval necessary to induce
maximum hypertrophy after PVE has not been established
yet, although some Japanese teams use to perform resection
as early as 2 weeks after the PVE. The majority of groups,
however, would usually use a 4 to 6 weeks of interval
between PVE and surgery.
PVE is safe and does not add significant morbidity. In our
series, a significant increase of liver volume following preop-
erative PVE was observed in 43% of patients, allowing 63% of
originally unresectable liver metastases to be subsequently
operated (99). The feasibility and the influence on the out-
come in patients requiring an extended hepatectomy has been
reported by other investigators also. Farges et al. (100) pub-
lished the results of a prospective study of PVE performed in
patients undergoing right hepatectomy for either primary liver
cancer or metastatic liver disease. They demonstrated signifi-
cantly fewer postoperative complications when PVE was used
to increase the FLR volume in patients with chronic liver dis-
ease whose anticipated FLR was <40%. In contrast, patients
with normal liver function who underwent a right hepatec-
tomy did not benefit from PVE, as it was expected, since the
remaining liver usually represents more than 30% of the
functional liver volume.
In summary, the PVE needs to be performed only in patients
who are being considered for an extended right hepatic resection.
PVE is rarely necessary prior to extended left hepatectomy
because the right posterior sector typically constitutes about
30% of the total liver volume (101,102). On the other hand, in
patients who have been treated with heavy neoadjuvant che-
motherapies with a high risk of induced parenchymal liver
lesions the PVE should be performed when the ratio of the
remnant liver volume to the total estimated liver volume is less
than 40%.
The selective use of PVE may enable safe and potentially
curative hepatic resection in a subset of patients with advanced
colorectal metastases who would otherwise have been mar-
ginal candidates for resection because of an inadequate FLR
or significant underlying liver disease.
 SURGERY FOR METASTATIC COLORECTAL CANCER

Two-stage Hepatectomy
The concept of “two-stage liver resection” to deal with
multinodular CRC metastatic disease that cannot be
resected in a single procedure owing to a too small volume
of the future remnant liver was first described by our group
(103). During the first stage, the less invaded hemiliver
(usually left) is completely cleared of metastases by resec-
tion, which could be associated with a simultaneous portal
vein ligation/embolization of the most involved hemiliver
(usually right) – or percutaneous portal vein embolization
1 week later. The aim of this step is to minimize the risk
of liver failure by performing a second and complete
resection once regeneration induced by the portal vein
embolization has taken place. Finally a second stage hepa-
tectomy will be carried out to completely remove the liver
harboring the remaining metastases (Fig. 13.5). The suc-
cess of this method relies on the liver regeneration between
the two interventions, allowing the second hepatectomy to
be performed with a lower risk of complications, including
liver failure.
Our experience, as well as that of others, has demonstrated
that this strategy can be carried safely and effectively in
selected patients with initially nonresectable multiple bilobar
CRLM (104–107) (Table 13.3). In our latest study, the 3- and
5-year survival rates were 60% and 42%. It should be men-
tioned that during the first stage performing nonanatomic

(A) (B)

(C) (D)

Figure 13.5 Radiological follow-up of a patient treated with combination of neoadjuvant chemotherapy and two-stage hepatectomy. 1A, hepatic metastases before
chemotherapy treatment. 1B, planning of surgery after tumor downstaging (before the first hepatectomy). 1C, first hepatectomy. 1D, liver remnant following the
second hepatectomy (segments IV and I).

Table 13.3 Reported Survival Outcomes after Two-Stage Hepatectomy for Colorectal Liver Metastases
Patient survival (%)
No of Success rate Mortality rate Morbidity rate Median
Author/Institution patients (%) (%) (%) (months) 3 years 5 years
Adam et al. (2000) 16 81 15 45 31 35 –
Jaeck et al. (2004) 33 76 0 56 – 54 –
Shimada et al. (2004) 12 100 0 NA – – –
Togo et al. (2005) 11 100 0 18 18 45 –
Adam et al. (2007) 45 69 6.5 48 35 47 28
NA, not available.
The mortality rates concern the second operation.

127
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
wedge resection is advantageous as it preserves a maximal
amount of liver parenchyma that will hypertrophy after PVE
to become the functional liver remnant. Also, our policy is to
perform portal ligation and embolization with absolute
alcohol during the first liver resection to avoid a second
procedure before the definitive hepatectomy.
Currently, the guidelines for two-stage hepatectomies
include the following:
● No residual tumor should be left in the future rem-
nant liver at the first intervention.
● If the resection alone cannot remove all lesions, one
of the ablative methods (RFA, cryotherapy) has to be
used for local tumor destruction in order to prevent
tumor progression during the regeneration of the
remnant liver.
● At the first intervention, portal dissection and mobi-
lization of the lobe that is to be resected during the
second intervention should be avoided.
In summary, based on the nature of the metastatic disease
(number, size, and distribution), the treatment strategies,
which can be applied with the aim of achieving a complete
treatment of CRC liver metastases include the following:
● Patients with unilobar multinodular metastases requir-
ing resection of more than 60% to 70% of the func-
tional liver parenchyma should undergo preoperative
portal vein embolization. Following PVE, the induced
hypertrophy of the future remnant liver allows for a
curative resection while minimizing the risk of postop-
erative hepatic insufficiency (Fig. 13.6A).
● Patients with bilobar multinodular metastases for
which a planned resection would leave no more than
three nodules and none larger than 3 cm in the
remnant liver are preferentially treated with a
multimodal approach consisting of hepatic resec-
tion combined with RFA or cryotherapy of the
unresectable nodules (Fig. 13.6B).
Right lobectomy Right hepatectomy
Remnant liver <30% ≤3 Metastases ≤ 30 mm (remnant liver)
Portal vein embolization Hepatectomy + RFA or cryo
(A) (B)
Figure 13.6 Diagrammatic illustration of the surgical strategies used when treating patients with “nonresectable” multimodal metastatic disease. (A) Multifocal
unilobar metastases. (B) Multifocal bilobar metastatases. (C) Multifocal bilobar metastases. RFA, radio frequency ablation; Cryo, cryotherapy.
128
● Patients with bilobar multinodular metastases for
which a planned resection would leave more than
three nodules or any nodule larger than 3 cm in the
remnant liver could be candidates for two-stage
hepatectomy (Fig. 13.6C).
Extended Liver Surgery (Total Vascular Exclusion and Cooling)
Involvement of the IVC and/or the confluence of hepatic
veins by liver metastases is another situation that can be con-
sidered as a contraindication to liver resection. Currently,
employing total vascular exclusion (TVE) of the liver and
vascular reconstruction techniques can make surgery possi-
ble without taking further risks for this specific group of
patients. As the experience has grown with TVE, an increas-
ing number of patients are being operated with acceptable
morbidity and mortality. Conventional TVE consists of
clamping of the liver inflow (Pringle maneuver) as well as
clamping of the supra and infrahepatic vena cava. Alterna-
tively, in cases with no caval involvement by the tumor, selec-
tive control of the hepatic veins can be achieved allowing
preservation of the caval flow. In cases whereby the caval
clamping is associated with hemodynamic disturbances
(hypotension), a venovenous bypass is necessary through
which venous blood from femoral and portal vein is diverted
to axillary or internal jugular vein. A drawback of these tech-
niques, however, is that almost inevitably would induce
warm ischemia for which the maximal duration of tolerance
is assumed to be around 60 to 90 minutes. For cases which
require interruption of hepatic blood flow for more than
60 minutes, hypothermic perfusion of the liver should be
instituted to prevent the consequences of a long warm isch-
emic time. Such combination was evaluated in a study con-
ducted in our center, which demonstrated that TVE combined
with hypothermic perfusion was associated with a better
ischemic tolerance and liver function as well as significantly
lower complication rates compared to TVE ≥ 60 min. Com-
bined liver and vena cava resection is another procedure
facilitated by combined TVE and hypothermic perfusion. In
Right hepatectomy
>3 Metastases > 3 mm (remnant liver)
Two – stage hepatectomy
(C)
 SURGERY FOR METASTATIC COLORECTAL CANCER

a series from our center (108), out of 22 patients who under-
went such a procedure, one patient died (4.5%) during the
perioperative course, whereas 14 patients (64%) developed
complications. Overall 5-year survival for the operated
patients was 38.3%, comparing favorably with other reported
results.
Hence, combining TVE with vascular reconstruction
techniques has resulted in an increased number of patients
undergoing surgery for CRC liver metastases involving
vena cava and/or the confluence of hepatic veins (which not
so long ago were considered as a contraindication to sur-
gery). This approach, however, seems justified only for sur-
gical teams experienced in both hepatobiliary and vascular
surgery.
Repeat Liver Resection for Recurrent Metastatic Disease
Despite hepatic resections with a curative intent in well-
selected patients, up to 60% subsequently will develop recur-
rent liver metastases. Of these, approximately 20% to 30%
present with isolated recurrent liver metastases, which are
potentially amenable to further resection.
Regardless of the technical challenges due to adhesions
and altered anatomy of the liver, the repeat hepatectomy is
safe with a postoperative mortality and morbidity not dif-
ferent from those reported after a first resection (median
survival approaches 2 years) ( Table 13.4). Five-year survival
rates ranging from 16% to as high as 41% have been
reported (109–111). Not surprisingly, the same prognostic
factors that predict favorable outcome after primary resec-
tion apply to the repeated liver resection, including com-
plete removal of metastatic lesions with satisfactory margins
and no extrahepatic disease.
Furthermore, a study conducted by our team demon-
strated that a third hepatectomy is safe, with complication
rates and survival benefit similar to first and second hepatec-
tomies (112) (Fig. 13.7). The overall 5-year survival follow-
ing the third hepatectomy was 32% and disease-free survival
was 17%. Similarly, Pessaux et al. showed overall 5-year sur-
vival rates of 33%, 21%, and 36%, respectively, after a first,
second, and third hepatectomy (113). Also, in repeat resec-
tions, the general rule applies that it does not matter how
many lesions the patient has, provided that an R0 resection

Table 13.4 Reported Survival Outcomes after Repeat Liver Resection for Recurrent Colorectal Metastases
Patient survival (%)
Author/Institution Year No of patients 1 years 3 years 5 years
Fernandez et al. 1995 170 – 45 32
Adam et al. 1997 64 87 60 41
Yamamoto 1999 75 48 31 –
Muratore et al. 2001 29 – 35 –
Suzuke et al. 2001 26 – 62 32
Petrowsky et al. 2002 126 86 51 34
Adam et al. 2003 199 89 46 32
Shaw et al. 2006 66 – – 44

(%)
100
89%
First hepatectomy
88% Second hepatectomy
80
Third hepatectomy
82%
54%
60
46% 36%
40
42% 32%

28%
20

0
0 1 2 3 4 5 Year

Patients at risk No 1 yr 2 yrs 3 yrs 4 yrs 5 yrs

First hepatectomy 416 267 169 120 83 60
Second hepatectomy 139 80 37 27 19 13
Third hepatectomy 6 49 31 15 10 6

Figure 13.7 Survival after 1st, 2nd, and 3rd hepatectomy from the time of the index operation. Source: From Ref. (112).

129
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
can be achieved within limits of safety in terms of liver volume
and function.
Therefore, hepatic recurrences should be regarded as onco-
logically similar to metastatic disease at initial presentation
and repeat hepatectomies should therefore be offered to
patients based on the same criteria as those used for initial
hepatectomy.
Special Considerations
Despite the advances made in the management of CRLM,
there are still some areas of uncertainty or debatable. For
instance, it is not clear what type of treatment is needed after a
complete clinical response (total disappearance of metastases
while on chemotherapy). Similarly, the management of syn-
chronous presentation of primary colorectal cancer and
hepatic metastases is still disputed (chemotherapy or upfront
surgery) and so is the issue of which site should be operated
first—bowel or liver?
Treatment of the Lesions That Have Disappeared After
Neoadjuvant Treatment
With the advances in chemotherapy efficacy, the frequency of
“missing metastases” has increased. Nevertheless, the treat-
ment strategies concerning such lesions are not well defined,
particularly so when trying to decide about the necessity to
resect, the time, and type of resection.
In a study conducted by our team (82), we initially reported
that up to 7.2% of the patients with unresectable CRLM
treated with systemic chemotherapy developed complete
metastatic necrosis. Hence, we recommended that preferably
all tumor-bearing sites must be resected during the surgery
for CRLM. And, while later on, it was suggested that “missing
metastases” are cured in 70% of the cases (114), increasingly,
the evidence indicates the contrary—a persistence of
histologically active tumor in as many as 83% of the lesions,
which have a complete radiological response on imaging
(115). Furthermore, a subsequent report from our unit (116)
demonstrated that the actual number of patients with no
more residual tumor cells (complete pathological response,
CPR) in CRLM after neoadjuvant chemotherapy was even
smaller (4.5%) than the one previously reported rate, which
is in keeping with reports from other centers (117). Consid-
ering these results, we can say that a complete radiological
response does not mean complete histological response, and
despite the favorable long-term results associated with the
CPR (5-year survival of 76%) the utility of surgery remains
unchallenged. This view is supported by several reasons: (1)
Confirmation of CPR depends primarily on the accuracy of
the pathologic examination and on the exhaustivity of histo-
logic sampling as undetected malignant cells could still be
present in the resected lesion/s. By resecting all metastases,
the possibility of leaving residual tumor cells behind is greatly
reduced; (2) During the laparotomy it is often possible to
diagnose additional metastatic disease, which otherwise
would have remained undetected by the standard investiga-
tive tools; (3) The diagnosis of the CPR is a retrospective
one as there is no imaging technique, which can reliably diag-
nose CPR preoperatively, hence, only surgical resection with
130
concomitant pathological examination is able to make a
definite diagnosis.
In practice, due to very low overall incidence of CPR (4%),
patients who have a complete radiological response should be
operated on.
Patients treated with neoadjuvant chemotherapy should be
referred to surgeons before the initiation of the treatment, so as
to avoid eventual difficult decisional situations brought about
by the inability to localize previously seen radiological lesions.
Synchronous Metastases
● Neoadjuvant chemotherapy or upfront surgery? The
interest in using preoperative chemotherapy for
resectable patients has been increasing. The rationale
for this policy has been supported by the better prog-
nosis obtained with neoadjuvant chemotherapy and
surgery, compared to upfront surgery in patients
with synchronous CRLM. Administering neoadju-
vant chemotherapy not only can be associated with a
lower rate of positive surgical margins compared to
the rates observed in patients treated with upfront
surgery (118), but also such approach provides time
to identify a subgroup of patients who will develop
progressive disease while on chemotherapy (119).
Concerning the later group (patients with progres-
sive disease while receiving neoadjuvant chemother-
apy), a study conducted by our team showed that
such patients had a 5-year survival of 8% versus that
of 37% observed on patients with an objective tumor
response to neoadjuvant chemotherapy (119). In
addition, a study conducted by Rubbia-Brandt et al.
(117), using a tumor regression grade scoring system,
identified that resected patients with a poor histologi-
cal response to chemotherapy had a lower disease-free
survival at 3 years and a lower overall survival at
5 years. Certainly taking into consideration these
results, the utility (benefit) of surgical intervention in
this subgroup of patients has to be questioned.
Therefore, the decision to give neoadjuvant chemotherapy should
be individualized and based on specific clinical situations.
● In patients who are chemonaïve with four or more
synchronous CRLM and a nonocclusive primary,
neodjuvant chemotherapy can be appropriate fol-
lowed by repeated MRI and PET CT.
● Neoadjuvant chemotherapy can also be adminis-
tered in patients with two to three bilobar CRLM. By
contrast, if a patient belonging to this group has
comorbidities or there is a concern about chemo-
therapy-related hepatotoxicity at a time when an
extended resection is required, initial surgery would
be indicated.
● Instead for patients with one to two unilobar meta-
static diseases, upfront surgery should be considered
first.
● Single or staged intervention? The optimal timing for
resection of synchronous CRLM and the primary
tumor remains a matter of controversy. Most surgeons
 SURGERY FOR METASTATIC COLORECTAL CANCER
prefer a staged approach with initial resection of the
colorectal primary followed by hepatic resection 8 to
12 weeks after. Supporters of this strategy argue that
the combined approach is associated with increased
morbidity and mortality (Level of evidence: 3). Nor-
dlinger et al. (120) reported an operative mortality of
7% for combined resection compared to 2% for
staged resection. Bolton and Fuhram (121) in their
series reported a mortality rate of 12% for combined
resections, which increased to 24% for those who
underwent major liver resection. Reddy et al. (122), in
a multi-institutional retrospective study comparing
postoperative outcomes after simultaneous and
staged colorectal and hepatic resections, concluded
that caution should be exercised before performing
simultaneous colorectal and major hepatic resections.
For major hepatectomy, simultaneous colorectal
resection increased mortality (8.3% vs. 1.4%, p < 0.05)
and severe morbidity (36.1% vs. 15.1%, p < 0.05) as
compared to combined minor liver and colorectal
resection. Similarly, a recent study demonstrated that
patients who underwent a combined resection had a
higher mortality rate (10%) compared with patients
treated by staged resection (1.1%), concluding that
combined interventions should be performed in well-
selected patients, <70 years old and not with rectal
surgery (123).
On the other hand, several studies have also reported that
simultaneous resection of the colon and liver tumors results
in morbidity and mortality comparable to staged resection
(124,125). However, in the majority of these studies, the
patients submitted to simultaneous resection, underwent lim-
ited liver resection, and were much more selected compared to
those who underwent staged surgery by the same teams. In
practice, simultaneous resections should be decided on an
individual basis. Combined resections may be more appropri-
ate in patients who require a straightforward colon resection
and a limited liver resection (≤2 segments). Patients who
require major liver resections particularly the elderly should
be dealt with by staged resection. Ultimately, the final decision
should be made by the operating surgeon based on the experi-
ence and the risk evaluation.
In summary, it is recommended that colorectal and major
liver resections (>3 segments) should not be performed dur-
ing the same time. One-stage procedure (combined liver and
colorectal resection) should be reserved for experienced teams
sharing both colorectal and liver surgery expertise.
Surgery for Synchronous Liver Metastases:
Liver or Colon Resection First?
The standard approach for synchronous CRLM consists of
resection of the primary tumor followed by chemotherapy for
3 to 6 months with the goal of resecting the liver metastases if
they stabilize or respond. However, this strategy has pitfalls as
many patients have progression of their metastatic disease
while being treated for their primary, precluding eventual
surgery with curative intent. Based on this observation, Mentha
et al. (126) designed a management strategy that involves high-
induction chemotherapy first, followed by liver surgery, and
completed by removal of the primary colorectal tumor. Such
strategy aims at controlling the CRLM at the same time as the
colorectal primary, optimize the chances of curative liver resec-
tion, and allowing the administration of well-programmed
chemoradiotherapy before rectal surgery (when indicated). The
authors have shown that the new “reverse” approach produced
resectability and survival rates better than those expected from
the published data on patients treated “conventionally” for dis-
ease of similar severity (3-year survival of 86%). The obvious
candidate for this treatment would be a patient with nonob-
structive primary colonic tumor. The rationale of this approach
is that in the majority of patients the most life-threatening site
is represented by the liver.
In summary, the first treatment should focus on the global
metastatic disease rather than locally treat the primary
tumor: primary chemotherapy seems to be better than pri-
mary resection.
For unresectable liver metastases with a primary colorectal
cancer in place, chemotherapy as the first treatment line
does not alter the survival expectancy. The first surgical pro-
cedure should logically deal with the tumor site, which is
more difficult to resect and more likely to be life threatening
for the patient.
conclusions
The surgical treatment of colorectal hepatic metastases rep-
resents the only potentially curative therapeutic option able
to achieve long-term survival and a hope for cure. Newer
treatment strategies have shifted from the traditional concept
of successive lines of medical therapy to that of a continuum
of care in which medical and surgical treatment combina-
tions are tailored to the clinical settings. To optimize the
treatment of CRLM, management by a multidisciplinary
team consisting of oncologists, surgeons, and radiologists is
of the utmost importance.
Advances in body and hepatic imaging has allowed for more
accurate selection of patients with colorectal liver metastases.
Imaging modalities are now able to detect minimal metastatic,
which not very long ago would have been very difficult to do so.
The significance of the prognostic factors has changed,
although helpful in stratifying patients with regards to prog-
nosis, should not be used to exclude otherwise resectable
patients from surgery.
Data on the use of neoadjuvant and adjuvant therapy to
decrease recurrence risk and improve survival in patients with
initially resectable metastases are encouraging, while further
evidence and assessment is needed.
With newer chemotherapy regimens, a significant propor-
tion of unresectable patients are currently switched to resect-
able, opening the way to a survival benefit, which is not very
different to that of initially resectable patients.
The use of modern surgical techniques has resulted in
a reduction of perioperative mortality and morbidity,
whereas tumor ablation techniques, PVE, and radical liver
131
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
surgery in combination with neoadjuvant chemotherapy
have positively influenced the expansion of candidates for
surgical resection. In addition, with the use of more active
systemic chemotherapy as adjuvant therapy, we hope that an
improved survival rate in resected patients will be observed.
In patients with tumor recurrence following hepatectomy
for CRLM, repeat hepatectomies provide long-term survival
benefit similar to that of first hepatectomy. In future, better
patient selection through improved imaging techniques and
identification of genomic markers as well as further advances
in pharmacotherapy will likely further improve the outcome
for patients with CRLM.
references
1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J
Clin 2005; 55: 10–30.
2. Steele G, Jr., Ravikumar TS. Resection of hepatic metastases from
colorectal cancer. Biologic perspective. Ann Surg 1989; 210: 127–38.
3. Blumgart LH, Allison DJ. Resection and embolization in the manage-
ment of secondary hepatic tumors. World J Surg 1982; 6: 32–45.
4. Jatzko G, Wette V, Muller M, et al. Simultaneous resection of colorectal
carcinoma and synchronous liver metastases in a district hospital. Int J
Colorct Dis 1991; 6: 111–14.
5. Wagner JS, Adson MA, Van Heerden JA, et al. The natural history of
hepatic metastases from colorectal cancer a comparison with respective
treatment. Ann Surg 1984; 199: 502–8.
6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irino-
tecan, fluorouracil, and leukovorin for metastatic colorectal cancer. N
Eng J Med 2004; 350: 233542.
7. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and
cetuximab plus irinotecan in irinotecan refractory metastatic colorectal
cancer. N Eng J Med 2004; 351: 33745.
8. Ambiru S, Miyazaki M, Isono T, et al. Hepatic resection for colorectal metas-
tases—analysis of prognostic factors. Dis Colon Rectum 1999; 42: 632–9.
9. Yazaki M, Ito H, Nakagava K, et al. Aggressive surgical resection for
hepatic metastases involving the inferior vena cava. Am J Surg 1999;
177: 294–8.
10. Kato K, Yasui K, Hirai T, et al. Therapeutic results for hepatic metastasis
of colorectal cancer with special reference to effectiveness of hepatec-
tomy: analysis of prognostic factors for 763 cases recorded in 18 institu-
tions. Dis Colon Rectum 2003; 46: S22–31.
11. Mutsaerts EL, van RS, Zoetmulder FA, et al. Prognostic factors and
evaluation of surgical management of hepatic metastases from
colorectal origin: a 10 year single institute experience. J Gastrointest
Surg 2005; 9: 178–86.
12. Wood CB, Gillis CR, Blumgart LH. A retrospective study of the natural
history of patients with liver metastases from colorectal cancer. Clin
Oncol 1976; 2: 285–8.
13. Wilson SM, Adson MA. Surgical treatment of hepatic metastases from
colorectal cancer. Arch Surg 1976; 111: 330–4.
14. Scheele J, Strangl R, Altendorf-Hofmann A, Gall FP. Indicators of prog-
nosis after hepatic resection for colorectal secondaries. Surgery 1991;
110: 13–29.
15. Mentha G, Huber O, Robert J, et al. Elective hepatic resection in the
elderly. Br J Surg 1992; 79: 557–9.
16. Belghiti J, Hiramatsu K, Benoist S, et al. Seven hundred forty seven
hepatectomies in the 1990s: an update to evaluate the actual risk of liver
resection. J Am Col Surg 2000; 191: 38–46.
17. Vauthey JN, Pawlik TM, Abdalla EK, et al. Is extended hepatectomy for
hepatobiliary malignancy justified? Ann Surg 2004; 239: 722–30.
18. Sica GT, Ji H, Ross PR. CT and MR imaging of hepatic metastases. AJR
Am J Roentgenol 2000; 174: 691–8.
19. Scott DJ, Guthrie JA, Arnold P, et al. Dual phase helical CT versus portal
venous phase CT for detection of colorectal liver metastases: correlation
with intraoperative sonography, surgical and pathological findings. Clin
Radiol 2001; 56: 235–42.
132
20. Kamel IR, Bluemke DA. MR imaging of liver tumors. Radiol Clin North
Am 2003; 41: 51–65.
21. Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal liver metastases: CT,
MR and PET for diagnosis: meta-analysis. Radiology 2005; 237: 123–31.
22. Truant S, Huglo D, Hebbar M, et al. Prospective evaluation of the
impact of [18F] fluoro-2-deoxy-d-glucose positron emission tomog-
raphy of resectable colorectal liver metastases. Br J Surg 2005; 92:
362–9.
23. Lubezky N, Metser U, Geva R, et al. The role and limitations of 18F
fluoro-2-deoxy-d-glucose positron emission tomography (FDG-
PET) scan and computerized tomography in restaging patients with
hepatic colorectal metastases following adjuvant chemotherapy: com-
parison with operative and pathological findings. J Gastrointest Surg
2007; 11: 472–8.
24. Rappeport ED, Loft A. Liver metastases from colorectal cancer: imaging
with superparamagnetic iron oxide (SPIO) enhanced MR imaging,
computer tomography and positron emission tomography. Abdom
Imaging 2007; 32: 624–34.
25. Wiering B, Crabbe PF, Jager GJ, et al. The impact of 18F fluoro-2-deoxy-
d-glucose positron emission tomography in the management of
colorectal liver metastases. Cancer 2005; 104: 2658–70.
26. Joyce DL, Wahl RL, Patel PV, et al. Preoperative positron emission
tomography to evaluate potentially resectable hepatic colorectal metas-
tases. Arch Surg 2006; 141: 1220–6.
27. Bipat S, van Leeuwen MS, Ijzermans JN, et al. Imaging and treatment of
patients with colorectal liver metastases in the Netherlands: a survey.
Neth J Med 2006; 64: 147–51.
28. Ekberg H, Tranberg KG, Anderson R, et al. Determinants of survival in
liver resection for colorectal secondaries. Br J Surg 1986; 73: 727–31.
29. Doci R, Gennari L, Bignami P, et al. Morbidity and mortality after
hepatic resection of metastases from colorectal cancer. Br J Surg 1995;
82: 377–81.
30. Scheele J, Strang R, Altendorfhofmann A, et al. resection of colorectal
liver metastases. World J Surg 1995; 19: 59–71.
31. Gayowski TJ, Iwatsuki S, Madariaga SR, et al. Experience in hepatic
resection of colorectal cancer – analysis of clinical and pathological risk
factors. Surgery 1994; 116: 703–71.
32. Fortner JG, Silva JS, Golbey RB, et al. Multivariate analysis of a per-
sonal series of 247 consecutive patients with liver metastases from
colorectal cancer. Treatment by hepatic resection. Ann Surg 1984;
199: 306–16.
33. Ercolani G, Grazi GL, Ravaioli M, et al. Liver resection for multiple
colorectal metastases : influence of parenchymal involvement and total
tumor volume versus number or location on long term survival. Arch
Surg 2002; 137: 1187–92.
34. www.LiverMetSurvey.org. Assessed: January 2009.
35. Elias D, Cavalcanti A, Sabourin JC, et al. Results of 136 curative hepatec-
tomies with a safety margin of less than 10 mm for colorectal metasta-
ses. J Surg Oncol 1998; 69: 88–93.
36. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal
metastases. J Clin Oncol 1997; 15: 938–46.
37. Figueras J, Burdio F, Torras J, et al. Effect of subcentimeter nonpositive
resection margin on hepatic recurrence in patients undergoing hepatec-
tomy for colorectal liver metastases. Evidence from 663 liver resections.
Ann Oncol 2007; 18: 1190–5.
38. Kokudo N, Miki Y, Sugai S, et al. Genetic and histological assessment of
surgical margins in resected liver metastases from colorectal carcinoma:
minimum surgical margins for successful resection. Arch Surg 2002;
137: 833–40.
39. de Hass RJ, Wicherts DA, Flores E, et al. R1 resection by necessity for
colorectal liver metastases is it still a contraindication to surgery? Ann
Surg 2008; 248: 626–36.
40. Elias D, Liberale G, Vernerey D, et al. Hepatic and extrahepatic
colorectal metastases: when resectable their localization does not
matter, but their total number has a prognostic effect. Ann Surg Oncol
2005; 12: 900–9.
41. Kangmatsu Y, Kato T, Hirai T, et al. Preoperative probability model for
predicting survival after resection of pulmonary metastases from
colorectal cancer. Brit J Surg 2004; 91: 112–20.
 SURGERY FOR METASTATIC COLORECTAL CANCER
42. Elias D, Benizri E, Pocard M, et al. Treatment of synchronous peritoneal
carcinomatosis and liver metastases from colorectal cancer. Eur J Surg
Oncol 2006; 32: 632–6.
43. Carmignani CP, Ortega Perez G, Sugarbaker PH. The management of
synchronous peritoneal carcinomatosis and hematogenous metastasis
from colorectal cancer. Eur J Surg Oncol 2004; 30: 391–8.
44. Elias D, Saric J, Jaeck D, et al. Prospective study of microscopic lym-
phnode involvement of the hepatic pedicule during curative hepa-
tectomy for colorectal liver metastases. Br J Surg 1996; 83: 942–5.
45. Jaeck D, Nakano H, Bachellier P, et al. Significance of hepatic pedicle
lymph node involvement in patients with colorectal liver metastases: a
prospective study. Ann Surg Oncol 2002; 9: 430–8.
46. Jaeck D. The significance of hepatic pedicle lymph node metastases in
surgical management of colorectal liver metastases and of other liver
malignancies. Ann Surg Oncol 2003; 10: 1007–11.
47. Adam R, de Haas RJ, Wicherts D, et al. Is hepatic resection justified after
chemotherapy in patients with colorectal liver metastases and lymph
node involvement? J Clin Oncol 2008; 26: 3672–80.
48. Nordlinguer B, Guiguet M, Vaillant JC, et al. Surgical resection of colorec-
tal carcinoma metastases to liver. A prognostic scoring system to improve
case selection, based on 1568 patients. Cancer 1996; 77: 1254–62.
49. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence
after hepatic resection for metastatic colorectal cancer: analysis of 1001
consecutive cases. Ann Surg 1999; 230: 309–18.
50. Mala T, Bohler G, Mathisen O, et al. Hepatic resection for colorectal
metastases: can preoperative scoring predict patient outcome. World J
Surg 2002; 26: 1348–53.
51. Schusser Fiorenza CM, Mahvi DM, Niederhuber J, et al. Clinical risk
score correlates with yield of PET scan in patients with colorectal
hepatic liver metastases. J Gastrointest Surg 2004; 8: 150–7.
52. Colucci G, Maiello E, Leo S, et al. Biochemical modulation of fluoroura-
cil with high dose metotrexate or folinic acid in advanced colorectal
cancer patients. Anticancer Res 1994; 14: 2157–62.
53. Leichmann CG, Fleming TR, Muggia FM, et al. Phase II study of fluoro-
uracil and its modulation in advanced colorectal cancer: a southewest
oncology group study. J Clin Oncol 1995; 13: 1303–11.
54. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and
leucovorin for metastatic colorectal cancer. N Eng J Med 2000; 343:
905–14.
55. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with
fluorouracil compared with fluorouracil alone as first line treatment for
metastatic colorectal cancer: a multicentre randomised trial. Lancet
2000; 355: 1041–7.
56. Goldberg RM, Sargent DJ, Morton RF, et al. A randomised controlled
trial of fluorouracil, plus leucovorin, irinotecan and oxaliplatin combi-
nations in patients with previously untreated metastatic colorectal can-
cer. J Clin Oncol 2004; 22: 23–30.
57. De Gramon A, Figer A, Seymour M, et al. Leucovorin and fluorouracil
with or without oxaliplatin as first line treatment in advanced colorectal
cancer. J Clin Oncol 2000; 18: 2938–47.
58. Nordlinger B, Sorbye H, Collette L, et al. Perioperative chemotherapy
with FOLFOX4 and surgery versus surgery alone for resectable liver
metastases from colorectal cancer: a randomosed controlled trial. Lan-
cet 2008; 371: 1007–16.
59. Tanaka K, Adam R, Shimada H, et al. Role of neoadjuvant chemother-
apy in the treatment of multiple colorectal metastases to the liver. Br J
Surg 2003; 90: 963–9.
60. Ozawa K. Hepatic function and liver resection. J Gastroenterol Hepatol
1990; 5: 296–309.
61. Fornari F, Civardi G, Cavanna L, et al. Complications of ultrasonically
guided fine-needle biopsy. Results of a multicenter Italian study and
rewied of the literature. Scand J Gastroenterol 1989; 24: 949–55.
62. Smith EH. Complications of percutaneous abdominal fine needle
biopsy. Radiology 1991; 178: 253–8.
63. Rogers MS, Collinson R, Desai S, et al. Risk of dissemination with
biopsy of colorectal liver metastases. Dis Colon Rectum 2003; 46: 454–9.
64. Ohlsson B, Nilsson J, Stenram U, et al. Percutaneous fine needle aspira-
tion cytology in the diagnosis and management of live tumors. Br J Surg
2002; 89: 757–62.
65. Thaler K, Kunneganti S, Khajanchee Y, et al. The evolving role of staging
laparoscopi in the treatment of colorectal hepatic metastasis. Arch Surg
2005; 140: 727–34.
66. Rahusen FD, Cuesta MA, Borgstein PJ, et al. Selection of patients for
resection of colorectal metastases to the liver using diagnostic laparos-
copy and laparoscopic ultrasounography. Ann Surg 1999; 230: 31–7.
67. Grobmyer SR, Fong Y, D’Angelica M, et al. Diagnostic laparoscopy prior
to planned hepatic resection for colorectal metastases. Arch Surg 2004;
139: 1326–30.
68. Zacherl J, Scheuba C, Imhof M, et al. Current value of intraoperative
sonography during surgery for hepatic neoplasms. World J Surg 2002;
26: 550–4.
69. Staren ED, Gambla M, Deziel DJ, et al. Intraoperative ultrasdound in
the management of liver neoplasms. Am Surg 1997; 63: 591–6.
70. Machi J, Sigel B, Zaren HA, et al. Operative ultrasound during hepato-
biliary and pancreatic surgery. World J Surgery 1993; 17: 640–5.
71. Portier G, Elias D, Bouche O, et al. Multicenter randomised trial of adju-
vant fluorouracil and folonic acid compared with surgery alone after
resection of colorectalliver metastases. J Clin Oncol 2006; 24: 4976–82.
72. Parks R, Gonen M, Kemeny N, et al. Adjuvant chemotherapy improves
survival after resection of hepatic colorectal metastases: analysis of data
from two continenets. J Am Coll Surg 2007; 204: 753–61.
73. Kusunoki M, Yanagi H, Noda M, et al. Results of pharmacokinetic mod-
ulating chemotherapy in combination with hepatic arterial 5-FU infu-
sion and oral UFT after resection of hepatic colorectal metastases.
Cancer 2000; 89: 128–35.
74. Kemeny MM, Adak S, Gray B, et al. Combined modality treatment for
resectable metastatic colorectal carcinoma to the liver: surgical
resection of the hepatic metastases in combination with continuous
infusion of chemotherapy—an intergroup study. J Clin Oncol 2002;
20: 1499–1505.
75. Kemeny NE, Gonen M. Jarnagin WR, et al. Hepatic arterial infusion
after liver resection. N Eng J Med 2005; 352: 734–5.
76. Wei AC, Greig PD, Grant D, et al. Survival after hepatic resection for
colorectal metastases: a ten year experience. Ann Surg Oncol 2006; 13:
668–76.
77. Hughes KS, Rosenstein RB, Songhoradobi S, et al. Resection of the liver
for colorectal carcinoma metastases – a multi institutional study of long
term survivors. Dis Colon Rectum 1988; 31: 1–4.
78. Nordlinger B, Jaeck D, Guiget M, et al. Surgical resection of hepatic
metastases: multicentric retrospective study by the French Association
of Surgery. In: Nordlinger B, Jaeck D, eds. Treatment of Hepatic Metas-
tases of Colorectal Cancer. Paris: Springer Verlag, 1992; 129–61.
79. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long term survival
following liver resection for hepatic colorectal metastases. Ann Surg
2002; 235: 759–66.
80. Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers
of surgical indications in the treatment of liver metastases from colorec-
tal cancer: long term results. Ann Surg 2000; 231: 487–99.
81. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver
metastases from colorectal cancer after neoadjuvant chemotherapy.
Ann Surg 1996; 224: 509–22.
82. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable
colorectal metastases downstaged by chemotherapy. Ann Surg 2004;
240: 644–58.
83. Miyanari N, Mori T, Takahashi K, et al. Evaluation of aggressively
treated patients with unresectable multiple liver metastases from
colorectal cancer. Dis Colon Rectum 2002; 45: 1503–9.
84. Tumor progression while on chemotherapy: a contraindication to
liver resection for multiple colorectal metastases? Ann Surg 2004;
240: 1052–61.
85. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unre-
sectable colorectal liver metastases: Correlation between tumor
response and resection rates. Ann Oncol 2005; 16: 1311–19.
86. Tabernero JM, Van Cutsem E, Sastre J, et al. An international phase II
study of cetuximab in combination with oxaliplatin/5-fluorouracil/
folinic acid (Folfox-4) in the first line treatment of patients with meta-
static cancer expressing epidermal growth factor receptor (EGFR). Proc
Am Soc Clin Oncol 2004; 23: 248.
133
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
87. Cervantes A. Cetuximab plus oxaliplatin/5-fluorouracil/folinic acid for
the epidermal growth factor receptor expressing metastatic colorectal
cancer in the first line setting: A phase II study. Eur J Cancer 2005; 3:
181–2.
88. Bokemeyer C, Staroslawsca E, Makhson A, et al. Cetuximab plus 5-FU/
FA/Oxaliplatin (FOLFOX 4) in the first line treatment of colorectal meta-
static cancer: a large scale phase II study. OPUS. Eur J Cancer 2007; 5: 4.
89. Van Custem E, Bodoky G, Kyung Roh J, et al. CRYSTAL, a randomised
phase III trial of cetuximab plus Folfiri vs Folfiri in first line treatment
of metastatic colorectal cancer. Eur J Cancer 2007; 5: 4.
90. Van Custem E, Lang I, D’haens G, et al. KRAS status and efficacy in the
first line treatment of patients with metastatic colorectal cancer treated
with Folfiri with and without Cetuximab: the CRYSTAL experience. J
Clin Oncol 2008; 26: (Abstr 2).
91. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and effi-
cacy in the first line treatment of patients with metastatic colorectal
cancer treated with Folfox with and without Cetuximab: the OPUS
experience. J Clin Oncol 2008; 26: (Abstr 4000).
92. Clavien PA, Selzner N, Morse M, et al. Dowstaging of hepatocellular
carcinoma and liver metastases from colorectal cancer by selective
intraarterial chemotherapy. Surgery 2002; 131: 433–42.
93. Leonard GD, Fong Y, Jarnagin W, et al. Liver resection after hepatic
arterial infusion plus sytemic oxaliplatin combinatins in pre treated pat-
ients with extensive unresectable colorectal liver metastases. J Cin Oncol
2004; 22: 3542–45.
94. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes follow-
ing hepatic resection, radiofrequency ablation, and combined resection
ablation for colorectal liver metastases. Ann Surg 2004; 239: 818–25.
95. Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable
primary and metastatic hepatic malignancies: results of 123 patients.
Ann Surg 1999; 230: 1–8.
96. Adam R, Akpinar E, Johhan M, et al. Place of cryosurgery in the treat-
ment of malignant liver tumors. Ann Surg 1997; 225: 39–50.
97. Brooks AJ, Wang F, Alfredson M, et al. syncronous liver resection and
cryotherapy for colorectal metastases: survival analysis. Surgeon 2005;
3: 265–8.
98. Kokudo N, Makuuchi M. Current role of portal vein embolization/
hepatic artery embolization. Surg Clin North Am 2004; 84: 643–57.
99. Azoulay D, Castaing D, Ismail A, et al. Resection of nonresectable liver
metastases from colorectal cancer after percutaneous portal vein embo-
lization. Ann Surg 2000; 231: 480–6.
100. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before
right hepatectomy: Prospective clinical trial. Ann Surg 2003; 237: 208–17.
101. Abdalla EK, Denys A, Chevalier P, et al. Total and segmental liver volume
variations: Implications for liver surgery. Surgery 2004; 135: 404–10.
102. Nagino M, Nimura Y, Kamiya J, et al. Right or left trisegment portal vein
embolization before hepatic trisegmentectomy for hilar bile duct carci-
noma. Surgery 1995; 117: 677–81.
103. Adam R, Laurent A, Azoulay D, et al. Two stage hepatectomy: a planed
strategy to treat irresectable liver tumors. Ann Surg 2000; 232: 777–85.
104. Jaeck D, Oussoultzouglou E, Rosso E, et al. A two stage hepatectomy
procedure combined with portal vein embolization to achieve curative
resection for initially unresectable multiple and bilobar colorectal liver
metastases. Ann Surg 2004; 240: 1037–51.
105. Adam R, Vinet E. Regional treatment of metastasis: surgery of colorectal
liver metastases. Ann Oncol 2004; 15: 103–6.
106. Togo S, Nagano Y, Masui H, et al. Two stage hepatectomy for multiple
bilobar liver metastases from colorectal cancer. Hepatogastroenterology
2005; 52: 913–19.
134
107. Jaeck D, Bachellier P, Nakano H, et al. One or two-stage hepatectomy
combined with portal vein embolization for initially nonresectable
colorectal liver metastases. Am J Surg 2003; 185: 221–9.
108. Azoulay D, Eshkenazy R, Andreani P, et al. In situ hypothermic perfu-
sion of the liver versus standard total vascular exclusion for complex
liver resection. Ann Surg 2005; 241: 277–86.
109. Adam R, Bismuth H, Castaing D, et al. Repeat hepatectomy for colorec-
tal liver metastases. Ann Surg 1997; 225: 51–60.
110. Stone MD, Cady B, Jenkins RL, et al. Surgical therapy for recurrent liver
metastases from colorectal cancer. Arch Surg 1990; 125: 718–21.
111. Petrowsky H, Gonen M, Jarnagin W, et al. Second liver resections are
safe and effective treatment for recurrent hepatic metastases from
colorectal cancer: a bi-institutional analysis. Ann Surg 2002; 235:
863–71.
112. Adam R, Pascal G, Azoulay D, et al. Liver resection for colorectal metas-
tases: the third hepatectomy. Ann Surg 2003; 235: 863–71.
113. Pessaux P, Lermite E, Brehant O, et al. Repeat hepatectomy for recurrent
colorectal liver metastases. J Surg Oncol 2006; 93: 1–7.
114. Elias D, Youssef O, Sideris L, et al. evolution of missing colorectal liver
metastases following inductive chemotherapy and hepatectomy. J Surg
Oncol 2004; 86: 4–9.
115. Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal
liver metastases after chemotherapy: does it mean cure? J Clin Oncol
2006; 24: 3939–45.
116. Adam R, Wicherts DA, de Haas R, et al. Complete pathological response
after preoperative chemotherapy for colorectal liver metastases: myth or
reality? J Clin Oncol 2008; 26: 1635–41.
117. Rubbia Brandt L, Giostra E, Brezault C, et al. Importance of histological
tumor response assessment in predicting the outcome in patients with
colorectal liver metastases treated with neoadjuvant chemotherapy fol-
lowed by liver surgery. Ann Oncol 2007; 18: 299–304.
118. Parikh AA, Gentner B, Wu TT, et al. Perioperative complications in
patients undergoing major liver resection with and without neoadju-
vant chemotherapy. J Gastrointest Surg 2003; 7: 1082–8.
119. Adam R, Pascal G, Castaign D, et al. Tumor progression while on che-
motherapy: a contraindication to liver resection for multiple colorectal
metastases? Ann Surg 2004; 240: 1052–61.
120. Nordlinger B, Guiet M, Vaillant JC, et al. Surgical resection of colorec-
tal carcinoma metastases to the liver. A prognostic scoring system to
improve case selection, based on 1568 patients. Cancer 1996; 77:
1254–62.
121. Bolton J, Fuhram GM. Survival after resection of multiple bilobar
hepatic metastases from colorectal carcinoma. Ann Surg 2000; 231:
743–51.
122. Reddy SK, Pawlik TM, Zorzi D, et al. Simultaneous resection of colorec-
tal cancer and synchronous liver metastases: a multi-institutional analy-
sis. Ann Surg Oncol 2007; 14: 3295–6.
123. Thelen A, Jonas S, Benckert C, et al. Simultaneous versus staged liver
resection of synchronous liver metastases from colorectal cancer. Int J
Colorectal Dis 2007; 22: 1269–76.
124. Tanaka K, Shimada H, Matsuo K, et al. Outcome after simultaneous
colorectal and hepatic resection for colorectal cancer with synchronous
metastases. Surgery 2004; 136: 650–9.
125. Weber JC, Bachellier P, Oussoultzoglou E et al. Simultaneous resection
of colorectal primary tumor and synchronous liver metastases. Br J Surg
2003; 90: 956–62.
126. Mentha G, Majno P, Roth A. Neoadjuvant chemotherapy and resection
of advanced synchronous liver metastases before treatment of the
colorectal primary. Br J Surg 2006; 93: 872–8.
14 Chemotherapy for metastatic colorectal cancer
Derek G. Power and Nancy E. Kemeny
introduction
Colorectal cancer (CRC) is a major cause of cancer-related
mortality worldwide and in Western countries, and it is the
second most frequent cause of cancer-related death (1). The
United States has the highest annual incidence of invasive
CRC, and in 2008 an estimated 148,810 cases of CRC were
diagnosed and 49,960 people died from the disease (2). At
diagnosis, 20% to 25% of all patients will have synchronous
liver metastases and at least another 60% of patients who
develop metastatic disease will have metachronous liver metas-
tases (3,4). The liver is the only metastatic site in about one-
third of patients and this can be explained by the portal venous
drainage of the colon and rectum to liver (5). Overall liver
metastases are seen in approximately 20% to 70% of patients
with CRC and lung metastases are seen in 10% to 20%. (6) For
many years, the approach to patients with metastatic CRC was
minimalist with fluorouracil-based chemotherapy being the
only palliative option and median survival rarely exceeding
one year (7).
Surgical developments over the last 10 years in resection of
liver metastases have resulted in improved long-term survival.
Several large surgical series have shown 5-year survival rates
averaging 30% to 40%, and in some patients a chance of cure,
with 20% survival at 10 years after hepatic resection (8–10).
Developments in chemotherapy, both systemic and regional,
have resulted in a radically changed landscape for patients
with metastatic CRC. Those patients who present with initially
unresectable liver metastases, 80% to 85% of cases, may now
have the chance of hepatic resection after chemotherapy
downstaging. Even if liver resection is not possible, median
survival has increased with modern chemotherapies (3,11).
This review will focus on developments in chemotherapy
and biologic therapy for the treatment of metastatic CRC and
highlight how a true multidisciplinary approach has resulted
in improved survival for this common disease.
systemic chemotherapy for unresectable
liver disease (first and second line)
The fluorinated pyrimidine antimetabolites have been the
cornerstone of systemic treatment for CRC for over 50 years.
Fluorouracil (5-FU) was the only chemotherapeutic agent
available for nearly 35 years. Response rates with bolus 5-FU
were 10% to 20% with median survival around 10 to 12 months
(12). Modifications of the 5-FU dosing schedule were studied
and it was found that a protracted infusion of the drug
increased response rates to 20% to 30% and median survival
to 12 to 14 months (13,14). The addition of the biomodulator
folinic acid [leucovorin (LV)] to 5-FU similarly increased
response rates and median overall survival (14,15), and it has
now become standard to combine 5-FU bolus plus 48-hour
infusion with bolus LV (deGramont – LV5FU-2) in a bimonthly
schedule as randomized data has shown the superiority of this
regimen compared with other 5-FU/LV schedules (16).
Over the last few years, three new chemotherapeutic
agents—irinotecan, oxaliplatin, and capecitabine (an oral ver-
sion of 5-FU)—have been approved for the treatment of meta-
static CRC.
Irinotecan is a topoisomerase inhibitor and activity in the
metastatic setting was established in randomized studies
comparing irinotecan with best supportive care. In patients
who progressed on fluorouracil therapy, one-year survival
rates were increased from 14% to 36% with the use of single
agent irinotecan (17). Combinations of irinotecan and 5-FU/
LV were then studied in the first-line setting. A randomized
trial of irinotecan added to infusional 5-FU/LV compared to
5-FU/LV alone demonstrated an increased response rate
(35% vs. 22%, respectively, p = 0.005) and a survival benefit
of 3 months (17 vs. 14 months, respectively, p = 0.031).
Grades 3 to 4 toxicities were more common in the irinotecan
group, e.g. diarrhea (44% vs. 26%) and neutropenia (29% vs.
2%) (18). A phase III study of 683 patients compared weekly
irinotecan and bolus 5-FU/LV (IFL) to 5-FU/LV alone. The
IFL regimen increased response rate (39% vs. 21%, p < 0.001)
and survival (14.8 vs. 12.6 months, respectively, p = 0.04)
(19). The FOLFIRI regimen, that is, irinotecan combined
with the deGramont 5-FU/LV combination, has been shown
to be safe and efficacious in the first-line setting and is now
accepted as the optimal way to combine irinotecan and FU/
LV. Response rates approaching 40% and median overall sur-
vival of 17 to 23 months have been reported (20,21). The
randomized BICC-C trial (before the addition of bevaci-
zumab) reported a median OS of 23.1 months for FOLFIRI
vs. 17.9 months for mIFL and 18.9 months for CapIRI
(capecitabine and irinotecan) with response rates of 47%,
42%, and 39%, respectively (21).
Oxaliplatin is a platinum derivative and works by alkylating
DNA. As a single agent, oxaliplatin is not superior to LV5FU-2
and has limited activity in advanced CRC (22,23). In the first-
line setting, the FOLFOX regimen, that is, combination oxali-
platin and LV5FU-2 given as the deGramont schedule, was
shown to be safe, efficacious, and superior to LV5FU-2 with
response rates of 50% and median overall survival of
16 months (24). FOLFIRI compared with FOLFOX showed
response rates of 56% and 54%, respectively, and no difference
in median overall survival 20.6 versus 21.5 months (p = NS)
(25). A phase III trial by Colucci and colleagues comparing
FOLFIRI and FOLFOX4 also showed essentially equal efficacy
in terms of response rate, time to progression, and overall sur-
vival (26). The intergroup trial showed that patients receiving
FOLFOX had a median survival of 19.5 months compared to
17.4 months for irinotecan plus oxaliplatin (IROX) or
15 months for IFL (p = 0.001) (27,28). Efficacy of the FOLFOX
135
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 14.1 Metastatic CRC Second-Line Regimens

Study First-line Second-line RR (%) mTTP mOS
Rothenberg (22) IFL FOLFOX4 9.9 4.6
Rothenberg (32) FOLFIRI FOLFOX4 12.4 4.8 12.6
XELOX 15.3 4.7 11.9
Tournigand (25) FOLFIRI FOLFOX6 15 4.2
FOLFOX6 FOLFIRI 4 2.5
Souglakos (33) Oxaliplatin FOLFIRI 18 7.5 14
Park (137) Irinotecan FOLFOX 15 2 5
RR, response rate; mTTP, median time to progression (in months).
mOS, median overall survival (in months).

regimen was also shown in the randomized TREE1 study,

which compared mFOLFOX6 to bolus FU/LV/oxaliplatin and
to capecitabine/oxaliplatin. Response rates were 41%,
20%, and 27%, respectively, and median OS was 19.2, 17.9,
and 17.2 months, respectively (29). Overall, the FOLFOX and
FOLFIRI regimens have improved response rate, time to pro-
gression, and overall survival compared to 5-FU/LV (30).
Replacing 5FU/LV with capecitabine and combining with
oxaliplatin (XELOX) has been shown to be noninterior to
FOLFOX and thus is a third alternative for first-line treatment
(31). The combination of capecitabine and irinotecan, however,
is not well tolerated and is associated with high rates of severe
vomiting and diarrhea. Therefore the bolus/infusional schedule Catheter in
artery
of FU, LV5FU-2 is the preferred mode of administration in
combination with irinotecan (21). In the second-line setting,
after treatment failure with oxaliplatin or irinotecan-based regi-
mens, results are less impressive (Table 14.1). Response rates of
Codman
up to 18% and median overall survival of 6 to 14 months have 3000
been reported (32,33). It is noteworthy that in those patients Pump
who are 5-FU refractory, there is no difference in outcome if
second-line therapy begins with either FOLFOX or irinotecan.
In a phase III study of 491 5-FU-resistant patients with mCRC,
median overall survival with second line FOLFOX was 13.8
versus 14.3 months for irinotecan alone (p = 0.38) (34).
Figure 14.1 Implantable HAI pump.
regional chemotherapy in unresectable
liver disease the study, initial extrahepatic disease in some studies, and the
The rationale for hepatic arterial infusion (HAI) of chemo- fact that HAI was not used in all cases though the patients are
therapy is that the hepatic metastases receive their blood sup- included in the survival data. The CALGB 9481 study compared
ply from the hepatic artery and the normal liver parenchyma is HAI FUDR + Dexamethasone (Dex) with systemic intravenous
fed by the portal vein (35). The development of an implant- (IV) FU/LV and did not have a crossover (39). Dexamethasone
able pump allowing continuous infusion of chemotherapy was added to the FUDR in the pump as it had previously been
and long-term patency of the catheter and hepatic artery made shown to decrease FUDR toxicity and increase efficacy (40).
the development of HAI therapy possible (Fig. 14.1). Floxuri- There was a significant increase in overall survival in the HAI
dine (FUDR) is the ideal drug for use via HAI as it has a high FUDR Dex arm versus the systemic FU/LV arm (24.4 vs.
hepatic extraction, a short half life, and a steep dose–response 20 months, respectively, p = 0.0034). Quality of life assessment
curve. These properties give FUDR a 400-fold advantage when showed that the HAI arm experienced significantly better phys-
given via HAI (36,37). ical functioning compared with the systemic arm. The 51%
Ten randomized phase III trials have compared HAI FUDR 2-year survival compared favorably with systemic combinations
with systemic FUDR or FU/LV in patients with unresectable of Oxaliplatin/5FU/LV (25), or irinotecan/5FU/LV (41). The use
CRC liver metastases. All of these trials showed superior of HAI alone, however, in a new meta-analysis using the old
response rates with HAI administration (42–62%) compared to flawed studies did not show an increased survival (38). With
systemic (9–21%) (38). Overall survival has been difficult to new systemic therapies, it is more appropriate to think of a
prove in many trials due to crossover design of small numbers in combination of these regimens with HAI FUDR/Dex.

136
 CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER
As over one-third of all patients with metastatic CRC will
have liver-only disease, the combination of HAI FUDR to treat
the liver disease and modern systemic chemotherapy to con-
trol potential extrahepatic micrometastases may show supe-
rior results as has been seen already in small studies. In a phase
I study of 46 patients previously treated with systemic chemo-
therapy, HAI FUDR/Dex in combination with systemic irino-
tecan produced response rates of 74% and a median overall
survival of 20 months (42). In an updated series of 49 patients
with unresectable liver metastases treated with HAI FUDR/
Dex plus systemic oxaliplatin/irinotecan, 53% of whom were
previously treated with systemic chemotherapy, Kemeny and
colleagues report a 92% response rate and a median overall
survival of 50.8 months and 35 months for chemotherapy in
naive and pretreated patients, respectively. The resection rate
in this study was 47%, in a population that was definitely unre-
sectable at baseline (43) [see section “Converting unresectable
liver disease to resection…” for further discussion on resection
of liver metastases and for comment on using HAI with other
chemotherapy besides FUDR, e.g., oxaliplatin].
systemic chemobiologic therapy
for unresectable liver disease
Our increasing understanding of molecular pathways in carci-
nogenesis has led to the development of novel targeted ther-
apy. Vascular endothelial growth factor (VEGF) plays a crucial
role in physiologic and pathologic angiogenesis. Preclinical
data with bevacizumab, a humanized monoclonal antibody
against VEGF, showed inhibition of growth of human tumor
xenografts as a result of inhibition of tumor angiogenesis (44)
and improved delivery of chemotherapy to the tumor by alter-
ing tumor vasculature and decreasing elevated interstitial
pressure in tumors (45). In a randomized phase III trial, the
addition of bevacizumab (bev) to IFL versus IFL alone resulted
in increased response rates, progression-free and overall sur-
vival (20.3 vs. 15.3 months, respectively, p < 0.001) (46). The
results were not as promising in a randomized phase III study
of 1400 patients where the addition of bevacizumab to both
FOLFOX4 and XELOX in the first-line setting improved
progression-free survival (9.4 vs. 8.0 months for the bev and
placebo groups, respectively, p = 0.0023), but not response
rates (47% vs. 45%) or median overall survival (21.3 and
19.9 months) in the bevacizumab and placebo groups, respec-
tively (p = 0.077). (47) The TREE and BICC-C studies showed
an increased response rate and overall survival when bevaci-
zumab was added to oxaliplatin- and irinotecan-based regi-
mens. However, these studies were sequential and not
randomized (29,48). There has been no trials comparing
FOLFOX/bevacizumab with FOLFIRI/bevacizumab. However,
based on the fact that FOLFOX and FOLFIRI have virtually
identical activity in the first-line setting, the addition of beva-
cizumab to either regimen is reasonable. Bevacizumab has
also shown activity in the second-line setting. The European
Cooperative Oncology Group (ECOG) showed that patients
treated with FOLFOX4 and bevacizumab after progression on
irinotecan and fluoropyrimidines had improved survival
compared with FOLFOX4 alone (12.9 vs. 10.8 months, p =
0.0011). (49)
The epidermal growth factor receptor (ERBB, EGFR) family
compromises four molecules: EGFR, HER2, HER3, and HER4.
EGFR is overexpressed in up to 70% of human CRCs and has
been associated with advanced stage disease (50). EGFR activa-
tion mediates multiple cell-signaling pathways including PI3K/
AKT/mTOR and Ras/Raf/MEK/ERK resulting in resistance to
apoptosis, proliferation, angiogenesis, and metastases. Two
monoclonal antibodies that target the EGFR have been
approved for the treatment of metastatic CRC. Panitumumab
(Pmab) is a fully humanized IgG2 molecule, while cetuximab
(Cmab) is an IgG1 chimeric molecule. A significant increase in
response rate (22.9% vs. 10.8%) and time to progression (4.1
vs. 1.5 months), but not overall survival (8.6 vs. 6.9 months; p =
0.48) has been reported with Cmab in combination with irino-
tecan versus Cmab alone in patients refractory to irinotecan or
oxaliplatin-based chemotherapy (51,52). The MABEL study of
1147 patients confirmed the results of the earlier Cmab studies.
In patients who had progressed on previous irinotecan-con-
taining regimens, the progression-free survival rate at 12 weeks
was 61% with the irinotecan and Cmab combination and
median overall survival was 9.2 months (53). Another second-
line study, EPIC (Erbitux Plus Irinotecan in Colorectal Can-
cer), compared Cmab plus irinotecan with irinotecan alone in
patients who had progressed on previous oxaliplatin-contain-
ing regimens. A significant improvement in PFS and response
rate was found with the combination (3.98 vs. 2.56 months, p <
0.001; 16% vs. 4%, p < 0.001, respectively) with no difference in
overall survival (10.7 vs. 10 months, p = 0.812) (54). The
National Cancer Institute of Canada (NCIC) evaluated the
effect of third-line Cmab in metastatic CRC patients who had
previously received FU, irinotecan, and/or oxaliplatin. Com-
pared to best supportive care, Cmab improved median overall
survival from 4.6 months to 6.1 months (p = 0.005). (55)
Results from these studies demonstrate that Cmab has activity
as monotherapy, but is more effective when combined with iri-
notecan. This is likely due to modulation of irinotecan resis-
tance by Cmab, which has been shown in preclinical work (56).
Pmab was approved on the basis of an open label randomized
phase III trial comparing Pmab with best supportive care in
patients who had progressed on previous chemotherapies.
Pmab significantly increased PFS (13.8 vs. 8.5 weeks, p = 0.001),
but not overall survival (57).
In the first-line setting, both Cmab and Pmab have shown
activity as well. The phase III CRYSTAL trial of 1,217 patients
compared FOLFIRI plus Cmab to FOLFIRI alone. Progres-
sion-free survival, the primary end-point, was significantly
greater with the combination (8.9 vs. 8 months, p = 0.0479,
respectively). Also there was a difference in response rate (47%
vs. 39%, p = 0.0038) and median overall survival (19.9 vs.
18.6 months, p = 0.30) [intention to treat data] (58). The
OPUS study randomized first-line FOLFOX4 plus Cmab with
FOLFOX4 alone and showed a 10% increased response rate
with the combination (46% vs. 36%, p = 0.084) and no change
in median PFS (7.2 vs. 7.2 months) [intention to treat data]
(59). Preliminary data from the phase III CALGB 80203 trial
showed a higher overall response rate for FOLFOX/FOLFIRI
plus Cmab versus chemotherapy alone (49% vs. 33%, p =
0.014) (60). There is less experience with Pmab, likely due to
137
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
its more recent approval. In a phase II study in the first-line
setting, an objective response rate of 47% and a median sur-
vival of 16.8 months was reported when Pmab was combined
with irinotecan-based regimens (61). Studies combing Pmab
with oxaliplatin in the first- and second-line settings are ongo-
ing (62). There are no data direct comparisons between Cmab
and Pmab and the decision to use one over the other may well
come down to physician preference or decreased rate of hyper-
sensitivity reactions seen with Pmab (63,64).
Many of the above trials with EGFR antibodies accrued
patients who had EGFR-expressing disease. It has since
emerged that there is a lack of correlation between EGFR
expression based on immunohistochemistry, gene expression, or
gene copy number and response to Cmab and Pmab (65–67).
More recently, the predictive value of KRAS mutations down-
stream of the EGFR has helped to define a subset of patients
more likely to respond to EGFR monoclonal antibodies and
possibly explains why the overall efficacy to EGFR inhibition
has been so poor. Retrospective analyses of many of the trials
discussed above show that response rates to EGFR antibodies
in patients who are KRAS mutant is very low (68–73). As a
result the drug licensing body in Europe (EMEA) and the
American Society of Clinical Oncology (ASCO) has restricted
the use of EGFR antibodies to KRAS wild-type patients in the
treatment of metastatic CRC. The CRYSTAL trial retrospec-
tively performed KRAS analysis and reported an increased
response rate (59% vs. 43%, p = 0.0025) and an overall sur-
vival benefit in KRAS wild-type patients (24.9 vs. 21.0 months,
p = 0.22) for the Cmab and chemotherapy versus chemother-
apy alone groups, respectively (58,74,75). The OPUS study
also reported the effect of EGFR inhibition in the KRAS wild-
type (wt) population. The addition of Cmab to FOLFOX in
wild type patients increased response rate (61% vs. 37%, p =
0.11) and median PFS from 7.2 to 7.7 months (p = 0.02) com-
pared to FOLFOX alone. In the mutant KRAS population
median PFS decreased from 8.6 months to 5.5 months with
the addition of Cmab to FOLFOX (p = 0.02), suggesting a det-
rimental effect with the addition of Cmab to FOLFOX in
KRAS mutant patients (59). The benefit of Cmab even in the
select KRASwt population, however, is modest with an overall
survival benefit of 3.9 months (in KRAS wild type tumors,
HR = 0.84 [95% CI: 0.64–1.11]), as reported in the CRYSTAL
trial and an improvement in PFS of 1.2 months, or approxi-
mately 37 days.
Genetic and biochemical evidence indicates that BRAF is the
principal downstream effector of KRAS and recent data has
shown that the BRAF mutation V600E (present in approxi-
mately 10% of CRCs, thus leaving at least 40% of nonrespon-
sive patients with no mutations in EGFR or BRAF associated
with resistance to EGFR antibody therapy) (76). Intact expres-
sion of PTEN and expression levels of EGFR ligands (amphi-
regulin, epiregulin) may also play a role in identifying those
who will benefit from anti-EGFR therapies (71,77).
As data emerged on activity with biologic agents, combina-
tions of biologics with chemotherapy was investigated. The
phase II BOND-2 study showed that adding bevacizumab and
Cmab to irinotecan in patients who were irinotecan refractory
suggested a benefit for the two antibodies versus one (overall
138
survival 14.5 vs. 11.4 months, respectively) (78). The random-
ized phase III PACCE study investigated the addition of Pmab
to a combination of bevacizumab and chemotherapy (either
oxaliplatin or irinotecan-based regimens) in the first-line set-
ting demonstrated a decreased PFS for the Pmab/bevacizumab
plus oxaliplatin versus bevacizumab/chemotherapy combina-
tion (10 vs. 11.4 months, respectively, p = 0.044). In the irino-
tecan-based chemotherapy group, median PFS was 10.1 months
for those the received two antibodies versus 11.7 months for
those receiving one (79). A trend toward worse OS was observed
with Pmab/Bev plus systemic chemotherapy vs Bev plus che-
motherapy in the KRAS wt group, 20.7 versus 24.5 months,
respectively. Additional toxicity was also seen in the Pmab/
bevacizumab/chemotherapy group. The CAIRO-2 study com-
pared the combination of Cmab with bevacizumab and
XELOX in the first-line treatment and showed that the Cmab/
bevacizumab/XELOX resulted in a decreased median PFS
compared with XELOX/bevacizumab (9.4 vs. 10.7 months, p =
0.018) (80). KRAS analysis was performed retrospectively and
when compared to patients with KRAS mutations in the che-
motherapy/bevacizumab group, cetuximab-treated patients
with KRAS mutated tumors had significantly shorter PFS (8.1
vs. 12.5 months, p = 0.003) and OS (17.2 vs. 24.9 months, p =
0.03). In those patients with KRAS wild-type tumors, there was
no difference in either PFS or OS with the addition of cetux-
imab. Thus the addition of VEGF/EGFR antibody combina-
tions to chemotherapy suggests a lack of benefit. The SWOG/
CALGB 80405 trial looking at FOLFIRI or FOLFOX in combi-
nation with Cmab or bevacizumab or both may help to answer
this question (60). To date, therefore, dual biologic therapy
with bevacizumab and an anti-EGFR antibody should not be
used in combination with chemotherapy in the first-line treat-
ment of metastatic CRC outside of a clinical trial.
converting unresectable liver disease
to resection
There is increasing literature supporting the use of modern
systemic chemotherapy, as described above, to decrease the
size and extent of liver disease, thus rendering previously unre-
sectable metastases resectable (81–83). While this is not neo-
adjuvant therapy in the strictest sense of the word, the end
point for patients with initially unresectable liver metastases
from CRC should hopefully be hepatic resection. It has been
shown that in nonresectable liver metastases, resection rate
correlates with response (84). In the largest study to date,
Adam and colleagues report an experience over 11 years in
1439 patients, of which 1104 had unresectable liver disease at
presentation. Chemotherapy consisted of FOLFOX (70%),
FOLFIRI (7%), or both (4%) and treatment was for an average
of 10 courses. Hepatic resection was possible in 138 patients
(12.5%) and the 5- and 10-year survival rates were 33% and
23%, respectively, which compares favorably to 335 patients
who were resectable from the start and had 5- and 10-year sur-
vival rates of 48% and 30%, respectively (p = 0.01) (85). This
study highlights the fact that modern chemotherapy can con-
vert unresectable liver metastases to resection with good 5-year
survival rates. Several other studies have looked at combina-
tions/comparisons of FOLFOX, FOLFIRI, and FOLFOXIRI
 CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER
Table 14.2 Neoadjuvant Systemic Chemotherapy for
Unresectable Liver Metastases
Resectability
Study Regimen rate (%) OS
Giacchetti (83) 5FU/LV/ 38 5 years, 50%
Oxaliplatin
Med, 48m
Bismuth (82) 5FU/LV/ 16 5years, 54%
Oxaliplatin
Pozzo (138) FOLFIRI 32.5 All alive
19m f/u
Alberts (139) FOLFOX4 33.3 Med, 26m
Masai (140) FOLFOXIRI 26 4 years, 37%
Med, 37m
m, months; Med, median; OS, overall survival;
f/u, follow-up.
(oxaliplatin, irinotecan and bolus/infusional 5FU/LV) in
patients with initially unresectable (or not optimally resect-
able) disease and report increasing rates of R0 hepatic resec-
tions and overall survival (Table 14.2). In a phase III study of
244 patients, conducted by the Gruppo Onclogico Nord-Ovest
(GONO) group, FOLFOXIRI was compared with FOLFIRI.
The rate of R0 hepatic resections was 36% for the triplet com-
pared with 12% for the doublet (p = 0.017) (86). This group
recently updated the long-term outcome of 196 patients with
initially unresectable mCRC treated with FOLFOXIRI in two
phase II and one phase I trials. The overall R0 resection rate
was 19% and at 5 years, 29% of patients are free of disease
(87). Another phase III study of 283 patients showed that
the addition of oxaliplatin to FOLFIRI increased the resection
rate of lung and liver metastases from 4% to 10%. Of those
who underwent surgery after FOLFOXIRI, 86% had an R0
resection (88). Subset analysis of the oxaliplatin stop-go
OPTIMOX-1 study showed that FOLFOX4 was superior to
FOLFOX7 in terms of overall survival after an R0/R1 resection
(51 vs. 38 months, respectively) (89).
HAI combined with systemic therapy in nonrandomized
studies has demonstrated high response and resection rates. In
a retrospective series examining HAI FUDR Dex in patients
who had all received prior oxaliplatin/5FU/LV and some had
prior irinotecan as well, the response rate for 39 patients was
44%, and median OS from the time of initiation of HAI was
20.1 months, while it was 32 months from the initiation of
treatment of their metastatic disease. Eighteen percent of
patients proceeded to surgical resection or ablation (90). HAI
FUDR/Dex combined with oxaliplatin and irinotecan based
regimens produced resectability rates of up to 47% in patients
who were definitely unresectable at presentation and 53% had
received prior systemic therapy. The median survival for all
patients was 41 months. Survival for the chemotherapy naive
group was 50 months while it was 38 months for those previ-
ously treated (43).
The benefit of HAI therapy given in a “neoadjuvant” setting
has also been highlighted by Auer and colleagues. Radiologic
complete response of liver metastases in patients treated with
HAI FUDR was more likely to represent a true CR when
compared to systemic neoadjuvant chemotherapy (68% vs.
29%), and the liver recurrence rate was 14% in the HAI group
versus 42% in the preoperative systemic chemotherapy group
(p < 0.001) (91,92). The benefit of HAI in the “neoadjuvant”
setting has also been reported with the use of other drugs
besides FUDR. In a phase II study, Ducreux and colleagues
reported the efficacy and relative safety of HAI Oxaliplatin
plus 5FU/LV in 26 patients with initially unresectable liver
metastases. Median overall survival and median disease free
survival was 27 months and 27 months, respectively (93). The
intention to treat response rate was 64% and 5 patients pro-
ceeded to R0 liver resection. Recent work by Boige and col-
leagues used HAI Oxaliplatin combined with systemic FU/LV
after systemic failure with either FOLFOX or FOLFIRI or both
(94). Median PFS and overall survival were 7 months and
16 months, respectively, and 7 out of 39 patients previously
deemed unresectable were able to undergo an R0 liver resec-
tion. The use of preoperative HAI Oxaliplatin has also been
reported by Elias and colleagues to be significantly associated
with a true pathologic complete response even when “missing”
metastases are left in place at hepatectomy (95). These studies
suggest that regional therapy may produce a higher rate of true
cured lesions than systemic therapy as described in the Benoist
study where persistent macroscopic or microscopic residual
disease or early recurrence in situ was observed in 83% of liver
metastases having a complete response on imaging (96).
The toxicity profile of HAI Oxaliplatin is abdominal pain
(grades 3–4, 14%) and neutropenia (grades 3–4, 43%) (97).
Irinotecan is not more useful via HAI route as the systemic
levels of the active metabolite SN-38 are similar to that seen
when irinotecan is given systemically (97–99).
Biologic agents are also being used in combination with sys-
temic chemotherapy in patients with initially unresectable
liver disease. Recent data has shown that bevacizumab in com-
bination with chemotherapy may increase hepatic resection
rates and does not appear to impact adversely on surgical out-
come or liver regeneration. In a nonrandomized phase II trial
by Gruenberger and colleagues, the addition of bevacizumab
to XELOX in patients with potentially resectable liver metasta-
ses resulted in an objective response rate of 73%, a resection
rate of 93%, and no intraoperative or wound healing compli-
cations (100,101). To evaluate whether preoperative bevaci-
zumab affects patients going for liver resection, the
Bevacizumab Expanded Access Trial (BEAT) was designed and
has thus far concluded that metastatectomy is feasible after
bevacizumab treatment (102).
Combination of EGFR antibodies with systemic chemo-
therapy may also have the potential to increase resection rates
of unresectable or possibly resectable liver metastases. Adam
and colleagues reported that combining Cmab with oxalipla-
tin- or irinotecan-based chemotherapy in chemorefractory
patients with unresectable liver metastases can result in sal-
vage liver resection rates of 17%. With a median follow-up of
16 months, 92% of resected patients (23/25) were alive and
10 patients (40%) were disease-free. There was no significant
increase in operative mortality or liver injury. Median overall
(OS) and progression-free survival (PFS) from initiation
of cetuximab therapy was 20 and 13 months, respectively
139
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
(for resected patients) (103). A phase II study of FOLFOX4
plus cetuximab in the treatment of patients with EGFR-
expressing initially unresectable liver metastases resection
rates were 23.8% (8/10 of whom had liver metastases only),
PFS of 12.8 months and median OS of 30 months (104). The
CRYSTAL trial compared FOLFIRI + Cmab versus FOLFIRI
alone and reported liver a resection rate (R0) of 9.8% for the
investigational arm versus 4.5% for the control arm (58). The
CELIM study reported an R0 resection rate of 34% for initially
unresectable liver metastases (n = 106) with “neoadjuvant”
FOLFOX/Cmab (n = 20) or FOLFIRI/Cmab (n = 16) (105).
The NSABP is currently planning a trial to study the rates of
conversion from unresectable to resectable liver disease using
an EGFR antibody. Ongoing phase II trials in our institution
are investigating the rate of conversion to complete resection
with initially unresectable liver metastases after treatment with
HAI FUDR Dex in combination with best systemic chemo-
therapy plus bevacizumab. Such studies will help to further
define the role of HAI in the neoadjuvant setting and should
lead to adequately powered phase III trials comparing HAI
plus systemic chemobiologic therapy with chemobiologic ther-
apy alone in this setting. Presently initial systemic chemother-
apy with or without biologic therapy is reasonable as first-line
therapy. If the liver disease is not resectable at this stage, then
consideration should be given to HAI in combination with fur-
ther systemic chemotherapy. If HAI therapy is not available,
then chemotherapy with EGFR inhibitors should be used.
scheduling strategies for treatment
of metastatic disease
Various strategies have been used in an attempt to improve the
inconvenience and toxicity of chemotherapy. An especially
troublesome toxicity is oxaliplatin-associated neurotoxicity.
The OPTIMOX1 study compared FOLFOX4 [ARM A] given
until progression with a “stop and go” regimen of FOLFOX7
(high-dose oxaliplatin and no bolus dose 5FU) X 6 cycles fol-
lowed by maintenance 5FU X 12 cycles and then reintroduc-
tion of FOLFOX7 [ARM B] (89). There was an insignificant
difference in prevalence of sensory neuropathy between the
two arms, and median PFS (9 and 8.7 months for arms A and
B, respectively) and overall survival (19.3 vs. 21.3) were equiv-
alent. Maintenance 5FU (without oxaliplatin) is therefore a
valid treatment option after initial exposure to FOLFOX. The
OPTIMOX2 study evaluated a chemotherapy-free window
compared to the “stop and go” schedule of OPTIMOX1. The
maintenance chemotherapy group had significantly superior
PFS and overall survival, the difference being especially seen in
those patients with a poor prognosis (overall survival in the
“stop and go” group versus chemotherapy free groups was 28.7
vs. 14.5 months, respectively), suggesting stopping all therapy
was not effective (106). The OPTIMOX3 study will evaluate
the use of targeted therapy with bevacizumab and erlotinib
during the maintenance phase.
Stopping irinotecan has been studied by Labianca and col-
leagues comparing FOLFIRI for 6 months with FOLFIRI X
2 months followed by 2 months of no treatment and then
FOLFIRI for another 2 months. There was no significant
difference in terms of efficacy between the two groups (107).
140
The CAIRO (Capecitabine, Irinotecan, and Oxaliplatin in
Advanced Colorectal Cancer) and FOCUS (Fluorouracil,
Oxaliplatin, and CPT11 [irinotecan]-Use and Sequencing) tri-
als investigated the strategy of sequential use of single agents
and combination chemotherapy (108,109). The CAIRO study
showed no significant difference in overall survival between
sequential capecitabine followed by irinotecan followed by
XELOX compared to XELIRI followed by XELOX (17.4 vs.
16.3 months, respectively, p = 0.3281). The FOCUS trial was a
three-arm study comparing 5-FU/LV followed by irinotecan
(control group) with either 5FU followed by 5-FU in combina-
tion with either irinotecan or oxaliplatin (group 1), or 5FU in
combination with either irinotecan or oxaliplatin from the out-
set (group 2). Groups 1 and 2 achieved a longer overall survival
time than the control group (13.9 months), but only the FOL-
FIRI regimen in group 2 achieved significance (16.7 months, p
= 0.01). Both the CAIRO and FOCUS trials challenge the
thinking that upfront combination regimens should be prefer-
entially used. The staged approach upgraded to combination
regimens has a role to play and can be considered.
The literature on bevacizumab in first-or second-line setting
has raised the question of continuing use of bevacizumab
beyond progression of disease. Grothey and colleagues
reported results from the large prospective observational study
of 1445 patients who were enrolled in the BRiTE registry (Bev-
acizumab Regimens: Investigation of Treatment Effects and
Safety). In multivariate analysis, bevacizumab beyond first
progression (BBP) was strongly and independently associated
with improved survival compared with no-BBP (31.8 vs.
19.9 months, p < 0.001) (110). Due to the substantial potential
for selection bias in the BRiTE analysis such as patients with
better performance scores or less disease receiving more Bev
after progression, a phase III SWOG 0600 study bevacizumab
continuation trial is planned to further investigate bevaci-
zumab continuation beyond progression (Irinotecan Bevaci-
zumab Continuation Trial iBET).
systemic therapy for resectable
and unresectable liver disease
Reasons for giving neoadjuvant chemotherapy to those
patients with clearly resectable liver metastases at presentation
are (1) decreasing tumor size may make the surgery easier and
(2) control micrometastatic disease. If a patient progresses in
an extrahepatic site while on chemotherapy before liver resec-
tion, one can eliminate these patients from the risks and mor-
bidity associated with hepatic resection. The LiverMetSurvey
group found that those patients with ≥5 liver metastases sur-
vived longer if they were given neoadjuvant chemotherapy,
with 5-year survival rates of 22% and 12% (p = 0.07) for the
preoperatively and nonpreoperatively treated groups, respec-
tively (3,111). (3) Assessment of chemotherapy activity preop-
eratively may help design appropriate postoperative therapy.
(4) Preliver resection patients may tolerate chemotherapy bet-
ter and full-dose treatment may impact on the ability to treat
microscopic disease. (5) Response to neoadjuvant chemother-
apy may reflect prognosis after liver resection (112). Adam and
colleagues studied 131 patients (74% with synchronous CRC
and resectable liver metastases) who underwent liver resection
 CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER
for multiple lesions (>4) after systemic chemotherapy. In a
multivariate analysis, tumor progression on chemotherapy
and the number of chemotherapy regimens were indepen-
dently associated with shorter survival duration (113). In con-
trast to this, a retrospective series at MSKCC of 111 patients
with synchronous CRC and resectable liver metastases who
received neoadjuvant chemotherapy were identified and it was
shown that response to chemotherapy was not related to over-
all survival after hepatic resection. The median overall survival
after liver resection was 62 months with a median follow-up of
63 months. Comparing response in three categories, that is,
complete or partial response, stable disease, or progression of
disease, median overall survival was similar (58 months –
65 months – 61 months, respectively, p = 0.98). Thus if
response to neoadjuvant chemotherapy is used as a criterion
for proceeding to liver resection, some patients may be denied
potentially curative liver resection and therefore long-term
survival (114). When patients with CRC and synchronous
resectable liver metastases are undergoing treatment with neo-
adjuvant chemotherapy, it is important to scan frequently and
consider short duration of preoperative chemotherapy.
Potential disadvantages of neoadjuvant chemotherapy
include: (1) liver toxicity from systemic chemotherapy, which
includes steatosis, portal fibrosis, sinusoidal alterations, pelio-
sis, and hemorrhagic centrilobular necrosis (3,115). These tox-
icities may increase the risk of liver resection, prevent liver
resection, and impair the functioning of the remaining hepatic
tissue (11). Oxaliplatin-based regimens are associated with a
higher risk for vascular lesions and sinusoidal dilation, and
irinotecan-based regimens are associated with higher risks for
steatosis and steatohepatitis (116,117). There is relatively little
data on the frequency or gravity of liver toxicity with the use of
biologic agents prior to liver resection. D’Angelica and col-
leagues report no statistically significant increase in periopera-
tive complications between perioperative bevacizumab versus
matched-control groups (118). Klinger reports that when bev-
acizumab is added to oxaliplatin-based chemotherapy there
was no impact on chemotherapy-induced hepatic steatosis
and fibrosis, and bevacizumab decreased the severity of sinu-
soidal obstruction syndrome (101). (2) Secondary splenomeg-
aly and resulting portal hypertension (3). (3) A complete
radiologic response that may make it difficult for surgeons to
resect appropriate areas (3). Benoist and colleagues report that
persistent residual disease or early recurrence in situ were
observed in 55 of 66 (83%) liver metastases having a complete
response on imaging (119).
The use of perioperative chemotherapy (FOLFOX) in patients
with initially resectable liver metastases (≤4 metastases) was
studied by the European Organization for the Research and
Treatment of Cancer (EORTC 40983 study). In a 364-patient
population, this trial showed that perioperative FOLFOX was
compatible with major liver surgery, however, there was
increased toxicities in treated group. The absolute increase in
PFS in patients who underwent liver resection and periopera-
tive FOLFOX was 9.2% (42.4% vs. 33.2%, p = 0.025). Reversible
postoperative complications occurred more often after chemo-
therapy than after surgery (40/159 [25%] vs. 27/170 [16%];
p = 0.04) and included, biliary fistulae [output >100 ml/day
for >10 days] (8% vs. 4%), hepatic failure [bilirubin >100 mg/
day for >3 days] (6% vs. 3%), and wound infection (3% vs.
2%). The clinical impact of these complications was not sig-
nificant (120). Survival data are not yet available and the long-
term benefit of neoadjuvant chemotherapy in those patients
with initially resectable liver metastases is still not clear, espe-
cially since both pre- and postchemotherapy was given. At pres-
ent, the EORTC 40051 BOS (Biologics, Oxaliplatin and
Surgery) trial is assessing perioperative chemotherapy with
FOLFOX6 and cetuximab with or without bevacizumab in
patients with resectable hepatic metastases form CRC.
Our advice, in clearly resectable lesions, is resection should
be preformed first or if systemic chemotherapy is given, it
should be for a short a period as possible (no more than six
treatments at two-weekly intervals) to avoid liver toxicity, and
liver lesions should be resected as soon as possible if the patient
is a suitable surgical candidate. Consideration should then be
given to “adjuvant” systemic chemotherapy in combination
with HAI (see below).
˝adjuvant˝ systemic therapy after
liver resection
The role of “adjuvant” systemic chemotherapy after liver resec-
tion is even more uncertain as the majority of data is with
5-FU/LV and it has been difficult to show a significant differ-
ence in disease-free and overall survival (121). Mitry and col-
leagues recently reported the combined results of two phase III
trials comparing adjuvant FU/LV after liver resection with sur-
gery alone. Median progression-free survival was 27.9 months
in the chemotherapy (CT) arm as compared with 18.8 months
in the surgery (S) arm (hazard ratio = 1.32; 95% CI: 1.00–1.76;
p = .058). Median overall survival was 62.2 months in the CT
arm compared with 47.3 months in the S arm (hazard ratio =
1.32; 95% CI: 0.95–1.82; p = .095). Adjuvant chemotherapy
was independently associated with both progression-free sur-
vival and overall survival in multivariable analysis. Ychou and
colleagues report no benefit with the addition of irinotecan to
FU/LV after liver resection compared to FU/LV alone. The
overall HR for DFS adjusted for the stratification factors was
0.89 (95% CI: 0.66–1.19, log-rank p = 0.47). Median DFS was
21.6 for FU/LV vs 24.7 months for FOLFIRI (122). No ran-
domized data to support the use of “adjuvant” biologic ther-
apy after liver resection have been published so far.
adjuvant regional therapy after
liver resection
Recurrence of liver disease after liver resection is a significant
problem with nearly 70% of patients developing recurrence in
either hepatic or extrahepatic sites. It is estimated that up to
60% of recurrences will be in the liver (123). As microscopic
liver disease is the most likely cause of this recurrence, there
has been much interest in “adjuvant” HAI. Level I evidence for
the role of HAI FUDR Dex in this setting is provided by
Kemeny and colleagues. In a population of 156 patients who
underwent complete liver resection, a phase III randomized
trial was performed that compared HAI FUDR Dex plus sys-
temic FU/LV with systemic FU/LV. After a median follow-up
time of 10 years, 41% of the HAI arm are alive at 10 years
141
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

compared to 27.2% of the FU/LV alone arm. The median
hepatic PFS has not yet been reached in the HAI arm and is
32.5 months in the systemic-only group (124,125). Other
groups have also shown a clear benefit to “adjuvant” HAI plus
systemic chemotherapy after liver resection (Table 14.3)
(126–130). HAI FUDR Dex has been combined with modern
systemic chemotherapy after liver resection. Kemeny and col-
leagues reported a two-year survival of 89% with HAI FUDR
Dex in combination with irinotecan at a median follow-up of
26 months (131). A phase I trial examining adjuvant HAI
FUDR Dex combined with systemic FOLFOX has been
reported. Disease-free survival at 2 and 5 years was 59% and
50%, respectively, and 2- and 5-year overall survival rates were
90% and 86%, respectively (132). Based on this evidence, we
recommend placement of an HAI pump at the time of liver
resection and a 4 to 6 months period of “adjuvant” HAI FUDR/
Dex in combination with best available chemotherapy.
Biologic therapy may be added in as part of a clinical trial.
The benefits of adjuvant HAI after liver resection were
recently demonstrated in a 1000-patient retrospective
review by Ito and colleagues (133). In a multivariate analy-
sis, one of the significant factors associated with survival
after liver resection was HAI therapy. The median overall
survival was 68 months with HAI therapy and 50 months
for those that did not receive HAI (p = 0.0001). Another ret-
rospective study of 250 patients who underwent liver resec-
tion compared adjuvant HAI FUDR + best available systemic
chemotherapy (n = 125) with adjuvant systemic FOLFOX or
FOLFIRI (n=125). Adjuvant HAI-FUDR plus modern sys-
temic chemotherapy was associated with an improved liver
recurrence-free survival (liver RFS) and disease-specific
survival (DSS). For the adjuvant HAI-FUDR plus modern
systemic group, the 5-year liver RFS, overall RFS, and DSS
were 75%, 46%, and 72%, respectively, compared to 52%,
26%, and 55% for the modern sys alone group (p < 0.01)
(134).

Table 14.3 True Randomized Trials of Adjuvant HAI FUDR

Chemotherapy No. Patients 2-year HPFS (%) 2-year OS(%) MS (Mths)
Study HAI IV HAI IV HAI IV HAI IV HAI IV
Tono (141) FU po FU 9 10 78 30 78^ 50^ 63 40
MSKCC (124) FUDR+IV FU/LV FU/LV 74 82 90 60 86 72 72 59
ECOG (126) FUDR+IVFU/LV FU 45 30 67 43 62 53 64 50
Lorenz (128) FU/LV None 113 113 67 63 62 65 44.8 39.7
Lygidakis (129) Multidrug** None 20 20 – – – – 20! 11!
PFS, hepatic progression-free survival;
OS, overall survival; MS, median survival.
**
Interleukin, carboplatin, mitomycin, epirubicin, LV, urographin.
!
Mean survival.
^
3-year overall survival.

Table 14.4 Dose Reductions for HAI FUDR

AST FUDR dose
Ref value (ref) *
≤50 U/L >50 U/L
Current value$ 0 to <3 X ref 0 to <2 X ref 100%
3 to <4 X ref 2 to <3 X ref 80%
4 to <5 X ref 3 to <4 X ref 50%
≥5 X ref ≥4 X ref HOLD
If held,restart when: <4 X ref <3 X ref 50% off last dose
Alk Phos FUDR
Ref value (ref) * ≤90 U/L >90 U/L
Current value$ 0 to <1.5 X ref 0 to <1.2 X ref 100%
1.5 to >2 X ref 1.2 to 1.5 X ref 80%
≥2 X ref ≥1.5 X ref HOLD
If held,restart when: <1.5 X ref <1.2 X ref 25% off last dose
Total Bilirubin FUDR
Ref value (ref)* ≤1.2 mg/dl >1.2 md/dl
Current value$ 0 to <1.5 X ref 0 to <1.2 X ref 100%
1.5 to <2 X ref 1.2 to <1.5 X ref 50%
≥2 X ref ≥1.5 X ref HOLD
If held, restart when: <1.5 X ref <1.2 X ref 25% off last dose
*
Reference value is the value obtained on the day patient received the last FUDR dose.
$
Current value is that obtained at pump emptying or on the day of planned treatment (whichever is higher).

142
 CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER
As preoperative chemotherapy for resectable or unresectable
liver metastases becomes more effective, surgeons may be faced
with the problem of “missing metastases,” that is, radiologic com-
plete response of liver lesions. As mentioned above, radiologic
response is more likely to be a true pathologic response when pre-
operative HAI is used. In the adjuvant setting, treatment with
HAI is also more likely to result in a true pathologic complete
response when “missing” liver metastases are left in place at hepa-
tectomy. Elias and colleagues reported, in a series of 228 patients,
that adjuvant HAI Oxaliplatin is significantly correlated with
definitive eradication of “missing” metastases (p < 0.01) (95).
Insertion of the implantable pump can be performed at the
time of liver resection. The pump is placed percutaneously in
the left lower quadrant and is fixed in position. The pump
chamber is filled by accessing a subcutaneous septum and
injecting. An expanding and contracting propellant liquid
pushes on a bellows and infuses the drug, for example, FUDR,
from the pump chamber via the hepatic artery catheter to the
liver. It takes 2 weeks for the chamber to empty and it is then
filled with glycerol or saline to keep the catheter patent. The
cycle is then repeated after another 2 weeks, that is, 2 weeks of
drug and 2 weeks of glycerol. Before insertion of the pump,
hepatic arterial anatomy is viewed with a CT angiogram to
make sure no aberrant vessels are present. Complication rates
are low. Allen and colleagues reported a series of 544 patients
with HAI pumps and complications were divided into early,
for example, misperfusions and late, for example, dislodge-
ment (135). Rates were less than 7% in both cases. A macroag-
gregated albumin nuclear scan is performed after all pump
insertions to make sure the perfusion of the liver is adequate.
Hepatotoxicity from HAI therapy depends on the drug being
used and the duration of therapy. Raised transaminase is not
uncommon (up to 70% of cases) and can be an early sign of
liver damage. Raised bilirubin or alkaline phosphatise are a
more serious sign of liver damage and may indicate sclerosing
cholangitis (136). The addition of dexamethasone to FUDR
has decreased the incidence of this side effect. An algorithm for
does reductions based on liver blood tests has been drawn up
and FUDR doses can be adjusted accordingly (Table 14.4).
conclusions
Liver resection should now be considered in all patients with liver-
confined metastatic disease from CRC. Modern systemic chemo-
therapy with irinotecan- and oxaliplatin-based regimens can
increase resection rates is a significant number of patients. The
addition of biologic agents in patients with the appropriate molec-
ular signature may increase repose rates and resectability rates
even further. Long-term cures are possible in patients who undergo
liver resection and series with 10-year survivors have been reported
(10). In those patients in whom resection is not possible, overall
survival has increased from less than 1 year with fluorouracil regi-
mens to over 2 years with chemobiologic regimens (74). Hepatic
arterial infusion with FUDR has consistently demonstrated
increased response rates and hepatic progression-free survival
compared to systemic chemotherapy. The combination of HAI
FUDR with modern chemotherapy and perhaps chemobiologic
therapy can result in increased resection rates of initially unresect-
able liver disease and also has a role to play after liver resection.
Treatment paradigms for metastatic CRC have changed
dramatically over the last decade and involvement of a multi-
disciplinary team of surgeons, oncologists, radiologists, and
pathologists can result in long-term survival becoming a reality.
references
1. Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and
mortality in Europe in 2006. Ann Oncol 2007; 18: 581–92.
2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin
2008; 58: 71–96.
3. Kemeny N. Presurgical chemotherapy in patients being considered for
liver resection. Oncologist 2007; 12: 825–39.
4. Rees M, Tekkis PP, Welsh FK, et al: Evaluation of long-term survival
after hepatic resection for metastatic colorectal cancer: a multifactorial
model of 929 patients. Ann Surg 2008; 247: 125–35.
5. Kemeny N. Management of liver metastases from colorectal cancer.
Oncology (Williston Park). Oncology (Williston Park) 2006; 20:
1161–76.
6. Penna C, Nordlinger B. Colorectal metastasis (liver and lung). Surg Clin
North Am 2002; 82: 1075–90, x–xi.
7. Meyerhardt JA, Mayer RJ. Drug therapy: Systemic therapy for colorectal
cancer. N Engl J Med 2005; 352: 476–87.
8. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes
following hepatic resection, radiofrequency ablation, and combined
resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:
818–27.
9. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after
resection of hepatic metastases from colorectal cancer in patients
screened by positron emission tomography with F-18 fluorodeoxyglu-
cose (FDG-PET). Ann Surg 2004; 240: 438–50.
10. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival
after resection of colorectal liver metastases defines cure. J Clin Oncol
2007; 25: 4575–80.
11. Alberts SR, Wagman LD: Chemotherapy for colorectal cancer liver
metastases. Oncologist 2008; 13: 1063–73.
12. Hoff PM, Cassidy J, Schmoll HJ. The evolution of fluoropyrimidine
therapy: from intravenous to oral. Oncologist 2001; 6 Suppl 4: 3–11.
13. Meta-Analysis Group in Cancer. Toxicity of fluorouracil in patients with
advanced colorectal cancer: effect of administration schedule and
prognostic factors. J Clin Oncol 1998; 16: 3537–41.
14. Meta-Analysis Group in Cancer. Efficacy of intravenous continuous
infusion of fluorouracil compared with bolus administration in
advanced colorectal cancer. J Clin Oncol 1998; 16: 301–8.
15. Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by
leucovorin in patients with advanced colorectal cancer: an updated
meta-analysis. J Clin Oncol 2004; 22: 3766–75.
16. de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing
monthly low-dose leucovorin and fluorouracil bolus with bimonthly
high-dose leucovorin and fluorouracil bolus plus continuous infusion
for advanced colorectal cancer: a French intergroup study. J Clin Oncol
1997; 15: 808–15.
17. Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irino-
tecan plus supportive care versus supportive care alone after fluoroura-
cil failure for patients with metastatic colorectal cancer. Lancet 1998;
352: 1413–8.
18. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with
fluorouracil compared with fluorouracil alone as first-line treatment for
metastatic colorectal cancer: a multicentre randomised trial. Lancet
2000; 355: 1041–7.
19. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leu-
covorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 905–14.
20. Maiello E, Gebbia V, Giuliani F, et al. FOLFIRI regimen in advanced
colorectal cancer: the experience of the Gruppo Oncologico dell’Italia
Meridionale (GOIM). Ann Oncol 2005; 16 Suppl 4: iv56–60.
21. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of
irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line
treatment of metastatic colorectal cancer: results from the BICC-C
Study. J Clin Oncol 2007; 25: 4779–86.
143
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
22. Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin
and fluorouracil-leucovorin compared with either therapy alone in
patients with progressive colorectal cancer after irinotecan and
fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol
2003; 21: 2059–69.
23. Zori Comba A, Blajman C, Richardet E, et al. A randomised phase II study
of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and
folinic acid (Mayo Clinic regimen) in previously untreated metastatic
colorectal cancer patients. Eur J Cancer 2001; 37: 1006–13.
24. De Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil
with or without oxaliplatin as first-line treatment in advanced colorec-
tal cancer. J Clin Oncol 2000; 18: 2938–47.
25. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6
or the reverse sequence in advanced colorectal cancer: a randomized
GERCOR study. J Clin Oncol 2004; 22: 229–37.
26. Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOL-
FIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a
multicenter study of the Gruppo Oncologico Dell’Italia Meridionale.
J Clin Oncol 2005; 23: 4866–75.
27. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled
trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combi-
nations in patients with previously untreated metastatic colorectal can-
cer. J Clin Oncol 2004; 22: 23–30.
28. Sanoff HK, Sargent DJ, Campbell ME, et al. Five-year data and prognos-
tic factor analysis of oxaliplatin and irinotecan combinations for
advanced colorectal cancer: N9741. J Clin Oncol 2008; 26: 5721–7.
29. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of
oxaliplatin and fluoropyrimidine regimens with or without bevaci-
zumab as first-line treatment of metastatic colorectal cancer: results of
the TREE Study. J Clin Oncol 2008; 26: 3523–9.
30. Goldberg RM, Köhne CH, Seymour MT, et al. A pooled safety and efficacy
analysis examining the effect of performance status (PS) on outcomes in
nine first-line treatment (rx) trials (cts) of 6,286 patients (pts) with meta-
static colorectal cancer (MCRC). J Clin Oncol 2007; 25: Abs# 4011.
31. Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of
capecitabine plus oxaliplatin compared with fluorouracil/folinic acid
plus oxaliplatin as first-line therapy for metastatic colorectal cancer.
J Clin Oncol 2008; 26: 2006–12.
32. Rothenberg ML, Navarro M, Butts C, et al. Phase III trial of capecitabine
+ oxaliplatin (XELOX) vs. 5-fluorouracil (5-FU), leucovorin (LV), and
oxaliplatin (FOLFOX4) as 2nd-line treatment for patients with meta-
static colorectal cancer (MCRC). J Clin Oncol 2007; 25: Abs# 4031.
33. Souglakos J, Vardakis N, Androulakis N, et al: Irinotecan plus weekly
5-fluorouracil and leucovorin as salvage treatment for patients with
metastatic colorectal cancer: a phase II trial. Dig Dis 2007; 25: 100–5.
34. Kim GP, Sargent DJ, Mahoney MR, et al. Phase III noninferiority trial
comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in
patients with advanced colorectal carcinoma previously treated with
fluorouracil: N9841. J Clin Oncol 2009; 20: 20.
35. Sullivan RD, Norcross JW, Watkins E, Jr. Chemotherapy of metastatic
liver cancer by prolonged hepatic-artery infusion. N Engl J Med 1964;
270: 321–7.
36. Ensminger WD. Intrahepatic arterial infusion of chemotherapy: phar-
macologic principles. Semin Oncol 2002; 29: 119–25.
37. Power DG, Kemeny NE. The role of floxuridine in metastatic liver dis-
ease. Mol Cancer Ther 2009; 21: 21.
38. Mocellin S, Pilati P, Lise M, et al. Meta-analysis of hepatic arterial infu-
sion for unresectable liver metastases from colorectal cancer: the end of
an era? J Clin Oncol 2007; 25: 5649–54.
39. Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion
versus systemic therapy for hepatic metastases from colorectal cancer: a
randomized trial of efficacy, quality of life, and molecular markers
(CALGB 9481). J Clin Oncol 2006; 24: 1395–403.
40. Kemeny N, Conti JA, Cohen A, et al. Phase II study of hepatic arterial
floxuridine, leucovorin, and dexamethasone for unresectable liver
metastases from colorectal carcinoma. J Clin Oncol 1994; 12: 2288–95.
41. Goldberg RM, Sargent DJ, Morton RF, et al. Randomized controlled
trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan
or infused fluorouracil plus leucovorin and oxaliplatin in patients with
144
previously untreated metastatic colorectal cancer: a North American
Intergroup Trial. J Clin Oncol 2006; 24: 3347–53.
42. Kemeny N, Gonen M, Sullivan D, et al. Phase I study of hepatic arterial
infusion of floxuridine and dexamethasone with systemic irinotecan for
unresectable hepatic metastases from colorectal cancer. J Clin Oncol
2001; 19: 2687–95.
43. Kemeny NE, Huitzil FD, Capanu M, et al. Conversion to resectability
utilizing hepatic artery infusion plus systemic chemotherapy for the
treatment of unresectable liver metastases from colorectal cancer. J Clin
Oncol Epub ahead of print, 2008.
44. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth
factor-induced angiogenesis suppresses tumour growth in vivo. Nature
1993; 362: 841–4.
45. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy:
a new paradigm for combination therapy. Nat Med 2001; 7: 987–9.
46. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irino-
tecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N
Engl J Med 2004; 350: 2335–42.
47. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination
with oxaliplatin-based chemotherapy as first-line therapy in metastatic
colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26:
2013–9.
48. Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irino-
tecan plus infusional, bolus, or oral fluoropyrimidines in first-line treat-
ment of metastatic colorectal cancer: updated results from the BICC-C
study. J Clin Oncol 2008; 26: 689–90.
49. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combina-
tion with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for pre-
viously treated metastatic colorectal cancer: results from the Eastern
Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25:
1539–44.
50. Goldstein NS, Armin M: Epidermal growth factor receptor immunohis-
tochemical reactivity in patients with American Joint Committee on
Cancer Stage IV colon adenocarcinoma: implications for a standardized
scoring system. Cancer 2001; 92: 1331–46.
51. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and
cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal
cancer. N Engl J Med 2004; 351: 337–45.
52. Saltz LB, Meropol NJ, Loehrer PJ, Sr., et al. Phase II trial of cetuximab in
patients with refractory colorectal cancer that expresses the epidermal
growth factor receptor. J Clin Oncol 2004; 22: 1201–8.
53. Wilke H, Glynne-Jones R, Thaler J, et al. Cetuximab plus irinotecan in
heavily pretreated metastatic colorectal cancer progressing on irinote-
can: MABEL study. J Clin Oncol 2008; 26: 5335–43.
54. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of
cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure
in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26:
2311–9.
55. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treat-
ment of colorectal cancer. N Engl J Med 2007; 357: 2040–8.
56. Prewett MC, Hooper AT, Bassi R, et al. Enhanced antitumor activity of
anti-epidermal growth factor receptor monoclonal antibody IMC-
C225 in combination with irinotecan (CPT-11) against human colorec-
tal tumor xenografts. Clin Cancer Res 2002; 8: 994–1003.
57. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of
panitumumab plus best supportive care compared with best supportive
care alone in patients with chemotherapy-refractory metastatic colorec-
tal cancer. J Clin Oncol 2007; 25: 1658–64.
58. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy
as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;
360: 1408–17.
59. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovo-
rin, and oxaliplatin with and without cetuximab in the first-line treat-
ment of metastatic colorectal cancer. J Clin Oncol 2008; 29: 29.
60. Venook AP, Niedzwiecki D, Hollis D, et al. Phase III study of
irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ±
cetuximab for patients (pts) with untreated metastatic adenocarcinoma
of the colon or rectum (MCRC): CALGB 80203 preliminary results. J
Clin Oncol 2006; 26: Abs: 3509.
 CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER
61. Hecht J, Posey J, Tchekmedyian S, et al. Panitumumab in combination
with 5-fluorouracil, leucovorin, and irinotecan (IFL) or FOLFIRI for
first-line treatment of metastatic colorectal cancer (mCRC). ASCO
Gastrointestinal Cancers Symposium: Abs 2006: 237.
62. Mano M, Humblet Y. Drug insight: panitumumab, a human EGFR-
targeted monoclonal antibody with promising clinical activity in
colorectal cancer. Nat Clin Pract Oncol 2008; 5: 415–25.
63. Helbling D, Borner M. Successful challenge with the fully human EGFR
antibody panitumumab following an infusion reaction with the chime-
ric EGFR antibody cetuximab. Ann Oncol 2007; 18: 963–4.
64. Saif MW, Peccerillo J, Potter V. Successful re-challenge with panitu-
mumab in patients who developed hypersensitivity reactions to cetux-
imab: report of three cases and review of literature. Cancer Chemother
Pharmacol 2008; 10: 10.
65. Cappuzzo F, Finocchiaro G, Rossi E, et al. EGFR FISH assay predicts for
response to cetuximab in chemotherapy refractory colorectal cancer
patients. Ann Oncol 2008; 19: 717–23.
66. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in
colorectal cancer patients with tumors that do not express the epider-
mal growth factor receptor by immunohistochemistry. J Clin Oncol
2005; 23: 1803–10.
67. Personeni N, Fieuws S, Piessevaux H, et al. Clinical usefulness of EGFR
gene copy number as a predictive marker in colorectal cancer patients
treated with cetuximab: a fluorescent in situ hybridization study. Clin
Cancer Res 2008; 14: 5869–76.
68. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for
panitumumab efficacy in patients with metastatic colorectal cancer.
J Clin Oncol 2008; 26: 1626–34.
69. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state pre-
dicts survival and is associated to early radiological response in metastatic
colorectal cancer treated with cetuximab. Ann Oncol 2008; 19: 508–15.
70. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and
benefit from cetuximab in advanced colorectal cancer. N Engl J Med
2008; 359: 1757–65.
71. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregu-
lin and amphiregulin and K-ras mutation status predict disease control
in metastatic colorectal cancer patients treated with cetuximab. J Clin
Oncol 2007; 25: 3230–7.
72. Lievre A, Bachet JB, Boige V, et al. KRAS mutations as an independent
prognostic factor in patients with advanced colorectal cancer treated
with cetuximab. J Clin Oncol 2008; 26: 374–9.
73. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive
of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;
66: 3992–5.
74. Van Cutsem E, Lang I, D’haens G, et al. KRAS status and efficacy in the
first-line treatment of patients with metastatic colorectal cancer
(mCRC) treated with FOLFIRI with or without cetuximab: The
CRYSTAL experience. J Clin Oncol 2008; 26: Abs 2.
75. Rougier P, Stroiakovski D, Köhne C, et al. Addition of cetuximab to
FOLFIRI in first-line metastatic colorectal cancer (mCRC): Updated
survival data and influence of KRAS status on outcome in the CRYSTAL
study. American Society of Clinical Oncology—Gastrointestinal Cancer
Symposium 2009; Abstract # 443.
76. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is
required for response to panitumumab or cetuximab in metastatic
colorectal cancer. J Clin Oncol 2008; 10: 10.
77. Razis E, Briasoulis E, Vrettou E, et al. Potential value of PTEN in pre-
dicting cetuximab response in colorectal cancer: an exploratory study.
BMC Cancer 2008; 8: 234.
78. Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetux-
imab, bevacizumab, and irinotecan compared with cetuximab and
bevacizumab alone in irinotecan-refractory colorectal cancer: the
BOND-2 study. J Clin Oncol 2007; 25: 4557–61.
79. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of
chemotherapy, bevacizumab, and panitumumab compared with che-
motherapy and bevacizumab alone for metastatic colorectal cancer.
J Clin Oncol 2008; 29: 29.
80. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetux-
imab in metastatic colorectal cancer. N Engl J Med 2009; 360: 563–72.
81. Baize N, Gerard B, Bleiberg H, et al. Long-term survival of patients
downstaged by oxaliplatin and 5-fluorouracil combination followed by
rescue surgery for unresectable colorectal liver metastases. Gastroen-
terol Clin Biol 2006; 30: 1349–53.
82. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver
metastases from colorectal cancer after neoadjuvant chemotherapy.
Ann Surg 1996; 224: 509–22.
83. Giacchetti S, Itzhaki M, Gruia G, et al. Long-term survival of patients
with unresectable colorectal cancer liver metastases following infusional
chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery.
Ann Oncol 1999; 10: 663–9.
84. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unre-
sectable colorectal liver metastases: correlation between tumour
response and resection rates. Ann Oncol 2005; 16: 1311–9.
85. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable
colorectal liver metastases downstaged by chemotherapy: a model to pre-
dict long-term survival. Ann Surg 2004; 240: 644–57; discussion 657–8.
86. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluoro-
uracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared
with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as
first-line treatment for metastatic colorectal cancer: the Gruppo Onco-
logico Nord Ovest. J Clin Oncol 2007; 25: 1670–6.
87. Masi G, Loupakis F, Pollina L, et al. Long-term outcome of initially
unresectable metastatic colorectal cancer patients treated with 5-fluoro-
uracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by
radical surgery of metastases. Ann Surg 2009; 249: 420–5.
88. Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI (folinic acid,
5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid,
5-fluorouracil and irinotecan) as first-line treatment in metastatic
colorectal cancer (MCC): A multicentre randomised phase III trial from
the Hellenic Oncology Research Group (HORG). Br J Cancer 2006; 94:
798–805.
89. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized
study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go
fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol
2006; 24: 394–400.
90. Gallagher DJ, Capanu M, Raggio G, et al. Hepatic arterial infusion plus
systemic irinotecan in patients with unresectable hepatic metastases
from colorectal cancer previously treated with systemic oxaliplatin: a
retrospective analysis. Ann Oncol 2007; 24: 24.
91. Taylor RA, White RR, Kemeny N, et al. Predictors of a true complete
response in colorectal liver metastases that disappear radiographically
following chemotherapy. J Clin Oncol 2007; 25: Abstract:4058.
92. Auer RC, White RR, Kemeny N, et al. Predictors of a true complete
response among disappearing liver metastases from colorectal cancer
following chemotherapy. Cancer 2010; 116(6): 1502–9.
93. Ducreux M, Ychou M, Laplanche A, et al. Hepatic arterial oxaliplatin
infusion plus intravenous chemotherapy in colorectal cancer with inop-
erable hepatic metastases: a trial of the gastrointestinal group of the
Federation Nationale des Centres de Lutte Contre le Cancer. J Clin
Oncol 2005; 23: 4881–7.
94. Boige V, Malka D, Elias D, et al. Hepatic arterial infusion of oxaliplatin and
intravenous LV5FU2 in unresectable liver metastases from colorectal can-
cer after systemic chemotherapy failure. Ann Surg Oncol 2008; 15: 219–26.
95. Elias D, Goere D, Boige V, et al. Outcome of posthepatectomy-missing
colorectal liver metastases after complete response to chemotherapy:
impact of adjuvant intra-arterial hepatic oxaliplatin. Ann Surg Oncol
2007; 14: 3188–94.
96. Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal
liver metastases after chemotherapy: Does it mean cure? J Clin Oncol
2006; 24: 3939–45.
97. Boige V, Malka D, Elias D, et al. Hepatic arterial infusion of oxaliplatin
and intravenous lv5fu2 in unresectable liver metastases from colorectal
cancer after systemic chemotherapy failure. Ann Surg Oncol 2007; 26: 26.
98. De Jong FA, Mathijssen RH, Verweij J. Limited potential of hepatic arte-
rial infusion of irinotecan. J Chemother 2004; 16 Suppl 5: 48–50.
99. van Riel JM, van Groeningen CJ, de Greve J, et al. Continuous infusion
of hepatic arterial irinotecan in pretreated patients with colorectal
cancer metastatic to the liver. Ann Oncol 2004; 15: 59–63.
145
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
100. Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine,
and oxaliplatin as neoadjuvant therapy for patients with potentially
curable metastatic colorectal cancer. J Clin Oncol 2008; 26: 1830–5.
101. Klinger M, Eipeldauer S, Hacker S, et al. Bevacizumab protects against
sinusoidal obstruction syndrome and does not increase response rate in
neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metas-
tases. Eur J Surg Oncol 2009; 4: 4.
102. Kretzschmar A, Cunningham D, Berry S. Feasibility of metastasectomy
in patients treated with first-line bevacizumab for metastatic colorectal
cancer: Preliminary results from the first BEAT study. 2007 Gastrointes-
tinal Cancers Symposium, 2007.
103. Adam R, Aloia T, Levi F, et al. Hepatic resection after rescue cetuximab
treatment for colorectal liver metastases previously refractory to con-
ventional systemic therapy. J Clin Oncol 2007; 25: 4593–602.
104. Tabernero J, Van Cutsem E, Diaz-Rubio E, et al. Phase II trial of cetux-
imab in combination with fluorouracil, leucovorin, and oxaliplatin in
the first-line treatment of metastatic colorectal cancer. J Clin Oncol
2007; 25: 5225–32.
105. Folprecht G, Gruenberger T, Hartmann JT, et al. Cetuximab plus
FOLFOX6 or cetuximab plus FOLFIRI as neoadjuvant treatment of
nonresectable colorectal liver metastases: A randomized multicenter
study (CELIM-study). American Society of Clinical Oncology—
Gastrointestinal Cancer Symposium 2009; Abstract # 296.
106. Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results of OPTI-
MOX2, a large randomized phase II study of maintenance therapy or
chemotherapy-free intervals (CFI) after FOLFOX in patients with met-
astatic colorectal cancer (MRC): A GERCOR study. J Clin Oncol 2007:
Abstract # 4013.
107. Labianca R, Floriani I, Cortesi E, et al. Alternating versus continuous
“FOLFIRI” in advanced colorectal cancer (ACC): A randomized
“GISCAD” trial. J Clin Oncol 2006; 24: Abstract #3505.
108. Koopman M, Antonini NF, Douma J, et al. Sequential versus combina-
tion chemotherapy with capecitabine, irinotecan, and oxaliplatin in
advanced colorectal cancer (CAIRO): a phase III randomised controlled
trial. Lancet 2007; 370: 135–42.
109. Seymour MT, Maughan TS, Ledermann JA, et al. Different strategies of
sequential and combination chemotherapy for patients with poor prog-
nosis advanced colorectal cancer (MRC FOCUS): a randomised con-
trolled trial. Lancet 2007; 370: 143–52.
110. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first
progression is associated with prolonged overall survival in metastatic
colorectal cancer: results from a large observational cohort study
(BRiTE). J Clin Oncol 2008; 26: 5326–34.
111. Adam R, Aloia T, Figueras J, et al. LiverMetSurvey: Analysis of clinico-
pathologic factors associated with the efficacy of preoperative chemo-
therapy in 2,122 patients with colorectal liver metastases. J Clin Oncol
2006; 24: Abstract #3521.
112. Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy
before liver resection for patients with unresectable liver metastases
from colorectal carcinoma. J Clin Oncol 2005; 23: 2038–48.
113. Adam R, Pascal G, Castaing D, et al. Tumor progression while on che-
motherapy: A contraindication to liver resection for multiple colorectal
metastases? Ann Surg 2004; 240: 1052–64.
114. Gallagher DJ, Zheng J, Capanu M, et al. Response to neoadjuvant che-
motherapy does not predict overall survival for patients with synchro-
nous colorectal hepatic metastases. Ann Surg Oncol 2009; 18: 18.
115. Chun YS, Laurent A, Maru D, et al. Management of chemotherapy-
associated hepatotoxicity in colorectal liver metastases. Lancet Oncol
2009; 10: 278–86.
116. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes
after preoperative chemotherapy with fluorouracil plus oxaliplatin in
colorectal cancer liver metastases. J Clin Oncol 2006; 24: 4983–90.
117. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen pre-
dicts steatohepatitis and an increase in 90-day mortality after surgery
for hepatic colorectal metastases. J Clin Oncol 2006; 24: 2065–72.
118. D’Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for
increased operative morbidity after hepatectomy with perioperative use
of bevacizumab: A matched case-control study. Ann Surg Oncol 2007;
14: 759–65.
146
119. Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal
liver metastases after chemotherapy: does it mean cure? J Clin Oncol
2006; 24: 3939–45.
120. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy
with FOLFOX4 and surgery versus surgery alone for resectable liver
metastases from colorectal cancer (EORTC Intergroup trial 40983): a
randomised controlled trial. Lancet 2008; 371: 1007–16.
121. Mitry E, Fields AL, Bleiberg H, et al. Adjuvant chemotherapy after poten-
tially curative resection of metastases from colorectal cancer: a pooled
analysis of two randomized trials. J Clin Oncol 2008; 26: 4906–11.
122. Ychou M, Hohenberger W, Thezenas S, et al. Randomized phase III trial
comparing infused 5-fluorouracil/folinic acid (LV5FU) versus LV5FU+
irinotecan (LV5FU+IRI) as adjuvant treatment after complete resection
of liver metastases from colorectal cancer (LMCRC). (CPT-GMA-301).
J Clin Oncol 2008; 26: Abs: LBA4013.
123. Nakajima Y, Nagao M, Ko S, et al. Clinical predictors of recurrence site
after hepatectomy for metastatic colorectal cancer. Hepatogastroenter-
ology 2001; 48: 1680–4.
124. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of
chemotherapy after resection of hepatic metastases from colorectal can-
cer. N Engl J Med 1999; 341: 2039–48.
125. Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection [7].
N Engl J Med 2005; 352: 734–5.
126. Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for
resectable metastatic colorectal carcinoma to the liver: surgical resection
of hepatic metastases in combination with continuous infusion of
chemotherapy—an intergroup study. J Clin Oncol 2002; 20: 1499–505.
127. Lygidakis NJ, Sgourakis G, Vlachos L, et al. Metastatic liver disease of
colorectal origin: the value of locoregional immunochemotherapy com-
bined with systemic chemotherapy following liver resection. Results of a
prospective randomized study. Hepatogastroenterology 2001; 48: 1685–91.
128. Lorenz M, Muller HH, Schramm H, et al. Randomized trial of surgery
versus surgery followed by adjuvant hepatic arterial infusion with
5-fluorouracil and folinic acid for liver metastases of colorectal cancer.
German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetas-
tasen). Ann Surg 1998; 228: 756–62.
129. Lygidakis NJ, Ziras N, Parissis J. Resection versus resection combined with
adjuvant pre- and post-operative chemotherapy—immunotherapy for
metastatic colorectal liver cancer. A new look at an old problem. Hepato-
gastroenterology 1995; 42: 155–61.
130. O’Connell MJ, Bolton JS, Mahoney MR, et al. Final results of hepatic
arterial infusion (HAI) plus systemic (SYS) chemotherapy after multi-
ple metastasectomy in patients with colorectal carcinoma metastatic
(M-CRC) to the liver: A North Central Cancer Treatment Group
(NCCTG) phase II study. J Clin Oncol 2004; 22: Abstract No 3527.
131. Kemeny N, Jarnagin W, Gonen M, et al. Phase I/II study of hepatic arte-
rial therapy with floxuridine and dexamethasone in combination with
intravenous irinotecan as adjuvant treatment after resection of hepatic
metastases from colorectal cancer. J Clin Oncol 2003; 21: 3303–9.
132. Kemeny N, Capanu M, D’Angelica M, et al. Phase I trial of adjuvant
hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexa-
methasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in
patients with resected liver metastases from colorectal cancer. Ann
Oncol 2009; 20: 20.
133. Ito H, Are C, Gonen M, et al. Effect of postoperative morbidity on long-
term survival after hepatic resection for metastatic colorectal cancer.
Ann Surg 2008; 247: 994–1002.
134. House MG, Kemeny N, Jarnagin WR, et al. Comparison of adjuvant
systemic chemotherapy with or without hepatic arterial infusional che-
motherapy after hepatic resection for metastatic colorectal cancer.
American Society of Clinical Oncology—Gastrointestinal Cancer Sym-
posium 2009; Abstract # 383.
135. Allen PJ, Nissan A, Picon AI, et al. Technical complications and durabil-
ity of hepatic artery infusion pumps for unresectable colorectal liver
metastases: an institutional experience of 544 consecutive cases. J Am
Coll Surg 2005; 201: 57–65.
136. Power DG, Healey-Bird BR, Kemeny NE. Regional chemotherapy for
liver-limited metastatic colorectal cancer. Clin Colorectal Cancer 2008;
7: 247–59.
 CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER
137. Park SH, Sung JY, Han SH, et al: Oxaliplatin, folinic acid and
5-fluorouracil (FOLFOX-4) combination chemotherapy as second-
line treatment in advanced colorectal cancer patients with irinote-
can failure: a Korean single-center experience. Jpn J Clin Oncol
2005; 35: 531–5.
138. Pozzo C, Basso M, Cassano A, et al. Neoadjuvant treatment of unresect-
able liver disease with irinotecan and 5-fluorouracil plus folinic acid in
colorectal cancer patients. Ann Oncol 2004; 15: 933–9.
139. Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil,
and leucovorin for patients with unresectable liver-only metastases
from colorectal cancer: A North Central Cancer Treatment Group phase
II study. J Clin Oncol 2005; 23: 9243–9.
140. Masi G, Marcucci L, Loupakis F, et al. First-line 5-fluorouracil/folinic
acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the fea-
sibility and the activity of second line treatments in metastatic colorec-
tal cancer. Ann Oncol 2006; 17: 1249–54.
141. Tono T, Hasuike Y, Ohzato H, et al. Limited but definite efficacy of pro-
phylactic hepatic arterial infusion chemotherapy after curative resec-
tion of colorectal liver metastases: A randomized study. Cancer 2000;
88: 1549–56.
147
15 Multimodal approaches to the management of colorectal liver metastases
Gerardo Sarno and Graeme J. Poston
This chapter focuses on the recent development of multimodal
strategies intended to increase the pool of patients with
colorectal liver metastases (CRLMs) for whom curative treat-
ment may be possible. These strategies include improved pre-
operative staging, new standards for surgical resection, novel
surgical strategies, the application of modern systemic chemo-
therapy in the neoadjuvant setting, an emerging role for
ablative therapies, greater emphasis on the collaborative, mul-
tidisciplinary management of this disease, and most recently,
the question of whether to resect the liver disease before the
primary bowel tumor. It is now clear that an aggressive multi-
disciplinary approach to the management of this problem can
result in one-third of these patients now being considered for
treatment that even if not achieving complete cure, offers sig-
nificant long-term survival.
Colorectal cancer is globally a growing cause of public health
concern (1,2). The prevalence is increasing at 5% per year among
the burgeoning middle classes in both China and India, and in
western society is expected to increase in incidence by over 30%
over the next 20 years because of evergrowing elderly (>70 years
of age) population (1,2).The liver is frequently the only site in
30% to 40% of patients with advanced disease (3). By the time of
initial diagnosis of colorectal cancer, nearly a quarter of patients
will have clinically detectable CRLMs, despite increasing patient
and clinician awareness of the disease (1,4,5). Historically, these
patients have a poorer prognosis when compared to those who
subsequently develop metachronous diseases (1,5). Of those who
undergo apparently successful resection of the primary tumor,
nearly half will develop liver metastases, usually within the first
3 years after colectomy (1,4,5).
Until recently, surgery was the only treatment that offered the
chance of cure for CRLM, and until recently, only far less than
20% of these patients were considered suitable for attempted
curative resection; historically, the remaining patients being
offered palliative and symptomatic treatment (6). Recent data
suggest that ablation therapy (radiofrequency or RFA, micro-
wave) might achieve long-term survival, but with poorer overall
results compared to surgical resection (7).
The other major advance in recent years has been the avail-
ability of medical oncology strategies using chemotherapeutic
and biologic agents not only to significantly prolong survival
in incurable disease, but also to bring initially inoperable
patients to surgical resection with curative intent (8).
Recently, it has become a legal requirement in a number of
European countries (UK, France, Belgium, and Spain) for all
cancer patients to be discussed within the setting of a multidis-
ciplinary team (MDT) before any treatment intervention
commences. In order for such an MDT to be effective in the
management of colorectal cancer liver metastases, the team
must undertake a number of specific steps in determining the
extent of spread of the cancer, and the best modalities for this
148
purpose, and then the role(s) of each of the possible treatment
modalities (surgery, ablation, systemic chemotherapy, regional
chemotherapy/radiotherapy, and biological therapies) as well
as the strategy of which treatment to use in which sequence.
building an effective
multidisciplinary team
An effective MDT needs to be built around a designated core
membership. Once this core group is established, then other
professionals from many disciplines can attend and become
involved. For the management of patients with CRLM, the key
disciplines of the core group include hepatobiliary surgery,
medical oncology, diagnostic radiology, interventional radiol-
ogy, and palliative care. It is essential that there is a designated
team member from each of these disciplines. Other disciplines
that we have found helpful in support of our CRLM MDT
include gastroenterology/hepatology, our specialist nursing
colleagues, and histopathology. However, having a dedicated
clerical coordinator who can pull together all the relevant cor-
respondence, documentation and investigations for each and
every patient to be discussed is absolutely essential for the suc-
cessful operation of such an MDT. With regard to diagnostic
radiology, it is our experience that the radiologist presenting
the images to the MDT will require at least 3 hours prepara-
tion time for every 20 patients to be discussed. This require-
ment for radiology time has major cost implications for the
running of a busy radiology department.
preoperative staging: the key to selection
of candidates for curative treatment
The uses of individual imaging techniques for diagnosing and
staging CRLM have differing strengths and weaknesses. How-
ever, with all modalities we are rapidly improving our ability
to detect low-volume metastatic disease much earlier in the
disease process. It must be remembered that all metastases
(those found at the time of initial presentation, and those sub-
sequently found metachronously after apparently “curative”
resection of the primary tumor) are synchronous to the time
of diagnosis of primary colorectal cancer. There is now emerg-
ing consensus on the optimal choice of technique, and the
sequence with which they should be employed (9–12).
computeed tomography
Recent advances in computed tomography (CT) technology
(helical CT and multidetector row helical CT) have improved
performance in speed of acquisition, resolution, and ability to
image the liver during various phases of contrast enhancement
with greater precision (9,12). Using intravenous iodinated con-
trast media these techniques characterize liver lesions based on
their enhancement patterns during the various phases of con-
trast circulation in the liver (12). CT has limitations, including
 MULTIMODAL APPROACHES TO THE MANAGEMENT OF COLORECTAL LIVER METASTASES
the need for a high radiation dose and low sensitivity in detect-
ing and characterizing lesions smaller than 1 cm.
magnetic resonance imaging
Magnetic resonance imaging (MRI) is highly effective in detect-
ing and characterizing smaller (<1 cm) liver lesions because of
the high lesion to liver contrast, most frequently using gadolin-
ium (9,12). The use of liver-specific contrast media, such as
super paramagnetic iron oxide (SPIO), further improves the
contrast between normal liver tissue and metastases (12,13).
However, MRI is limited by low sensitivity for detecting extrahe-
patic disease, especially in the peritoneum and chest.
positron emission tomography
Positron emission tomography (PET-CT) has emerged as an
important diagnostic tool in detecting and staging metastatic
colorectal cancer. Although the modality appears to be highly
sensitive, specificity is lower because any focal area of hyper-
metabolism (including inflammation and abscesses) can gen-
erate false-positive results. Other disadvantages include higher
cost, poorer lesion localization and limited sensitivity for
lesions smaller than 1 cm. (13,14).
surgery
There are many substantial prospective and retrospective series
of surgical resection of CRLM consistently show 5-year survival
rates following liver resection of 30% to 50%, depending on
selection criteria (15). The problem encountered when attempt-
ing to interpret these reports is that although there are more
than 600 in the literature, barely 30 series are prospective stud-
ies, reporting more than 100 patients from reliable high-volume
centers, and with median follow-up of >24 months (15).
However, from these reports nearly all patients who survive for
more than 5 years can usually be considered cured of the disease.
defining resectability of liver only disease
Historically, resectability of CRLM was relatively straightfor-
ward. The definition of resectability was based of old studies
that identified certain adverse clinicopathological factors, and
so liver resection was only attempted in patients who had one
to three unilobar metastases, preferably presenting at least
12 months after resection of the primary tumor, whose disease
was resectable with at least a 1 cm margin of healthy liver tis-
sue and who had no hilar lymphadenopathy or extrahepatic
disease (16). Such patients accounted for <10% of the total
population with liver only metastatic disease (16).
We now know that patients outside these traditionally
accepted criteria can benefit from long-term survival following
hepatectomy (17,18). Resectability is now based on whether a
macroscopically and microscopically complete (R0) resection of
the liver can be achieved. Therefore resectability is now defined
by what healthy liver volume will remain.
Our definition of liver resectability is now (19):
1. Disease can be completely resected.
2. At least two adjacent liver segments can be spared
with adequate vascular inflow and outflow and biliary
drainage.
3. The volume of the liver remaining after resection, i.e.,
the “future remnant liver” (FRL) will be adequate (13).
Clearly, the FRL limit for safe resection varies from
patient to patient, and from institution to institution
but in those with an otherwise normal liver, the safe
FRL volume is 20% to 30% (19).
resection margins
Historically, resection was only considered if the hepatobiliary
surgeon believed that the metastasis could be resected with a
margin of healthy surrounding liver that was >1 cm. The new
standards challenge the “1 cm rule.” More recent studies show
that size of the resection margin has no effect on survival, as
long as the margin is microscopically clear of disease (20,21).
new strategies to improve resectability
Other strategies are being increasingly employed in patients
with unresectable CRLM to improve resectability. Portal
vein embolization induces atrophy of the liver to be resected
with hypertrophy of the liver that is to remain (i.e., increases
the FRL). Similarly, two-stage hepatectomies, employing
delayed rehepatectomy after hypertrophy of the residual
liver, may be used for large bilateral lesions in which a sin-
gle-stage resection of all involved segments would result in
acute liver failure (22,23).
Disease outside the liver that may be resected with curative
intent includes direct diaphragmatic invasion, adrenal metas-
tases and lung metastases when few in number and readily
resectable (1). Recent reports demonstrate that up to 35% of
patients are still alive 5 years after resection of pulmonary
colorectal metastases (24).
combining chemotherapy and surgery
Modern chemotherapeutic regimens utilizing oxaliplatin with
5-FU and folinic acid (FOLFOX), also irinotecan (FOLFIRI) are
associated with high response rates of up to 50% and median
survival in incurable disease that exceeds 2 years (25,26). Most
significantly, such high response rates can now bring 10% to
30% of patients with disease initially considered unresectable to
subsequent secondary liver resection (22,25,26).
Within a consecutive series of 1104 patients with CRLM ini-
tially considered unresectable and treated with chemotherapy,
138 (12.5%) had a sufficiently good response to chemotherapy
to enable potentially curative liver surgery to be performed in
93% of these cases (22). Survival was 33% and 23% at 5 and
10 years, respectively, with a median survival of 39 months,
although this was significantly lower than that for patients
resected primarily within the same period at the same institu-
tion (48% and 30% at 5 and 10 years, respectively) (22). Evalu-
ation of these and other data suggest that the ability to achieve
secondary liver resection of initially inoperable CRLM is
directly proportional to the degree of response to the chemo-
therapy regimen (26).
Phase II and III studies evaluating novel biological agents,
such as the monoclonal antibodies directed against vascular
endothelial growth factor (VEGF) (bevacizumab) and the epi-
dermal growth factor receptor (cetuximab and panetumumab),
suggest even greater response rates (and possibly higher
149
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
100
HR = 0.73; CI:0.55–0.97, p = 0.025
90
80
70 Periop CT
60
50
42.4%
40
Surgery only
30
33.2%
20
10
0 (years)
0 1 2 3
O N Number of patients at risk:
104 152 85 59 39
93 151 118 76 45
Figure 15.1 Three-year progression-free survival comparing surgery alone to surgery with perioperative chemotherapy in the EORTC 40983 (EPOC) trial (30).
secondary CRLM resection rates) when compared to conven-
tional chemotherapy alone. Therefore, even more patients with
initially unresectable CRLM may respond to treatment with
combinations of systemic treatments in the future (27–29).
Recent data from the German Phase II CELIM study have sug-
gested that as many as 40% of patients with unresectable kras
wild type colorectal cancer metastases confined to the liver may
now be brought to liver resection with curative intent using
combinations of cetuximab with either oxaliplatin-based or
irinotecan-based chemotherapy regimens (30).
Recent data have suggested that the addition of periop-
erative (both neoadjuvant with adjuvant) chemotherapy
using FOLFOX to surgical resection confers improved dis-
ease-free survival when compared to surgery alone (31).
These data need to be interpreted with caution since the
study did not demonstrate its primary endpoint (3-year
disease-free survival on intention to treat at the point of
initial randomization), and only achieved significance on
the analysis of operated patients, when ineligible patients
were excluded (Fig. 15.1).
the role of tumor ablation
Much interest in tumor ablation (mostly using RFA) derives
from its low morbidity and mortality (32). A recent meta-
analysis of 95 published series reported complication rates of
<9% (33), the commonest complications being intra-abdomi-
nal bleeding, sepsis, and biliary injury. Mortality rates range
from 0% to 0.5%. However, the most reported disadvantage of
RFA are the higher rates of local recurrence, ranging from
1.8% to 12% using the surgical approach, to as high as 40%
with radiologic guided percutaneous placement of the probe.
Undoubtedly, some of this higher local failure rate relates to
the type of lesions being treated by percutaneous RFA. Ablative
therapies are often used for the treatment of metastases that
150
+9.2%
At 3 years
4 5 6
24 10
23 6
are often too close to major vascular structures to be consid-
ered resectable with a clear margin. Just as a surgical margin
would be likely to be compromised, high blood flow immedi-
ately adjacent to the tumor will conduct away heat, leading to
incomplete ablation and tumor recurrence (2).
The efficacy of RFA in unresectable CRLM has been estab-
lished by several large cohort studies with median survivals of
28.9 to 36 months being achieved (32,33). Presently the dearth
of prospective randomized controlled trials comparing RFA
with chemotherapy over chemotherapy alone in unresectable
CRLM is being addressed by the EORTC CLOCC trial (EORTC
40004). Early progression-free survival data from this study
have suggested that the addition of RFA to FOLFOX-based
chemotherapy confers a statistically significant improved pro-
gression-free survival of 17 months compared to 10 months
for FOLFOX alone (T Ruers, personal communication).
Microwave ablation therapy is now becoming commercially
available. The major advantage of microwave ablation over
RFA is speed. Whereas it may take 20 to 30 minutes to achieve
an adequate ablation of a 3-cm metastasis using RFA, micro-
wave can achieve the same degree of tumor destruction in only
3 to 4 minutes.
management strategies for synchronously
detectable crlm
Patients who present with technically “easily” resectable pri-
mary tumor (right, transverse, left, and sigmoid colon) and
peripherally placed, low-volume liver disease (segments 2, 3,
4B, 5, 6, and subcapsular lesions in segments 4A, 7, and 8) are
amenable to synchronous resection of both primary tumor
and metastatic liver disease at the same procedure, without
significantly increased morbidity or mortality (34–37). Those
patients (a decreasing minority) who present with large bowel
obstruction, perforation or life-threatening hemorrhage and
 MULTIMODAL APPROACHES TO THE MANAGEMENT OF COLORECTAL LIVER METASTASES

CRC metastases

Up-to-date CT or MRI of chest, abdomen, and pelvis

Extrahepatic disease
Determine if patient is
candidate for
hepatic resection or
HR and RFA or
Hepatic metastases only Consider chemotherapy
RFA alone

Not candidate for HR or RFA

Response No response
Consider chemotherapy

Hepatic resection HR and RFA RFA alone

All tumor(s) Some tumor(s) resectable All tumor(s) ablatable
Response and some ablatable
resectable but not resectable
(Laparotomy – HR and RFA) Lapartomy, Laparoscopic
or Percutaneous)

No response Consider HR and/or RFA

Consider HR and/or RFA

Follow-up CT or MRI of the chest, abdomen, and pelvisand CRC surveillance

Incomplete ablation or
new metastases

Consider
repeat or serial RFA
and/or
repeat HR

Figure 15.2 The possible treatment strategy algorithm for patients with colorectal liver metastases (40).

synchronous CRLM should have immediate definitive life-
saving treatment (endoscopic stenting, resection with either a
stoma or immediate reconstruction).
Most surgical oncologists would recommend that in situa-
tions where resection of the primary tumor may be more
demanding (T2–T3 rectal carcinoma), or when the manage-
ment strategy for the primary tumor requires neoadjuvant
treatment (chemoradiotherapy for T3–T4 rectal carcinoma),
or the liver disease (albeit technically resectable) is of such an
extent that it requires at least a hemi-hepatectomy or more,
then planned sequential staged procedures carry lower periop-
erative risk (36,37).
However, when considering staged sequential treatment
strategies, concerned must remain about the risk of tumor
progression at both sites during treatment (31,38–40). For
patients presenting with asymptomatic primary tumors in
the presence of unresectable liver metastases, it would be rea-
sonable to propose a course of systemic chemotherapy and
base subsequent treatment strategies on the degree of
response (38). Those patients whose chemotherapy response
is sufficient that their liver disease is now amenable to poten-
tial hepatectomy can now be considered for surgery with
curative intent (31,38–40). For the 6% to 10% of patients
with present with inoperable disease and continue to progress
while on chemotherapy (23,31), consideration can be given to
further lines of chemotherapy, but overall the outlook is poor
and futile surgery can be avoided.
For patients with primary colon cancer (as opposed to pri-
mary rectal tumors) with initially unresectable liver whose
disease responds so well that an R0 resection of all tumor sites

151
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
can be achieved using a relatively minor liver resection, then
synchronous liver–bowel surgery is feasible (38).
should the liver resection take
precedence over the bowel surgery?
The fundamental question is now whether or not, having
achieved a window of therapeutic opportunity to deal with
the liver disease, does the liver disease takes precedence over
the primary tumor (39,40)? It has been proposed that the
liver disease should be resected first, and then following
eradication of the liver disease, subsequently deal with the
primary bowel tumor. Using this strategy, potentially cura-
tive surgery for both primary and secondary disease has been
achieved in 16 of 20 (80%) such patients in small single-
center series (38).
conclusions
If feasible, surgical resection remains the gold standard of
treatment for CRLM. Unfortunately, patients still present
with advanced colorectal cancer. Modern chemotherapy reg-
imens offer increasing numbers of patients with initially
unresectable CRLM the chance of being brought to poten-
tially curative liver surgery (Fig. 15.2) (41). The remaining
controversies in this field are the timing of such surgery and
the strategic decisions of which operation (bowel first, liver
first, or synchronous combined surgery) is now the first pro-
cedure of choice?
The role of the MDT in the management of colorectal can-
cer liver metastases is to collate all the available data that can
lead to an accurate assessment of disease spread and stage,
then using these data, to plan an effective treatment strategy
that ideally is focused on possible cure, but in any event is
aimed at gaining maximal survival advantage for our patients.
references
1. Poston GJ. Surgical strategies for colorectal liver metastases. Surg Oncol
2004; 13: 125–36.
2. Primrose JN. Treatment of colorectal metastases: Surgery, cryotherapy or
radiofrequency ablation. Gut 2002; 50: 1–5.
3. Weiss L, Grundmann E, Torhorst J, et al. Hematogenous metastatic pat-
terns in colonic carcinoma: An analysis of 1541 necropsies. J Pathol 1986;
150: 195–203.
4. Sugarbaker PH. Surgical decision making for large bowel cancer meta-
static to the liver. Radiol 1990; 174: 621–6.
5. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influ-
encing the natural history of colorectal liver metastases. Lancet 1994; 343:
1405–10.
6. Geoghegan JG, Scheele J. Treatment of colorectal liver metastases. Br J
Surg 1994; 86: 158–69.
7. Abdalla E, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following
hepatic resection, radiofrequency ablation and combined resection/abla-
tion for colorectal liver metastases. Ann Surg 2004; 239: 818–25.
8. Bismuth H, Adam R, Levy F, et al. Resection of nonresectable metastases
from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996;
224: 509–20.
9. Sahani DV, Kalva SP. Imaging the liver. Oncologist 2004; 9: 385–97.
10. McLoughlin JM, Jensen EH, Malafa M. Resection of colorectal liver
metastases. Cancer Control 2006; 13: 32–41.
11. Vauthey JN. Patients with hepatic colorectal metastases. Program of the
AHPBA 2006 consensus conference; January 25, 2006; San Francisco, CA.
152
12. Martinez L, Puig I, Valls C. Colorectal liver metastases: Radiological diag-
nosis and staging. Eur J Surg Oncol 2007; 33(S2): S5–S16.
13. Charnsangavej C. Selection for resection: Preoperative imaging evalua-
tion. Program of the AHPBA 2006 consensus conference; January 25,
2006; San Francisco, CA.
14. Israel O, Mor M, Gaitini D, et al. Combined structural and functional
evaluation of cancer patients with a hybrid camera based PET/CT system
using (18) F-FDG. J Nucl Med 2002; 43: 1129–36.
15. Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical resection of
hepatic metastases from colorectal cancer: A systematic review of pub-
lished studies. Br J Cancer 2006; 94: 982–99.
16. Hughes KS, Simon R, Songhorabodi S, et al. Resection of the liver for
colorectal carcinoma metastases: A multi-institutional study of patterns
of recurrence. Surgery 1986; 100: 278–284.
17. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence
after hepatic resection for metastatic colorectal cancer: Analysis of 1001
consecutive cases. Ann Surg 1999; 230: 309–18.
18. Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers of
surgical indications in the treatment of liver metastases from colorectal
cancer: Long-term results. Ann Surg 2000; 231: 487–99.
19. Vauthey JN, Pawlik TM, Abdalla EK, et al. Is extended hepatectomy for
hepatobiliary malignancy justified? Ann Surg 2004; 239: 722–32.
20. Scheele J, Stangl R, Altendorf-Hofmann A, Paul M. Resection of colorectal
liver metastases. World J Surg 1995; 19: 59–71.
21. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on
survival and site of recurrence after hepatic resection for colorectal metas-
tases. Ann Surg 2005; 241: 715–24.
22. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable
colorectal liver metastases downstaged by chemotherapy: A model to pre-
dict long-term survival. Ann Surg 2004; 240: 644–57.
23. Petrowsky H, Gonen M, Jarnagin W, et al. Second liver resections are safe
and effective treatment for recurrent hepatic metastases from colorectal
cancer: A bi-institutional analysis. Ann Surg 2002; 235: 863–71.
24. Kanemitsu Y, Kato T, Hirai T, Yasui K. Preoperative probability model for
predicting overall survival after resection of pulmonary metastases from
colorectal cancer. Br J Surg 2004; 91: 112–20.
25. Pozzo C, Basso M, Cassano A, et al. Neoadjuvant treatment of unresect-
able liver disease with irinotecan and 5-fluorouracil plus folinic acid in
colorectal cancer patients. Ann Oncol 2004; 15: 933–39.
26. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant chemotherapy of
unresectable colorectal liver metastases: correlation between tumour
response and resection rates. Ann Oncol 2005; 16: 1311–9.
27. Wicherts DA, de Haas RJ, Adam R. Bringing unresectable liver disease to
resection with curative intent. Eur J Surg Oncol 2007; 33(S2): S42–S51.
28. Adam R, Aloia T, Levy F, et al. Hepatic resection after rescue cetuximab
treatment for colorectal liver metastases previously refractory to conven-
tional systemic chemotherapy. J Clin Oncol 2007; 25: 4593–602.
29. Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine
and oxaliplatin as neoadjuvant treatment for patients with potentially
curable metastatic colorectal cancer. J Clin Oncol 2008; 26: 1830–5.
30. Folprecht G, Gruenberger T, Hartmann JT, et al. Cetuximab plus
FOLFOX6 or cetuximab plus FOLFIRI as neoadjuvant treatment of non-
resectable colorectal liver metastases: a randomized multicenter study
CELIM-study. ASCO GI, San Francisco 2009, abstract 296.
31. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy
with FOLFOX-4 and surgery for respectable liver metastases from
colorectal cancer. Lancet 2008; 371: 1007–16.
32. Feliberti EC, Wagman LD. Radiofrequency ablation of liver metastases
from colorectal cancer. Cancer Control 2006; 13: 48–51.
33. Mulier S, Mulier P, Ni Y, et al. Complications of radiofrequency coagula-
tion of liver tumors. Br J Surg 2002; 89: 1206–22.
34. Poston GJ, Byrne C. Decision making for patients with colorectal cancer
liver metastases. Ann Surg Oncol 2006; 13: 10–1.
35. Verghese M, Pathak S, Poston GJ. Increasing long-term survival in
advanced colorectal cancer. Eur J Surg Oncol 2007; 33(S2): S1–S4.
36. Nesbitt C, Glendinning RJ, Byrne C, Poston GJ. Factors influencing treat-
ment strategies in advanced colorectal cancer. Eur J Surg Oncol 2007;
33(S2): S88–S94.
 MULTIMODAL APPROACHES TO THE MANAGEMENT OF COLORECTAL LIVER METASTASES
37. Weber JC, Bachellier P, Oussoultzoglou E, Jaeck D. Simultaneous resec-
tion of colorectal primary tumour and synchronous liver metastases. Br J
Surg 2003; 90: 956–62.
38. Benoist S, Pautrat K, Mitry E, et al. Treatment strategy for patients with
colorectal cancer and synchronous irresectable liver metastases. Br J Surg
2005; 92: 1155–60.
39. Mentha G, Majno PE, Andres A, et al. Neoadjuvant chemotherapy and
resection of advanced synchronous liver metastases before treatment of
the colorectal primary. Br J Surg 2006; 93: 872–8.
40. Mentha G, Majno P, Terraz S, et al. Treatment strategies for the man-
agement of advanced colorectal liver metastases detected synchro-
nously with the primary tumour. Eur J Surg Oncol 2007; 33(S2):
S76–S83.
41. Blokhius TJ, van der Schaaf MP, van den Tol MP, et al. Results of
radiofrequency ablation of primary and secondary liver tumors: Long-
term follow-up with computed tomography and positron-emission
tomography-18F-deoxyglucose scanning. Scand J Gastroenterol 2004;
241: 93–7.
153
16 Management of neuroendocrine tumor hepatic metastasis
Kaori Ito
introduction
Neuroendocrine tumors (NET), including both carcinoid
tumors and islet tumors, are derived from primitive neuroec-
todermal cells that are distributed throughout the body dur-
ing embryonic development (1–4). Therefore, NETs originate
from various organs but most commonly involve the lungs,
bronchi, and gastrointestinal tract (2,5). NETs were tradition-
ally classified into foregut, midgut, and hindgut derivatives
based on their presumed origin of gut. Currently, it is replaced
by the WHO classification system of 2000 according to the
histological differentiation (6). Clinical presentations widely
differ depending on both their organ and excess hormone
production (e.g., serotonin, histamine, tachykinins, and pros-
taglandins) (3,5). The overall incidence of NET has been
reported to be 1 to 2 cases per 100,000 people (5) (Tables 16.1
and 16.2).
Hepatic metastasis is the second common metastasis follow-
ing lymph node metastasis in NETs (3) (Fig. 16.1). Up to 45%
of patients with abdominal carcinoid will present with bowel
obstruction and more than half of patients who were explored
for bowel obstruction due to NETs are found to have hepatic
metastases. Despite of the fact that liver is the common meta-
static site of NETs, primary hepatic NET is extremely rare
(0.6% of all NETs) (2). In this chapter, we describe specifically
about the management of hepatic metastases of NETs.
diagnosis
Clinical Features
Hepatic metastases of NET could be diagnosed preoperatively
following investigation of a specific hormonal syndrome or
following the incidental finding of hepatomegaly or an abdom-
inal mass. Or it could be discovered at the abdominal explora-
tion for primary gastrointestinal NETs. Besides hormonal
symptoms, patients will complain local symptoms due to
tumor bulk (pain, early satiety, or palpable mass). Subclinical
hepatic metastasis does not require treatments, however,
lifestyle-altering symptoms or biologically aggressive tumors
require treatment (7). Demographics, presentation, symptoms,
tumor histology, and primary tumor location of patients with
NET-hepatic metastasis are summarized in Table 16.3 (8).
The most representative symptom of patients with NETs is
carcinoid syndrome. It is caused by systemic circulation of
hormonal products from bulky metastatic NETs. This syn-
drome is a manifestation of late stage of NET and 5% to 10%
of all NET patients present with this syndrome (1,5,9,10). In
patients with NET-hepatic metastasis, carcinoid syndrome is
frequently evident, at least biochemically (1). Common
symptoms and signs include cutaneous flushing (71–80%),
diarrhea (76–80%), hepatomegaly (71%), carcinoid heart dis-
ease (41–70%), asthma (9–25%), pellagra (2%) (3,11–15).
154
Wessels et al. proposed the Carcinoid Symptom Severity Scale
(Table 16.4) (16). This scaling system well illustrates the dis-
ease severity and is used to evaluate the symptomatic change
before/after treatment (17).
Carcinoid crisis is an acute life-threatening presentation,
which is precipitated by anesthesia or interventional proce-
dures (18,19). When large amounts of hormonal products are
suddenly released into the systemic circulation, they trigger
hypotension, tachyarrhythmias, bronchospasm, and neuro-
logical abnormalities. Carcinoid crisis is treated by the intrave-
nous administration of somatostatin (SST) (50–100 μg).
Premedication with SST analogs before interventional thera-
pies can prevent crisis (19–23).
Carcinoid-associated fibrosis should also be of concern.
Carcinoid tumors cause fibrosis of the surrounding tissue. The
pathogenesis of fibrosis is not well studied. Fibrosis in the
peritoneum leads to bowel ischemia or mechanical bowel
obstruction (24,25), in the retroperitoneum leads to hydrone-
phrosis (24,26), in heart leads to tricuspid/pulmonary valve
disease (carcinoid heart disease) (27), and in the thorax leads
to thickening of pleura (28). These lesions can be the major
cause of morbidity and mortality of the patients in the
advanced stage.
Laboratory Investigation
Blood
Patients with suggestive symptoms of NET should undergo
laboratory tests to confirm the diagnosis of NET. Elevated
plasma chromogranin A (CgA) level is the most sensitive
marker of carcinoid tumors. CgA is a water-soluble acidic gly-
coprotein, which is stored in the secretory granules of NET
cells. The sensitivity of plasma CgA level in NETs is reported
up to 100%, however, it is not specific because the elevation of
CgA is observed in prostate carcinoma too (1,29–31).
Other biomarkers include bradykinin, serum substance P,
neurotensin, human chorionic gonadotropin (hCG), neuro-
peptide K, and neuropeptide PP (1).
Urine
The measurement of 24-hour urinary 5-hydroxyindoleacetic
acid (5-HIAA) can provide a summation of paroxysmal tumor
secretion activity. 5-HIAA is a metabolite of serotonin, which
is released by carcinoid tumors. The specificity of this test is
around 90%. False-positive can will occur with consumption
of serotonin-rich foods (bananas, avocados, plums, eggplant,
tomatoes, plantain, pineapples, and walnuts) (32,33).
If the laboratory findings were equivocal, a provocative test
such as a pengastrin test (injection) or alcohol ingestion might
be performed under the careful monitoring (31) (Grade III.
Recommendation C).
 MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS

Table 16.1 WHO Classification of Neuroendocrine Tumors (NET) of the Gastrointestinal Tract with Portal Venous Drainage
Stomach, ileum, colon Pancreas
Well-differentiated Endocrine Tumor (Carcinoid) Well-differentiated endocrine tumor
(1) Benign behavior (1) Benign behavior
Non-functioning Confined to the pancreas, non-angioinvasive
Confined to mucosa-submucosa, nonangioinvasive Size: <2 cm
Size ≤1 cm (stomach or small intestine) or ≤2 cm (colon) Mitosis: ≤2
(2) Uncertain behavior Ki67 positive cells/10 HPF: ≤2%
Nonfunctioning (2) Uncertain behavior
Confined to mucosa-submucosa, nonangioinvasive Confined to the pancreas
Size >1 cm (stomach or small intestine) or >2 cm (colon) Size: ≥2 cm
Well-differentiated Endocrine Carcinoma (Malignant Carcinoid) Mitosis: >2, or angioinvasive
Low-grade malignant tumor Ki67 positive cells/10 HPF: >2%
Deeply invasive (muscularis propria or beyond) or with Well differentiated Endocrine Carcinoma
metastases (liver) Functioning or non-functioning
Poorly-differentiated endocrine carcinoma Low-grade malignant tumor with gross local invasion and/or
Small-cell carcinoma metastases (liver)
High-grade malignant tumor Ki67 positive cells/10 HPF: >5%
Mixed Endocrine/Exocrine Carcinoma Poorly-differentiated Endocrine Carcinoma
Moderate to high-grade malignant tumor Small cell carcinoma
High-grade malignant tumor
Ki67 positive cells/10 HPF: >15%
Source: Adapted from Ref. (6).

the primary site. Sensitivity of CT/MRI is reported to be about

Table 16.2 Anatomical Location of NETs (Carcinoid Only,
80%. The detection rates are 76% to 100% for CT alone and
Except for Islet Cell Tumors) from SEER 1973–1999
67% to 81% for MRI alone (31). Triple phase spiral CT is the
% most informative to evaluate NET-hepatic metastasis. NET-
Lung, bronchi, and trachea 28 hepatic metastasis-associated findings are defined as mass
Stomach 5 lesions with calcification and radiating strands of fibrosis (36)
Duodenum 3 (Fig. 16.3) (Grade III. Recommendation C).
Jejunum 2
Ileum 15
Appendix 5 Positron Emission Tomography (PET)
Cecum 4 [18F]Fluoro-2-deoxy-d-glucose (FDG)-PET scan became an
Colon 5 essential tool for many cancers to detect cancer cells, which
Rectum 14 were not seen in other imaging, or to quantify metastatic
Other 6 sites by the whole body image. The utility of 18F-PET scan
Source: Adapted from Ref. (2). for NETs is not well supported. Because typically NETs are
slow growing with a low metabolic rate, the uptake of 18F by
NETs cannot be visualized (37,38). The detection rates are
Diagnostic Imaging reported as 25% to 73% (1,39). Instead, PET scan with the
Somatostatin Receptor (SSTR) Scintigraphy radioactive serotonin precursor 11C-5 HT, and 68Ga/64Cu
Given the clinical presentation and biochemical confirmation coupled to octreotide revealed an excellent detection
of NETs, topographical localization of primary tumor and rate (40). Since there were no large studies to assess the effi-
metastases should be pursued. SSTR scintigraphy utilizing cacy of PET scan compared to other diagnostic imaging
111
In-labelled SST analog (octreotide) can detect NETs that (41), the role of PET scan for NETs is still unclear (Grade III.
express SSTRs. Sensitivity of this test is reported as 84% (57– Recommendation C).
93%) (1,34,35) (Fig. 16.2). The simultaneous use of single
positron emission computed tomography (SPECT) can Radiolabeled Metaiodobenzylguanidine (MIBG)
enhance the sensitivity. This is the first choice of diagnostic Because NETs concentrate MIBG, the administration of
imaging test to find the primary site of carcinoid tumors 123
I-MIBG is another option to detect metastatic NETs. Sensi-
(Grade III. Recommendation C). tivity and specificity were reported as 55% to 70% and 95%,
respectively (42,43). Although the accuracy of this test is infe-
Computed Tomography (CT) and Magnetic Resonance rior to that of SSTR scintigraphy, MIBG is a useful alternative
Imaging (MRI) of SSTR scintigraphy in patients on long-acting SST analog in
CT and MRI are utilized to obtain more precise image of local whom SSTRs may have been occupied by SST analogue already
extent of tumor if surgery is contemplated, but not to look for (42,43) (Grade III. Recommendation C).

155
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Figure 16.1 Macroscopic (A) and microscopic (B) views of large resected hepatic neuroendocrine liver metastasis (stained for chromogranin-A). Note the hyper-
vascularity of the metastasis compared to the background liver and comparable colorectal liver metastases.

Hepatic Resection
Table 16.3 Clinical Features of NET-Hepatic Metastasis
Surgical resection of NET-hepatic metastasis is categorized
Demographics into curative intent resection or palliation intent resection
Gender % (debulking/cytoreductive surgery). Both of approaches con-
Men 40 tribute to the improvement of symptoms and the prolonged
Women 60 survival.
Age 52 years Curative intent resection is indicated for patients with soli-
Metastatic presentation % tary or localized hepatic metastasis. Only 10% to 25% of
Synchronous 74 NET-hepatic metastasis is found in this category. Palliation
Metachronous 26 intent resection is applied to patients with considerable
Symptoms % symptom due to multiple, bulky extended tumor. The removal
Hormonal 55 of more than 90% of the tumor bulk allows a significant pal-
Pain 55 liation. Concurrent resection of extrahepatic tumors is often
Mechanical, progressive tumor growth 36 performed. Regional lymphadenectomy should be done
Weight loss 15 because lymph node metastasis is common in NETs.
Jaundice 5 Administration of SST analogs will be required for patients
Asymptomatic with progressive tumor growth 4 with residual tumors. Curative resection is associated with
Gastrointestinal bleeding 1 longer survival than noncurative resection (91% vs. 76% at
Tumor histology %
5 years; median 30–50 vs. 16–32 months, respectively).
Carcinoid 48
Summary of literature review regarding postoperative
Nonfunctional islet cell tumor 31
Functional islet cell tumor 21
outcomes is shown in Table 16.5 (8,47–58). Postoperative mor-
% bidity and mortality rates are 22% (3-26%) and 3% (0–6%).
Primary tumor location
Pancreas 49 Although perioperative carcinoid crisis is not very frequent
Gastrointestinal bleeding 25 (0–3%), precaution should be always taken. Relief of symptom
Lung 9 was achieved in 92% (46–100) of patients. Disease-free survival
Unknown 16 is 17 to 60 months (median 41 months) and 36% (16–42%) at
Source: Adapted from Ref. (8). 5 years. Hepatic recurrence is reported in 82% of patients (52).
Survivals have an estimated median of 67 (52–81) months.
Five-year survival rate extends up to 73% (31–85%). Ten-year
survival is reported as 35% (Grade III. Recommendation C).

treatment Hepatic Artery Embolization

Treatment of NET-hepatic metastasis is required for patients
with lifestyle-altering symptoms, or biologically aggressive
tumors. The principal requirements are to remove the pri-
mary and metastatic sites in order to reduce levels of bioactive
agents (27,44–46). Therefore, surgical resection is the first
choice as long as patients fit to surgery. Treatment options
include hepatic resection, hepatic artery occlusion, radiofre-
quency ablation, cryoablation, liver transplantation, and
medical therapy. Indications and timing of therapy are still
controversial.
Hepatic artery embolization (HAE) is a rational approach against
liver malignancies by using the discrepancy of blood supply
between liver tumor and normal liver. The selective occlusion of
hepatic artery causes hypoxic damage of tumor. Patients with
NET-hepatic metastasis who don’t fit for surgery will benefit
from this therapy. Indications include (i) rapid enlargement of
tumor mass, (ii) increasing symptoms, and (iii) patient preference
for the procedure in lieu of other treatment (46).
Occlusive and/or chemotherapeutic agents are infused
into the hepatic artery through an angiography catheter (5).

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 MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS

Table 16.4 Carcinoid Symptom Severity Scale

Score Description
1 No symptoms
2 Mild symptoms
3 Symptoms impact
daily living
4 Sever symptoms
5 Disabling symptoms
Source: Adapted from Ref. (16).
Description
Symptoms: None
Frequency: None
Lifestyle effects: None
Symptoms: Diarrhea, flushing, or wheezing
Frequency: Up to 4 times daily
Lifestyle effects: None to minimal
Symptoms: Diarrhea, flushing, or wheezing
Frequency: 5–7 times weekly
Lifestyle effects: Restricts patient from leaving home for prolonged periods of time.
Symptoms: Diarrhea, flushing, or wheezing
Frequency: Multiple daily episode
Lifestyle effects: Symptoms require significant recognization of daily activities to accommodate for these
symptoms; patients rarely leave home, must be close to bathroom facilities and medical supplies.
Symptoms: Diarrhea, flushing, or wheezing (severe) or of sufficient severity to warrant hospitalization for
treatment of dehydration, electrolyte imbalance, refractory hypertension, or asthma
Frequency: Numerous (>4) daily
Lifestyle effects: Symptoms are disabling; patients are unable to leave home or require hospitalization.

Figure 16.3 Computed tomography scan of multiple neuroendocrine hepatic

metastases from a primary small bowel carcinoid.

Figure 16.2 Indium-111 Octreotide scan demonstrating octreotide avid liver

metastases.
A diagnostic angiography should be obtained from a femo-
ral approach to confirm the anatomy of artery and the
patency of portal vein before the administration of the ther-
apeutic agents (Fig. 16.4). Patients should receive SST
analogs before the procedure to prevent hormonal adverse
events (59).
There are no definitive data to support the agents for embo-
lization such as Gelfoam, Ivalon, starch particles, lipidol, or
radio isotope-loaded spheres. Selection of chemotherapeutic
agents is also still inconclusive. Cisplatin, doxorubicin, and
mitomycin are most commonly utilized.
Almost all of patients experience postprocedural abdominal
pain, nausea, vomiting, and fever. Transaminase levels will
shoot up dramatically, and then followed by the elevation of
alkaline phosphatase and or serum bilirubin. Tumor-related
hormone level will increase temporarily, however, it can be
obviated with SST analogs administration (59). Major compli-
cations include gastrointestinal bleeding, gastric and duodenal
ulceration, hepatic abscess, ischemic necrosis of gallbladder or
small intestine, pancreatitis, sepsis, renal failure, hepatorenal
syndrome, portal vein thrombosis, sclerosing cholangitis,
arterial thrombosis, and arrythmias (60).
Since these complications are common and even can be
fatal, patient selection should be strict and postprocedural
hospital stay with careful monitoring is warranted. Overall,
morbidity rate ranges from 3% to 20%, mortality rate ranges
from 0% to 7% (Table 16.6).
Successful symptomatic relief and the reduction of tumor
size can be achieved; however, the duration of palliation may

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 16.5 Hepatic Resection (Literature review: 1996–2008)

Disease Disease Disease Disease
Follow-up Relief of free free specific specific
No. of period Morbidity Mortality symptoms survival survival survival survival
Year patients (months) (%) (%) (%) (%) (months) (%) (months)
Dousset (Paris, 1996 17 6–108 24 6 100 36% at 17 46% at NA
France) (47) 5 years 5 years

Chen (MD, USA) 1998 15 27 NA 0 NA NA 21 73% at not

(48) 5 years reached
Chamberlain (NY, 2000 34 27 NA 6 86–100 NA NA 76% at not
USA) (8) 5 years reached
Jaeck (Strasbourg, 2001 13 42 NA 0 46 69% at NA 68% at NA
France) (49) 3 years 6 years
Yao (IL, USA) (50) 2001 16 30 12 0 100 42% at 73% at not
5 years 5 years reached
Chung (CA, USA) 2001 31 26 26 3 90 NA 60 31% at NA
(51) 5 years
Sarmiento (MN, 2003 170 NA 14 1 96 16% at 46 61% at 81
USA) (52) 5 years 5 years
Knox (TN, USA) (53) 2004 17 NA 24 0 82 NA 9–104 85% at 135
5 years
Mazzaferro (Milan, 2007 36 NA NA 0 NA 19% at NA 59% at NA
Italy) (54) 10 years 10 years
Osborne (FL, USA) 2006 61 NA 3 2 92 NA 35 NA 43
(55)
Musunuru (WI, USA) 2006 13 20 NA NA 100 NA 50 83% at NA
(56) 3 years
Landry (KT, USA) 2008 23 NA 26 0 NA NA NA 75% at 52
(112) 5 years
Eriksson (Uppsala, 2008 42 18 20 0 71 NA NA NA NA
Sweden) (58)
Median 27 22 3 92 36% at 41 73% at 67
5 years 5 years

be limited due to recurrence or rearterization of tumors. The

occlusive agent alone is associated with a relief of symptom
rate 49% (33–100%), median disease-free survival at 15 (8–37)
months, and median disease-specific survival at 24 (24–120)
months (55,56,61–68). Whereas the embolization with che-
motherapeutic agents results in a relief of symptom rate 75%
(61–92%), median disease-free survival is 14 (10–19) months,
and median disease-specific survival 33 (25–49) months. The
summary of recent literature review is shown in Table 16.7
(Grade III. Recommendation C).

Hepatic Radiofrequency Ablation

Radiofrequency ablation (RFA) can be performed percuta-
neously or laparoscopically for patients who are unfit
for hepatic resection or intraoperative RFA in addition to
hepatic resection is also advantageous. High-frequency
alternating current causes ionic agitation that is converted
into heat, and leads coagulation necrosis of tumor. The
probes can deploy 4 to 5 cm in a single session with up to
Figure 16.4 Typical angiogram of multiple neuroendocrine hepatic metastases
prior to embolization.
200 W of power (Fig. 16.5).

158
 Table 16.6 Hepatic Artery Occlusion (Literature Review: 1989–2008)
Disease
Relief of Disease free specific
No. of Morbidity Mortality symptoms Disease free survival Disease specific survival
Year patients Agent(s) used (%) (%) (%) survival (%) (months) survival (%) (months)
Occlusive agent alone (HAE)
Nobin (Lund, Sweden) (63) 1989 8 Gelfoam NA 0 38 38% at 1 NA 13% died in NA
year 5 months
Eriksson (Uppsala, Sweden) (64) 1998 55 Gelfoam NA 0 38–52 NA 8 83% at 5 years 80–120
Brown (NY, USA) (113) 1999 35 Polyvinyl alcohol particles 17 6 89–100 NA 15 54% at 5 years 24
Schell (FL, USA) (17) 2002 24 Lipiodol/Gelfoam 0 0 64 NA NA 72% at 5 years NA
Osborne (FL, USA) (55) 2006 59 Polyvinyl alcohol particles 5 0 59 NA 37 NA 24
Granberg (Uppsala, Sweden) (65) 2007 15 Trisacryl gelatin microsphere 0 0 33 NA NA NA NA
(embosphere)
Median 3 0 49 38% at 1 15 72 24
year
HAE with systemic chemotherapy
Moertel (MN, USA) (68) 1994 111 NA, including surgical ligation 12 5 98.0 NA NA NA 49
Loewe (Vienna, Austria) (67) 2003 23 N-Butyl-2-cyanoacrylate, NA 9 NA NA NA 65% at 5 years 39
Lipiodol
Median 12 7 98 NA NA 65% at 5 years 44
Combination with chemothera-
peutic agents (HACE)
Ruszniewski (Paris, France) (114) 1993 24 Doxorubicin, Lipiodol 8 0 NA NA 13 NA NA
Drougas (TN, USA) (60) 1998 15 Doxorubicin, cisplatin, 60 0 75 NA NA NA 25
mitomycin C +5FU
Roche (Villejuif, France) (115) 2003 14 Doxorubicin, Lipiodol 14 0 64 NA 17 83% at 5 years 48
Ho (MO, USA) (116) 2007 46 Cisplatin, doxorubicin, 20 4 78 NA 14 29% at 5 years 33
mitomycin, Lipiodol
Bloomston (OH, USA) (117) 2007 122 Cisplatin, doxorubicin, 23 5 92 5% at 10 28% at 5 years 33
mitomycin, ioxaglate 5 years
sodium, Lipiodol
Christante (OR, USA) (118) 2008 59 Cisplatin, doxorubicin, NA 7 61 NA 19 27% at 5 years 39
mitomycin
Median 20 5 75 5% at 5 years 14 29% at 5 years 33
HAE and HACE
Gupta (TX, USA) (66) 2005 123 HAE, polyvinyl alcohol 9 0 NA NA 23 NA 34
particle or gelfoam powder.
MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS

HACE, for carcinoid tumor:

cisplatin+doxorubicin. For
islet cell tumor:
5FU+streptozocin
Musunuru (WI, USA) (56) 2006 18 NA NA NA 83 31% at 25 NA NA
3 years
Median 9 0 83 31% at 24 NA 34
3 years

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Table 16.7 Milan Criteria
Inclusion criteria
1. Confirmed histology of carcinoid tumor (low-grade neuroen-
docrine tumors) with or without syndrome
2. Primary tumor drained by the portal system (pancreas and
intermediate gut: from distal stomach to sigmoid colon)
removed with a curative resection (pre-transplant removal of
all extra-hepatic tumor deposits) through surgical procedures
different and separate from transplantation
3. Metastatic diffusion to liver parenchyma < or + 50%
4. Good response or stable disease for at least 6 months during
the pre-transplant period
5. Age < or + 55 years
Exclusion criteria
1. Small-cell carcinoma and high-grade neuroendocrine
carcinomas (non-carcinoid tumors)
2. Other medical/surgical conditions contraindicationg liver
transplantation, including previous tumors
3. Non-gastrointestinal carcinoids or tumors not-drained by the
portal system
Source: Adapted from Ref. (54).
Figure 16.5 CT guided radiofrequency ablation of single small liver metastasis
1 day after arterial embolization.
This treatment is suitable for relatively small tumors. Indica-
tions for RFA include (i) fewer than 4 in number, (ii) smaller
than 5 cm, (iii) accessible location in liver, and (iv) not in con-
tiguity to vascular structures, bowel, or the gall bladder (46).
Complications include bleeding, sepsis, and intrahepatic
biliary duct damage. Morbidity rate is around 5%. No RFA-
related mortality has been reported (58,69).
RFA is associated with the high incidence of the recurrence
at previously ablated sites (58,70,71). Local recurrence rate is
reported to be 5 to 6% (69,70,72). The assessment of outcome
of this procedure is somewhat difficult to be specific because
many of RFA are combined with surgical resection. A large
160
study by Mazzaglia et al. (69) detailed the outcomes of 80 lapa-
roscopic RFA sessions in 63 patients who underwent RFA
alone for NET-hepatic metastasis (54). Relief of symptoms
was achieved more than 90% of the patients. Median disease-
free survival was 11 months. Median disease-specific survival
was close to 4 years. Five-year survival rate was 48% (Grade III.
Recommendation C).
Hepatic Cryoablation
Cryoablation can be applied for patients with unresectable
refractory NETs. Intraoperative approach combined with
hepatic resection is common rather than cryoablation alone.
The cryoprobe is inserted into tumor under ultrasound guid-
ance. The freezing temperature of cryoprobe is maintained
liquid nitrogen perfusing in the uninsulated tip. Tumor is
monitored until the “ice ball” enveloped the tumor with a
1-cm margin of normal tissue. Multiple freezing–thaw cycles
lead to tumor destruction (73). Indications for this procedure
are still unclear.
Complications include coagulopathy, bleeding, acute renal
failure, and pulmonary embolism. Morbidity rate is reported
variously but at a minimum of 23%. Mortality rate is 0% to
2% (74–76).
Of note, this procedure is usually combined with hepatic
resection; therefore, the outcomes of reported studies are not
specific for cryoablation. Almost all patients experienced the
relief of symptoms and biochemical response. Local recur-
rence at the ablated site is reported as 17% in a study from
Seifert et al. (75). Median recurrence-free survival is
10 months. Median disease-specific survival is 20 to 49 months.
Three-year survival rate is up to 91% (74–76) (Grade III.
Recommendation C).
Liver Transplantation
Liver transplantation is a therapeutic alternative of hepatic
resection for unresectable NET-HM patients. Whereas the
results of liver transplantation for other metastatic tumors are
poor (77), patients with NET-hepatic metastasis have been
more likely benefit from liver transplantation (57,78–85).
Although this approach is still controversial, “Milan criteria”
for indication to liver transplantation in patients with NET-
hepatic metastasis are widely referred (Table 16.7) (54).
Patients will receive a full graft, a split graft or a domino
graft from deceased or living donor (78). The general principle
of complete resection of both primary and metastatic tumor
has to be pursued in the setting of this treatment. Therefore,
transplantation could be performed with concurrent resection
of extrahepatic tumor including lymphadenectomy of hepatic
pedicle and hepato-duodenal ligament (54,78,86). Standard
immunosuppression should be administered postoperatively.
Adjuvant chemotherapy or long-acting SST analogs will be
applied as appropriately (54).
Table 16.8 shows the summary of literature review. Postop-
erative morbidity includes acute rejection episodes, acute
cholangitis, and bacteremia. Overall morbidity rate are
reported as 56% (32–75%). Mortality rate is 10% (5–44%).
Recent studies report that 5-year survival of 21% (36–90%),
with symptomatic relief occurring in all of the patients.
 MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS

Table 16.8 Liver Transplantation (Literature Review, 1996–2008)

Follow- Disease- Disease Disease
up Relief of free specific specific
No. of period Morbidity Mortality symptoms survival survival survival
Year patients (months) (%) (%) (%) (%) 43.795 pt (%) (months)
Dousset (Paris, 1996 9 NA NA 44 NA Rec rate 58 NA 24
France) (47) 11%
Lang (Gottingen, 1997 12 NA NA 8 100 Rec rate 6 weeks to NA 55
Germany) (57) 57.1% 48 months
Lehnert(Heidelberg, 1998 103 60 NA 14 NA 24% at NA 47% at NA
Germany) (87) 5 years 5 years
Rosenau (Hannover, 2002 19 60 NA 5 NA 21% at 11 80% at NA
Germany) (88) 5 years 5 years
Florman (NY, USA) 2004 11 34 NA 27 NA 9% at NA 36% at NA
(89) 5 years 5 years
V.Vilsteren (MN, 2006 19 22 32 5 NA 80% at NA 87% at NA
USA) (86) 1 years 1 years
Mazzaferro (Milan, 2007 24 60 NA NA NA 77% at NA 90% at NA
Italy) (54) 5 years 5 years
Olausson (Goteborg, 2007 15 54 NA 7 NA Rec rate 25 NA NA
Sweden) (90) 33.3%
Marin (Murcia, 2007 10 36 75 10 NA 57% at NA 57% at NA
Spain) (91) 3 years 3 years
Le Treut (Marseille, 2008 85 46 NA 14 NA 20% at NA 47% at 56
France) (78) 5 years 5 years
Median 50 56 10 100 21% at 25 47% at 55
5 years 5 years

Disease-free survival is 21% (9–77%) at 5 years. Median time
to recurrence is 25 (1.5–58) months (47,54,57,78,86–91)
(Grade III. Recommendation C).
Medical Treatment
SSTR-targeted Therapy
SST analogs are effective in improving hormonal symptoms
due to NETs. SST inhibits the release of serotonin and other
hormones from NETs (92). Because SST has a short half-life
(about 2 minutes), it is not suitable for clinical use (92). Long-
acting SST analogues (octreotide and lanreotide) are widely
applied. The response rate ranges 70% to 80% when adminis-
tered subcutaneously every 6 to 12 hours (93,94). Dosage
should be adjusted with clinical use from 50 to 500 μg 3 times
a day. Adverse effects include gallstones, steatorrhea, sinus bra-
dycardia, cardiac conduction abnormalities, arrhythmias,
hypothyroidism, hypoglycemia, and hyperglycemia (92,95).
SSTR analogs are utilized for preoperative symptomatic con-
trol, preprocedural medication to prevent carcinoid crisis, and
postoperative supportive therapy if residual tumors were evi-
dent (1) (Grade III. Recommendation C).
Chemotherapy
Chemotherapeutic agents for NETs include streptozotocin,
5-FU, doxorubicin, cyclophosphamide, etoposide, cisplatin,
temozolomide, thalidomide, paclitaxel, and docetaxel (1,4).
Overall response rate of chemotherapeutic alone is reported to
be only 20% to 40%. At least there is one randomized trial
comparing streptozocin +5FU and doxorubicin +5FU (96).
The patients were enrolled this study were 249. Response rate
in two groups were similar (16% vs. 15.9%). Streptozocin +
5 FU was associated a subtle increase of survival (24.3 vs.
15.7 months), however, renal toxicity was significantly frequent
in that group. Unfortunately, there are no data existing to reveal
the benefit of each chemotherapeutic agent, or the combina-
tion of agents (92,97–99) (Grade Ib. Recommendation B).
Interferon
Interferon inhibits tumor growth by directly blocking the G0/G1
phase of cell cycle. Applications of interferon to NETs have been
investigated since 1982 (100–103). Interferon alpha alone resulted
in biochemical response rate of 7% to 66%, and tumor response
rate 0% to 25%. The combination of interferon alpha and SST ana-
logs failed to be effective (104) (Grade III. Recommendation C).
Radionuclide Therapy
Receptor targeted therapy with radionuclides is an emerging
treatment for patients with disseminated NET metastases.
131
I-MIBG, [111In-DTPA-D-Phe] octreotide, 90yttrium, and
177
lutetium-labeled SST analogs are utilized (35,105–111).
Agents will be selected by uptake at diagnostic imaging. This
treatment is specific and tolerated. Fair levels of biochemical
response and volume reduction are reported. Symptomatic
relief can be achieved. Reported adverse effect is renal damage.
Adequate renal protection should be added before treatment
(Grade III. Recommendation C).
summary
Summary of treatment for NET-hepatic metastasis is shown in
Table 16.9.

161
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 16.9 Summary of Treatment for NET-Hepatic Metastasis

Disease- Disease- Disease- Disease-
Relief of free free specific specific
Morbidity Mortality symptoms survival survival survival survival
Indication (%) (%) (%) (%) (months) (%) (months)
Hepatic resection Tumor restricted to one lobe 22 3 92 36% at 41 73% at 67
(8,47–56,58,112) 5 years 5 years
Hepatic artery (1) Rapid enlargement of
occlusion tumor mass, (2) Increasing
HAE (17,55, symptoms, (3) Patient 3 0 49 38% at 15 72% at 24
63–65,113) preference for the procedure 1 year 5 years
HACE (60,114–118) in lieu of other treatment, (4) 20 5 75 5% at 14 29% at 33
Patients with adequate liver 5 years 5 years
function and patent portal
vein
Hepatic radiofre- (1) Fewer than 4 in number, 5 0 82 NA 11 NA 48
quency ablation (2) Smaller than 5cm, (3)
(58,69,119,120) Accessible location in liver,
and (4) Not in contiguity to
vascular structures, bowel, or
the gall bladder
Hepatic cryotherapy Small lesions. Usually 23 0 95 32% at 10 91% at 45
(74–76) combined with hepatic 3 years 3 years
resection
Liver transplantation Milan criteria. See Table 16.7. 56 10 100 21% at 25 47% at 55
(47,54,57,78,86–91) 5 years 5 years

key points
Diagnosis:
● Hormonal symptoms (carcinoid syndrome) and/or
symptoms due to hepatic mass
● Laboratory investigations: CgA (blood) and
5-HIAA (urine)
● Identify the primary and metastatic sites by SSTR
scintigraphy
● Assess the resectability of hepatic metastasis by CT
or MRI
Treatment:
● Surgical resection (curative or palliative)
● Other liver targeted therapy (HAE/HACE, RFA,
and cryotherapy)
● Liver transplantation for selected unresectable
patients
● SST analogues for symptomatic control
● Radionuclide therapy is emerging for the dissemi-
nated disease
● No proven survival benefit in chemotherapy
references
1. Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal
carcinoids. Gastroenterology 2005; 128(6): 1717–51.
2. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid
tumors. Cancer 2003; 97(4): 934–59.
3. Moertel CG. Karnofsky memorial lecture. An odyssey in the land of
small tumors. J Clin Oncol 1987; 5(10): 1502–22.
4. Kvols LK. Revisiting C.G. Moertel’s land of small tumors. J Clin Oncol
2008; 26(31): 5005–7.
5. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340(11):
858–68.
6. Solcia E, Capella C, Kloppel G, Heitz PU, Sobin LH, Rosai J. Endocrine
tumours of the gastrointestinal tract. In: Solcia E, Kloppel G, Sobin LH,
eds. Histologic typing of endocrine tumours. WHO international histo-
logical typing of endocrine tumours. Heidelberg, New York: Springer
Verlag, 2000: 57–67.
7. DeMatteo RP, Fong Y, Blumgart LH. Surgical treatment of malignant liver
tumours. Baillieres Best Pract Res Clin Gastroenterol 1999; 13(4): 557–74.
8. Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine
metastases: does intervention alter outcomes? J Am Coll Surg 2000;
190(4): 432–45.
9. Moertel CG, Sauer WG, Dockerty MB, et al. Life history of the carcinoid
tumor of the small intestine. Cancer 1961; 14: 901–12.
10. Burke AP, Thomas RM, Elsayed AM, et al. Carcinoids of the jejunum and
ileum: an immunohistochemical and clinicopathologic study of 167 cases.
Cancer 1997; 79(6): 1086–93.
11. Grahame-Smith DG. The carcinoid syndrome. Am J Cardiol 1968; 21(3):
376–87.
12. Feldman JM. Carcinoid tumors and the carcinoid syndrome. Curr Probl
Surg 1989; 26(12): 835–85.
13. Tilson MD. Carcinoid syndrome. Surg Clin North Am 1974; 54(2): 409–23.
14. Lundin L. Carcinoid heart disease. A cardiologist’s viewpoint. Acta Oncol
1991; 30(4): 499–502.
15. Berge T, Linell F. Carcinoid tumours. Frequency in a defined population
during a 12-year period. Acta Pathol Microbiol Scand [A] 1976; 84(4):
322–30.
16. Wessels FJ, Schell SR. Radiofrequency ablation treatment of refractory
carcinoid hepatic metastases. J Surg Res 2001; 95(1): 8–12.
17. Schell SR, Camp ER, Caridi JG, et al. Hepatic artery embolization for
control of symptoms, octreotide requirements, and tumor progression in
metastatic carcinoid tumors. J Gastrointest Surg 2002; 6(5): 664–70.
18. Debas HT, Mulvihill SJ. Neuroendocrine gut neoplasms. Important lessons
from uncommon tumors. Arch Surg 1994; 129(9): 965–71; discussion
971–2.
19. Kinney MA, Warner ME, Nagorney DM, et al. Perianaesthetic risks and
outcomes of abdominal surgery for metastatic carcinoid tumours. Br J
Anaesth 2001; 87(3): 447–52.

162
 MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS
20. Kvols LK, Martin JK, Marsh HM, et al. Rapid reversal of carcinoid crisis
with a somatostatin analogue. N Engl J Med 1985; 313(19): 1229–30.
21. Marsh HM, Martin JK, Jr., Kvols LK, et al. Carcinoid crisis during anesthe-
sia: successful treatment with a somatostatin analogue. Anesthesiology
1987; 66(1): 89–91.
22. Muralidhar V, Sharma A. Carcinoid crisis during a partial hepatic resection;
lack of essential drugs: a cause for concern in the tropics. Trop Gastroen-
terol 1996; 17(1): 26–9.
23. Dery R. Theoretical and clinical considerations in anaesthesia for secreting
carcinoid tumors. Can Anaesth Soc J 1971; 18(3): 245–63.
24. Warner TF, O’Reilly G, Lee GA. Mesenteric occlusive lesion and ileal carci-
noids. Cancer 1979; 44(2): 758–62.
25. Marshall JB, Bodnarchuk G. Carcinoid tumors of the gut. Our experience
over three decades and review of the literature. J Clin Gastroenterol 1993;
16(2): 123–9.
26. Sakai D, Murakami M, Kawazoe K, et al. Ileal carcinoid tumor complicat-
ing carcinoid heart disease and secondary retroperitoneal fibrosis. Pathol
Int 2000; 50(5): 404–11.
27. Norheim I, Oberg K, Theodorsson-Norheim E, et al. Malignant carcinoid
tumors. An analysis of 103 patients with regard to tumor localization, hor-
mone production, and survival. Ann Surg 1987; 206(2): 115–25.
28. Moss SF, Lehner PJ, Gilbey SG, et al. Pleural involvement in the carcinoid
syndrome. Q J Med 1993; 86(1): 49–53.
29. O’Connor DT, Deftos LJ. Secretion of chromogranin A by peptide-
producing endocrine neoplasms. N Engl J Med 1986; 314(18): 1145–51.
30. Nobels FR, Kwekkeboom DJ, Coopmans W, et al. Chromogranin A as
serum marker for neuroendocrine neoplasia: comparison with neuron-
specific enolase and the alpha-subunit of glycoprotein hormones. J Clin
Endocrinol Metab 1997; 82(8): 2622–8.
31. Modlin IM, Tang LH. Approaches to the diagnosis of gut neuroendocrine
tumors: the last word (today). Gastroenterology 1997; 112(2): 583–90.
32. Tormey WP, FitzGerald RJ. The clinical and laboratory correlates of
an increased urinary 5-hydroxyindoleacetic acid. Postgrad Med J 1995;
71(839): 542–5.
33. Feldman JM, Lee EM. Serotonin content of foods: effect on urinary excre-
tion of 5-hydroxyindoleacetic acid. Am J Clin Nutr 1985; 42(4): 639–43.
34. Raderer M, Kurtaran A, Leimer M, et al. Value of peptide receptor scintig-
raphy using (123)I-vasoactive intestinal peptide and (111)In-DTPA-D-
Phe1-octreotide in 194 carcinoid patients: Vienna University Experience,
1993 to 1998. J Clin Oncol 2000; 18(6): 1331–6.
35. Hoefnagel CA. Metaiodobenzylguanidine and somatostatin in oncology:
role in the management of neural crest tumours. Eur J Nucl Med
1994;21(6):561–81.
36. Paulson EK, McDermott VG, Keogan MT, et al. Carcinoid metastases to
the liver: role of triple-phase helical CT. Radiology 1998; 206(1): 143–50.
37. Eriksson B, Lilja A, Ahlstrom H, et al. Positron-emission tomography as a
radiological technique in neuroendocrine gastrointestinal tumors. Ann N
Y Acad Sci 1994; 733: 446–52.
38. Rege SD, Hoh CK, Glaspy JA, et al. Imaging of pulmonary mass lesions
with whole-body positron emission tomography and fluorodeoxyglucose.
Cancer 1993; 72(1): 82–90.
39. Jadvar H, Segall GM. False-negative fluorine-18-FDG PET in metastatic
carcinoid. J Nucl Med 1997; 38(9): 1382–3.
40. Sundin A, Eriksson B, Bergstrom M, et al. PET in the diagnosis of neuro-
endocrine tumors. Ann N Y Acad Sci 2004; 1014: 246–57.
41. Adams S, Baum RP, Hertel A, et al. Metabolic (PET) and receptor (SPET)
imaging of well- and less well-differentiated tumours: comparison with
the expression of the Ki-67 antigen. Nucl Med Commun 1998; 19(7):
641–7.
42. Krenning EP, Kooij PP, Bakker WH, et al. Radiotherapy with a radiolabeled
somatostatin analogue, [111In-DTPA-D-Phe1]-octreotide. A case history.
Ann N Y Acad Sci 1994; 733: 496–506.
43. Hanson MW, Feldman JM, Blinder RA, et al. Carcinoid tumors: iodine-131
MIBG scintigraphy. Radiology 1989; 172(3): 699–703.
44. McEntee GP, Nagorney DM, Kvols LK, et al. Cytoreductive hepatic surgery
for neuroendocrine tumors. Surgery 1990; 108(6): 1091–6.
45. Martin JK, Jr, Moertel CG, Adson MA, et al. Surgical treatment of func-
tioning metastatic carcinoid tumors. Arch Surg 1983; 118(5): 537–42.
46. Garrot C, Stuart K. Liver-directed therapies for metastatic neuroendocrine
tumors. Hematol Oncol Clin North Am 2007; 21(3): 545–60; ix–x.
47. Dousset B, Saint-Marc O, Pitre J, et al. Metastatic endocrine tumors: medi-
cal treatment, surgical resection, or liver transplantation. World J Surg
1996; 20(7): 908–14; discussion 914–5.
48. Chen H, Hardacre JM, Uzar A, et al. Isolated liver metastases from neuro-
endocrine tumors: does resection prolong survival? J Am Coll Surg 1998;
187(1): 88–92; discussion 92–3.
49. Jaeck D, Oussoultzoglou E, Bachellier P, et al. Hepatic metastases of gastro-
enteropancreatic neuroendocrine tumors: safe hepatic surgery. World J
Surg 2001; 25(6): 689–92.
50. Yao KA, Talamonti MS, Nemcek A, et al. Indications and results of liver
resection and hepatic chemoembolization for metastatic gastrointestinal
neuroendocrine tumors. Surgery 2001; 130(4): 677–82; discussion 682–5.
51. Chung MH, Pisegna J, Spirt M, et al. Hepatic cytoreduction followed by a
novel long-acting somatostatin analog: a paradigm for intractable neuro-
endocrine tumors metastatic to the liver. Surgery 2001; 130(6): 954–62.
52. Sarmiento JM, Heywood G, Rubin J, et al. Surgical treatment of neuroen-
docrine metastases to the liver: a plea for resection to increase survival.
J Am Coll Surg 2003; 197(1): 29–37.
53. Knox CD, Feurer ID, Wise PE, et al. Survival and functional quality of life
after resection for hepatic carcinoid metastasis. J Gastrointest Surg 2004;
8(6): 653–9.
54. Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to
the liver: how to select patients for liver transplantation? J Hepatol 2007;
47(4): 460–6.
55. Osborne DA, Zervos EE, Strosberg J, et al. Improved outcome with cytore-
duction versus embolization for symptomatic hepatic metastases of carci-
noid and neuroendocrine tumors. Ann Surg Oncol 2006; 13(4): 572–81.
56. Musunuru S, Chen H, Rajpal S, et al. Metastatic neuroendocrine hepatic
tumors: resection improves survival. Arch Surg 2006; 141(10): 1000–4;
discussion 1005.
57. Lang H, Oldhafer KJ, Weimann A, et al. Liver transplantation for meta-
static neuroendocrine tumors. Ann Surg 1997; 225(4): 347–54.
58. Eriksson J, Stalberg P, Nilsson A, et al. Surgery and radiofrequency abla-
tion for treatment of liver metastases from midgut and foregut carcinoids
and endocrine pancreatic tumors. World J Surg 2008; 32(5): 930–8.
59. Caplin ME, Buscombe JR, Hilson AJ, et al. Carcinoid tumour. Lancet 1998;
352(9130): 799–805.
60. Drougas JG, Anthony LB, Blair TK, et al. Hepatic artery chemoemboliza-
tion for management of patients with advanced metastatic carcinoid
tumors. Am J Surg 1998; 175(5): 408–12.
61. Brown KT, Nevins AB, Getrajdman GI, et al. Particle embolization for
hepatocellular carcinoma. J Vasc Interv Radiol 1998; 9(5): 822–8.
62. Lauffer JM, Zhang T, Modlin IM. Review article: current status of gastro-
intestinal carcinoids. Aliment Pharmacol Ther 1999; 13(3): 271–87.
63. Nobin A, Mansson B, Lunderquist A. Evaluation of temporary liver dearte-
rialization and embolization in patients with metastatic carcinoid tumour.
Acta Oncol 1989; 28(3): 419–24.
64. Eriksson BK, Larsson EG, Skogseid BM, et al. Liver embolizations of
patients with malignant neuroendocrine gastrointestinal tumors. Cancer
1998; 83(11): 2293–301.
65. Granberg D, Eriksson LG, Welin S, et al. Liver embolization with trisacryl
gelatin microspheres (embosphere) in patients with neuroendocrine
tumors. Acta Radiol 2007; 48(2): 180–5.
66. Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and
chemoembolization for the treatment of patients with metastatic neuro-
endocrine tumors: variables affecting response rates and survival. Cancer
2005; 104(8): 1590–602.
67. Loewe C, Schindl M, Cejna M, et al. Permanent transarterial embolization
of neuroendocrine metastases of the liver using cyanoacrylate and lipi-
odol: assessment of mid- and long-term results. AJR Am J Roentgenol
2003; 180(5): 1379–84.
68. Moertel CG, Johnson CM, McKusick MA, et al. The management of
patients with advanced carcinoid tumors and islet cell carcinomas. Ann
Intern Med 1994; 120(4): 302–9.
69. Mazzaglia PJ, Berber E, Milas M, et al. Laparoscopic radiofrequency abla-
tion of neuroendocrine liver metastases: a 10-year experience evaluating
predictors of survival. Surgery 2007; 142(1): 10–19.
70. Berber E, Siperstein A. Local recurrence after laparoscopic radiofrequency
ablation of liver tumors: an analysis of 1032 tumors. Ann Surg Oncol 2008;
15(10): 2757–64.
163
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
71. Ahmad A, Chen SL, Kavanagh MA, et al. Radiofrequency ablation of
hepatic metastases from colorectal cancer: are newer generation probes
better? Am Surg 2006; 72(10): 875–9.
72. Hellman P, Lundstrom T, Ohrvall U, et al. Effect of surgery on the outcome
of midgut carcinoid disease with lymph node and liver metastases. World
J Surg 2002; 26(8): 991–7.
73. Siperstein AE, Berber E. Cryoablation, percutaneous alcohol injection, and
radiofrequency ablation for treatment of neuroendocrine liver metastases.
World J Surg 2001; 25(6): 693–6.
74. Bilchik AJ, Sarantou T, Foshag LJ, et al. Cryosurgical palliation of meta-
static neuroendocrine tumors resistant to conventional therapy. Surgery
1997; 122(6): 1040–7; discussion 1047–8.
75. Seifert JK, Cozzi PJ, Morris DL. Cryotherapy for neuroendocrine liver
metastases. Semin Surg Oncol 1998; 14(2): 175–83.
76. Goering JD, Mahvi DM, Niederhuber JE, et al. Cryoablation and liver
resection for noncolorectal liver metastases. Am J Surg 2002; 183(4):
384–9.
77. Penn I. Hepatic transplantation for primary and metastatic cancers of the
liver. Surgery 1991; 110(4): 726-34; discussion 734–5.
78. Le Treut YP, Gregoire E, Belghiti J, et al. Predictors of long-term survival
after liver transplantation for metastatic endocrine tumors: an 85-case
French multicentric report. Am J Transplant 2008; 8(6): 1205–13.
79. Makowka L, Tzakis AG, Mazzaferro V, et al. Transplantation of the liver for
metastatic endocrine tumors of the intestine and pancreas. Surg Gynecol
Obstet 1989; 168(2): 107–11.
80. Arnold JC, O’Grady JG, Bird GL, et al. Liver transplantation for primary
and secondary hepatic apudomas. Br J Surg 1989; 76(3): 248–9.
81. Routley D, Ramage JK, McPeake J, et al. Orthotopic liver transplantation in
the treatment of metastatic neuroendocrine tumors of the liver. Liver
Transpl Surg 1995; 1(2): 118–21.
82. Le Treut YP, Delpero JR, Dousset B, et al. Results of liver transplantation in
the treatment of metastatic neuroendocrine tumors. A 31-case French
multicentric report. Ann Surg 1997; 225(4): 355–64.
83. Ihse I, Persson B, Tibblin S. Neuroendocrine metastases of the liver. World
J Surg 1995; 19(1): 76–82.
84. McDermott EW, Guduric B, Brennan MF. Prognostic variables in patients
with gastrointestinal carcinoid tumours. Br J Surg 1994; 81(7): 1007–9.
85. Frilling A, Rogiers X, Malago M, et al. Liver transplantation in patients
with liver metastases of neuroendocrine tumors. Transplant Proc 1998;
30(7): 3298–300.
86. van Vilsteren FG, Baskin-Bey ES, Nagorney DM, et al. Liver transplanta-
tion for gastroenteropancreatic neuroendocrine cancers: Defining selec-
tion criteria to improve survival. Liver Transpl 2006; 12(3): 448–56.
87. Lehnert T. Liver transplantation for metastatic neuroendocrine carci-
noma: an analysis of 103 patients. Transplantation 1998; 66(10):
1307–12.
88. Rosenau J, Bahr MJ, von Wasielewski R, et al. Ki67, E-cadherin, and p53
as prognostic indicators of long-term outcome after liver transplantation
for metastatic neuroendocrine tumors. Transplantation 2002; 73(3):
386–94.
89. Florman S, Toure B, Kim L, et al. Liver transplantation for neuroendocrine
tumors. J Gastrointest Surg 2004; 8(2): 208–12.
90. Olausson M, Friman S, Herlenius G, et al. Orthotopic liver or multivisceral
transplantation as treatment of metastatic neuroendocrine tumors. Liver
Transpl 2007; 13(3): 327–33.
91. Marin C, Robles R, Fernandez JA, et al. Role of liver transplantation in the
management of unresectable neuroendocrine liver metastases. Transplant
Proc 2007; 39(7): 2302–3.
92. Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of soma-
tostatin analogs for the management of neuroendocrine tumors of the
gastroenteropancreatic system. Ann Oncol 2004; 15(6): 966–73.
93. Welin SV, Janson ET, Sundin A, et al. High-dose treatment with a long-
acting somatostatin analogue in patients with advanced midgut carcinoid
tumours. Eur J Endocrinol 2004; 151(1): 107–12.
94. Garland J, Buscombe JR, Bouvier C, et al. Sandostatin LAR (long-acting
octreotide acetate) for malignant carcinoid syndrome: a 3-year experience.
Aliment Pharmacol Ther 2003; 17(3): 437–44.
95. Schnirer, II, Yao JC, Ajani JA. Carcinoid--a comprehensive review. Acta
Oncol 2003; 42(7): 672–92.
164
96. Sun W, Lipsitz S, Catalano P, et al. Phase II/III study of doxorubicin
with fluorouracil compared with streptozocin with fluorouracil or
dacarbazine in the treatment of advanced carcinoid tumors: Eastern
Cooperative Oncology Group Study E1281. J Clin Oncol 2005; 23(22):
4897–904.
97. Saltz L, Kemeny N, Schwartz G, et al. A phase II trial of alpha-interferon
and 5-fluorouracil in patients with advanced carcinoid and islet cell
tumors. Cancer 1994; 74(3): 958–61.
98. Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic
carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials
1979; 2(4): 327–34.
99. Hughes MJ, Kerr DJ, Cassidy J, et al. A pilot study of combination therapy
with interferon-alpha-2a and 5-fluorouracil in metastatic carcinoid and
malignant endocrine pancreatic tumours. Ann Oncol 1996; 7(2): 208–10.
100. Oberg K. Neuroendocrine gastrointestinal tumours. Ann Oncol 1996;
7(5): 453–63.
101. Dirix LY, Vermeulen PB, Fierens H, et al. Long-term results of continuous
treatment with recombinant interferon-alpha in patients with metastatic
carcinoid tumors—an antiangiogenic effect? Anticancer Drugs 1996;
7(2): 175–81.
102. Di Bartolomeo M, Bajetta E, Zilembo N, et al. Treatment of carcinoid
syndrome with recombinant interferon alpha-2a. Acta Oncol 1993;
32(2): 235–8.
103. Jacobsen MB, Hanssen LE, Kolmannskog F, et al. Interferon-alpha 2b,
with or without prior hepatic artery embolization: clinical response and
survival in mid-gut carcinoid patients. The Norwegian carcinoid study.
Scand J Gastroenterol 1995; 30(8): 789–96.
104. Janson ET, Oberg K. Long-term management of the carcinoid syndrome.
Treatment with octreotide alone and in combination with alpha-inter-
feron. Acta Oncol 1993; 32(2): 225–9.
105. Waldherr C, Pless M, Maecke HR, et al. The clinical value of
[90Y-DOTA]-d-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treat-
ment of neuroendocrine tumours: a clinical phase II study. Ann Oncol
2001; 12(7): 941–5.
106. McCarthy KE, Woltering EA, Espenan GD, et al. In situ radiotherapy
with 111In-pentetreotide: initial observations and future directions.
Cancer J Sci Am 1998; 4(2): 94–102.
107. De Jong M, Breeman WA, Bernard HF, et al. Therapy of neuroendocrine
tumors with radiolabeled somatostatin-analogues. Q J Nucl Med 1999;
43(4): 356–66.
108. Anthony LB, Woltering EA, Espenan GD, et al. Indium-111-pentetreo-
tide prolongs survival in gastroenteropancreatic malignancies. Semin
Nucl Med 2002; 32(2): 123–32.
109. Buscombe JR, Caplin ME, Hilson AJ. Long-term efficacy of high-activity
111
In-pentetreotide therapy in patients with disseminated neuroendo-
crine tumors. J Nucl Med 2003; 44(1): 1–6.
110. Kwekkeboom DJ, Bakker WH, Kam BL, et al. Treatment of patients with
gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled
somatostatin analogue [177Lu-DOTA(0), Tyr3]octreotate. Eur J Nucl Med
Mol Imaging 2003; 30(3): 417–22.
111. Mukherjee JJ, Kaltsas GA, Islam N, et al. Treatment of metastatic carci-
noid tumours, phaeochromocytoma, paraganglioma and medullary car-
cinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)
I-mIBG]. Clin Endocrinol (Oxf) 2001; 55(1): 47–60.
112. Landry CS, Scoggins CR, McMasters KM, et al. Management of hepatic
metastasis of gastrointestinal carcinoid tumors. J Surg Oncol 2008;
97(3): 253–8.
113. Brown KT, Koh BY, Brody LA, et al. Particle embolization of hepatic neu-
roendocrine metastases for control of pain and hormonal symptoms. J
Vasc Interv Radiol 1999; 10(4): 397–403.
114. Ruszniewski P, Rougier P, Roche A, et al. Hepatic arterial chemoemboli-
zation in patients with liver metastases of endocrine tumors. A prospec-
tive phase II study in 24 patients. Cancer 1993; 71(8): 2624–30.
115. Roche A, Girish BV, de Baere T, et al. Trans-catheter arterial chemoembo-
lization as first-line treatment for hepatic metastases from endocrine
tumors. Eur Radiol 2003; 13(1): 136–40.
116. Ho AS, Picus J, Darcy MD, et al. Long-term outcome after chemoembo-
lization and embolization of hepatic metastatic lesions from neuroendo-
crine tumors. AJR Am J Roentgenol 2007; 188(5): 1201–7.
 MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS
117. Bloomston M, Al-Saif O, Klemanski D, et al. Hepatic artery chemoembo-
lization in 122 patients with metastatic carcinoid tumor: lessons learned.
J Gastrointest Surg 2007; 11(3): 264–71.
118. Christante D, Pommier S, Givi B, et al. Hepatic artery chemoinfusion
with chemoembolization for neuroendocrine cancer with progressive
hepatic metastases despite octreotide therapy. Surgery 2008; 144(6):
885–93; discussion 893–4.
119. Berber E, Tsinberg M, Tellioglu G, et al. Resection versus laparoscopic
radiofrequency thermal ablation of solitary colorectal liver metastasis.
J Gastrointest Surg 2008; 12(11): 1967–72.
120. Hellman P, Ladjevardi S, Skogseid B, et al. Radiofrequency tissue ablation
using cooled tip for liver metastases of endocrine tumors. World J Surg
2002; 26(8): 1052–6.
165
17 Noncolorectal, nonneuroendocrine metastases
C. Kahlert, R. DeMatteo, and J.Weitz
introduction
Approximately 90% of malignant hepatic lesions are metas-
tases of extrahepatic primary tumors. Despite enormous
progress of multimodal therapeutical options, surgical
resection remains the only option for curative treatment in
most of these cases. However, in contrast to colorectal or
neuroendocrine hepatic metastases, the surgical approach
for noncolorectal and nonneuroendocrine hepatic metasta-
ses is highly controversial. From a critical point of view, it is
argued that noncolorectal, nonneuroendocrine liver metas-
tases often belong to very aggressive types of cancer. In addi-
tion, they partly derive from extraabdominal primary
tumors. In contrast to intraabdominal tumors metastasizing
through the portal vein with the liver theoretically being the
first filter organ, liver metastases of extraabdominal primary
tumors imply a simultaneous systemic spread of tumor cells.
However, resection of hepatic tumors can be accomplished
safely with an appropriate risk of perioperative mortality
and morbidity, and patients with favorable tumor biology
might benefit from a surgical approach. Therefore, proper
selected patients should be offered resection of noncolorec-
tal, nonneuroendocrine liver metastases. Since noncolorec-
tal, nonneuroendocrine hepatic metastases encompass a
heterogeneous group of primary tumors, the management
of these metastases needs to be discussed individually for
each primary tumor type.
breast cancer
Breast cancer is the most frequent malignant tumor and the
second most common cause of cancer death in women (1).
Patients with breast cancer rarely present with isolated liver
metastases, in only 10% to 20% of metastatic breast cancer,
metastases are restricted solely to the liver (2,3) (Fig. 17.1).
Therefore, the risk of systemic tumor relapse after removal of
liver metastases is high and ought to be accounted before a
surgical liver resection is contemplated. Retrospective studies
report a median survival between 36 and 63 months (4–6)
( Table 17.1) when patients underwent surgical treatment in
addition to systemic chemotherapy. In contrast, in patients
treated with chemotherapy alone, the median overall sur-
vival will rarely exceed two years (7). Predictive risk factors,
which should be considered for selecting appropriate
patients, are lymph node status, extensive hepatic lesions
requiring a major resection (8), recurrence of liver metasta-
ses within one year after resection of the primary tumor (9),
R2 resection, and failure to respond to preoperative chemo-
therapy (4).
Applying these criteria on patients with breast cancer and
isolated hepatic metastases enables to select a subset of patients
where liver resection may improve progression-free and overall
survival compared to systemic treatment alone.
166
gynecological tumors
The most common gynecological types of cancer comprise of
ovarian cancer, endometrial cancer, and cervical cancer.
Ovarian cancer is the leading cause of tumor-related death
among gynecological malignancies. Epithelial tumors are the
most frequent, followed by sarcomas, germ cell and stromal
tumors (10). These tumors commonly metastasize to the peri-
toneal cavity and lymph nodes, however, liver metastases are
also a common site of systemic spread (10). Since there is an
inverse correlation between the volume of the residual tumor
and the overall patient survival, resection of liver metastases
should be performed with optimal cytoreduction of extrahe-
patic lesions (11,12). By this, median overall survival can be
prolonged significantly (11).
Despite a significant decline of the incidence of uterine
cancer for the last 70 years, it still remains the fourth most
frequent tumor among women (1). Endometrial cancer usu-
ally metastasizes by lymphatic vessels. The most common
sites for hematogenous dissemination are bone, lung, and
liver (13). Recently, a multicenter study by Adam et al.
reported that resection of uterine liver metastases resulted in
a 5-year survival of 35% and a median overall survival of
32 months. Similar results were observed in smaller study by
Kollmar et al. (14).
Cervical cancer, similar to uterine cancer, spreads most
frequently via the lymphatic system, whereas hematogenous
dissemination is a rare event. This may explain why liver metas-
tases occur only in 1.2% to 2.2% of the patients (15,16). Fur-
thermore, in many cases, liver metastases are accompanied by
uncontrolled locoregional disease or extrahepatic lesions (15).
Only in 0.3% to 5% of cases, isolated liver metastases are found.
Up to date, only a few case reports report data regarding liver
resection in hepatic metastasized cervical cancer (17–19), prov-
ing the feasibility of hepatectomy in this tumor stage, but still
lacking profound data regarding the medical benefit.
In summary, as for other noncolorectal, nonneuroendocrine
liver metastases, liver resection for hepatic lesions of gyneco-
logical tumors can be accomplished safely. For evaluating the
benefit of a surgical intervention, more data should be acquired
by further clinical studies. Despite the lack of more data, liver
resection is offered to carefully selected patients with second-
ary liver disease of these types of cancer.
renal cell cancer
Since 1950, the incidence of renal cell cancer (RCC) has more
than doubled. Based on advances in renal imaging, improved
staging, and refinement in surgical technique the 5-year
survival has notably improved (20). The clinical outcome in
early-stage RCC is excellent with a high probability of
complete remission. However, since renal cell carcinoma is
characterized by high resistance to chemotherapy, the median
 NONCOLORECTAL, NONNEUROENDOCRINE METASTASES

overall survival in metastatic disease remains still unsatisfac-

Figure 17.1 Solitary liver metastases originating from breast cancer.
tory. Even by introduction of immunotherapy and targeted
therapy, median overall survival reaches approximately only
two years (21), making systemic therapy a merely palliative
approach.
Resection of isolated liver metastases (4,22) (Fig.17.2) as
well as other distant metastases of renal cell cancer (23,24)
resulted in 5-year survival rates between 38% and 88%.
Though the results of these retrospective studies are certainly
influenced by a selection bias, they should be used to evaluate
carefully whether in patients with metastatic renal cancer a
complete surgical resection of the distant disease is possible.
These patients will most likely benefit from a surgical approach
if all disease can be resected. Whether the results of surgical
resection can be further improved by a multimodal therapeutic
regimen including immunotherapy and moleculary targeted
therapy needs to be further evaluated.

Table 17.1 Selected Retrospective Studies Reporting Clinical

pancreatic cancer
Outcome in Patients after Resection of Liver Metastases
Pancreatic cancer is one of the most aggressive tumors. It is the
from Breast Cancer
fourth leading cause of cancer death in females and the fifth
Median leading cause in males worldwide (1). When pancreatic cancer
Number overall is first diagnosed, the majority of patients are not amenable to
of patients survival 5-year
Author Year included (months) survival
surgical treatment according to the established standard crite-
ria. Approximately only 15% to 25% of patients are eligible to
Caralt et al. (5) 2008 12 35.9 33% curative operation procedures. One of the most frequent
Adam et al. (4) 2006 454 45 41%
exclusion criteria for a curative surgical intervention is the
Vlastos et al. (6) 2004 31 63 61%
presence of distant metastases, namely, liver metastases. In
metastasized pancreatic cancer, palliative systemic chemother-
apy is considered to provide the best therapeutical option. Yet,
in many cases, R0 resection of liver metastases in addition to
resection of the primary tumor would be technically feasible.
By palliative systemic chemotherapy, median overall survival
reaches approximately 6 months (25–27). The impact of a
curative-intent surgical intervention is still unanswered. In
several retrospective studies of resection of liver metastases of
pancreatic cancer, the median overall survival ranges from
6 months to 20 months (4,19,28–37) (Table 17.2). In single
cases, single patients have even survived longer than 5 years
(30). Though, despite some encouraging results, the decision
for the resection of pancreatic cancer liver metastases should
be made on an individual basis where the patient is aware of a
nonstandard treatment approach. Currently, resection of liver
metastases is highly controversial and certainly far from being
accepted by the medical community.
Figure 17.2 Solitary liver metastases originating from renal cancer.

gastric cancer
The incidence of gastric cancer has steadily decreased in
Table 17.2 Selected Retrospective Studies Reporting About
Europe and the United States, however, it still remains the
Clinical Outcome in Patients after Resection of Liver
second most common cancer worldwide. For locally advanced
Metastases from Pancreatic Cancer
gastric cancer, the overall survival has been improved by
Number Median treating patients with perioperative chemotherapy (38).
of patients overall 5-year However, for gastric adenocarcinoma with distant metasta-
Author Year included survival survival
ses, overall survival is still not favorable. The presence of liver
Gleisner et al. (29) 2007 17 5.9 Not published metastases (Fig. 17.3) is generally considered to define a non-
Shrikande et al. (28) 2006 10 11.4 Not published curative state of the disease. Patients treated by palliative che-
Adam et al. (4) 2006 40 20 25% motherapy survive approximately 9 to 10 months on average

167
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 17.3 Solitary liver metastases originating from gastric cancer.
Table 17.3 Selected Retrospective Studies Reporting about
Clinical Outcome in Patients after Resection of Liver
Metastases from Gastric Cancer
Number Median
of patients overall
Author Year included survival
Koga et al. (41) 2007 42 34 Not published
Adam et al. (4) 2006 64 15 27%
Ambiru et al. (46) 2001 40 12 18%
(39,40). Retrospective studies, reporting outcome after
hepatic resection as treatment for liver metastases of gastric
adenocarcinoma, estimate the overall survival between 19
and 34 months (41–45) (Table 17.3). These numbers exceed
the outcome of patients having merely received systemic che-
motherapy. As each of these studies have included only a
small number of patients probably affected by a selection
bias, the data are still insufficient. To select patients with liver
metastases of gastric cancer who might benefit from a surgi-
cal approach, different strategies have been implemented.
Summarizing the available literature, resection of hepatic
metastases seems to be associated with a better survival if
solitary or metachronous lesions are being resected. As in
many other tumor types, patient selection therefore seems to
be the most important factor ensuring a benefit for the
patients undergoing liver resection for liver metastases of
gastric cancer.
respiratory tract⁄head and neck tumors
Both tumors deriving from the lungs and from the head and
neck regions are usually associated with poor prognosis in
the presence of distant metastases. Therefore, albeit tumors
from these sites often form liver metastases (46–48), only
recently the impact of surgical resection has been documented
168
in two retrospective multicenter studies with an appropriate
number of patients (4,49). In general, the histological type of
these tumors was squamous cell carcinoma. The clinical out-
come after hepatic resection was unfavorable with median
overall survival of 16 and 18 months, respectively, and a
5-year survival below 20%. This may lead to the conclusion
that for hepatic metastasized tumors of the lungs and the
head and neck region, nonsurgical interventions should be
favored for management of these patients. However, bearing
in mind that surgical resection is the only hope for cure,
patients should not be categorically excluded, but carefully
evaluated for a surgical approach as an individual curative
attempt.
sarcoma
For surgical evaluation, liver metastases originating from
sarcomas can be divided into two subtypes: gastrointestinal
stromal tumors and non-GIST sarcomas.
Gastrointestinal stromal tumors emerge most often in the
stomach, second most in the small bowl and in the colon and
most rarely in the duodenum, the esophagus or nonintestinal
organs (50). Almost half of the patients suffer from distant
metastases and in more than 50%, the metastatic disease is iso-
lated to the liver (51). One decade ago, a large retrospective
study regarding hepatic resection for GIST metastatic to the
liver reported about a median overall survival of 39 months
and 5-year survival of 30% (52). Since the introduction of
5-year
survival imatinib mesylate in the therapy of GIST (53), the oncological
management has changed in favor of a multimodal treatment,
improving the patient outcomes significantly. In recent retro-
spective studies including patients treated with imatinib
mesylate, the 5-year survival was 70% (4) and median overall
survival was not reached despite long periods of follow-
up (54) (Table 17.4). However, DeMatteo et al. and Gronchi
et al. observed in two retrospective studies that mainly patients
with metastatic GIST responding to a preoperative tyrosine
kinase inhibitor therapy profit by a surgical approach whereas
nonresponder do not seem to benefit by tumor resection
(55,56). These data should be taken into account when select-
ing appropriate patients for surgery with liver metastases of
gastrointestinal stromal tumors.
In summary, gastrointestinal stromal tumors metastatic to
the liver require interdisciplinary therapy regimens. Besides to
surgical resection, this should involve application of new med-
ical agents such as imatinib or radiofrequency ablation for
small lesions not accessible to surgical resection (54,57).
Non-GIST sarcomas have a worse prognosis than gastroin-
testinal stromal tumors. While extremity and trunk soft tissue
sarcomas most frequently metastasize to the lung, primary vis-
ceral and retroperitoneal sarcomas often disseminate to the
liver (51) (Fig. 17.4). After surgical resection of liver metasta-
ses, patients have a median overall survival of 32 to 37 months
and 5-year survival probability of 27% to 32% (4,54) (Table 17.4).
These data demonstrate that most patients with hepatic metas-
tases of sarcomas will succumb to their disease. Patients with a
disease-free interval exceeding two years, however, seem to
have a better prognosis after hepatic resection (52). These data
again point to the fact that selected patients should be offered
 NONCOLORECTAL, NONNEUROENDOCRINE METASTASES

Table 17.4 Selected Retrospective Studies Reporting about Clinical Outcome in Patients after Resection of Liver Metastases
from GIST- And Non-GIST Sarcoma
Number of patients Median overall
Author Year Histological type included survival (months) 5-year survival
Adam et al. (4) 2006 GIST 33 Not reached 70%
Non-GIST sarcoma 125 32 31%
Pawlik et al. (54) 2006 GIST and leiomyosarcoma 54 Not reached Ca. 50%
Non-GIST sarcoma 12 37 No survivor after 5 years
DeMatteo et al. (52) 2001 GIST 34
39* 30%*
Non-GIST sarcoma 22
*Including patients with GIST- and non-GIST sarcoma.

Figure 17.4 Solitary liver metastases originating from a non-GIST-sarcoma.

resection of liver metastases, as they most likely will benefit

from this treatment.
melanoma
Melanomas belong to the most frequent types of tumors with
an increasing incidence over the last 30 years. Of the melano-
mas, 90% derive from the skin, 5% have an ocular origin, and
5% develop at other sites (58). Noteworthy, depending on the
primary site, melanomas display a different metastasizing pat-
tern. Cutaneous melanomas disseminate to the liver only in
15% to 20% of patients with metastatic disease (Fig. 17.5).
This often happens with simultaneous metastatic decay of
other organs (59). By contrast, in 40% of patients with liver
metastases from uveal melanoma, the liver is the only site of
the disease (60). Therefore, the number of liver metastases
resected from uveal melanoma is nearly equivalent to that of
cutaneous melanoma.
While excision of early stage melanoma results in an excel-
lent prognosis, chemotherapy achieves barely a median overall
survival of 12 months in disseminated tumor stage (60,61).
Hence, surgical resection of metastases offers the only chance
for cure. However, patients amenable to a surgical intervention
at the liver account for approximately only 2% to 3% of all
patients representing with liver metastases of melanoma
(62,63). In these cases, the median overall survival is estimated
to be between 19 and 28 months and the median 5-year sur-
vival reaches 20% (4,49,62) (Table 17.5). This may justify the
Figure 17.5 Solitary liver metastases originating from cutaneous melanoma.
resection of liver metastases from cutaneous or uveal mela-
noma in individual patients.
predictive factors determining
clinical outcome
For a successful preoperative assessment, several predictive
factors can be taken into account to decide whether a patient
with noncolorectal, nonneuroendocrine hepatic metastases
might benefit from surgical resection.
Several studies examined factors associated with improved sur-
vival after resection of noncolorectal, nonneuroendocrine liver
metastases. In the study of Weitz et al. (19), 141 patients undergo-
ing hepatic resection between April 1981 and April 2002 were
analyzed, length of disease-free interval, primary tumor type, and
completeness of resection were independent prognostic factors
regarding cancer-specific survival (Table 17.6).
Adam et al. analyzed the outcome of 1452 patients from
41 centers undergoing hepatectomy between 1983 and 2004.
The majority of primary tumors were breast cancer (32%),
gastrointestinal cancers (16%), and urologic cancers (14%).
Five-year overall survival for the entire cohort of patients was

169
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 17.5 Selected Retrospective Studies Reporting About Clinical Outcome in Patients After Resection of Liver Metastases
from Cutaneous and Ocular Melanoma
Number of Median overall
Author Year Site of melanoma patients included survival (months) 5-year survival
Pawlik et al. (49) 2006 Cutaneous 24 24 No survivor
Ocular 16 29 20%
Herman et al. (62) 2001 Cutaneous 5 22* 70%†
*Including patients with both cutaneous and ocular melanoma.
†
Within a mean follow-up of 25.4 months.

Table 17.6 Analysis of Prognostic Factors for Cancer-Specific Survival

Univariate Multivariate
Median CSS Hazard Ratio
No. (mo) p-Value (95% CI) p-Value
Gender Male Female 48 93 52 40 NS
Age (years) ≤50 55 86 42 NS
>50 41
Presentation Synchronous (1) 39 37 48 NS
Metachronous 102
Disease-free ≤24 mo 71 34 0.04 1.4(1.0–1.8) 0.03
interval
>24 mo 70 52 Reference
Primary minor Adrenocortical 15 40 0.0! 0.7(0.4–1.3) 0.02
Breast 29 48 1.0(0.6–1.7)
Gastrointestinal 12 21 0.8 (0.3–1.5)
Reproductive tract
Melanoma
Renal 39 115 0.4 (0.2–0.7)
Other 17 17 1.5(0.7–2.7)
Unknown II 48 0.7 (0.3–1.3)
13 32 1.7(0.3–1.3)
5 11 Reference
Primary tumor Reproductive tract 39 115 36 0.02
Nonreproductive 102
tract
Prior metastases* Yes 24 48 NS
No 117 40
Extrahepatic Yes 41 100 42 NS
disease No 46
Size ≤5 cm 88 42 NS
>5 cm 53 37
Number I 88 49 NS
>l 53 34
Distribution Unilobar 100 46 NS
Bi lobar 41 40
Margin status RO 116 49 <0.0I Reference <0.01
Rl 19 17 2.1 (1.1–4.1)
R2 6 10 2.7 (0.8–7.9)
Resection type Minor major* 65 40 NS
76 52
Blood transfusion Yes 79 52 NS
No 62 37
Postoperative Lions Yes 46 40 NS
complies (1) No 95 49
Source: From Ref. (19).
*Major liver resection: resection of 3 or more liver segments.
Prior extrahepatic metastases.
Presentation of the liver metastases: the same time as the primary tumor.
CSS indicates cancer-specific survival; CI, confidence interval; NS, not significant.

170
 NONCOLORECTAL, NONNEUROENDOCRINE METASTASES
36% and the 10-year overall survival of 23%. The following
independent adverse prognostic factors could be identified:
patient age over 60 years, nonbreast origin, melanoma or
squamous histology, disease-free interval of less than
12 months, extrahepatic disease, incomplete macroscopic
resection, and major hepatectomy. The authors went on to
stratify patients according to the number of adverse prognos-
tic factors present and stratified them into low-risk patients
(0–3 points, 5-year survival: 46%), mid-risk patients (4–6
points, 5-year survival: 33%), and high-risk patients (>6
points, 5-year survival of less than 10%). This model may help
to guide the decision regarding the best approach to patients
with noncolorectal, nonneuroendocrine liver metastases.
summary
Resection of noncolorectal, nonneuroendocrine liver metas-
tases is associated with an improved progression-free and
overall survival in a selected subgroup of patients. However,
until now, these data have been mainly obtained by retro-
spective studies and probably are affected by selection bias, as
patients with lower performance status and poorer prognosis
are less likely to have undergone surgery. Due to these limita-
tions, a conclusion regarding a direct comparison to non-
surgical approaches cannot be drawn. Each individual case
needs to be carefully assessed prior to a decision regarding a
surgical approach. Furthermore, to reduce the risks of post-
operative morbidity and mortality, it is recommendable to
perform the surgical intervention on the liver at high-volume
centers (64).
references
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin
2008; 58: 71–96.
2. Atalay G, Biganzoli L, Renard F, et al. Clinical outcome of breast cancer
patients with liver metastases alone in the anthracycline-taxane era: a ret-
rospective analysis of two prospective, randomised metastatic breast can-
cer trials. Eur J Cancer 2003; 39: 2439–49.
3. Er O, Frye K, Kau Sd CW, et al. Clinical course of breast cancer patients
with metastases limited to the liver treated with chemotherapy. Cancer J
2008; 14: 62–68.
4. Adam R, Chiche L, Aloia T, et al. Hepatic resection for noncolorectal non-
endocrine liver metastases: analysis of 1,452 patients and development of
a prognostic model. Ann Surg 2006; 244: 524–35.
5. Caralt M, Bilbao I, Cortes J, et al. Hepatic resection for liver metastases as
part of the “oncosurgical” treatment of metastatic breast cancer. Ann Surg
Oncol 2008; 15: 2804–10.
6. Vlastos G, Smith D L, Singletary S E, et al. Long-term survival after an
aggressive surgical approach in patients with breast cancer hepatic metas-
tases. Ann Surg Oncol 2004; 11: 869–74.
7. Alba E, Martin M, Ramos M, et al. Multicenter randomized trial compar-
ing sequential with concomitant administration of doxorubicin and
docetaxel as first-line treatment of metastatic breast cancer: a Spanish
Breast Cancer Research Group (GEICAM-9903) phase III study. J Clin
Oncol 2004; 22: 2587–93.
8. Pocard M, Pouillart P, Asselain B, et al. [Hepatic resection for breast
cancer metastases: results and prognosis (65 cases)]. Ann Chir 2001;
126: 413–20.
9. Selzner M, Morse M A, Vredenburgh J J, et al. Liver metastases from breast
cancer: long-term survival after curative resection. Surgery 2000; 127:
383–9.
10. Rose PG, Piver MS, Tsukada Y. Metastatic patterns in histologic variants
of ovarian cancer. An autopsy study. Cancer 1989; 64: 1508–13.
11. Bristow RE, Montz FJ, Lagasse LD, Leuchter RS, Karlan BY. Survival
impact of surgical cytoreduction in stage IV epithelial ovarian cancer.
Gynecol Oncol 1999; 72: 278–87.
12. Lim MC, Kang S, Lee KS, et al. The clinical significance of hepatic paren-
chymal metastasis in patients with primary epithelial ovarian cancer.
Gynecol Oncol 2009; 112: 28–34.
13. Aalders JG, Abeler V, Kolstad P. Recurrent adenocarcinoma of the endo-
metrium: a clinical and histopathological study of 379 patients. Gynecol
Oncol 1984; 17: 85–103.
14. Kollmar O, Moussavian MR, Richter S, et al. Surgery of liver metastasis in
gynecological cancer - indication and results. Onkologie 2008;31: 375–9.
15. Kim GE, Lee SW, Suh CO, et al. Hepatic metastases from carcinoma of the
uterine cervix. Gynecol Oncol 1998; 70: 56–60.
16. Carlson V, Delclos L, Fletcher GH. Distant metastases in squamous-cell
carcinoma of the uterine cervix. Radiology 1967; 88: 961–6.
17. Kaseki H, Yasui K, Niwa K, et al. Hepatic resection for metastatic squa-
mous cell carcinoma from the uterine cervix. Gynecol Oncol 1992; 44:
284–7.
18. Wolf RF, Goodnight JE, Krag DE, et al. Results of resection and proposed
guidelines for patient selection in instances of non-colorectal hepatic
metastases. Surg Gynecol Obstet 1991; 173: 454–60.
19. Weitz J, Blumgart LH, Fong Y, et al. Partial hepatectomy for metastases
from noncolorectal, nonneuroendocrine carcinoma. Ann Surg 2005; 241:
269–76.
20. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of
renal cell carcinoma. J Urol 2001; 166: 1611–23.
21. Motzer RJ, Bukowski RM, Figlin RA, et al. Prognostic nomogram for
sunitinib in patients with metastatic renal cell carcinoma. Cancer 2008;
113: 1552–8.
22. Thelen A, Jonas S, Benckert C, et al. Liver resection for metastases from
renal cell carcinoma. World J Surg 2007; 31: 802–7.
23. Piltz S, Meimarakis G, Wichmann MW, et al. Long-term results after pul-
monary resection of renal cell carcinoma metastases. Ann Thorac Surg
2002; 73: 1082–7.
24. Zerbi A, Ortolano E, Balzano G, et al. Pancreatic metastasis from renal cell
carcinoma: which patients benefit from surgical resection? Ann Surg
Oncol 2008; 15: 1161–8.
25. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine com-
pared with gemcitabine alone in patients with advanced pancreatic can-
cer: a phase III trial of the National Cancer Institute of Canada Clinical
Trials Group. J Clin Oncol 2007; 25: 1960–6.
26. Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of
gemcitabine plus cisplatin compared with gemcitabine alone in advanced
pancreatic cancer. J Clin Oncol 2006; 24: 3946–52.
27. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with
oxaliplatin compared with gemcitabine alone in locally advanced or met-
astatic pancreatic cancer: results of a GERCOR and GISCAD phase III
trial. J Clin Oncol 2005; 23: 3509–16.
28. Shrikhande V, Kleeff J, Reiser C, et al. Pancreatic resection for M1 pancre-
atic ductal adenocarcinoma. Ann Surg Oncol 2007; 14: 118–27.
29. Gleisner AL, Assumpcao L, Cameron JL, et al. Is resection of periampul-
lary or pancreatic adenocarcinoma with synchronous hepatic metastasis
justified? Cancer 2007; 110: 2484–92.
30. Yamada H, Hirano S, Tanaka E, et al. Surgical treatment of liver metastases
from pancreatic cancer. HPB (Oxford) 2006; 8: 85–8.
31. Karavias DD, Tepetes K, Karatzas T, et al. Liver resection for metastatic
non-colorectal non-neuroendocrine hepatic neoplasms. Eur J Surg Oncol
2002; 28: 135–9.
32. Laurent C, Rullier E, Feyler A, et al. Resection of noncolorectal and non-
neuroendocrine liver metastases: late metastases are the only chance of
cure. World J Surg 2001; 25: 1532–6.
33. Benevento A, Boni L, Frediani L, et al. Result of liver resection as treat-
ment for metastases from noncolorectal cancer. J Surg Oncol 2000; 74:
24–9.
34. Lang H, Nussbaum KT, Weimann A, et al. [Liver resection for non-colorec-
tal, non-neuroendocrine hepatic metastases]. Chirurg 1999; 70: 439–46.
35. Takada T, Yasuda H, Amano H, et al. Simultaneous hepatic resection with
pancreato-duodenectomy for metastatic pancreatic head carcinoma: does
it improve survival? Hepatogastroenterology 1997; 44: 567–73.
171
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
36. Howard JM. Pancreatoduodenectomy (Whipple resection) with resection
of hepatic metastases for carcinoma of the exocrine pancreas. Arch Surg
1997; 132: 1044.
37. Klempnauer J, Ridder GJ, Piso P, et al. [Is liver resection in metastases
of exocrine pancreatic carcinoma justified?]. Chirurg 1996; 67:
366–70.
38. Cunningham D, Allum WH, Stenning S P, et al. Perioperative chemother-
apy versus surgery alone for resectable gastroesophageal cancer. N Engl J
Med 2006; 355: 11–20.
39. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for
advanced esophagogastric cancer. N Engl J Med 2008; 358: 36–46.
40. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of
docetaxel and cisplatin plus fluorouracil compared with cisplatin and
fluorouracil as first-line therapy for advanced gastric cancer: a report of
the V325 Study Group. J Clin Oncol 2006; 24: 4991–7.
41. Koga R, Yamamoto J, Ohyama S, et al. Liver resection for metastatic
gastric cancer: experience with 42 patients including eight long-term sur-
vivors. Jpn J Clin Oncol 2007; 37: 836–42.
42. Morise Z, Sugioka A, Hoshimoto S, et al. The role of hepatectomy for
patients with liver metastases of gastric cancer. Hepatogastroenterology
2008; 55: 1238–41.
43. Okano K, Maeba T, Ishimura K, et al. Hepatic resection for metastatic
tumors from gastric cancer. Ann Surg 2002; 235: 86–91.
44. Roh HR, Suh KS, Lee HJ, et al. Outcome of hepatic resection for meta-
static gastric cancer. Am Surg 2005; 71: 95–9.
45. Sakamoto Y, Ohyama S, Yamamoto J, et al. Surgical resection of liver
metastases of gastric cancer: an analysis of a 17-year experience with
22 patients. Surgery 2003; 133: 507–11.
46. Kotwall C, Sako K, Razack MS, et al. Metastatic patterns in squamous cell
cancer of the head and neck. Am J Surg 1987; 154: 439–42.
47. Pieterman RM, van Putten JW, Meuzelaar JJ, et al. Preoperative staging of
non-small-cell lung cancer with positron-emission tomography. N Engl J
Med 2000; 343: 254–61.
48. Spector G J. Distant metastases from laryngeal and hypopharyngeal
cancer. ORL J Otorhinolaryngol Relat Spec 2001; 63: 224–8.
49. Pawlik TM, Zorzi D, Abdalla EK, et al. Hepatic resection for metastatic
melanoma: distinct patterns of recurrence and prognosis for ocular ver-
sus cutaneous disease. Ann Surg Oncol 2006; 13: 712–20.
50. Wente MN, Buchler MW, Weitz J. [Gastrointestinal stromal tumors
(GIST). Surgical therapy]. Chirurg 2008; 79: 638–43.
172
51. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stro-
mal tumors: recurrence patterns and prognostic factors for survival. Ann
Surg 2000; 231: 51–8.
52. DeMatteo RP, Shah A, Fong Y, et al. Results of hepatic resection for
sarcoma metastatic to liver. Ann Surg 2001; 234: 540–7; discussion 547–8.
53. Demetri GD, von Mehren M, Blake CD, et al. Efficacy and safety of ima-
tinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med
2002; 347: 472–80.
54. Pawlik TM, Vauthey JN, Abdalla EK, et al. Results of a single-center expe-
rience with resection and ablation for sarcoma metastatic to the liver.
Arch Surg 2006; 141: 537–43; discussion 543–4.
55. DeMatteo RP, Maki RG, Singer S, et al. Results of tyrosine kinase inhibitor
therapy followed by surgical resection for metastatic gastrointestinal stro-
mal tumor. Ann Surg 2007; 245: 347–52.
56. Gronchi A, Fiore M, Miselli F, et al. Surgery of residual disease following
molecular-targeted therapy with imatinib mesylate in advanced/meta-
static GIST. Ann Surg 2007; 245: 341–6.
57. Gomez D, Al-Mukthar A, Menon KV, et al. Aggressive surgical resection
for the management of hepatic metastases from gastrointestinal stromal
tumours: a single centre experience. HPB (Oxford) 2007; 9: 64–70.
58. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report
on cutaneous and noncutaneous melanoma: a summary of 84,836 cases
from the past decade. The American College of Surgeons Commission on
Cancer and the American Cancer Society. Cancer 1998; 83: 1664–78.
59. Leiter U, Meier F, Schittek B, et al. The natural course of cutaneous mela-
noma. J Surg Oncol 2004; 86: 172–8.
60. Becker JC, Terheyden P, Kampgen E, et al. Treatment of disseminated ocu-
lar melanoma with sequential fotemustine, interferon alpha, and interleu-
kin 2. Br J Cancer 2002; 87: 840–5.
61. Avril MF, Aamdal S, Grob JJ, et al. Fotemustine compared with dacarba-
zine in patients with disseminated malignant melanoma: a phase III
study. J Clin Oncol 2004; 22: 1118–25.
62. Herman P, Machado M A, Montagnini A L, et al. Selected patients with
metastatic melanoma may benefit from liver resection. World J Surg 2007;
31: 171–4.
63. Rose D M, Essner R, Hughes T M, et al. Surgical resection for metastatic
melanoma to the liver: the John Wayne Cancer Institute and Sydney
Melanoma Unit experience. Arch Surg 2001; 136: 950–5.
64. Weitz J, Koch M, Friess H, et al. Impact of volume and specialization for
cancer surgery. Dig Surg 2004; 21: 253–61.
18 Chemotherapy-associated hepatotoxicity
Martin Palavecino, Daria Zorzi, and Jean-Nicolas Vauthey
introduction
Hepatic resection is the only therapy that offers a chance for
cure in patients with colorectal liver metastases, but only 20%
of the patients are candidates for resection at the time of diag-
nosis (1–3). For those patients who are resected, the 5-year
survival has been reported up to 58% (4–8). After hepatic
resection, the majority of patients will develop recurrence
within the liver with or without extrahepatic metastases. Sys-
temic chemotherapy has been used preoperatively (9) or as an
adjuvant therapy after surgery to decrease the risk of disease
recurrence (10). During the last decade, an increasing number
of new therapeutic agents has been developed to improve the
response rates of the existing drugs (Fig. 18.1). Initially,
5-fluorouracil (5-FU)-based chemotherapy had a 20% response
rate with a modest improvement in survival (11). Capecitabine
was introduced as an oral alternative to intravenous 5-FU.
The addition of oxaliplatin and irinotecan in combination with
5-FU increased the response rate to 50% and the conversion of
unresectable metastases to resectable was subsequently repor-
ted in up to 38% of patients (12,13). Most recently, bevaci-
zumab and cetuximab, antibodies vascular endothelial growth
factor and an antiepidermal growth factor receptor, respec-
tively, have been associated with response rates of up to 70%,
when combined with standard chemotherapy (14).
The rationale for preoperative chemotherapy includes
(i) the downsizing of metastases, thus decreasing the amount
of resected parenchyma and increasing the rate of curative
resection; (ii) the identification of patients who will not ben-
efit from surgical resection due to disease progression during
chemotherapy; (iii) the early treatment of micrometastases
(8–10). Nordlinger et al. (15) reported the results of a multi-
centric randomized controlled trial (EORTC Intergroup trial
40983), evaluating the outcome of patients with resectable
colorectal liver metastases (no more than four metastases, no
extrahepatic disease) with two arms: surgery alone versus six
cycles of FOLFOX4 before and after surgery. The trial showed
an increased progression-free survival at 3 years of 8.1%
(from 28.1% to 36.2%, p = 0.041) in all eligible patients; and
9.2% (from 33.2% to 42.4%, p = 0.025) in all patients under-
going resection (15).
Clinical and pathological studies have established associa-
tions between specific chemotherapeutic agents and histologic
changes in the liver. Current evidence suggests there are two
broad categories of chemotherapy-induced liver injury: non-
alcoholic fatty liver disease (NAFLD), including steatosis and
steatohepatitis, and sinusoidal obstruction syndrome (9)
(Figs. 18.2 and 18.3). The use of sequential or combined treat-
ments may result in mixed patterns of injuries. The objective
of the present chapter is to summarize the changes induced in
the liver parenchyma by chemotherapy and its effects on
surgical outcomes.
chemotherapy-associated nonalcoholic
fatty liver disease
Nonalcoholic fatty liver disease (NAFLD) encompasses dif-
ferent types of pathological changes in the liver, ranging
from steatosis to steatohepatitis. NAFLD affects up to 24% of
the general population and increases to 75% in patients with
a body mass index equal or greater to 30 kg/m2 (16). Usually,
NAFLD is asymptomatic, but it may progress to cirrhosis
and develop hepatocellular carcinoma in later stages of
disease (17,18).
The diagnosis of NAFLD can be suspected by laboratory
routine tests and imaging findings. However, the gold stan-
dard diagnostic method is the histological assessment of the
liver. Steatosis is defined as the fat accumulation in the hepa-
tocytes. It can be graded according to the percentage of
affected cells (mild when less than 30% of the hepatocytes are
involved, moderate with involvement of 30% to 60% of the
hepatocytes, and severe with >60% hepatocytes involved).
Steatohepatitis is defined as steatosis associated with inflam-
mation (neutrophilic portal and lobular infiltration, perisinu-
soidal fibrosis, hepatocellular ballooning, glycogenated nuclei)
(8). Kleiner et al. proposed a score based on three features (ste-
atosis, lobular inflammation, and ballooning) evaluated semi-
quantitatively. A Kleiner score of 5 or greater correlates with a
diagnosis of steatohepatitis, while a score of 3 or 4 is consid-
ered borderline (19).
Steatosis
Different chemotherapeutic regimens, such as intraarterial
floxuridine (20), 5-FU and folinic acid (21), interferon α and
5-FU (22), 5-FU, and levamisole (23) were reported to induce
steatosis. However, none of these early studies reported the
effects of steatosis on surgical outcomes (8). In 1998, Behrns
et al. (24) evaluated outcomes after major hepatectomy in
patients with steatosis. The authors found that patients with
moderate to severe steatosis (>30%) had a higher BMI, longer
operative times, and higher rates of postoperative morbidity,
mortality, and intraoperative blood transfusion. Similarly,
Kooby et al. (25) analyzed a cohort of patients with steatosis
who underwent liver resection. Steatosis was associated with
infectious complications but not with major complications or
postoperative mortality.
Two studies were carried out at The University of Texas M.D.
Anderson Cancer Center. The first showed an increased rate of
steatosis in patients treated with irinotecan, but Parikh et al.
found no increased mortality in patient with steatosis, even
when severe (26). In the second study, Vauthey et al. (9) studied
406 resected patients using the Kleiner’s score (19), and no
agent was found to be associated with steatosis and there
was no increased postoperative morbidity or mortality rate
(Table 18.1). However, many patients with steatosis have other
173
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

comorbid conditions, such as obesity and diabetes that can factors for steatohepatitis. In the previously mentioned study,
increase the risk of complications. In a recent study of patients Vauthey et al. (9) analyzed the relationship between preopera-
who underwent major hepatectomy, patients with steatosis had tive chemotherapy and liver injury. Using the Kleiner’s score
increased blood loss, morbidity, and intensive care unit stays (19), 8% of the patients had steatohepatitis. Steatohepatitis
compared to matched control patients with normal livers (27). rate was higher in those patients treated with irinotecan-based
The prevalence of obesity (BMI ≥ 30 kg/m2) was 26% in the chemotherapy (20% vs. 4%, p < 0.001). The incidence of steato-
steatotic patients compared with 2% in controls, which may hepatitis was higher in patients with BMI higher than 25 kg/m2.
have contributed to the poorer outcome in steatotic patients. The 90-day mortality rate for patients with steatohepatitis was
15%, compared to 2% for patients without steatohepatitis (p =
Steatohepatitis 0.001). The main cause of death was liver failure. The conclu-
An increased rate of steatohepatitis in patients undergoing sion of the study was to cautiously use irinotecan in patients
preoperative chemotherapy was first observed by Fernandez with BMI higher than 25 kg/m2, especially in patients under-
et al. (28). Multivariate analysis showed that treatment with going major hepatic resections (Table 18.1). Unlike simple ste-
irinotecan or oxaliplatin and high BMI were independent risk atosis, which does not significantly impact postoperative
outcome, steatohepatitis is an ominous finding and a relative
contraindication to major liver resection. Given the associa-
1980 1985 1990 1995 2000 2005 RR% Median tions between irinotecan, steatohepatitis, and increased post-
survival
(months)
operative mortality, major hepatic resection should probably
not be performed in patients with known steatohepatitis, and
5-FU irinotecan should be avoided in patients with known steatosis
Capecitabine 20–25 13
or steatohepatitis or the features of metabolic syndrome if
Irinotecan ~55 20–22
Oxaliplatin major hepatic resection is anticipated.
Cetuximab ~70 >24?
Bevacizumab Sinusoidal obstruction syndrome
Figure 18.1 During the last 10 years, several new drugs were incorporated to The association between sinusoidal obstruction syndrome and
the armamentarium for the treatment of colorectal liver metastases. 5-FU, oxaliplatin-based chemotherapy was first described by
5-fluorouracil; RR, response rate. Source: Modified from Ref. (33). Rubbia-Brandt et al. (29) in 2004. Changes associated with

(A) (B)

(C) (D)
Figure 18.2 Nonalcoholic fatty liver disease (NAFLD). (A) Macroscopic view of a fatty liver (yellow liver). (B) Pathology specimen showing the aspect of a fatty
liver. (C) Microscopic view of a simple steatosis: accumulation of large globules of fat in the cells. (D) Microscopic view of steatohepatitis: different degrees of
inflammation in the field (ballooned and apoptotic cells). Source: Modified from Ref. (8).

174
 CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY

(A)

(B) (C)
Figure 18.3 Sinusoidal obstruction syndrome. (A) Macroscopic view of a liver with oxaliplatin-related sinusoidal injury (blue liver). (B) Pathology specimen
showing the aspect of a liver with sinusoidal injury. (C) Microscopic view of sinusoidal injury: centrilobular sinusoidal dilatation with scattered macrovesicular
steatosis. Source: Modified from Ref. (8).

Table 18.1 Published Data on Chemotherapy-Associated Hepatotoxicity and Its Effect on Postoperative Outcomes
Number of Major
Author, year patients hepatectomy Drugs Type of liver injury Morbidity Mortality
Behrns, 1998 (24) 135 100% Steatosis NS NS
Kooby, 2003 (25) 325 chemo, 160 69% chemo, 5-FU ± irinotecan Steatosis Higher NS
controls 63% controls
Parikh, 2003 (26) 61 chemo, 47 100% 5-FU ± irinotecan Steatosis NS NS
controls
Fernandez, 2005(28) 37 49% 5-FU ± irinotecan/ Steatohepatitis N/A N/A
oxaliplatin
Karoui, 2006(39) 45 chemo, 22 100% 5-FU ± irinotecan/ Sinusoidal injury Higher NS
controls oxaliplatin
Vauthey, 2006 (9) 248 chemo, 158 68% 5-FU ± irinotecan Steatohepatitis NS NS+
controls 5-FU ± oxaliplatin Sinusoidal injury NS NS
Nordlinger, 2008(15) 151 chemo, 152 N/A 5-FU ± oxaliplatin N/A Higher NS
controls
Nakano, 2008(40) 36 chemo 100% 5-FU ± oxaliplatin Sinusoidal injury Higher N/A
Reddy, 2008 (44) 39 chemo, 57 69% Bevacizumab + N/A NS NS
controls oxaliplatin
Source: Modified from Ref. (45).
NS, not significant; chemo, chemotherapy; 5-FU, 5-fluorouracil; N/A, not available. + Subset of patients with steatohepatitis had increase 90-day mortality.

175
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
sinusoidal injury (dilation and congestion, venous occlusion,
and fibrosis) were in found in 78% of patients treated with
oxaliplatin. This study did not analyze the effects of the injury
on outcomes after resection. The association between oxalipla-
tin and sinusoidal injury has been confirmed in other studies,
in which the incidence of sinusoidal injury in patients treated
with oxaliplatin ranges from 19% to 52%. In the study by
Vauthey et al. (9), the incidence of sinusoidal dilatation was
higher in those patients with oxaliplatin-based chemotherapy
compared to patients with other chemotherapy regimen (19% vs.
2%, p < 0.001). The analysis also demonstrated that oxaliplatin-
based chemotherapy for a median of 12 weeks preoperatively
was not associated with increased morbidity or mortality after
surgery. Likewise, the pathological findings of sinusoidal injury
itself were not associated with an increased rate of perioperative
complications.
In patients receiving preoperative 5-FU ± oxaliplatin, Aloia
et al. (30) found severe forms of vascular alterations, specifi-
cally hemorrhagic centrilobular necrosis and regenerative
nodular hyperplasia in patients treated for greater than
6 months preoperatively (12 cycles). In these patients, a higher
rate of preoperative blood transfusions was noted.
The EORTC Intergroup trial 40983 showed an increase in
postoperative complications with perioperative chemotherapy
with oxaliplatin plus surgery compared to surgery alone (26%
vs. 16%, respectively, p = .04). However, this complication rate
of 26% for combined chemotherapy and surgery compares
favorably with the 36% complication rate previously reported
for resection without preoperative chemotherapy in single
center studies (31). Of note, in the surgery only arm of the
EORTC Intergroup Trial 40983, 18 patients (11%) underwent
an unnecessary laparotomy (open and close) compared to
only 8 patients (5%) in the perioperative chemotherapy arm.
If the total open and close is added to the total complications
in each arm of the study, the difference between the two arms
becomes nonsignificant for all unfavorable events (surgical
complications plus open and close) in the comparison between
perioperative chemotherapy plus surgery versus surgery alone
(30% vs. 26%, p = 0.5). Taken together, limited preoperative
chemotherapy (four to six cycles preoperatively) remains a
valid option and is used at major centers in patients with
resectable and unresectable liver metastases. Short-course pre-
operative chemotherapy is currently used at our institution in
most patients with colorectal liver metastases considered for
resection (Fig. 18.4) (32).
the effects of monoclonal antibodies
Targeted biologic agents are increasingly being used for the
systemic treatment of colorectal liver metastases. In the past
5 years, bevacizumab and cetuximab were approved by the
Food and Drug Administration for the treatment of colorectal
liver metastases (33). Bevacizumab is a monoclonal antibody
against vascular endothelial growth factor (VEGF).
D’Angelica et al. (34) studied the effects of bevacizumab on
outcomes after liver surgery. The authors compared patients who
underwent surgery with or without preoperative bevacizumab.
They found no increase in morbidity and suggested a waiting
time of 6 to 8 weeks between the last dose of bevacizumab and
176
Diagnosis of colorectal liver metastasis
Resectable Unresectable
Preoperative
therapy First-line
2–3 months Resectable chemotherapy
re-evaluate 2–3 months
Hepatectomy
(one-stage or
two-stage) Second-line
± PVE* chemotherapy
Postoperative
therapy Third-line
3–4 months chemotherapy
Figure 18.4 Treatment recommendation for liver metastases of colorectal cancer.
Source: Adapted from Ref. (32).
surgery. More recently, a study by Gruenberger et al. provided
evidence to suggest that this interval may be shortened to
5 weeks without increase in perioperative complications (35).
Ribero et al. (36) analyzed the effect of bevacizumab in patients
receiving oxaliplatin-based chemotherapy. The response to
therapy was measured with the percentage of viable cells in the
surgical specimen. Patients who received preoperative bevaci-
zumab had a significant lower rate of viable cells compared to
those patients who did not receive preoperative bevacizumab
(33% vs. 45%, p = 0.02). The incidence and severity of sinusoi-
dal injury were lower in patients receiving preoperative beva-
cizumab (27% vs. 54%, p = 0.006). The antiangiogenic effects
of bevacizumab have raised concerns regarding potential
effects on bleeding, wound healing, and liver regeneration. A
study from the MDACC reported that the addition of bevaci-
zumab to chemotherapy before portal vein embolization did
not impair liver regeneration (37).
Cetuximab is a monoclonal antibody against epidermal
growth factor receptor (EGFR). No specific liver injury has
been so far identified and related to the preoperative adminis-
tration of cetuximab. Preclinical data in animal models inves-
tigated the effects of anti-EGFR antibodies after partial
hepatectomy in mice and found that their blockade does not
impair liver regeneration (38). Future investigations are
needed to further study possible specific histologic changes in
the liver in patients treated with biologic agents.
diagnosis
Liver function tests cannot be used to assess chemotherapy-
associated liver injury, since many patients have normal labo-
ratory values despite significant hepatic injury. A heightened
index of suspicion for chemotherapy-associated hepatic injury
is necessary in patients at risk for NAFLD due to obesity, dia-
betes, or hyperlipidemia, as well as patients who have received
prolonged courses of chemotherapy. Computed tomography
can identify patients with fatty infiltration by determining
the density of the liver compared to the spleen (at least 10
Hounsfield units lower than the spleen). Magnetic resonance
 CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY
imaging (MRI) accurately predicts steatosis on the basis of
signal differences between fat and water. However, modern
imaging methods cannot differentiate between steatosis and
steatohepatitis. For these reasons, liver biopsy is the gold stan-
dard diagnostic procedure to confirm liver injury. Percutane-
ous liver biopsy may be associated with false-negative results,
due to the patchy distribution of the injuries. To overcome this
issue, laparoscopy with direct inspection and core biopsy may
be an alternative to image-guided percutaneous biopsy in
patients suspected of chemotherapy-associated liver injury,
especially in those patients who are candidates for major
hepatic resection. Grossly, sinusoidal injury results in the
so-called blue liver syndrome, characterized by a bluish, edem-
atous, spongiform appearance and consistency (Fig. 18.3),
while steatosis results in a yellow liver (Fig. 18.2).
prevention
Several issues should be taken into account to prevent
chemotherapy-associated liver injuries. First of all, prolonged
unnecessary courses of preoperative chemotherapy should be
avoided. Different studies demonstrated that hepatotoxicity is
strongly related to chemotherapy duration. Karoui et al. (39)
analyzed two groups of patients who underwent liver resection
with or without chemotherapy (5-FU ± irinotecan/oxaliplatin).
In the chemotherapy group, five patients developed liver insuf-
ficiency versus none in the control group. Morbidity was
higher in patients who received at least six cycles of chemo-
therapy compared to those who received five cycles or less
(54% vs. 19%, p = 0.047). In another study, Aloia et al. (30)
concluded that patients who received more than 12 cycles of
oxaliplatin-based chemotherapy had a higher rate of reopera-
tions and a longer length of stay compared to patients who
received 12 or fewer cycles. The optimal duration of preopera-
tive chemotherapy to maximize therapeutic benefit, while avoid-
ing hepatotoxicity, is likely up to 4 months (i.e., 8 cycles). In the
study from MDACC, patients received relatively short-course
oxaliplatin for 3 to 4 months, which was not associated with
increased morbidity or mortality after hepatic resection (9).
Another issue to be considered is the duration of the interval
between chemotherapy and liver resection. Several studies show
that a longer interval between chemotherapy and hepatic resec-
tion for CLM reduces hepatotoxicity and surgical complications.
However, this interval should be balanced with the risk of tumor
progression during the treatment-free interval. In the European
trial, Nordlinger et al. (15) reported an interval between the last
dose of chemotherapy and liver resection (in the chemotherapy
arm) of 2 to 5 weeks. Nakano et al. (40) observed a mean interval
between the last chemotherapy and surgery of 6.5 months in
patients without sinusoidal injury compared to 3.6 months in
patients with sinusoidal injury. Welsh et al. (41) observed a mor-
bidity rate of 2.6%, 5.5%, and 11% when the intervals between
the last chemotherapy and surgery was 9 to 12 weeks, 5 to 8 weeks,
and ≤5 weeks, respectively (p = 0.009).
In patients with suspected chemotherapy-associated
liver injury, the functional future liver remnant should be
assessed prior to major liver resection to minimize postopera-
tive complications. The future liver remnant (FLR) can be
assessed using three-dimensional contrast-enhanced computed
tomography. Briefly, the contours of the FLR are delineated on
the screen, and volume is calculated by adding each slice’s
volume, determined by the surface area, slice thickness, and
space between slices (42). To calculate the total liver volume,
Vauthey et al. (42) determine a formula based on body surface
area. The estimated liver volume is calculated using the follow-
ing formula: total liver volume = –794.41 + 1267.28 × body
surface area.
The ratio of the FLR to total estimated liver volume is
defined as the standardized FLR (sFLR), which has been shown
to reflect the function of the remnant liver and correlate with
surgical outcome. When the sFLR is predicted to be insuffi-
cient for safe hepatic resection, portal vein embolization (PVE)
is a strategy to induce hypertrophy of the FLR (42). In normal
livers, if the standardized future liver remnant is ≤20% of total
liver volume, portal vein embolization (PVE) should be con-
sidered. In patients who received extensive chemotherapy, pre-
operative PVE should be considered when the standardized
future liver remnant is ≤30% of total liver volume (13).
In this context, PVE is used as a procedure to test the capacity
of the injured liver to regenerate. In a study by Ribero et al. (36),
a degree of hypertrophy (DH = sFLR post-PVE – sFLR
pre-PVE) ≤ 5% predicted the occurrence of postoperative
complications, either overall, liver-related complications, or
liver dysfunction. Patients with significant chemotherapy-
associated liver injury who have inadequate liver hypertrophy
after a technically successful PVE are not candidates for a
major liver resection.
Another strategy for patients with chemotherapy-associated
hepatotoxicity to undergo complete resection of metastases is
two-stage liver resection. This approach allows resection in
patients with extensive bilateral liver metastases that have
responded or remain stable on chemotherapy. In the first
stage, metastases in the FLR are removed with a minor resec-
tion. After the first surgery, the hepatic regenerative capacity is
assessed and PVE should be performed, if the sFLR is insuffi-
cient. After adequate regeneration, a second-stage major resec-
tion is performed up to 8 weeks after PVE. In a study from
MDACC, using this approach, in patients with a median of
seven liver metastases, the 3-year overall and disease-free sur-
vival rates were 86% and 51%, respectively, after perioperative
chemotherapy and two-stage hepatectomy (43).
summary
During the last decade, several new chemotherapeutics agents
were introduced in the armamentarium for the treatment of
colorectal liver metastases. These new drugs were used as adju-
vant treatment as well as preoperative treatment before liver
resection. The rationale for preoperative chemotherapy is as
follows:
● To increase resectability in patients initially deemed
unresectable, by downsizing the metastases
● To improve progression-free survival in patients
with resectable metastases, when compared to sur-
gery alone
● To select patients who may not benefit from surgery
due to tumor progression while on chemotherapy.
177
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
However, preoperative treatment may increase the incidence
of chemotherapy-associated hepatotoxicity, including steato-
sis, steatohepatitis, and sinusoidal injury. Each injury has been
associated with the use of specific agents, such as steatohepatitis
in patients who received irinotecan-based chemotherapy and
sinusoidal injury in patients who received oxaliplatin-based
chemotherapy. Steatohepatitis is associated with increased risk
of mortality due to liver failure and represents a relative con-
traindication to major hepatic resection. Significant sinusoidal
injury with fibrosis and regenerative nodular hyperplasia may
increase the risk of bleeding from liver resection, but no
increased mortality was associated with sinusoidal injury and
oxaliplatin.
Preoperative chemotherapy should be administrated only in
short courses. Several studies suggested limiting the use of
chemotherapy to less than 4 months. In patients receiving bev-
acizumab, the period between the last dose of the drug and
surgery should be at least 5 weeks. Before liver surgery, the
future liver remnant should be assessed. In patients who have
received prolonged chemotherapy, PVE is indicated if the
standardized future liver remnant is ≤30%.
Preoperative chemotherapy should be coordinated by a
multidisciplinary team and should be adjusted according to
patient, tumor, and liver characteristics.
references
1. Steele G, Jr., Ravikumar TS. Resection of hepatic metastases from colorec-
tal cancer. Biologic perspective. Ann Surg 1989; 210: 127–38.
2. Scheele J. Hepatectomy for liver metastases. Br J Surg 1993; 80: 274–6.
3. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver metas-
tases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg
1996; 224: 509–20.
4. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes
following hepatic resection, radiofrequency ablation, and combined
resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:
818–25.
5. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival
following liver resection for hepatic colorectal metastases. Ann Surg 2002;
235: 759–66.
6. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after
resection of hepatic metastases from colorectal cancer in patients screened
by positron emission tomography with F-18 fluorodeoxyglucose (FDG-
PET). Ann Surg 2004; 240: 438–47; discussion 447–50.
7. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on
survival and site of recurrence after hepatic resection for colorectal metas-
tases. Ann Surg 2005; 241: 715–22.
8. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepato-
toxicity and surgery for colorectal liver metastases. Br J Surg 2007; 94:
274–86.
9. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts
steatohepatitis and an increase in 90-day mortality after surgery for
hepatic colorectal metastases. J Clin Oncol 2006; 24: 2065–72.
10. Chun YS, Vauthey JN. Risks of neoadjuvant chemotherapy for resectable
colorectal carcinoma hepatic metastases. Curr Colorectal Cancer Rep
2008; 4: 87–92.
11. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovo-
rin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med
2000; 343: 905–14.
12. Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic
resection after neoadjuvant therapy for nonresectable colorectal. Ann
Surg Oncol 2001; 8: 347–53.
13. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorec-
tal liver metastases downstaged by chemotherapy: a model to predict long-
term survival. Ann Surg 2004; 240: 644–57.
178
14. Adam R, Aloia T, Levi F, et al. Hepatic resection after rescue cetuximab
treatment for colorectal liver metastases previously refractory to conven-
tional systemic therapy. J Clin Oncol 2007; 25: 4593–602.
15. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy
with FOLFOX4 and surgery versus surgery alone for resectable liver
metastases from colorectal cancer (EORTC Intergroup trial 40983): a ran-
domised controlled trial. Lancet 2008; 371: 1007–16.
16. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:
1221–31.
17. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic
fatty liver disease: a population-based cohort study. Gastroenterology
2005; 129: 113–21.
18. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of
nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular
carcinoma. Gastroenterology 2002; 123: 134–40.
19. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a
histological scoring system for nonalcoholic fatty liver disease. Hepatol-
ogy 2005; 41: 1313–21.
20. Zeiss J, Merrick HW, Savolaine ER, et al. Fatty liver change as a result
of hepatic artery infusion chemotherapy. Am J Clin Oncol 1990; 13:
156–60.
21. Peppercorn PD, Reznek RH, Wilson P, Slevin ML, Gupta RK. Demonstra-
tion of hepatic steatosis by computerized tomography in patients receiv-
ing 5-fluorouracil-based therapy for advanced colorectal cancer. Br J
Cancer 1998; 77: 2008–11.
22. Sorensen P, Edal AL, Madsen EL, Fenger C, Poulsen MR, Petersen OF.
Reversible hepatic steatosis in patients treated with interferon alfa-2a and
5-fluorouracil. Cancer 1995; 75: 2592–6.
23. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA. Hepatic
toxicity associated with fluorouracil plus levamisole adjuvant therapy. J
Clin Oncol 1993; 11: 2386–90.
24. Behrns KE, Tsiotos GG, DeSouza NF, et al. Hepatic steatosis as a
potential risk factor for major hepatic resection. J Gastrointest Surg
1998; 2: 292–8.
25. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on periop-
erative outcome following hepatic resection. J Gastrointest Surg 2003;
7: 1034–44.
26. Parikh AA, Gentner B, Wu TT, et al. Perioperative complications in
patients undergoing major liver resection with or without neoadjuvant
chemotherapy. J Gastrointest Surg 2003; 7: 1082–8.
27. McCormack L, Petrowsky H, Jochum W, Furrer K, Clavien PA. Hepatic
steatosis is a risk factor for postoperative complications after major
hepatectomy: a matched case-control study. Ann Surg 2007; 245:
923–30.
28. Fernandez FG, Ritter J, Goodwin JW, et al. Effect of steatohepatitis associ-
ated with irinotecan or oxaliplatin pretreatment on resectability of
hepatic colorectal metastases. J Am Coll Surg 2005; 200: 845–53.
29. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal
obstruction associated with oxaliplatin-based chemotherapy in patients
with metastatic colorectal cancer. Ann Oncol 2004; 15: 460–6.
30. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes
after preoperative chemotherapy with fluorouracil plus oxaliplatin in
colorectal cancer liver metastases. J Clin Oncol 2006; 24: 4983–90.
31. Metreveli RE, Sahm K, Denstman F, Abdel-Misih R, Petrelli NJ. Hepatic
resection at a major community-based teaching hospital can result in
good outcome. Ann Surg Oncol 2005; 12: 133–7.
32. Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic
metastases. Lancet 2008; 371: 963–5.
33. Chun YS, Vauthey JN. Extending the frontiers of resectability in advanced
colorectal cancer. Eur J Surg Oncol 2007; 33 Suppl 2: S52–8.
34. D’Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for
increased operative morbidity after hepatectomy with perioperative
use of bevacizumab: a matched case-control study. Ann Surg Oncol
2007; 14: 759–65.
35. Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine,
and oxaliplatin as neoadjuvant therapy for patients with potentially cur-
able metastatic colorectal cancer. J Clin Oncol 2008; 26: 1830–5.
36. Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic
response and protects against hepatic injury in patients treated with
 CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY
oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer
2007; 110: 2761–7.
37. Zorzi D, Chun YS, Madoff DC, Abdalla EK, Vauthey JN. Chemotherapy
with bevacizumab does not affect liver regeneration after portal vein
embolization in the treatment of colorectal liver metastases. Ann Surg
Oncol 2008; 15: 2765–72.
38. Van Buren G, 2nd, Yang AD, Dallas NA, et al. Effect of molecular thera-
peutics on liver regeneration in a murine model. J Clin Oncol 2008; 26:
1836–42.
39. Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative
chemotherapy on the risk of major hepatectomy for colorectal liver
metastases. Ann Surg 2006; 243: 1–7.
40. Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases
morbidity after major hepatectomy in patients with colorectal liver
metastases receiving preoperative chemotherapy. Ann Surg 2008; 247:
118–24.
41. Welsh FK, Tilney HS, Tekkis PP, John TG, Rees M. Safe liver resection fol-
lowing chemotherapy for colorectal metastases is a matter of timing. Br J
Cancer 2007; 96: 1037–42.
42. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and body
weight predict total liver volume in Western adults. Liver Transpl 2002;
8: 233–40.
43. Chun YS, Vauthey JN, Ribero D, et al. Systemic chemotherapy and two-
stage hepatectomy for extensive bilateral colorectal liver metastases: peri-
operative safety and survival. J Gastrointest Surg 2007; 11: 1498–1504.
44. Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to iri-
notecan- and oxaliplatin-based preoperative chemotherapy regimens
does not increase morbidity after resection of colorectal liver metastases.
J Am Coll Surg 2008; 206: 96–106.
45. Chun YS, Laurent A, Maru D, Vauthey JN. Management of chemotherapy-
associated hepatotoxicity in colorectal liver metastases. Lancet Oncol 2009;
278–86.
179
19 Thermal ablation of liver metastases
Samir Pathak and Graeme J. Poston
introduction
Colorectal cancer is a common malignancy and as many as
25% of patients will have liver metastasis (CRLM) at presenta-
tion and a further 20% to 30% will develop metachronous
disease following colorectal surgery (1). The vast majority of
disease-related deaths are due to metastatic disease. In meta-
static disease the median length of survival without treatment
is approximately between 5 and 12 months (2).
Currently hepatic resection is established as the treatment
modality of choice for colorectal liver metastases (CRLM)
with 5-year survival rates of up to 60% being reported by some
groups (3–6). Unfortunately at the time of presentation only
20% to 30% are deemed suitable to resection because of tumor
location, number of metastases, other comorbidities, and lack
of hepatic reserve (7). Consequently, in recent times there has
been considerable interest in the use of oxaliplatin-based neo-
adjuvant therapy to reduce tumor burden, so increasing the
probability of achieving a curative resection and hence
improve overall disease-free survival. Even patients who ini-
tially had unresectable hepatic disease may respond to chemo-
therapy and become resectable (8). However, despite a more
aggressive approach to surgical resection and the use of com-
bination regimens of highly active chemotherapy drugs, a
significant proportion of patients are still not eligible for resec-
tion. Additionally, the high rate of recurrence seen in the liver,
affecting 53% to 68% of patients requiring repeat resections
can only be tolerated by a subset of patients (9).
Hence, recently there has been considerable interest in
thermoablative techniques and their potential role in the man-
agement of CRLM. Ablative technologies involve the delivery
of localized treatment via open, laparoscopic, or percutaneous
route. Theoretical advantages include less physiological stress,
making treatments suitable for patients who may not other-
wise be appropriate for formal resection. The potential for
either percutaneous or laparoscopic approach offers an alter-
native for patients unfit or unwilling to undergo major
abdominal surgery and general anaesthesia (9–13). Formal
resection is guided by vasculobiliary anatomy, with significant
amounts of healthy parenchyma being removed along with
disease. Targeted ablations minimize the removal of healthy
parenchyma, making it useful in patients with borderline
parenchymal volume and function. Anatomically difficult
lesions may not be amenable to formal resection, but accessi-
ble by probe ablation. Ablation can also be performed as an
adjunct to surgical resection in patients with bilobar disease,
where patients have the majority of their tumor burden for-
mally resected with remnant disease burden being ablated.
However, there remains a need for more long-term survival
data regarding ablative therapies. There have been no random-
ized control trials comparing any ablative therapy to resections
in patients who would be candidates for either therapy or
180
comparing ablative techniques against each other, and only
one trial has shown survival superiority of ablation combined
with chemotherapy over chemotherapy alone in liver only dis-
ease (see later). This chapter aims to detail the mechanism of
action of the various ablative therapies available, and also to
review the available literature regarding the implementation
of these techniques.
limitations of the literature
Apart from the European CLOCC Study (EORTC 40004) (see
later), there are no published randomized controlled trials
(RCTs) comparing the use of radiofrequency ablation (RFA),
ethanol ablation, or cryoablation with hepatectomy in the
treatment of colorectal liver metastases. Furthermore, there is
only one study comparing microwave ablation (MCT) with
partial hepatectomy for the treatment of CRLM (14). There-
fore the majority of the data reviewed come from single-arm,
retrospective, and prospective single-center studies. The results
derived from each study must be viewed with caution as the
number and ethnicity of patients in each study varied greatly
(e.g., studies from Japan vs. Western populations). Possible
selection bias and varying end-points between studies also
existed. Additionally, it must be borne in mind that the defini-
tion of resectability has evolved over the course of time and
this resultantly would have led to differing cohorts of patients
between studies.
Clinical results for distinct patient populations (neuroendo-
crine metastases, noncolorectal GI metastases, hepatocellular
carcinoma, etc.) were often combined. Some articles reported
independent tumor outcomes whereby others gave a com-
bined outcome. Furthermore, other baseline characteristics
such as extrahepatic disease and the use of neoadjuvant or
adjuvant chemotherapy varied greatly between studies.
End points were not always reported uniformly. Some con-
sidered survival or recurrence from the time of diagnosis,
whereas other studies looked at these end points from time of
first treatment.
We have therefore tried to assess comparative treatment effi-
cacy using 1-, 2-, 3-, 4-, and 5-year survival rates, median sur-
vival rates, complication rates, local (hepatic) recurrence,
site-specific (at ablation site) recurrence, and overall recur-
rence. No single study reported all of the above.
The heterogeneity of the studies and the absence of long-term
data for microwave ablation, in particular, make it difficult to
offer an evidence based recommendation for the ablative man-
agement of unresectable colorectal hepatic metastases.
cryotherapy
Cryoablation of hepatic metastases using insulated probes con-
taining liquid nitrogen/argon have been used for the destruction
of CLRM (15). They are placed into each metastasis, whereupon
 THERMAL ABLATION OF LIVER METASTASES
liquid nitrogen or argon is used to freeze the lesion, using tem-
peratures as low as −30°C. The progress of the enlarging ice ball
may be monitored radiologically using MRI/CT or ultrasound
scanning (16). Initially this was seen to be advantageous, how-
ever subsequently it has been demonstrated that the peripheries
of the ice ball may not have reached a sufficiently low tempera-
ture to cause cellular death (17). Furthermore, histopathological
assessment of lesions produced by cryotherapy has also shown
that there is significant amount of tissue adjacent to blood ves-
sels that remains undamaged by the ablation (18). This “heat
sink” effect may result in viable tumor remaining in seemingly
“treated” lesions, explaining high local recurrence rates.
The physiological basis of cryotherapy has been well investi-
gated and is dependent upon the rapid formation of ice crys-
tals during the freezing process. Additionally, cellular hypoxia
due to disruption of the surrounding microvascular structures
also induces cell destruction and enhances the direct damage
resulting from ice ball formation (19).
There are no clearly defined indications for the use of cryo-
therapy but patients with unresectable metastatic disease sec-
ondary to either extensive bilobar involvement or difficult
anatomical location may benefit. Tumors, which lie in close
proximity to major blood vessels such as the inferior vena cava,
large portal branches or large hepatic veins, may make cryo-
therapy difficult due to the “freeze-thaw” effect previously
described. Conventionally, a laparotomy was required for the
direct application of probes; however probes have now been
developed that are small enough to be placed percutaneously.
In the studies reviewed, reports of 3- and 5-year survival were
sparse, and varied between 30.9% to 44% and 13% to 26%,
respectively. Median survival ranged between 22.9 and
94.2 months (Table 19.1). However, the marked heterogeneity of
these studies makes direct comparison difficult. Major complica-
tion rates (defined as complications requiring the patient to
remain in hospital) were high, ranging from 22% to 70%. The
major concern with use of cryotherapy is the “cryoshock” phe-
nomenon, where patients develop a systemic response to ablation,
consisting of marked thrombocytopenia leading to coagulopathy,
pleural effusion, acute respiratory distress syndrome, and myo-
globinuria (30–33). The true incidence of cryoshock is difficult to
establish, though reports from the literature suggest a mortality of
0% to 8%. A large multicentre survey estimated that it was respon-
sible for 18% of perioperative deaths (31).
The high rate of local complications (hemorrhage from a
cracked liver, subphrenic abscess, bilomas, and biliary fistulae)
and fear of cryoshock has led to this technique falling out of
favor as other safer and equally efficient techniques have evolved.
edge cryotherapy
Edge cryotherapy employs the application of cryotherapy to
the resection margins posthepatectomy in order to extend the
margins of resectability.
Several studies describe the use of cryotherapy when a histo-
pathologically positive margin is expected. During this proce-
dure, flat cryoprobes are placed against the resection edge of the
remnant liver, whereupon remnant liver tissue is frozen to a
depth of at least 1 cm (34). Reported 3- and 5-year survival for
these patients was 43% to 60% and 26% to 44%, respectively,
with a median survival of 29 to 39 months. Major complication
rates were reported as 0.22% to 25%. Again, these outcomes
reflect the heterogeneity of these studies. Major hepatic resec-
tions have an overall complication rate (major and minor com-
plications) of around 20% (5). The fact that two studies report
major complication rate of a similar magnitude (35,36), with
survival data in keeping with most major series assessing
resection alone, would suggest that edge cryotherapy presents
a theoretical advantage for patients deemed “unresectable.”
radiofrequency ablation
Radiofrequency ablation (RFA) uses radiofrequency radiation
to produce heat locally within the hepatic parenchyma. The
radiofrequency current generates ionic agitation, which in
turn is translated into heat, resulting in the subsequent break-
down of proteins and cell membranes (43). The main advan-
tage when compared to cryotherapy is that the probes can be
placed percutaneously. However, as with all locally ablative
techniques, the efficacy of the treatment diminishes with
increasing size of the lesion. Hence, manufacturers have
designed a variety of electrodes that can be deployed in situ to
produce a number of tips.
RFA refers to coagulation from all electromagnetic resources
with a frequency less than 900 kHz, with the majority function-
ing within the parameters of 300 to 500 kHz. Initially, problems
existed with early radiofrequency designs due to the effects of
high temperatures in the tissue surrounding the probe. This is
due to tissue impedance secondary to tissue charring. Subse-
quently, this impedance results in reduced dissipation of cur-
rent (44,45). This problem has been the major drawback of
RFA, though it has been countered somewhat by the use of
cooled electrode tips. However, the principle limiting factor of
RF ablation remains the size of the achievable ablated tissue.
This is because only the tissue immediately adjacent to the tip is
heated by ionic agitation. The remainder of the tissue is ablated
via heat produced via thermal conduction. This effect is magni-
fied in the presence of large blood vessels, which further reduce
heat via a phenomenon known as “the heat sink” effect (19).
Both normal liver parenchyma and metastatic liver are
water-rich and also have an extensive blood supply (via angio-
genesis in the case of metastases). Hence, thermal conduction
is facilitated, but as mentioned previously, this is a less efficient
means of ablation than ionic agitation. Therefore, current
opinion suggests that RFA is more susceptible to the heat sink
effect than microwave ablation. Various measures have been
used previously to reduce the heat sink effect, such as occlu-
sion of the portal vein and hepatic artery at the time of abla-
tion. Although the ablative area is increased, the risk of bile
duct damage and portal vein thrombosis is increased.
Because of the relative simplicity of the technique, the fact
that it can be performed percutaneously and the compara-
tively cheap devices employed, RFA is a technique that remains
widely practised (32).
review of the literature regarding rfa
Previous reviews have suggested that there are no compelling
data supporting the use of RFA in patients with viable extrahe-
patic disease (EHD) (46). EHD is known to be a poor prognostic
181
182
Table 19.1 Summary of Studies Looking at Cryotherapy (Survival and Complications)
Median
Metastases survival
Author Year N (n) Size (cm) EHD 1 year 2 years 3 years 4 years 5 years (months) Major Minor
Seifert (20) 1998 44 1 5 — — — — — — 33 22%
Seifert (21) 1998 116 3.9 4.4 9.5 82 56 32.3 — 13 26 31%
Seifert (22) 2003 55 — — 18 — — 44 — 26 29 — —
Yan (23) 2003 172 4.2 3.6 16 89 65 41 24 19 28 28% —
Kerkar (24) 2004 56 — — — — 67 43 — 22 30 — —
Brooks (25) 2005 86 4 — — 85 — 43 — 19 33 — —
Joosten (26) 2005 30 3 2 0 76 61 — — — — 30% —
Chen (27) 2006 61 3.38 4 16 87 54 36 — — 26 — —
Kornprat (28) 2007 20 1.7 2 — — — — — — — 30% 20%
Paganini (open) (29) 2007 49 5.1 — 0 — — 30.9 — — 22.9 26% 55%
Paganini (29) (lap) 2007 15 1.4 — 0 — — — 94.2 70% 53%

Table 19.2 Summary of Studies Looking at Edge Cryotherapy (Survival and Complications)
1 year 2 years 3 years 4 years 5 years Median
Metastases Extrahepatic survival survival survival survival survival survival
Author Year N (n) Size (cm) disease % % % % % % (months) Major Minor
Korpan (35) 1997 63 — 3.1 0 — — 60 — 44 — 25 —
Dwerryhouse (37) 1998 26 1 5 — — — — — — 29 0.27 —
Seifert (38) 1998 44 1 5 — — — — — — 33 0.22 —
Finlay (39) 2000 75 2 — 0 — 50.5 — — — 33 — —
Gruenberger (40) 2001 86 2 5 0 — — 54.7 — — — 0.34 34%
Rivoire (36) 2002 24 2.9 4.5 — 92 — 58 37 — 39 21 —
SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Seifert (41) 2005 55 2.4 3.5 18 — — — — 26 29 — —

Niu (42) 2006 124 4.1 5 15 84 61 43 28 24 29 — —
 THERMAL ABLATION OF LIVER METASTASES
indicator, predicting decreased overall survival and disease-free
survival compared to patients without EHD (3,47). The authors
remain unconvinced of this conclusion, since several studies
consisting of patients with EHD (range 8.7–30%) have demon-
strated reasonable median survival (range 18–37 months).
Berber et al. (48) evaluated their 10-year experience with RFA
in 234 patients who had a variety of neoplastic process occur-
ring within the hepatic parenchyma. Their results showed that
80% of patients had progressive disease, despite aggressive che-
motherapy, with the oncological intervention failing approxi-
mately 8 months before RFA. The authors also found no
significant difference in patients who had EHD at the time of
treatment, against those who did not. This observation strength-
ens our opinion that EHD is not an accurate predictor of out-
come in patients with unresectable colorectal liver metastases.
Hence, patients should not be denied RFA on this basis alone.
There does not appear to be a maximum number of metas-
tases that may be treated via RFA. However, there is a percep-
tion that local recurrence and survival rates appear to be
negatively correlated with number and size of treated metasta-
ses. This review did not identify evidence clearly supporting
this hypothesis, although a trend toward it is evident. The rea-
sons for this conclusion are not obvious but it may be that
patient factors, such as age, comorbidity, and operator experi-
ence have a significant influence.
Generally, the highest ablation success rates were achieved in
patients with solitary colorectal liver metastases or patients with a
few metastases smaller than 3 cm (49–53). As with formal resec-
tion, the aim of any tumor eradication therapy is to achieve a clear
negative margin. It follows therefore that that the best results are
obtainable when the tumor is smaller than the size of coagulative
necrosis produced by a single ablation probe, and it is therefore
the size of ablation zone that limits the use of RFA. Most ablation
devices can produce single ablations of around 4 cm in diameter.
As probe delivery is performed by hand, either “blindly” or using
two-dimensional imaging techniques (USS, CT), probes may be
inadvertently placed away from the geometric centre of a lesion,
resulting in a rim of untreated tissue. This opinion may explain
higher recurrence rates in lesions larger than 3 cm. Attempts have
been made to increase the ablation size and overcome the inher-
ent limit of RFA by developing probes that deploy multiple “tines”
around a lesion, as well as adopting techniques that reduce blood
flow through parenchyma, another method known to increase
lesion size by increasing the area which reaches sufficient tem-
perature by indirect heating (54).
The location of metastases within the liver is an important fac-
tor in determining the success of RFA. Tumors adjacent to large
hepatic vessels are problematic, as larger vessels act as a heat sink,
making it more difficult to ablate the tumor. Several studies com-
mented on the increased failure rates in tumors adjacent to major
blood vessels (26,55). Ablation near portal vein pedicles is also
associated with an increased risk of major bile duct injuries, pos-
sibly as a result of de-epithelialization injuries related to heat.
microwave ablation
Microwave coagulation (MCT) was initially developed in the
early 1980s by Tabuse et al. in order to optimize haemostasis along
the plane of dissection during hepatic resection. The microwave
coagulation of tissue surfaces was slower and produced deeper
areas of tissue necrosis, compared to normal electrocautery units.
This led to it being investigated as a technique for the treatment of
unresectable hepatic malignancies (81).
Microwave radiation lies between infrared radiation and
radiofrequency, with frequencies from 900 to 2450 MHz. Tis-
sue heating is based on the agitation of water molecules, which
in turn cause cellular death via coagulation necrosis. Thus it is
different from RFA as the frequency of the electromagnetic
radiation used is considerably higher. This results in a greater
ability to localize the dissipation of energy, though the tissue
penetration is reduced (81–83).
The microwave generators available for clinical use have an
output of between 70 and 90 W. The microwave emitting nee-
dle is placed directly into the tumor, usually under radiological
guidance. The emitting needle is attached to the microwave
generator and when the generator is activated, each area of the
tumor is treated for 30 to 60 seconds at 70 to 90 W. The rapid
generation of heat using MCT produces 10 to 25 mm zones of
coagulative necrosis after only 30 to 60 seconds. The rapid
development of coagulative necrosis precludes the further dis-
sipation of heat to surrounding tissues.
Thus, microwave offers many of the benefits of RFA, with
some substantial theoretical advantages. These benefits include
higher intratumoral temperatures, faster ablation times, larger
tumor ablation volumes, ability to use simultaneous multiple
applicators and less procedural pain (30,32).
With RFA, the zone of active tissue heating is limited to a
zone of a few millimeters surrounding the active electrode,
with the remainder of the ablation zone being created via ther-
mal conduction. However, via a superior convection profile,
microwave produces a larger zone of active heating, allowing a
more uniform destruction of cells within the target area. RFA
is also limited by the impedance with tissue boiling and char-
ring, because water vapor and char act as electrical insulators.
Due to the electromagnetic nature of microwaves, microwave
ablations appear unaffected by the effect of water vapor and
charring.
MCT technology allows for open, laparoscopic, and percuta-
neous routes of delivery. Ablation is performed using a thin
antenna that is attached to the microwave generator. In the lit-
erature, different protocols for time and power of ablation have
been proposed, dependent on the tissue and antenna type (84).
Seki et al. (85) treated 15 patients with solitary colorectal
liver metastases who declined formal resection using percu-
taneous microwave ablation. Ten patients were alive at the
end of the follow-up period (9–37 months), with a median
survival of 24.2 months. This is broadly similar to best che-
motherapy, but obviously direct comparisons are difficult
between such homogeneous studies. No recurrence was
detected in adequately treated lesions, although two patients
experienced recurrence due to inadequate treatment at pre-
sentation as defined by incomplete destruction on posttreat-
ment imaging.
Another Japanese group (14) performed a small random-
ized control study on 30 patients comparing hepatic resec-
tion versus MCT. One, 2- and 3-year survival rates for the
microwave group were 71%, 57%, and 14% compared to
183
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

69%, 56%, and 23% for the resection group. The mean sur-
vival time was 25 months for the microwave group versus Ultrasound
23 months for the resection group. Statistically, there was no probe
difference in survival between the two groups. A significant
proportion of patients in both arms of this study developed
hepatic failure without explanation as to why this occurred.
Tanaka et al. (88) performed a retrospective analysis of
53 patients who underwent hepatectomy or hepatectomy Ultrasound
plus microwave ablation. Their results suggested no differ- beam
Iceball Probe
ence between the two groups in terms of recurrence or sur-
surrounding within
vival. This suggests that ablative therapies may be used to and encompassing liver
extend the margins of resectability. tumor
In a review of 31 patients by Bhardwaj et al. (93), of whom Ultrasound
Cryoprobe
the majority had unresectable colorectal metastases, median
survival was 29 months, with a 3-year survival of 40%, and
local recurrence was only 2%. Despite the variety of primary (A) (B)
and secondary lesions, these figures illustrate the potential for
MCT in the treatment of hepatic metastases. Figure 19.1 Cryoablation (surgical view A) under intra-operative ultrasound
control (B).

percutaneous ethanol injection

Percutaneous ethanol injection (PEI) involves passing single
or multiple fine needles followed by intratumoral injection of
pure ethanol, causing cytotoxic cell death mainly via dehydra-
tion. The main disadvantage with PEI is that treatment in
patients with large metastases has been found to be inadequate
due to incomplete alcohol diffusion within the tumor mass.
Additionally, the results for PEI in the treatment of CLRM
have not been as promising as for primary hepatocellular
carcinoma, due mainly to the difference in tumor characteris-
tics (94). HCC is usually hypervascular and may be encapsu-
lated, qualities which will reduce leakage into the surrounding
hepatic parenchyma, while ensuring diffusion through the
lesion. However, CRLM tend to be dense and infiltrative, mak-
ing the diffusion of ethanol more unpredictable, resulting in
pockets of untreated tumor. For this reason, thermoablative
techniques are preferred for CRLM (16).
There was a paucity of data regarding use of PEI for the Figure 19.2 Radiofrequency ablation.
treatment of colorectal liver metastases. Only three series were
identified, which looked at the feasibility of PEI as a treatment, randomized Phase II, with an actual accrual of 119 patients.
as opposed to survival and complication rates. It is unlikely However, it remains a unique landmark study, probably
that future research will be channeled in this direction as the never to be repeated, and the only prospective study to
tumor characteristics of metastases make them unfavorable address the question of the real survival benefit of thermal
for PEI. ablation therapy for metastatic liver disease.
Although there was a significant improvement in 3-year
the clocc study progression free-survival (PFS) of 27.6% for RFA + chemo-
Finally, at the time of coming to press, Ruers and colleagues therapy compared to 10.7% for chemotherapy alone (p =
presented the final results of the EORTC CLOCC (EORTC 0.025) (Fig. 19.3), a secondary end point, overall survival (OS)
40004) Study at the 2010 ASCO meeting in Chicago (97). at 30 months (the primary study end point) was no different
This study was conceived as a 400-patient Phase III random- for RFA + chemotherapy (63.8%) over chemotherapy alone
ization of patients with up to nine unresectable liver-only (58.6%) (p = 0.218) (Fig 19.4). It must be remembered that
metastases to receive either oxaliplatin-based chemotherapy when designed, the study was never powered to demonstrate a
or chemotherapy plus RFA (open, laparoscopic, or percuta- significant result for its primary end point with such low num-
neous) with or without concomitant resection of easily bers, and it is extremely unlikely that any investigators will ever
resectable lesions. The primary end-point was powered to be bold enough to try to repeat such a study. Therefore in the
test for a 38% overall survival benefit in the RFA arm. This pragmatic real world, we must accept the evidence that we
was an extremely ambitious project, and recruitment was have, which in our opinion suggests a survival benefit for
understandably extremely difficult. After a period of extreme thermal ablation therapies in the treatment of relatively
frustration, the trial objective was reduced to a 100-patient low-volume unresectable liver metastases.

184
 THERMAL ABLATION OF LIVER METASTASES

Progression free survival

100

90

80
Overall logrank test: p = 0.025
70

60

50
18.08%
40

30

RF + Chemo
20

10
Chemo

0 (years)
0 1 2 3 4 5 6 7

O N Number of patients at risk: Treatment

53 59 24 12 5 4 2 1 CT
44 60 34 20 13 8 3 0 RF+\-resection+CT
Figure 19.3 Three year PFS in the CLOCC study comparing RFA + chemotherapy (27.6%) to chemotherapy alone (10.7%) (p = 0.025).

Overall survival
100

90

80

70

60

50

40 RF + Chemo

30

20

Overall logrank test: p = 0.218 Chemo

10

0 (years)
0 1 2 3 4 5 6 7

O N Number of patients at risk: Treatment

39 59 52 43 27 15 5 1 CT
31 60 53 44 27 19 7 1 RF+\-resection+CT
Figure 19.4 Thirty month OS comparing RFA+chemotherapy (63.8%) to chemotherapy alone (58.6%) (p = 0.218).

185
186
Table 19.3 Summary of Studies Looking at RFA (Survival and Complications)
Median
Ablative Metastases survival
Author Year type Number (n) Size (cm) EHD 1 year 2 years 3 years 4 years 5 years (months) Major Minor
De Baere (56) 2000 RFA 54 1.8 1.3 — 81 — — — — — — —
Elias (57) 2000 RFA 14 6.2 1.4 — — 95 — — — — 33.3 —
Park (58) 2008 RFA 30 1.2 2 No — — — — — 36 — —
Knudsen (59) 2009 RFA 36 — 2.1 No — — 26 — 34 39 11 —
Sorensen (60) 2007 RFA 102 3.25 2.2 No 87 62 46 26 — 32 6.9 4
Lee (61) 2008 RFA 37 — 2.25 — — — — — 46.5 40 — —
Hur (62) 2009 RFA 25 — 2.5 No — — 60 — 25.5 — 0 0
Lermite (51) 2006 RFA 14 2 2.7 — 90 54 54 — — — 11.5 —
Veltri (63) 2008 RFA 122 1.63 2.9 20.5 79 — 38 — 22 31.5 1.1 7
Aloia (64) 2006 RFA 30 — 3 — — — 57 — 27 — — —
Oshowo (65) 2003 RFA 25 — 3 28 — — 52.6 — — 37 4 —
Suppiah (66) 2007 RFA 30 1.9 3.1 — 75 45 7 3 — 23.2 — 5
Reuter (67) 2009 RFA 66 2.8 3.2 15 — — — — 21 27 10 49.1
Hildebrand (68) 2006 RFA 56 3.5 3.5 — 92 67 42 — — 28 3.4 —
Berber (69) 2008 RFA 68 1 3.7 38 — — 20.6 — 30 20.5 — 2.9
Siperstein (70) 2007 RFA 235 2.8 3.9 23 — — 20.2 — 18.4 24 overall — —
Gilliams (53) 2005 RFA 73 4.1 3.9 No 91 — 28 — 25 38 4 6
Berber (71) 2005 RFA 135 3.2 4.1 30 — — — — — 28.9 — —
Iannitti (72) 2002 RFA 52 2.7 5.2 — 87 77 50 — — — 7.1 —
Solbiati (73) 2001 RFA 109 1.6 — — — 67 33 — — 30 0.9 6.4
Terraz (74) 2007 RFA 16 1.75 — — 84 68 — — — — 2.9 2.9
Abitabile (52) 2007 RFA 47 3.12 — — 88 80 57 — — 39 13
Stippel (75) 2002 RFA 23 5.57 — 8.7 — — — — — 18 7 —
SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
 Table 19.4 Summary of Studies looking at RFA ± Resection (Survival and Complications)
Median
Metastases survival
Author Year Ablative type Number (n) size (cm) EHD 1 year 2 years 3 years 4 years 5 years (months) Major Minor
Pawlik (76) 2003 RFA ± resection 124 3 1.8 No — — — — — 37.3 20 —
Scaife (77) 2003 RFA ± resection 50 2 2 No — 66 — — — — 22 —
Abdalla (3) 2004 RFA ± resection 158 — — — — — 43/37 36/22 — — —
Elias (78) 2005 RFA ± resection 63 2.4 15 No 92 67 47 — — 36 27 —
Joosten (26) 2005 RFA ± resection 28 3 2 No 93 75 — — — — 11 —
Amersi (49) 2006 RFA ± resection 74 3.3 3.56 No — — — — — 29.7 13
Kornprat (28) 2007 RFA ± resection 19 5 2 — — — — — — — — —
Gleisner (79) 2008 RFA ± resection 66 2 2.5 — 92 — 51.2 — 28 38.1 — —
Nikfarjam (80) 2009 RFA ± resection 23 — — — — — — — 68 — 11 —

Table 19.5 Summary of Studies Looking at MCT (Survival and Complications)

Median
Ablative Metastases survival Major Minor
Author Year type N (n) Size (cm) EHD (%) 1 year 2 years 3 years 4 years 5 years (months) (%) (%)
THERMAL ABLATION OF LIVER METASTASES

Seki (85) 1999 MCT 15 1 2.1 0 — — — — — 24.2 — 6.7

Shibata (86) 2000 MCT 14 4.1 2.7 0 71 — 57 — 14 27 14.0 —
Liang (11) 2003 MCT 28 2 3.12 5 91.4 59.5 46.4 29 — 20.5 0.0
Yokoyama (87) 2003 MCT/RFA 12 2.8 2.4 — — — — — — — — —
Tanaka (88) 2005 MCT 16 2.2 4.8 5 80 — 51 — 17 28 19.0 —
Iannitti (89) 2007 MCT 33 2.57 3.6 — — — — — — — 16.1 —
Kuang (90) 2007 MCT 11 1.47 2.75 0 — — — — — — 4.0 7.8
Ogata (91) 2008 MCT/RFA 32 4 2.8 22 — — — — 32 43 3.4 —
Zhang (92) 2008 MCT 34 — — — 82.1 — — — — — — 76.3
Bhardwaj (93) 2009 MCT 24 2.87 2 0 40 — — — — 29 0.0 0
— — — — — — — — 2.6 80.1

187
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 19.6 Summary of Studies Looking at PEI (Survival and Complications)

Recurrence Median
Author Year Number Metastases (n) Size (cm) EHD rates survival Major Minor
Kessler (95) 2002 13 (inc HCC) Unknown Unknown Unknown 50% (inc Unknown 8% 25%
HCC)
Giorgio (96) 2003 47 Unknown Unknown Unknown Unknown Unknown 3% 17.7%

Table 19.7 Overall Comparison of Studies Reviewed (Cumulative)

Recurrence (Range %) Survival rates (%) Major
Ablative complication
technique Local Overall 1 year 2 years 3 years 4 years 5 years rates (%)
Cryotherapy 12–39 78–88 84 59 37 21 17 29
Ethanol — — — — — — — 5
MCT 5–13 50–78 73 60 30 29 16 7
RFA 10–31 47–86 85 67 36 30 24 6

Median
RFA + resection

Edge cryotherapy
5 Year

4 Year

3 Year

2 Year

1 Year

0 10 20 30 40 50 60 70 80 90 100
Figure 19.5 Survival figures for studies reviewed (ablation as adjunct to surgery).

conclusions result in tumor viability even within a seemingly completed

The ideal ablative therapy should cause complete tumor abla-
tion, yet be parenchyma sparing, reproducible, safe, and be
minimally invasive. Current advancements, particularly in
RFA and MCT, are promising but the perfect ablative model is
still elusive.
The literature cannot support the use of percutaneous etha-
nol injection for the treatment of colorectal metastases, though
we accept that it has a role in the management of hepatocel-
lular carcinoma. Similarly, the literature demonstrates that
although cryoablation has acceptable survival figures, its
ongoing use cannot be advocated given the high rate of local
complications (Table 19.7).
Ablative therapies offer great potential for lesions that can-
not be formally resected. The increasing burden of metastatic
colorectal disease means that a growing number of patients
will have unresectable metastases and hence will be candidates
for ablation.
It is important that the ablation causes complete tumor
destruction within the treatment zone. Heat sink effect may
ablation. The ability to accurately place the probe is also vital
to ensure that the treatment zone encompasses the focus of
disease. Currently, most centers use RFA or microwave abla-
tion as treatment of choice.
Microwave offers the theoretical advantage of larger abla-
tion volumes, shorter ablation duration, and the ability to per-
form multiple simultaneous ablations to increase ablation
volume as well as more predictable ablation zones around ves-
sels. The lower local recurrence rate found in this review prob-
ably reflects the more predictable ablation characteristics on
MCT. Conversely the larger body of evidence surrounding
RFA is probably a manifestation of its maturity as a technol-
ogy, rather than an implicit endorsement of its superiority
over other technologies.
The role of ablative technology in a palliative setting is unclear.
However, 3-year survival of between 30% and 37% compares
favorably with best supportive chemotherapy (Figs. 19.5 and
19.6). The underlying mechanism behind this remains unclear,
though it may be related to decreasing the tumor burden.

188
 THERMAL ABLATION OF LIVER METASTASES

Median Radiofrequency ablation

Microwave ablation

5 Year Cryotherapy

4 Year

3 Year

2 Year

1 Year
0 10 20 30 40 50 60 70 80 90
Survival (%)
Figure 19.6 Survival figures for ablative studies reviewed.

Ethanol ablation
Radiofrequency ablation
Microwave ablation
Cryotherapy
RFA+resection
Edge cryotherapy

0 5 10 15 20 25 30 35 40
Complication rates(%)
Figure 19.7 Complication rates for all studies reviewed.

The safety profiles of RFA and MCT appear similar and in
the current climate, both are safe and effective therapies, which
should be deployed (Fig 19.7). Further studies are needed to
demonstrate long-term outcomes and ongoing research will
ensure that ablative technologies continue to evolve rapidly.
references
1. (2003)CRUIC. CancerStats. Cancer Research UK Information Centre
(2003)]. Available from: http://www.info.cancerresearch.org/cancerstats.
2. Hugh TJ, Kinsella AR, Poston GJ. Management strategies for colorectal
liver metastases—Part I. Surg Oncol 1997; 6(1): 19–30.
3. Abdalla EK, Vauthey JN, et al. Recurrence and outcomes following hepatic
resection, radiofrequency ablation, and combined resection/ablation for
colorectal liver metastases. Ann Surg. 2004; 239(6): 818–25; discussion 25–7.
4. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after
resection of hepatic metastases from colorectal cancer in patients scree-
ned by positron emission tomography with F-18 fluorodeoxyglucose
(FDG-PET). Ann Surg 2004; 240(3): 438–47; discussion 47–50.
5. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival
following liver resection for hepatic colorectal metastases. Ann Surg 2002;
235(6): 759–66.
6. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on
survival and site of recurrence after hepatic resection for colorectal metas-
tases. Ann Surg 2005; 241(5): 715–22, discussion 22–4.
7. Adam R, Huguet E, Azoulay D, et al. Hepatic resection after down-staging
of unresectable hepatic colorectal metastases. Surg Oncol Clin N Am
2003; 12(1): 211–20, xii.
8. Nordlinger B, Van Cutsem E, Rougier P, et al. Does chemotherapy prior to
liver resection increase the potential for cure in patients with metastatic
colorectal cancer? A report from the European Colorectal Metastases
Treatment Group. Eur J Cancer 2007; 43(14): 2037–45.
9. Goldberg SN, Solbiati L, Hahn PF, et al. Large-volume tissue ablation with
radio frequency by using a clustered, internally cooled electrode tech-
nique: laboratory and clinical experience in liver metastases. Radiology
1998; 209(2): 371–9.
10. Jiao LR, Habib NA. Experimental study of large-volume microwave abla-
tion in the liver (Br J Surg 2002; 89: 1003–7). Br J Surg 2003; 90(1): 122.

189
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
11. Liang P, Dong B, Yu X, Yang Y, Yu D, Su L, et al. Prognostic factors for
percutaneous microwave coagulation therapy of hepatic metastases. AJR
Am J Roentgenol 2003; 181(5): 1319–25.
12. Sato M, Watanabe Y, Kashu Y, et al. Sequential percutaneous microwave
coagulation therapy for liver tumor. Am J Surg 1998; 175(4): 322–4.
13. Shen P, Geisinger KR, Zagoria R, Levine EA. Pathologic correlation study
of microwave coagulation therapy for hepatic malignancies using a three-
ring probe. J Gastrointest Surg 2007; 11(5): 603–11.
14. Shibata T, Niinobu T, Ogata N, Takami M. Microwave coagulation ther-
apy for multiple hepatic metastases from colorectal carcinoma. Cancer.
2000; 15: 89(2): 276–84.
15. Hugh TJ, Kinsella AR, Poston GJ. Management strategies for colorectal
liver metastases—Part II. Surg Oncol 1997; 6(1): 31–48.
16. Evans J. Ablative and catheter-delivered therapies for colorectal liver
metastases (CRLM). Eur J Surg Oncol 2007; 33 Suppl 2: S64–75.
17. Mala T, Edwin B, Samset E, et al. Magnetic-resonance-guided percutane-
ous cryoablation of hepatic tumours. Eur J Surg 2001; 167(8): 610–7.
18. Bhardwaj N, Strickland AD, Ahmad F, Atanesyan L, West K, Lloyd DM. A
comparative histological evaluation of the ablations produced by microwave,
cryotherapy and radiofrequency in the liver. Pathology. 2009; 41(2): 168–72.
19. Bhardwaj N, Strickland AD, Ahmad F, Dennison AR, Lloyd DM. Liver
ablation techniques: a review. Surg Endosc 2010; 24(2): 254–65.
20. Seifert JK, Morris DL. Indicators of recurrence following cryotherapy for
hepatic metastases from colorectal cancer. Br J Surg 1999; 86(2): 234–40.
21. Seifert JK, Morris DL. Prognostic factors after cryotherapy for hepatic
metastases from colorectal cancer. Ann Surg 1998; 228(2): 201–8.
22. Seifert JK, Junginger T. Cryotherapy for liver tumors: current status, per-
spectives, clinical results, and review of literature. Technol Cancer Res
Treat 2004; 3(2): 151–63.
23. Yan DB, Clingan P, Morris DL. Hepatic cryotherapy and regional chemo-
therapy with or without resection for liver metastases from colorectal car-
cinoma: how many are too many? Cancer 2003; 15: 98(2): 320–30.
24. Kerkar S, Carlin AM, Sohn RL, et al. Long-term follow up and prognostic
factors for cryotherapy of malignant liver tumors. Surgery. 2004; 136(4):
770–9.
25. Brooks AJ, Wang F, Alfredson M, Yan TD, Morris DL. Synchronous liver
resection and cryotherapy for colorectal metastases: survival analysis.
Surgeon 2005; 3(4): 265–8.
26. Joosten J, Jager G, Oyen W, Wobbes T, Ruers T. Cryosurgery and radiofre-
quency ablation for unresectable colorectal liver metastases. Eur J Surg
Oncol 2005; 31(10): 1152–9.
27. Chen YY, Perera DS, Yan TD, Schmidt LM, Morris DL. Applying Fong’s
CRS liver score in patients with colorectal liver metastases treated by cryo-
therapy. Asian J Surg 2006; 29(4): 238–41.
28. Kornprat P, Jarnagin WR, DeMatteo RP, et al. Role of intraoperative ther-
moablation combined with resection in the treatment of hepatic metasta-
sis from colorectal cancer. Arch Surg 2007; 142(11): 1087–92.
29. Paganini AM, Rotundo A, Barchetti L, Lezoche E. Cryosurgical ablation of
hepatic colorectal metastases. Surg Oncol 2007; 16 Suppl 1: S137–40.
30. Seifert JK, Achenbach T, Heintz A, Bottger TC, Junginger T. Cryotherapy
for liver metastases. Int J Colorectal Dis 2000; 15(3): 161–6.
31. Seifert JK, Morris DL. World survey on the complications of hepatic and
prostate cryotherapy. World J Surg. 1999; 23(2): 109–13; discussion 13–4.
32. Primrose JN. Treatment of colorectal metastases: surgery, cryotherapy, or
radiofrequency ablation. Gut 2002; 50(1): 1–5.
33. Stubbs RS, Alwan MH, Booth MW. Hepatic cryotherapy and subsequent
hepatic arterial chemotherapy for colorectal metastases to the liver. HPB
Surg 1998; 11(2): 97–104.
34. Seifert JK, Junginger T, Morris DL. A collective review of the world litera-
ture on hepatic cryotherapy. J R Coll Surg Edinb 1998; 43(3): 141–54.
35. Korpan NN. Hepatic cryosurgery for liver metastases. Long-term follow-
up. Ann Surg 1997; 225(2): 193–201.
36. Rivoire M, De Cian F, Meeus P, et al. Combination of neoadjuvant chemo-
therapy with cryotherapy and surgical resection for the treatment of
unresectable liver metastases from colorectal carcinoma. Cancer 2002;
95(11): 2283–92.
37. Dwerryhouse SJ, Seifert JK, McCall JL, et al. Hepatic resection with cryo-
therapy to involved or inadequate resection margin (edge freeze) for
metastases from colorectal cancer. Br J Surg 1998; 85(2): 185–7.
190
38. Seifert JK, Morris DL. Cryotherapy of the resection edge after liver resec-
tion for colorectal cancer metastases. Aust N Z J Surg 1998; 68(10): 725–8.
39. Finlay IG, Seifert JK, Stewart GJ, Morris DL. Resection with cryotherapy
of colorectal hepatic metastases has the same survival as hepatic resection
alone. Eur J Surg Oncol 2000; 26(3): 199–202.
40. Gruenberger T, Jourdan JL, Zhao J, King J, Morris DL. Reduction in recur-
rence risk for involved or inadequate margins with edge cryotherapy after
liver resection for colorectal metastases. Arch Surg. 2001; 136(10): 1154–7.
41. Seifert JK, Junginger T. Prognostic factors for cryotherapy of colorectal
liver metastases. Eur J Surg Oncol 2004; 30(1): 34–40.
42. Niu R, Yan TD, Zhu JC, Black D, Chu F, Morris DL. Recurrence and survival
outcomes after hepatic resection with or without cryotherapy for liver metas-
tases from colorectal carcinoma. Ann Surg Oncol 2007; 14(7): 2078–87.
43. Ruers T, Bleichrodt RP. Treatment of liver metastases, an update on the
possibilities and results. Eur J Cancer 2002; 38(7): 1023–33.
44. Livraghi T, Goldberg SN, Monti F, et al. Saline-enhanced radio-frequency
tissue ablation in the treatment of liver metastases. Radiology 1997;
202(1): 205–10.
45. Wright AS, Sampson LA, Warner TF, Mahvi DM, Lee FT, Jr. Radiofre-
quency versus microwave ablation in a hepatic porcine model. Radiology
2005; 236(1): 132–9.
46. Wong SL, Mangu PB, Choti MA, et al. American Society of Clinical Oncol-
ogy 2009 clinical evidence review on radiofrequency ablation of hepatic
metastases from colorectal cancer. J Clin Oncol 2010; 28(3): 493–508.
47. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the
liver. J Gastrointest Surg 2007; 11(8): 1057–77.
48. Berber E, Siperstein A. Local recurrence after laparoscopic radiofrequency
ablation of liver tumors: an analysis of 1032 tumors. Ann Surg Oncol
2008; 15(10): 2757–64.
49. Amersi FF, McElrath-Garza A, Ahmad A, et al. Long-term survival after
radiofrequency ablation of complex unresectable liver tumors. Arch Surg
2006; 141(6): 581–7; discussion 7–8.
50. Jiang HC, Liu LX, Piao DX, et al. Clinical short-term results of radiofre-
quency ablation in liver cancers. World J Gastroenterol 2002; 8(4): 624–30.
51. Lermite E, Lebigot J, Oberti F, et al. Radiofrequency thermal ablation of
liver carcinoma. Prospective study of 82 lesions. Gastroenterol Clin Biol
2006; 30(1): 130–5.
52. Abitabile P, Hartl U, Lange J, Maurer CA. Radiofrequency ablation per-
mits an effective treatment for colorectal liver metastasis. Eur J Surg
Oncol 2007; 33(1): 67–71.
53. Gillams AR, Lees WR. Radio-frequency ablation of colorectal liver metas-
tases in 167 patients. Eur Radiol 2004; 14(12): 2261–7.
54. Kim SK, Lim HK, Ryu JA, et al. Radiofrequency ablation of rabbit liver
in vivo: effect of the pringle maneuver on pathologic changes in liver sur-
rounding the ablation zone. Korean J Radiol 2004; 5(4): 240–9.
55. Lu DS, Raman SS, Limanond P, et al. Influence of large peritumoral ves-
sels on outcome of radiofrequency ablation of liver tumors. J Vasc Interv
Radiol 2003; 14(10): 1267–74.
56. de Baere T, Elias D, Dromain C, et al. Radiofrequency ablation of
100 hepatic metastases with a mean follow-up of more than 1 year. AJR
Am J Roentgenol 2000; 175(6): 1619–25.
57. Elias D, Goharin A, El Otmany A, et al. Usefulness of intraoperative radio-
frequency thermoablation of liver tumours associated or not with hepa-
tectomy. Eur J Surg Oncol 2000 Dec; 26(8): 763–9.
58. Park IJ, Kim HC, Yu CS, et al. Radiofrequency ablation for metachronous
liver metastasis from colorectal cancer after curative surgery. Ann Surg
Oncol 2008; 15(1): 227–32.
59. Knudsen AR, Kannerup AS, Mortensen FV, Nielsen DT. Radiofrequency
ablation of colorectal liver metastases downstaged by chemotherapy. Acta
Radiol 2009; 50(7): 716–21.
60. Sorensen SM, Mortensen FV, Nielsen DT. Radiofrequency ablation of
colorectal liver metastases: long-term survival. Acta Radiol 2007; 48(3):
253–8.
61. Lee WS, Yun SH, Chun HK, et al. Clinical outcomes of hepatic resection
and radiofrequency ablation in patients with solitary colorectal liver
metastasis. J Clin Gastroenterol 2008; 42(8): 945–9.
62. Hur H, Ko YT, Min BS, et al. Comparative study of resection and radiofre-
quency ablation in the treatment of solitary colorectal liver metastases.
Am J Surg 2009; 197(6): 728–36.
 THERMAL ABLATION OF LIVER METASTASES
63. Veltri A, Sacchetto P, Tosetti I, et al. Radiofrequency ablation of colorectal
liver metastases: small size favorably predicts technique effectiveness and
survival. Cardiovasc Intervent Radiol 2008; 31(5): 948–56.
64. Aloia TA, Vauthey JN, Loyer EM, et al. Solitary colorectal liver metastasis:
resection determines outcome. Arch Surg 2006; 141(5): 460–6; discussion
6–7.
65. Oshowo A, Gillams A, Harrison E, Lees WR, Taylor I. Comparison of
resection and radiofrequency ablation for treatment of solitary colorectal
liver metastases. Br J Surg 2003; 90(10): 1240–3.
66. Suppiah A, White TJ, Roy-Choudhury SH, et al. Long-term results of per-
cutaneous radiofrequency ablation of unresectable colorectal hepatic
metastases: final outcomes. Dig Surg 2007; 24(5): 358–60.
67. Reuter NP, Woodall CE, Scoggins CR, McMasters KM, Martin RC. Radio-
frequency ablation vs. resection for hepatic colorectal metastasis: thera-
peutically equivalent? J Gastrointest Surg 2009; 13(3): 486–91.
68. Hildebrand P, Leibecke T, Kleemann M, et al. Influence of operator expe-
rience in radiofrequency ablation of malignant liver tumours on treat-
ment outcome. Eur J Surg Oncol 2006; 32(4): 430–4.
69. Berber E, Tsinberg M, Tellioglu G, Simpfendorfer CH, Siperstein AE.
Resection versus laparoscopic radiofrequency thermal ablation of
solitary colorectal liver metastasis. J Gastrointest Surg 2008; 12(11):
1967–72.
70. Siperstein AE, Berber E, Ballem N, Parikh RT. Survival after radiofre-
quency ablation of colorectal liver metastases: 10-year experience. Ann
Surg 2007; 246(4): 559–65; discussion 65–7.
71. Berber E, Pelley R, Siperstein AE. Predictors of survival after radiofre-
quency thermal ablation of colorectal cancer metastases to the liver: a
prospective study. J Clin Oncol 2005; 23(7): 1358–64.
72. Iannitti DA, Dupuy DE, Mayo-Smith WW, Murphy B. Hepatic radiofre-
quency ablation. Arch Surg 2002; 137(4): 422–6; discussion 7.
73. Solbiati L, Ierace T, Tonolini M, Osti V, Cova L. Radiofrequency thermal
ablation of hepatic metastases. Eur J Ultrasound 2001; 13(2): 149–58.
74. Terraz S, Constantin C, Majno PE, et al. Image-guided multipolar radio-
frequency ablation of liver tumours: initial clinical results. Eur Radiol
2007; 17(9): 2253–61.
75. Stippel DL, Bohm S, Beckurts KT, Brochhagen HG, Holscher AH. Intra-
operative radiofrequency ablation using a 3D navigation tool for treat-
ment of colorectal liver metastases. Onkologie 2002; 25(4): 346–50.
76. Pawlik TM, Izzo F, Cohen DS, Morris JS, Curley SA. Combined resection
and radiofrequency ablation for advanced hepatic malignancies: results in
172 patients. Ann Surg Oncol 2003; 10(9): 1059–69.
77. Scaife CL, Curley SA, Izzo F, et al. Feasibility of adjuvant hepatic arterial
infusion of chemotherapy after radiofrequency ablation with or without
resection in patients with hepatic metastases from colorectal cancer. Ann
Surg Oncol 2003; 10(4): 348–54.
78. Elias D, Sideris L, Pocard M, et al. Incidence of unsuspected and treatable
metastatic disease associated with operable colorectal liver metastases dis-
covered only at laparotomy (and not treated when performing percutane-
ous radiofrequency ablation). Ann Surg Oncol 2005; 12(4): 298–302.
79. Gleisner AL, Choti MA, Assumpcao L, et al. Colorectal liver metastases:
recurrence and survival following hepatic resection, radiofrequency abla-
tion, and combined resection-radiofrequency ablation. Arch Surg 2008;
143(12): 1204–12.
80. Nikfarjam M, Shereef S, Kimchi ET, et al. Survival outcomes of patients
with colorectal liver metastases following hepatic resection or ablation in
the era of effective chemotherapy. Ann Surg Oncol 2009; 16(7): 1860–7.
81. Izzo F. Other thermal ablation techniques: microwave and interstitial laser
ablation of liver tumors. Ann Surg Oncol 2003; 10(5): 491–7.
82. Wemyss-Holden SA, Dennison AR, Berry DP, Maddern GJ. Local ablation
for unresectable liver tumors: is thermal best? J Hepatobiliary Pancreat
Surg 2004; 11(2): 97–106.
83. Martin LW, Warren RS. Current management of colorectal liver metasta-
ses. Surg Oncol Clin N Am 2000; 9(4): 853–76; discussion 77–8.
84. Carrafiello G, Lagana D, Mangini M, et al. Microwave tumors ablation:
principles, clinical applications and review of preliminary experiences. Int
J Surg 2008; 6 Suppl 1: S65–9.
85. Seki T, Wakabayashi M, Nakagawa T, et al. Percutaneous microwave coag-
ulation therapy for solitary metastatic liver tumors from colorectal can-
cer: a pilot clinical study. Am J Gastroenterol 1999; 94(2): 322–7.
86. Shibata T, Murakami T, Ogata N. Percutaneous microwave coagulation
therapy for patients with primary and metastatic hepatic tumors during
interruption of hepatic blood flow. Cancer. 2000; 88(2): 302–11.
87. Yokoyama T, Egami K, Miyamoto M, et al. Percutaneous and laparoscopic
approaches of radiofrequency ablation treatment for liver cancer. J Hepa-
tobiliary Pancreat Surg 2003; 10(6): 425–7.
88. Tanaka K, Shimada H, Nagano Y, Endo I, Sekido H, Togo S. Outcome after
hepatic resection versus combined resection and microwave ablation for
multiple bilobar colorectal metastases to the liver. Surgery. 2006; 139(2):
263–73.
89. Iannitti DA, Martin RC, Simon CJ, et al. Hepatic tumor ablation with
clustered microwave antennae: the US Phase II Trial. HPB (Oxford) 2007;
9(2): 120–4.
90. Kuang M, Lu MD, Xie XY, et al. Liver cancer: increased microwave delivery
to ablation zone with cooled-shaft antenna—experimental and clinical
studies. Radiology 2007; 242(3): 914–24.
91. Ogata Y, Uchida S, Hisaka T, et al. Intraoperative thermal ablation therapy
for small colorectal metastases to the liver. Hepatogastroenterology 2008;
55(82–83): 550–6.
92. Zhang X, Zhou L, Chen B, et al. Microwave ablation with cooled-tip elec-
trode for liver cancer: an analysis of 160 cases. Minim Invasive Ther Allied
Technol 2008; 17(5): 303–7.
93. Bhardwaj N, Strickland AD, Ahmad F, et al. Microwave ablation for unre-
sectable hepatic tumours: clinical results using a novel microwave probe
and generator. Eur J Surg Oncol 2010; 36(3): 264–8.
94. Bartolozzi C, Lencioni R. Ethanol injection for the treatment of hepatic
tumours. Eur Radiol 1996; 6(5): 682–96.
95. Kessler A, Blank A, Merhav H, Orron D, Konikoff F, Oren R, et al. Mini-
mally invasive techniques in the treatment of liver tumors. Isr Med Assoc
J 2002; 4(12): 1106–10.
96. Giorgio A, Tarantino L, de Stefano G, et al. Complications after interven-
tional sonography of focal liver lesions: a 22-year single-center experi-
ence. J Ultrasound Med 2003; 22(2): 193–205.
97. Ruers T, Punt C, v Coevorden F, et al. Final results of the EORTC Intergroup
randomized study 40004 (CLOCC) evaluating the benefit of radiofre-
quency ablation combined with chemotherapy for unresectable colorectal
liver metastases. Proc ASCO 2010; J Clin Oncol 2010; 28 (15): A-3526.
191
20 Resection for hepatocellular carcinoma
Rajesh Satchidanand, Stephen W. Fenwick, and Hassan Z. Malik
introduction
Hepatocellular carcinoma (HCC) is one of the most common
malignancies with more than a million cases reported every year
worldwide. It is a common cause of death in the Far East because
of high endemecity of hepatitis B virus (HBV) infection. In the
West, the rising trend in the incidence of HCC is parallel to the
epidemic of Hepatitis C (HCV) virus infection (1). Alcohol
excess, genetic hemochromatosis, aflatoxin B1 (2), and primary
biliary cirrhosis are other associated risk factors. In the West, the
majority of HCC patients have associated cirrhosis of which a
significant number is alcohol related. More than a third of these
cases present with HCC as the initial presentation in contrast to
the Far East where HCC is often diagnosed at an early stage by
surveillance of the at-risk population (3).
Symptomatic HCC has a poor prognosis with a median
survival of 1 to 8 months (4). A multi-disciplinary approach
involving the surgeons, hepatologist, clinical oncologist, and
radiologist is needed to formulate the best treatment
options. Surgical resection offers the best possible treatment
outcome but a large proportion of patients are not suitable
for such an approach.
diagnosis
Asymptomatic HCC is diagnosed either as an incidental
finding or on routine surveillance of at-risk population.
Ultrasound scan (with or without contrast enhancement)
with measurement of serum alfa-feto protein (AFP) is rou-
tinely used for screening (5,6). Once a suspicion of a focal
lesion is raised, further assessment with contrast-enhanced
computerized tomography (CECT) and/or magnetic reso-
nance imaging (MRI) with contrast enhancement is needed
to confirm the diagnosis of HCC. Tumor biopsy is rarely
needed and in fact should be avoided in potentially resect-
able lesion due to the risk of tumor seeding along the needle
track and intra-celomic spread. Furthermore, CECT is a
good modality to look for the presence of cirrhosis, ascites,
and metastases. A typical HCC shows hyper vascular
enhancement with characteristic feature of early uptake of
contrast and portal venous washout, an enhanced pseudo-
capsule, vascular invasion on CECT which gives more than
80% accuracy in diagnosing these lesions (7). MRI is more
sensitive in detecting lesions 1 to 2 cm in size. A quarter of
intra-hepatic lesions smaller than 10 mm is miss-diagnosed
on pre-operative investigations. Diagnosing any lesion ≥2 cm
with characteristics CECT/MRI findings is possible with a
high degree of accuracy. In lesions 1 to 2 cm without concor-
dance with two radiological investigations, a raised AFP of
≥400 µ/L and one radiological modality with positive fea-
tures, diagnosis is possible (8). In lesions <10 mm, expectant
follow-up with repeat imaging at 3 to 6 months is an appro-
priate management algorithm (Fig. 20.1).
192
staging systems
A staging system allows for separation of patients into groups
and selection of appropriate treatment modality. A number of
staging systems are used in HCC using tumor characteristics
and underlying liver pathology. The most commonly used
method of tumor, nodes, and metastases (TNM) in the Amer-
ican Joint Committee on Cancer–Tumor–Metastases (AJCC),
TNM staging dependant on resection and postoperative his-
tology (9). The Okuda Classification includes variables related
to the tumor and liver function (10). The Cancer of the Liver
Italian Program Investigators staging systems includes Child-
Turcotte-Pugh (Child A/B/C) score, tumor morphological
characteristics, AFP, and vascular invasion/portal vein throm-
bosis. The Japan Integrated Staging score uses a combination
of Child A/B/C score and TNM staging system. By far, The
Barcelona Clinic Liver Cancer (BCLC) using tumor variables
and the current available treatment options gives a better
prognostic value in early cases (Fig. 20.2) (11).
treatment
A number of treatment options are available for patients with
HCC. These include
1. Liver resection (LR)
2. Orthotopic liver transplant (OLT) including deceased/
cadaveric donor liver transplant (DDLT/CLT) and liv-
ing donor liver transplant (LDLT)
3. Treatment prior to OLT: bridging the gap
4. Less invasive procedure involving chemical or
thermal destruction of liver parenchyma
5. Regional or systemic chemotherapy
6. Radiotherapy including external beam irradiation
or embolization with radioactive particles
Before selecting a treatment option, careful consideration
should be given to preoperative staging, underlying condition
of the liver and the general fitness of the patient. Staging lapa-
roscopy is a mandatory prior to LR or OLT to rule out extra-
hepatic disease. Assessing the residual liver function in chronic
liver disease is very important before LR, as any major resec-
tion in a cirrhotic patient may result in fatal liver failure in the
immediate post-operative period. Traditionally, the Child
A/B/C scoring system has been used to assess the residual liver
function. However, the Model for End-stage Liver Disease
(MELD) scoring is used as an alternative in United States.
Ascites on CECT, bilirubin of >2 mg/dL, and iodocyanine
green retention test (used extensively in the East) (8) at
15 minutes of <30% bodes ill for residual liver function. Clin-
ically relevant portal hypertension with hepatic vein gradient
of >10 mm of mercury, esophageal varices, splenomegaly, and
a platelet count of <100 × 109/L are accurate predictors of
post-operative liver decompensation (12). Patients with Child
 RESECTION FOR HEPATOCELLULAR CARCINOMA

HCC
within Milan criteria

Child-Pugh A Child-Pugh B–C

Solitary < 3 cm Solitary 3–5 cm 2–3 nodules Solitary < 5 cm

< 3 cm 2–3 nodules < 3 cm

Deep Peripheral Deep

location location location

Portal hypertension
Varices, platelets < 100,000/mm3

No Yes

Portal vein embolization

If right hepatectomy required

RF Laparoscopic Open
ablation resection resection

Transplantable Transplantation

Recurrence
RF, TACE, resection,
Not transplantable New drugs, supportive care

Figure 20.1 Algorithm for management of transplantable hepatocellular carcinoma used at Henri-Mondor Hospital. Source: From Ref. (29).

A can withstand up to 50% liver resection, but in those with
Child B, a future remnant liver value of less than 75% is associ-
ated with major complications.
LR remains the treatment of choice in early cases of non-
cirrhotic HCC, in tumors of <5 cm size, or up to three tumor
nodules each <3 cm in size. Even though early experience with
OLT yielded good results, it was fraught with recurrence (13).
Increasing incidence of HCC with scarcity of donor livers
available for transplant meant stringent criteria for patient
selection. Hence, with the adoption of the more restrictive
Conventional Milan Criteria (CMC: 1 lesion <5 cm, 2–3
lesions <3 cm), OLT has resulted in better long-term results (14).
With increasing experience, some groups have suggested
expanding the boundaries of CMC. One such recommenda-
tion is University of California, San Francisco (UCSF), criteria
for patients with one lesion ≤6.5 cm or two to three lesions
≤4.5 cm with a total tumor diameter of <8 cm (15).
early stage hcc
Patients with one lesion <5 cm in size or two to three lesions
<3 cm in size with good residual liver functions are considered
as having early stage disease. In these patients LR, OLT or per-
cutaneous ablative therapy with a curative intent yielding high
response rate are possible (16). Both LR and OLT have the best
outcomes and treatment of choice is dependent on the avail-
ability of a donor liver. Tumor progression while waiting for a
donor liver may decide the treatment option.
Liver Resection
Liver resection in early HCC can be used in three different
settings: (a) primary therapy, (b) to obtain material for
morphological assessment of the tumor and to select patients
who would benefit OLT, and (c) as a bridge therapy for those
who are enlisted for OLT.

193
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

HCC

Stage 0 Stage A–C Stage D

PST 0, child-pugh A, okuda 1 Okuda 1–2, PST 0–2, Child-Pugh A–B Okuda 3, PST > 2, Child-Pugh C

Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal
single < 2 cm. Single or 3 nodules < 3 cm, PS 0 Multinodular, PS 0 Portal invasion, N1, M1, PS 1–2 stage (D)
Carcinoma in situ

Single 3 nodules ≤ 3 cm

Portal pressure/bilirubin
Associated diseases Portal invasion, N1, M1
Increased

Normal No Yes No Yes

Liver transplantation New

Resection PEI/RF Chemoembolization
(CLT/LDLT) agents

Symptomatic
Curative treatments Randomized controlled trials
treatment

Figure 20.2 Barcelona Clinic Liver Cancer staging classification and treatment schedule. Stage 0: Patients who have very early HCC are optimal candidates for
resection. Stage A: Patients who have early HCC are candidates for radical therapies (resection and ablation, liver transplantation, or percutaneous treatments).
Stage B: Patients who have intermediate HCC may benefit from chemoembolization. Stage C: Patients who have advanced HCC may receive new agents in the
setting of a randomized, controlled trial. Stage D: Patients who have end stage disease receive symptomatic treatment. Abbreviations: LDLT, living-related donor
liver transplantation; PEI, percutaneous ethanol injection; RF, radiofrequency. Source: From Ref. (30).

Primary Resection Therapy hepatectomy. Preoperative portal vein embolization (PVE)

LR for HCC has come a long way from early attempts with
more than 50% mortality and no 5-year survival. With better
understanding of tumor morphology, availability of advanced
imaging modalities, patient selection, greater understanding
of liver anatomy, improvement in surgical techniques, intra-
operative ultrasound scan, and well-trained dedicated liver
surgeons has resulted in up to 70% 5-year survival rates com-
parable to OLT, but a recurrence of 40% to 70% still represents
a major cause of death (8,16).
LR can be performed as a wedge resection, segmentectomy,
or major resection. The extent of the liver resection is depen-
dent on the size of the tumor, whether it is unifocal or multifo-
cal and the presence or absence of cirrhosis in the residual
liver. A peripherally located small lesion especially in segment
2 or 3 of liver can be safely resected either laparoscopically or
by open resection. But in the presence of cirrhosis, wedge
resection or non-anatomical resection in a rigid liver can be
difficult and associated with significant blood loss. A hemi
hepatectomy can achieve a good tumor clearance with least
postoperative complications in lesions measuring 2 to 3 cm.
This could be managed either laparoscopically or by hand-
port assisted laparoscopic surgery (17).
Deeply seated lesions or large single lesions measuring 3 to
5 cm with no evidence of portal hypertension need major
can be used to increase the functional residual volume of liver.
Though theoretically this could overcome the problems of
postoperative hepatic decompensation, barring few smaller
studies, randomized controlled trials have not shown benefit
from PVE (18). The ratio of functional residual volume to
total liver volume should be more than 25% in non-cirrhotic
livers and >40% in cirrhotic livers. In high-volume centers and
in the Far East, major hepatectomies are undertaken with min-
imal postoperative complication rates.
Tumor recurrence following primary resection has an inci-
dence of 70%. Recurrence is more common after resection in
the cirrhotic liver due to the ongoing process of carcinogene-
sis. It is more common in multifocal lesions, vascular invasion,
and positive resection margin. Salvage OLT can be used for
those with recurrence following resection, although patients
will still have to fulfil the criteria for transplant.
Resection Prior to OLT
LR can be used to help select patients for OLT (19). This gives
an opportunity to examine not only the surrounding liver but
also the specimen for histo-pathological examination. A tumor
with adverse morphological features (such as satellite nodules,
vascular invasion) could preclude a patient for OLT even
though it meets the CMC. Conversely, a large tumor which

194
 RESECTION FOR HEPATOCELLULAR CARCINOMA
falls just outside the CMC, but with good prognostic features
could be considered for transplant. With more experience in
managing this condition, there is constant urge to push the
boundaries of CMC.
Resection to Bridge the Gap Prior to OLT
Tumor progression in patients waiting for OLT is a common
problem, especially in aggressive tumors. In centers with a
long wait for OLT, traditionally transarterial chemo-emboli-
zation (TACE), percutaneous ablation with ethanol injection
(PEI), or radiofrequency (RFA) is used. The amount of tumor
necrosis cannot be accurately quantified. Moreover, inade-
quate tumor necrosis can lead to tumor recurrence following
OLT. LR can be used instead to bridge the gap prior to OLT
(20). LR is better at tumor control than either TACE or RFA
while waiting for OLT. This strategy is restricted to Child A
and to a lesser extent in Child B and subsequent OLT can be
technically challenging.
Liver Transplant
In patients with early HCC which are unresectable due to
underlying chronic liver disease, OLT offers the best possible
outcome. This not only removes the tumor but also the under-
lying causative factor. In carefully selected patients who meet
the CMC, 5-year survival rates in excess of 70% can be achieved
(11,14). With a paucity of donor liver, especially in the Far East
where the incidence of HCC is high, tumor progression leads
to dropout from the waiting list. Though it is difficult to ascer-
tain the exact rate of dropout, about 22% on the waiting list
for OLT drop out in the first year due to tumor progression
(5,21). Tumors with more than two nodules on presentation
and those measuring >3 cm have a higher likelihood of drop
out from the waiting list. OLT can be used as (a) primary ther-
apy and (b) salvage OLT
Primary Therapy
Primary OLT without any pre-transplant treatment, in patients
with early HCC who meet the CMC within first 6 months of
diagnosis, is the ideal treatment. But due to scarcity of avail-
able donor liver, this is not always possible. Traditionally, in the
West, DDLT is the method of choice. To make the status of
patient amenable for OLT while on the waiting list and to pre-
vent drop out various adjuvant therapies can used. Commonly
used are TACE, RFA, and to a lesser extent LR. Furthermore,
LDLT has been used, more so in the Far East to overcome the
lack of donor organs. The survival of the graft in low-volume
liver transplant in LDLT is dependent not only on the extent of
ischemia–reperfusion injury but also on the presence or
absence of portal hypertension in the recipient. Early interest
in the West has not been sustained due to adverse publicity
following donor mortality risk. Even in the Far East, LR seems
to be initial choice of therapy with LDLT being used in case of
tumor recurrence. Pushing the boundaries of CMC has
resulted in more and more patients falling just outside the
accepted norms being referred to the transplant units. The
idea of expanded criteria is mooted on the basis of Metro Rail
paradigm “the farther you travel, the higher the price” (22).
Salvage OLT
In patients who have had LR, PEI, or RFA as the primary treat-
ment survival figures at the end of 5 years is 70% (11,14), 53%
(23), and 60% (24), respectively. In those with recurrence, sal-
vage surgery in the form of OLT can be offered. In the Far East,
with perpetual shortage of donor liver, LDLT is being used more
frequently for salvage OLT. The selection criteria for LDLT are
far more liberal than the stringent CMC used for DDLT.
Chemical or Thermal Ablation
In patients with small tumor located deeply within the liver
parenchyma, tumor ablation performed percutaneously or
trans-arterially is possible. RFA (24,25) is used routinely not
only as a primary therapy but also as a pre-transplant therapy
to reduce the dropout rate. The limiting factor is the tumor
size and presence of larger vessel close to the tumor with com-
plications occurring in 8% to 23% including abscess forma-
tion, biliary injury, and a potential for tumor seeding along the
track. PEI (26) is a cheaper alternative with fewer side effects,
but the use is limited by tumor size given the fact that best
results are seen for tumors <2 cm. Both provide a good cumu-
lative survival benefits.
intermediate and advanced stage hcc
Those patients who have larger asymptomatic tumor which
does not fall into CMC category, Child B, compensated chronic
liver disease and the absence of extra hepatic spread is consid-
ered to have intermediate stage HCC. LR though controversial
has been used as an initial therapy option in large HCC with
comparable outcomes (27). TACE and RFA either exclusively
or in combination have been used to downstage HCC with
good results (28). This could be used not only as a prognostic
indicator for post transplant outcome, but also for selection of
patients for OLT. Application of expanded criteria such as
UCSF still needs full validation and has been used in relatively
few centers. However, some centers do routinely offer primary
OLT with acceptable 5-year survival figures. In the Far East, LR
is being offered as a first-line therapy with salvage OLT being
used for recurrence.
Patients with unresectable HCC with vascular invasion and/or
extra hepatic spread are considered to have advanced HCC.
Treatment for advanced HCC is restricted to TACE, RFA, or
radio sphere embolization. TACE has shown significant benefit
in unresectable HCC with good response rates. Patients have a
transient post-embolization syndrome with pain, fever, and
transient raise in liver enzymes. Major complications such as
ischemic necrosis of gall bladder, liver abscess, and biliary stric-
ture are rare. Systemic chemotherapy is rarely being used because
of poor response rates. Furthermore, in patients with cirrhosis,
hypersplenism, worsening of portal hypertension, major variceal
bleeding, or bleeding from gastrointestinal tract and onset of
encephalopathy are some of the serious complications
references
1. Okuda K, Fujimoto I, Hanai A, et al. Changing incidence of hepatocellular
carcinoma in Japan. Cancer Res 1987; 47: 4967–72.
2. Ross, RK, Yuan JM, Yu MC, et al. Urinary aflatoxin biomarkers and risk of
hepatocellular carcinoma. Lancet 1992; 339: 943–6
195
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
3. Okuda K. Clinical presentation and natural history of hepatocellular car-
cinoma and other liver cancers. In: Okuda K, Tabor E, eds. Liver Cancer.
New York: Churchill Livingstone, 1997: 1–12.
4. Forner A, Hessheimer AJ, Real MI, et al. Treatment of hepatocellular car-
cinoma. Crit Rev Oncol Hematol 2006; 60(2): 89–98.
5. Makuuchi M, Sano K. The surgical approach to HCC: our progress and
results in Japan. Liver Transpl 2004; 10(2 Suppl 1): S46–52.
6. Spangenberg HC, Thimme R, Blum HE. Serum markers of hepatocellular
carcinoma. Semin Liver Dis 2006; 26(4): 385–90.
7. Jacobs JE, Birnbaum BA. Computed tomography imaging for focal
hepatic lesions. Semin Roentgenol 1995; 30: 308–323.
8. Cormier JN, Thomas KT, Chari RS, et al. Management of hepatocellular
carcinoma. J Gastrointest Surg 2006; 10(5): 761–80.
9. Vauthey J, Lauwers G, Esnaola N, et al. Simplified staging for hepatocel-
lular carcinoma. J Clin Oncol 2002; 20: 1527–36.
10. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepato cellular
carcinoma and prognosis in relation to treatment: a study of 850 patients.
Cancer 1985; 56: 918–28.
11. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the
BCLC staging classification. Semin Liver Dis 1999; 19: 329–38.
12. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular
carcinoma in cirrhotic patients: prognostic value of preoperative portal
pressure. Gastroenterology 1996; 111(4): 1018–22.
13. Ringe B, Pichlmayr R, Wittekind C, Tusch G. Surgical treatment of hepa-
tocellular carcinoma: experience with liver resection and transplantation
in 198 patients. World J Surg 1991; 2: 270–85.
14. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treat-
ment of small hepatocellular carcinomas in patients with cirrhosis. N
Engl J Med 1996; 334: 693–699.
15. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular
carcinoma: Expansion of the tumor size limits does not adversely impact
survival. Hepatology 2001; 33: 1394–1403.
16. Lopez PM, Villanueva A, Llovet JM. Systematic review: evidence-based man-
agement of hepatocellular carcinoma–an updated analysis of randomized
controlled trials [review]. Aliment Pharmacol Ther 2006; 23(11): 1535–47.
17. Cherqui D, Laurent A, Tayar C, et al. Laparoscopic liver resection for
peripheral hepatocellular carcinoma in patients with chronic liver disease:
mid-term results and perspectives. Ann Surg 2006; 243(4): 499–506.
196
18. Kianmanesh R, Regimbeau JM, Belghiti J. Selective approach to major
hepatic resection for hepatocellular carcinoma in chronic liver disease.
Surg Oncol Clin N Am 2003; 12(1): 51–63.
19. Belghiti, J, Carr BI, Greig PD, Lencioni R, Poon RT. Treatment before liver
transplantation for HCC. Ann Surg Oncol 15(4): 993–1000.
20. Sala M, Fuster J, Llovet JM, et al. High pathological risk of recurrence after
surgical resection for hepatocellular carcinoma. An indication for salvage
transplantation. Liver Transpl 2004; 10: 1294–300.
21. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treat-
ment for early hepatocellular carcinoma: resection versus transplantation.
Hepatology 1999; 30: 1434–40.
22. Yao FY. Liver transplantation for hepatocellular carcinoma: beyond the
Milan. Crit Am J Transplant 2008; 8: 1982–9.
23. Livraghi T, GiorgioA, Marin G, et al. Hepatocellular carcinoma and cir-
rhosis in 746 patients : long term results of percutaneous ethanol injec-
tion. Radiology 1995; 197: 101–8.
24. Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for
early-stage hepatocellular carcinoma as a first-line treatment: long-term
results and prognostic factors in a large single-institution series. Eur
Radiol 2007; 17(3): 684–92.
25. Lencioni R, Pina CD, Bartolozzi C. Percutaneous image-guided radiofre-
quency ablation in the therapeutic management of hepatocellular carci-
noma. Abdom Imaging 2005; 30(4): 401–8.
26. Ebara M, Okabe S, Kita K, et al. Percutaneous ethanol injection for small
hepatocellular carcinoma: therapeutic efficacy based on 20-year observa-
tion. J Hepatol 2005; 43(3): 458–64.
27. Pandey D, Lee K-H, Wai C-T, Wagholikar G, Tan K-C. Long term outcome
and prognostic factors for large hepatocellular carcinoma (10 cm or
more) after surgical resection. Ann Surg Oncol 14(10): 2817–23.
28. Cheng BQ, Jia CQ, Liu CT, et al. Chemoembolization combined with
radiofrequency ablation for patients with hepatocellular carcinoma larger
than 3 cm: a randomized controlled trial. J Am Med Assoc 2008; 299(14):
1669–77
29. Cherqui D, Laurent A, Mocellin N, et al. Liver resection for transplantable
hepatocellular carcinoma: long term survival and role of secondary liver
transplantation. Ann Surg 2009; 250(5): 738–46.
30. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;
362: 1914.
21 Treatment of laparoscopically discovered gallbladder cancer
Jason K. Sicklick, David L. Bartlett, and Yuman Fong
introduction
Traditionally a great deal of pessimism has been associated
with the treatment of gallbladder cancer (1). There are many
reasons for the skepticism associated with this disease entity
since its first description in 1778 (2). Foremost is the aggres-
sive nature of this cancer for dissemination. Gallbladder can-
cer spreads early by direct invasion into the liver, as well as
through lymphatics to regional nodes, by peritoneal dissemi-
nation to produce carcinomatosis, and by hematogenous
means to produce synchronous liver and other distant metas-
tases. As a result, gallbladder cancer often presents at a time
when surgical excision is either no longer possible or is techni-
cally difficult while alternative therapies including chemother-
apy and radiation are generally ineffective. Therefore, it is not
surprising that in 1924 Blalock recommended that surgery be
avoided for gallbladder cancer if the diagnosis could be made
preoperatively (3). In fact, until recently, the 5-year survival in
most large series was less than 5%, and the median survival
was less than 6 months (4,5). In the modern era, liver resection
has become increasingly safe. More recent experience has
demonstrated that radical surgery may be a sensible and
potentially curative option in the treatment of this disease (6,7).
The data have demonstrated that surgical excision is the treat-
ment option of choice for those patients whose gallbladder
cancers are confined to the local region of the liver and porta
hepatis (8–10).
Beginning in late 1980s, when the techniques for laparo-
scopic cholecystectomy were introduced, a new presentation
for gallbladder cancer was conceived. With the advent and
popularization of laparoscopic cholecystectomy, increasing
number of cases of gallbladder cancer were being discovered
laparoscopically. Currently, approximately 750,000 cholecys-
tectomies are performed in the United States annually for pre-
sumed calculous biliary disease (11). Since gallbladder cancer
is encountered in 1% of cholecystectomies for choleli-
thiasis (7), a significant number of patients will present with
this clinical scenario. Therefore, meticulous inspection of the
gallbladder should be mandatory (12). The current chapter
will review data addressing the utility of subsequent radical
resection for laparoscopically discovered gallbladder cancer.
We will begin with a brief general review of gallbladder cancer,
which focuses on the natural history and results of surgical
treatment. Summarized data on presentation and results of
treatment for laparoscopically discovered disease will be dis-
cussed, including the differences of discovery by an open
rather than laparoscopic operation.
epidemiology
Gallbladder cancer is the most common biliary tract malig-
nancy and the fifth most common gastrointestinal malignancy
in the United States. In fact, there are approximately 5,000 new
diagnoses each year (13). It has an annual incidence of 1.3 per
100,000 in females and 0.8 per 100,000 in males, with an aver-
age incidence of 1.2 cases per 100,000 population per year (14).
This cancer is responsible for approximately 2,800 deaths per
year. The most obvious associated conditions for gallbladder
cancer are gallstone disease and chronic cholecystitis. Between
75% and 98% of all patients with carcinoma of the gallbladder
have cholelithiasis (15). Most importantly, gallbladder cancer
will be found once in every 100 cases of presumed gallstone
disease.
The natural history of gallbladder cancer has been defined
through many retrospective reviews and large surveillance
programs. The overall 5-year survival is consistently less than
5%, with a median survival of 5 to 8 months. Piehler et al. (5)
reviewed 5,836 cases in the world’s literature from 1960 to
1978. They reported an overall 5-year survival of 4.1% and a
1-year survival of 11.8%. Only about 25% were resectable for
cure, and of those resected for cure, 16.5% survived 5 years.
Perpetuo et al. (4) reviewed the M.D. Anderson Cancer
Center experience with gallbladder cancer over 36 years and
reported a 5-year survival rate of less than 5% and median
survival of 5.2 months. Cubertafond et al. (16) reported the
results of a French Surgical Association Survey of 724 carcino-
mas of the gallbladder. They reported a median survival of
3 months, a 5-year survival rate of 5%, and a 1-year survival
rate of 14%. They observed no differences among the different
surgical procedures adopted, and concluded that no progress
had been made in the treatment of gallbladder cancer. A sur-
vey of gallbladder cancer in Wessex, United Kingdom, revealed
only four patients out of 95 surviving from 8 to 72 months
after the time of diagnosis (17). A review of gallbladder cancer
from Australia revealed a 12% 5-year survival rate, with all
survivors having stage I or II disease. The median survival for
patients with stage III or IV disease was only 46 days (18).
SEER data from the United States demonstrated similarly
unsatisfying results, with only marginal improvement over
earlier studies with median overall survival time being
10 months (95% CI 9 to 11 months), as well as 1-year, 2-year,
3-year, and 5-year overall survival rates of 46%, 30%, 23%, and
17%, respectively, in 4,180 patients (19).
A multi-institutional review from Japan, on the other hand,
reported a 50.7% 5-year survival for 984 patients undergoing
radical resection versus 6.2% for 702 patients undergoing
more conservative management (20). These results suggest
that it may be possible for surgery to have a role in changing
the natural history of this tumor. Therefore, it is clear that
radical liver resection, or extended liver resection, in gallblad-
der cancer does have survival benefit in selected cases (7,21,22).
Despite this data, it is important to emphasize that there has
been only one small randomized, prospective trial on the
treatment of gallbladder cancer. Moreover, there are no
197
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
randomized trials comparing extended resection to conserva-
tive management. The routine use of more radical resections,
including those of segments IV and V and the common bile
duct, despite a negative cystic duct margin, has gained some
popularity. There is no randomized data in the literature to
show that this is mandatory in patients with Tis, T1, or T2
disease where a negative margin is obtained.
pathology
At early stages, gallbladder carcinomas are difficult to grossly
differentiate from chronic cholecystitis. As a result, they are
often found incidentally upon pathologic section. Even at late
stages, when the tumor can obstruct the common bile duct
and produce jaundice, gallbladder cancer is often mistaken for
benign disease since associated gallstones and Mirizzi’s syn-
drome are common (23). Therefore, a long-term obstruction
of the mid-common bile duct should be considered a gallblad-
der cancer until proven otherwise. Tumors that arise in the
neck and within Hartmann’s pouch may also infiltrate the
common hepatic duct, making them clinically and radio-
graphically indistinguishable from hilar cholangiocarcinomas.
Approximately 60% of tumors originate in the fundus of the
gallbladder, 30% in the body, and 10% in the neck (24). These
tumors grow most commonly in a diffusely infiltrative
form (25), with a tendency to involve the entire gallbladder,
and spread in a subserosal plane, which is the same as the sur-
gical plane used for routine cholecystectomy. If such a tumor
is unrecognized at the time of surgery, a simple cholecystec-
tomy will not completely excise the disease and may lead to
dissemination of tumor. Although the nodular type of tumor
may show early invasion through the gallbladder wall into the
liver or adjacent structures, it may be easier to control surgi-
cally than the infiltrative type because the margins are better
defined. The papillary growth pattern has the best prognosis
because even large tumors have only minimal invasion of the
gallbladder wall (14).
The most common histologic cell type of gallbladder can-
cers is adenocarcinoma (26). Other rare subtypes of gallblad-
der cancer include papillary carcinoma, mucinous carcinoma,
clear cell carcinoma, signet ring carcinoma, squamous cell car-
cinoma, small cell (oat cell) carcinomas (27), adenosquamous
tumors (28), sarcomas, carcinosarcoma, carcinoid, lymphoma,
melanoma, and gastrointestinal stroma tumors (GIST) (29,30).
patterns of spread
Gallbladder carcinoma commonly disseminates by four modes:
1. Direct extension and invasion of the liver and adja-
cent organs
2. Lymphatic spread
3. Shedding and peritoneal dissemination, and
4. Hematogenous spread to distant sites.
The gallbladder lies on segments IVb and V of the liver and
these segments are involved early in tumors of the fundus and
body. Direct extension into the portal structures (i.e., portal
vein, hepatic artery, and bile duct) commonly occurs and is a
major cause of symptoms. Lymphatic spread is also common
and most often involves cystic and pericholedochal nodes.
198
Tumor may then pass to lymph nodes posterior to the pan-
creas, portal vein, and common hepatic artery. Advanced dis-
ease may ultimately reach the interaortocaval, celiac axis, and
superior mesenteric artery lymph nodes. Gallbladder cancer
also has a remarkable propensity to seed and grow within the
peritoneal cavity, which may account for its ability to grow
along the tracts of needle biopsy sites and laparoscopic port
sites. Growth in those sites may be further exacerbated by bile
spillage during laparoscopic cholecystectomy (31,32). In fact,
another group demonstrated that the incidence of port site/
peritoneal recurrence was higher in patients with gallbladder
perforation (3/7, 43%) than in those without (0/21, 0%;
p = 0.011) (33). The long-term survival was worse in the seven
patients with gallbladder perforation (cumulative 5-year sur-
vival of 43%) as opposed to those without perforation (cumu-
lative 5-year survival of 100%; p < 0.001). Hematogenous
spread is less common but will present most often as noncon-
tiguous liver metastases, and more rarely as lung or brain
metastases. At postmortem examination, Perpetuo et al. (4)
reported that 91% of patients had liver metastasis and 82%
had intra-abdominal lymph node involvement, 60% had peri-
toneal spread, 32% had lung metastases, and 5% had
brain metastases.
staging
The multitude of staging systems (Table 21.1) used for this
disease has made it difficult to compare treatment results.
Nevin et al. (34) originally classified patients into five stages
based primarily on the thickness of invasion, and combined
patients with direct liver extension or distant metastases into
stage V. Donahue et al. (35) modified the Nevin system to
include tumors with contiguous liver invasion as stage III and
noncontiguous liver involvement as stage V. Stage IV contin-
ued to include lymph node metastases. The Japanese Biliary
Surgical Society staging system separated tumors into four
stages according to the degree of lymph node metastasis, sero-
sal invasion, peritoneal dissemination, hepatic invasion, and
bile duct infiltration. The main weakness of this staging system
is that lymph node metastases are considered in the same stage
as microinvasion of the liver.
Despite these various systems, the most common system for
evaluating gallbladder cancer worldwide has been the Ameri-
can Joint Committee on Cancer (AJCC) TNM staging system
for gallbladder cancer (26). Unfortunately, the 6th edition of
the AJCC staging system underwent radical changes due to a
desire to match the staging of other biliary cancers. The staging
system was therefore not consistent with data. A recent paper
documented the deficiencies of the 6th edition staging system
using 10,705 cases of this disease from the National Cancer
Database (36). Thus, the new 7th edition staging will revert to a
system much more in line with past staging (Table 21.1).
According to this system, tumors without perimuscular inva-
sion are considered stage I. Tumors with invasion into the peri-
muscular connective tissue but without extension beyond the
serosa or into the liver are considered stage II. Tumors that per-
forate the serosa and/or directly invade the liver and/or adja-
cent structures, such as the stomach, duodenum, colon,
pancreas, omentum, or extrahepatic biliary tree are stage IIIA if
 TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER

Table 21.1 Summary of Most Commonly Used Staging Systems

Proposed 7th
Stage AJCC 5th edition (TNM) AJCC 6th edition (TNM) Modified Nevin Japanese edition AJCC
I Mucosal (T1N0M0) IA: Mucosal or muscular In situ carcinoma Confined to Mucosal
invasion (T1N0M0) gallbladder (T1N0M0)
IB: Perimuscular invasion capsule
(T2N0M0)
II Muscular invasion (T2N0M0) IIA: Perforate the serosa and/ Mucosal or N1 lymph nodes; Muscular invasion
or directly invade the liver muscular minimal liver (T2N0M0)
and/or adjacent structures invasion orbile duct
(T3N0M0 invasion
IIB: Tumors with regional
nodal lymph node
metastases but no invasion
of the main portal vein,
hepatic artery, or multiple
extrahepatic organs/
structures (T1-3N1M0)
III Liver invasion <2 cm; lymph Tumor invades the main portal Transmural direct N2 lymph nodes; Transmural
node mets (T3N1M0) vein, hepatic artery, or liver invasion marked liver or (T3N0M0), or
multiple extrahepatic organs/ bile duct invasion T-3 with nodal
structures. (T4NxM0) involvement
IV (1) Liver invasion >2 cm (Distant metastases (TxNxM1) Lymph node Distant metastases Metastatic disease,
(T4N0M0, TxN1M0 (2) metastasis or vascular
Distant metastases involvement with
(TxN2M0, TxNxM1) N2 nodal metastases
lymphadenopathy [peripan- (T4N1M0)
creatic (head only), periduo-
denal, perioportal, celiac,
superior mesenteric, or
paraaortic nodes]
V [—] [—] Distant metastases [—]

there is no regional lymph node metastasis. Stage IIIB tumors

have nodal metastases but no vascular invasion. Stage IVA
includes those patients with vascular invasion, and stage IVB
includes patients with distant metastases or those with vascular
invasion and nodal metastases.

clinical presentation
The clinical presentation of gallbladder cancer is often identical
to biliary colic and/or chronic cholecystitis, making it difficult to
diagnose preoperatively. It is also difficult to easily distinguish
gallbladder cancer from benign gallstone disease from blood
tests. Elevated alkaline phosphatase and/or bilirubin levels are
found in cases of advanced tumors, but may also be found for
patients with gallstones. A CEA greater than 4 ng/ml is 93% spe-
cific for the diagnosis of gallbladder cancer, but is only 50% sen-
sitive (37). A serum Ca 19–9 level (38) greater than 20 units/ml Figure 21.1 CT scan demonstrating a papillary carcinoma of the gallbladder.
has 79.4% sensitivity and 79.2% specificity, but neither test is This patient was subjected to a laparoscopic cholecystectomy in spite of this
scan and required a subsequent reoperation for a potentially curative radical
routine in patients suspected of having benign disease. Vigilance resection.
for cancer in examination of preoperative sonograms or CT
scans is essential. Any mass or polyp associated with the gall-
bladder (Fig. 21.1) or the presence of a porcelain gallbladder benign calculous disease. In a report of 42 laparoscopically dis-
should raise concerns of a gallbladder cancer.Figure 21.1 covered gallbladder cancers, in only two of the cases did the
It is often difficult to make the diagnosis of gallbladder can- laparoscopic surgeon suspect a cancer prior to the surgical
cer based upon clinical history as it often presents similarly to procedure (39). The laparoscopic procedure consisted of 19

199
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
cases of laparoscopic cholecystectomy, one laparoscopic chole-
cystectomy with intraoperative cholangiogram, and six lapa-
roscopic biopsies only. There were 16 cases that were converted
to open procedures, including 12 open cholecystectomies,
three open cholecystectomies with common bile duct explora-
tion, and one cholecystectomy with hepaticojejunostomy.
Even at the conclusion of the laparoscopic procedure, in only
20 of the 42 cases (47.6%) was there any suspicion of cancer.
This underscores the difficulties in diagnosing gallbladder
cancer and the ease with which this aggressive malignancy is
confused with benign stone disease.
Recent studies (40–42) have evaluated the role of meticulous
inspection of gallbladder specimens at the time of laparo-
scopic cholecystectomy. Akyurek et al. (40) inspected 548 lapa-
roscopic cholecystectomy specimens by making an incision in
the gallbladder wall and palpating the mucosa after removing
the gallbladder from the abdominal cavity. If an abnormal
mucosa was observed or palpated, it was marked and then his-
topathologic examination was performed. They identified 50
cases to be suspicious and histopathologic examination of
frozen sections revealed incidental pathologies in 15 speci-
mens. Moreover, five of these specimens had gallbladder can-
cers. The sensitivity and specificity of the procedure was 78.9%
and 93%, respectively, suggesting that this is a simple method
for identifying incidental gallbladder cancers and may allow
for a definitive resection to be performed at the time of the
initial operation. In another study of 983 cases, 11 cancers
were identified. Based upon frozen sections, cancer was diag-
nosed in 40% of Tis lesions, whereas it was found in 83% of T2
or T3 lesions, which required conversion to a more radical
operation (41). A larger cohort of 1452 patients identified four
patients with gallbladder cancers and, in all cases, there was
either preoperative or intraoperative suspicion (43). Together,
these studies would suggest that careful inspection and selec-
tive evaluation of suspicious gallbladder lesions using frozen
sections should be performed.
radiologic workup
Most patients with laparoscopically discovered gallbladder
cancer will have had an ultrasound performed for suspected
cholelithiasis. Review of this ultrasound may provide informa-
tion concerning liver involvement by tumor, biliary extension
of tumor, and/or vascular involvement. However, it is most
often that another cross-sectional imaging test is indicated for
further assessment of these sites for disease, as well as to assess
for presence of nodal disease. The combination of CT scan-
ning and ultrasonography (44) is the most common combina-
tion for initial assessment, although MRI scanning can be
substituted for CT (45).
If the initial assessment suggests evidence of laboratory or
radiologic signs of biliary obstruction, assessment of the extent
of biliary involvement by another imaging technique may be
necessary. Gallbladder cancer can cause obstructive jaundice
by direct invasion of the common hepatic duct, or by com-
pression and involvement of the common hepatic duct by
pericholedochal lymph nodes. A high correlation between
Mirizzi’s syndrome and gallbladder cancer exists (23). Endo-
scopic or percutaneous cholangiograms (PTC) are the
200
traditional methods for such assessment. For small tumors,
the pattern of obstruction seen on PTC or ERCP may assist in
differentiating gallbladder cancer from other tumors or benign
disease (46). In the last decade, MR cholangiopancreatography
(MRCP) (Fig. 21.2) has improved to become a suitable, nonin-
vasive substitute for direct cholangiography (47).
Historically, clinical suspicion for main portal venous and/or
hepatic arterial involvement by tumor usually prompted angi-
ography to definitively demonstrate resectability. Improve-
ments in Doppler ultrasound and in MR angiography provide
noninvasive substitutes for such assessment. We will often
assess a patient presenting with known gallbladder cancer with
a single MR scan (48). Detailed information on liver involve-
ment, biliary extension, vascular proximity and involvement,
and nodal disease can all be gleaned from this single noninva-
sive test. With the quality of current cross-sectional imaging, it
is rare that direct cholangiography or angiography is necessary.
Recently, a role for fluorodeoxyglucose positron emission
tomography in the management of patients with gallbladder
cancer has been established. This test is useful in diagnosing
nodal, peritoneal, and distant metastases (49). In a series of
31 patients with gallbladder cancer, 7 (23%) had therapy
altered by staging with FDG-PET.
surgical management
A wide range of operations has been advocated for gallbladder
cancer from simple cholecystectomy to combined extended
hepatectomy, common bile duct resection, and pancreatico-
duodenectomy (50). Debate still exists as to the extent of sur-
gery (51). A survey of prominent gastrointestinal surgeons in
the United States indicated that 49% recommended lymph
node dissection and 64% recommended some form of liver
resection for stage T2–4 disease. The cynical attitude toward
this disease is reflected by the recommendation of 21% of
surgeons to perform only a simple cholecystectomy for node-
positive disease (52).
Studying the earliest stages of the disease, incidental Tis or
T1A gallbladder cancer discovered in specimens following
Figure 21.2 Magnetic resonance cholangiopancreatography demonstrating
extent of gallbladder cancer. Extension of tumor within and obstructing the
common bile duct is shown with isolation of the left and right hepatic duct.
The portal vein (white arrow) is patient and not involved by tumor.
 TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER

laparoscopic cholecystectomy does not warrant further sur-
gery if the cancer is limited to the lamina propria-muscularis
layer and if a subsequent staging workup is negative. These
patients have a 5-year survival rate ranging from 90% to
100% (53). Data would indicate that a potentially curative
approach for gallbladder cancer, except for disease at the earli-
est stages, would require a liver resection and a lymphadenec-
tomy. In the past, some argued that T2 cancers with negative
margins may only require a simple cholecystectomy. More
recent data suggests that this is not the case. A study from
Memorial Sloan-Kettering Cancer Center (MSKCC) demon-
strated that even in T2 gallbladder cancer, extended or radical
resection affords improved survival over cholecystectomy
alone (54). It is clear from pathologic data that T2, T3, or T4
tumors were all associated with greater than a 50% chance of
metastases to the regional lymph nodes (Table 21.2). As liver
resections have become increasingly safe, increasing numbers
of surgical centers are performing radical resections for this
disease and data are consequently accumulating that justifies
such an aggressive approach. Unless a patient has clear contra-
indications to resection, including medical comorbidities or
unresectable disease, surgical exploration should be attempted.
We will review the data supporting radical resection for gall-
bladder cancer at various stages of disease. Then a discussion
of the justification of such treatment in patients with laparo-
scopically discovered gallbladder cancer will be presented.
The most practical way of thinking about laparoscopically
discovered gallbladder cancer is to base therapy upon clinical
T stage of disease. Not only is there a close correlation of T
stage with prognosis, but patients presenting in this setting
will usually have had the gallbladder excised and the extent of
Table 21.2 Findings Related to T stage of Disease
Total Peritoneal Nodal
Stage metastases (%) metastases (%) metastases (%)
T2 9 12 50
T3 16 43 50
T4 16 68 66
T2, submucosal invasion; T3, full thickness invasion through gallbladder
wall with <2 cm extension into liver; T4, > 2 cm extension into liver.
Source: From Ref. (39).
local disease defined pathologically. Knowing the likelihood of
further local, nodal, peritoneal disease will allow for rational
therapeutic choices.
Tumors Confined to the Muscular Propria (T1 Tumors)
There are abundant data to indicate that early gallbladder can-
cer, which has not penetrated through the muscular layer of
the gallbladder, is adequately treated by simple cholecystec-
tomy. Tsukada et al. (55) demonstrated that in 15 cases with T1
lesions, there were no cases with lymph node metastasis.
Table 21.3 (6,20,21,28,35,56–61) summarizes results of resec-
tion for stage I disease. After simple cholecystectomy alone, the
5-year survival was 78% to 100% (59,62). In a report of
56 patients treated with simple cholecystectomy alone, only
two patients recurred and subsequently died of their disease.
Both had submucosal spread of the tumor to involve the cystic
duct margin (21).
When patients present after laparoscopic cholecystectomy
with a pathologic diagnosis of T1 gallbladder cancer, a careful
review of the pathology is imperative. Care must be taken to
verify both negative margins including the cystic duct stump
and that there are no areas of deeper invasion. If the gallblad-
der margin is involved by tumor, a liver resection is required. If
the cystic duct stump is involved, an excision of the common
bile duct, including the junction with the cystic duct, is indi-
cated. No nodal dissection is necessary.
Tumor Invading into the Subserosal Layer (Stage II)
By definition, T2 tumors do not transgress the serosal plane.
However, the recommended management for T2 disease is an
extended or radical cholecystectomy to include a liver resec-
tion and regional lymph node dissection including periportal,
peripancreatic, and celiac nodes. This recommendation is
based on the pattern of spread of disease. In the most common
infiltrative form of gallbladder cancer (25), the cancer often
spreads in a subserosal plane, which is the same as the surgical
plane used for routine cholecystectomy. This results in a higher
likelihood of positive margins after simple cholecystectomy. In
the review by Yamaguchi and Tsuneyoshi (59), patients had
tumor extending into the subserosal layer and 11 of these had
positive microscopic margins after simple cholecystectomy.
Furthermore, the likelihood of metastatic disease to regional

Table 21.3 Actuarial Survival Results Reported In Retrospective Reviews after Resection of Stage I Gallbladder Cancers
Author Year N Procedure 3-Year survival (%) 5-Year survival (%)
Ouchi et al. (56) 1987 14 Not specified 78 71.4
Yamaguchi and Enjoji (28) 1988 11 Not specified 100 Not reported
Donohue et al. (35) 1990 6 Simple cholecystectomy: 83% 100 100
Gall et al. (57) 1991 7 Simple cholecystectomy 86 86
Ogura et al. (20) 1991 366 Not specified 87 78
Shirai et al. (58) 1992 39 Simple cholecystectomy 100 100
Yamaguchi and Tsuneyashi (59) 1992 6 Simple cholecystectomy 100 100
Shirai et al. (21) 1992 56 Simple cholecystectomy 100 100
38 Extended cholecystectomy 100 100
Matsumoto et al. (6) 1992 4 Extended cholecystectomy 100 100
Oertli et al. (60) 1993 6 Simple cholecystectomy 100 100
de Aretxabala et al. (61) 1992 32 Simple cholecystectomy: 69% 94 94

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

lymph nodes exceeds 50% (7,39,52). Indeed, it is perhaps this
group of T2 lesions which will have the best chance of benefit-
ing from definitive extended re-resection (61). Five-year sur-
vival of patients subjected to simple cholecystectomy is 20% to
57% while the survival of patients subjected to radical resec-
tion is 70% to 100% (Table 21.4) (63–66).
For patients presenting with T2 gallbladder cancer discov-
ered at laparoscopic cholecystectomy, a re-exploration with the
intent to perform a liver resection and regional nodal dissection
is recommended. During this re-exploration, inflammation
from the previous operation will make it difficult to determine
the exact extent of disease. Furthermore, all of the laparoscopic
port sites should be excised in a full thickness manner. The
patients must be informed that final pathology may not
demonstrate residual tumor.
Advanced Tumors (stages III and IV)
Patients with T3 or T4 gallbladder cancer will present after
laparoscopic cholecystectomy not only with an obvious patho-
logically positive margin for tumor, but also with a hepatic
mass on cross-sectional imaging. Debate raged in the past
regarding justification of radical surgery for such advanced
disease. As radical resections have become increasingly safe,
reports of long-term survivors after aggressive surgical man-
agement are abundant in the literature; Table 21.5 reviews
these studies. Onoyama et al. (67) reported a 63.6% 5-year
survival for Japanese Biliary Surgical Society stage II and
44.4% 5-year survival for stage III disease after extended cho-
lecystectomy (AJCC 5th edition stage III). They reported a
5-year survival rate of 8.3% for stage IV disease. In addition,
they noted a 5-year survival rate of 60% for patients having
metastatic disease to N1 nodes. Shirai et al. (21) reported a
45% 5-year survival for patients with node-positive tumors,
documenting nine patients surviving over 5 years after radical
resection. Gall et al. (57) reported that four of eight patients
undergoing curative resection for AJCC stages III and IV gall-
bladder carcinoma at the initial operation were alive after 81,
50, 13, and 8 months. Our data from MSKCC revealed a
median overall survival for the 435 patient cohort of
10.3 months. The median survival for those presenting with
stages Ia–III disease was 12.9 months and 5.8 months for those
presenting with stage IV disease (68). We previously reported
a 67% actuarial 5-year survival for patients with completely
resected stage III and 33% 5-year survival for patients with
completely resected stage IV tumors (7, 66) These results rep-
resent marked alteration of the natural history of this tumor.
These data would indicate that radical surgery for
advanced gallbladder cancer may be potentially curative
(Table 21.5) (64–66). Patients presenting with T3 and T4
disease after laparoscopic cholecystectomy should have imag-
ing performed to rule out signs of unresectable disease, includ-
ing noncontiguous liver metastases or signs of carcinomatosis.
Barring any contraindications to surgery (i.e., medical contra-
indications to major abdominal surgery, cirrhosis, or insuffi-
cient remnant liver volume to maintain adequate hepatic
function), patients should be re-explored for radical resection
of tumor, which usually requires a major liver resection and
regional lymphadenectomy.
Re-resection after Laparoscopic Cholecystectomy
Data available for re-resection for gallbladder cancer treated
initially with open simple cholecystectomy suggest that, for
tumors with a depth of penetration greater or equal to the peri-
muscular coat (i.e., T2), a radical re-resection is warranted
(62). However, the prognosis for patients subjected to two
operations for gallbladder cancer is thought to be less favorable
than for patients treated with a single procedure. Gall et al. (57)
reported a median survival of 42 months for patients

Table 21.4 Actuarial Survival Results Reported in Retrospective Reviews after Resection of Stage II Gallbladder Cancers
Author Year N Procedure 3-year survival (%) 5-year survival (%)
Yamaguchi and Enjoji (28) 1988 73 Not specified 40.1 Not reported
Donohue et al. (35) 1990 12 67% Extended chole 58 22
Ogura et al. (20) 1991 499 Not specified 53 37
Gall et al. (57) 1991 7 86% Simple chole 86 86
Shirai et al. (58) 1992 35 Simple chole 57 40.5
10 Extended chole 90 90
Yamaguchi and Tsuneyashi (59) 1992 25 Simple chole 36 36
Matsumoto et al. (6) 1992 9 Extended chole 100 100
Oertli et al. (60) 1993 17 Simple chole 29 24
Cubertafond et al.a (16) 1994 52 88% Simple chole 20 Not reported
Bartlett et al. (7) 1996 8 Extended chole 100 88
Paquet (107) 1998 5 Extended chole 100 80
Shih (63) 2007 34 Extended chole 49 49
Kai (64) 2007 9 Simple chole Extended chole 22 22
25 60 60
Jensen (65) 2008 769 Simple chole Extended chole 40 29
196 55 42
D’Angelica (66) 2008 41 Extended chole 84 79
a
Multi-institutional survey.
Chole, cholecystectomy.

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 TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER

undergoing a curative resection at the first operation versus
12.5 months for those undergoing a curative resection at a sec-
ond operation. Our experience over a 10-year period demon-
strated a median survival of 15.7 months for those discovered
incidentally at laparoscopic cholecystectomy (68). More recent
data would suggest that there is no difference in outcomes in
patients who undergo laparoscopic cholecystectomy for unsus-
pected gallbladder cancer (69,70). Moreover, there appears to
be no difference in survival or recurrence between patients that
have undergone initial open or laparoscopic cholecystectomy
(71). However, it is clear that obtaining an R0 resection signifi-
cantly improves survival in patients undergoing re-resection
(72,73). To that end, a study from Johns Hopkins Hospital (63)
showed that there was no survival difference between patients
who were immediately converted to an open resection when
identified to have gallbladder cancer intraoperatively (N = 6)
versus those patients who had a completed laparoscopic chole-
cystectomy and were re-explored at a later point after discovery
of a gallbladder cancer at histopathological review (N = 33).
This study would suggest that gallbladder carcinoma discov-
ered during a laparoscopic cholecystectomy does not require
immediate conversion to an open resection and should be
referred to a tertiary care center for further exploration.
In a recent series of 206 cases of laparosocpically discovered
gallbladder cancer, 136 patients were re-explored (68). Thirty-
five of these patients were found to have no cancer on explora-
tion or in the final re-excision specimen, while 101 had residual
tumor re-excised. Of note, those without residual disease still
had a 50% chance of eventually dying of cancer. The 5-year
survival of the patients with no residual disease was 63% and
median survival 72 months. Those completely resected of
residual disease had a 5-year survival of 22% and a median
survival of 19 months. Those with incompletely resected
residual disease had a median survival of 12.7 months, and no
patient survived 5 years.
Liver Resection
Except for the patient with T1 tumors who has a positive cystic
duct margin, because of the possibility of residual disease
remaining within the gallbladder bed, all other patients under-
going re-exploration for re-resection should have some form
of liver resection (i.e., a radical or extended cholecystectomy).
Even patients with T2 tumors have a likelihood of residual
gallbladder bed disease because the most common plane for
simple cholecystectomy is subserosal. Recommendations for
liver resection for gallbladder cancer have ranged from a lim-
ited wedge excision of 2 cm of liver around the gallbladder
bed to routine extended right hepatic lobectomy. We prefer an
anatomic segment IVb and V resection when possible, because
this anatomic operation allows the greatest chance of tumor
clearance while minimizing the amount of functional
liver removed.
In cases of previous cholecystectomy, such a limited resection
may not be possible. Scars from the previous surgery may be
difficult to distinguish from tumor and a more radical resection
may be necessary to ensure complete eradication of disease. It

Table 21.5 Actuarial Survival Results reported in Retrospective Reviews after Resection of Stage III and IV Gallbladder Cancers
3-Year 5-Year
Author Year N Stage survival (%) survival (%) Comments
Matsumoto et al. (6) 1992 8 III 38 – Majority with common bile duct
resection
Chijiiwa and Tanaka (102) 1994 12 III 80 – Extended resections only
Onoyama et al. (67) 1995 12 III 44 44 Extended resections only
Bartlett et al. (7) 1996 8 III 63 63 Extended resections only
Ouchi et al. (56) 1987 12 III/IV 17 – Extended resections only
Nakamura et al. (103) 1989 13 III/IV 16 16 Includes 5 HPD, 10 extended
hepatectomy
Donohue et al. (35) 1990 17 III/IV 50 29 Extended resections only
Gall et al. (57) 1991 8 III/IV 50 – Includes only curative resection at initial
surgery
Shirai et al. (58) 1992 20 III/IV – 45 All patients have lymph node metastases
Ogura et al. (20) 1991 453 IV 18 8 Multi-institutional series with 25%
simple cholecystectomy
Todoroki et al. (92) 1991 27 IV 7 – All patients had IORT
Nimura et al. (50) 1991 14 IV 10 – All patients underwent HPD
Matsumoto et al. (6) 1992 27 IV 25 – Includes 3 HPD, 6 extended
hepatectomy, 11 CBD resection
Chijiiwa and Tanaka (102) 1994 11 IV 11 – Extended resections only
Onoyama et al. (67) 1995 14 IV 8 8 Japanese staging
Bartlett et al. (7) 1996 7 IV 25 25 Long-term survivors with no lymph
node metastases
Kai (64) 2007 16 III/IV 40 36
D’Angelica (66) 2008 63 III/IV 45 28
Jensen (65) 2008 119 III 18 9
CBD, common bile duct; HPD, hepatopancreatoduodenectomy; IORT, intraoperative radiation therapy.

203
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
must be emphasized that complete excision of any suspicious
areas must be performed since any residual tumor will result in
recurrence that is usually rapidly fatal. Often, therefore, a right
lobectomy or trisegmentectomy will be necessary.
Lymph Node Dissection
Studies of lymphatic spread of gallbladder cancer have been
published and reviewed (74). Recommendations for lymph
node dissection for gallbladder cancer have ranged from exci-
sion of the cystic duct node alone to en bloc portal lymphad-
enectomy with pancreaticoduodenectomy (6). Justification for
more radical procedures comes from the propensity for early
spread to the superior, anterior, and posterior pancreaticoduo-
denal nodes. Combined liver and pancreatic resections have
high operative mortalities of near 20%, and are not justified by
long-term results.
Portal lymphadenectomy for tumor penetrating the gall-
bladder beyond T2 is supported by our findings of positive
nodes in over 50% of patients with T2, T3, or T4 gallbladder
cancer (39). We also believe that an adequate portal lymphad-
enectomy requires resection of the common bile duct. Par-
ticularly in patients who have just had a cholecystectomy, the
portal lymph nodes are often intimately associated with the
bile duct. Resection of the common bile duct greatly facili-
tates nodal clearance. In general, a full Kocher maneuver
should be performed. The lymphatic tissue should then be
dissected behind the duodenum and pancreas and subse-
quently swept superiorly. Any interaortocaval nodes or supe-
rior mesenteric nodes should be included in the specimen if
possible. The common bile duct should be transected as it
courses posterior to the duodenum into the pancreas. The
portal vein and hepatic artery should be skeletonized and all
tissue swept superiorly along with the transected duct. At the
confluence of the right and left hepatic ducts, the common
bile duct should be divided again (assuming the cystic duct
does not enter the right hepatic duct). A Roux-en-Y hepatico-
jejunostomy should be performed to re-establish biliary–
enteric continuity.
Laparoscopic Port Sites
A number of studies have demonstrated the propensity of
tumor to recur in the laparoscopic port sites because gallblad-
der cancer has a great potential for peritoneal seeding and dis-
semination (Table 21.6) (75–82). Indeed, our preliminary
report of the first ten patients we encountered with laparo-
scopically discovered gallbladder cancer included two patients
in whom the tumor recurrence was found in a port site (79).
The incidence of peritoneal metastases is higher than reported
in the pre-laparoscopic era. One report found a 32% recur-
rence rate appearing as a new or enlarging abdominal wall
mass on physical examination and/or CT scanning for follow-
up of disease (83). Another study by Paolucci (84) found 174
cases of port site metastasis after laparoscopic cholecystectomy
and 12 recurrences in the surgical scar after converted or open
cholecystectomy. This report found a 14% incidence of port
site metastases at 7 months after laparoscopic cholecystectomy
for cancer. Therefore, it has become our standard practice to
excise laparoscopic port sites at the re-exploration. During
204
Table 21.6 Recurrence of Tumor in Laparoscopic Port Sites
Author N Port
Drouard et al. (75) 1 Umbilical
Clair et al. (76) 1 Umbilical
Landen (77) 1 Umbilical
Fligelstone et al. (78) 1 Umbilical
Fong et al. (79) 2 Umbilical
Nduka et al. (80) 1 Epigastric
Nally and Preshaw (81) 1 Umbilical
Kim and Roy (82) 1 Umbilical
Antonakis et al. (42) 0
Cucinotta et al. (108) 3 Not specified
Hamila et al. (109) 4 Not specified
Paolucci (84) 174 Various
that operation, care must be taken to perform a full abdominal
inspection to rule out peritoneal disease (85). Whether such
excision of port sites is useful requires further investigation,
since port recurrence may be just a marker for diffuse perito-
neal dissemination of disease.
Complications
The operations described above are extensive procedures with
substantial risks. In particular, the majority of patients under-
going treatment for gallbladder cancer are in their seventh or
eighth decade of life and may be at increased risk as a conse-
quence of concomitant medical comorbidites. In a multi-insti-
tutional review of 1686 gallbladder cancer resections from
Japan, a comparison of morbidity by procedure was made (20).
A morbidity of 12.8% was reported for cholecystectomy,
21.9% for extended cholecystectomy, and 48.3% for hepatic
lobectomy. The mortality rates were 2.9%, 2.3%, and 17.9%,
respectively. There were 150 hepatopancreatoduodenectomies
for gallbladder cancer, with a 54% morbidity rate and a 15.3%
mortality rate. The morbidity and mortality rates of major
liver resections have decreased in later reports, even in the aged
population (86). In our report of re-resection for laparoscopi-
cally discovered gallbladder cancer, all resected patients were
subjected to some form of liver resection and the operative
mortality was 5% (39).
The most common complications are bile collections, liver
failure, intra-abdominal abscess, and respiratory failure. The
risk of resection for each patient and for each type of resection
needs to be weighed against the chance of benefiting from the
procedure based on the stage of disease.
adjuvant therapy
Because of the rarity of gallbladder cancer in general, as well as
the rarity of completely resected disease, there is only one pro-
spective, randomized trial examining the utility of adjuvant
therapy for gallbladder cancer. This trial assessed 5-year over-
all survival in patients following noncurative resection who
received postoperative adjuvant chemotheraoy using mitomy-
cin C and 5-FU. Survival was improved with adjuvant therapy
(26% vs. 1%, P = 0.03). (87) However, most data available is
derived from retrospective series. Conclusive data do not sup-
port the routine use of chemotherapy (88–90).
 TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER
Data regarding radiation therapy are more substantial, but
still far from conclusive (91). Todoroki et al. (92) examined
intraoperative radiation therapy after complete resection for
stage IV gallbladder cancer. They reported a 10.1% 3-year sur-
vival for patients receiving intraoperative radiation therapy
versus 0% for surgery alone. Bosset et al. (93) examined post-
operative external beam irradiation after complete resection in
seven patients. They concluded that it was a safe treatment,
and five of the seven patients were still alive at a median fol-
low-up of 11 months. Hanna and Rider (94) reported radiation
therapy in 51 patients and reported survival to be significantly
longer in patients receiving postoperative radiotherapy com-
pared with those who had surgery alone. In a retrospective
review from Finland, the median survival of patients receiving
postoperative radiation was 63 months compared with
29 months for patients receiving surgery alone (95). Another
small study from the Mayo clinic evaluated 21 patients follow-
ing curative resection along with adjuvant combined modality
therapy with external beam radiation and 5-FU (96). These
21 patients had a 5-year survival rate of 64% versus a historical
surgical cohort with a 5-year survival rate of 33% after R0
resection alone. Currently, in patients with node-positive
disease, we are recommending radiation therapy. Chemotherapy
is only used as a potential radiation-sensitizing agent.
palliative management
Palliative therapy should be considered in the context that the
median survival for patients presenting with unresectable
gallbladder cancer is 2 to 4 months (60,97). The goal of pallia-
tion should be relief of pain, jaundice, and bowel obstruction,
as well as prolongation of life. These should be done as simply
as possible given the aggressive nature of this disease. Biliary
bypass for obstruction can be difficult because of advanced
disease in the porta hepatis. A segment III bypass is usually
necessary if surgical bypass is chosen to relieve jaun-
dice (98,99). However, such bypasses have a 12% 30-day mor-
tality rate (99) In the event of a preoperative diagnosis of
advanced, unresectable gallbladder cancer in the jaundiced
patient, therefore, a noninvasive radiologic approach to bili-
ary drainage is justified.
Systemic chemotherapy (100) and radiation therapy (101)
have little effect on these tumors. Patients with unresectable
disease and good functional status who desire therapy should
be directed to investigational studies to determine whether any
novel therapies may be of benefit.
summary
Gallbladder cancer is an aggressive disease with a dismal prog-
nosis. It should not, however, be approached with a fatalistic
attitude. Appropriate workup and extended resection can
result in a cure. Gallbladder cancer will be encountered
approximately once every 100 times that a gallbladder is
removed for presumed benign gallstone disease. For those
patients discovered to have a T1 cancer during pathologic
analysis, no further therapy is indicated as long as all the mar-
gins, including the cystic duct margin, are negative (56,58).
However, T2, T3, or T4 tumors deserve consideration for re-
exploration (54,61,102–106). Selection for re-resection relies
upon evaluation of the patient’s general medical fitness as well
as rigorous radiologic workup to rule out disseminated dis-
ease. Evidence of distant nodal (i.e., N2) disease on preopera-
tive workup precludes a curative resection as no long-term
survivors have been reported with gross N2 disease. These
patients should be treated only as symptoms develop but
should not be offered a reoperation for curative intent. Those
re-explored for resection should undergo a standard extended
cholecystectomy, including an extensive nodal dissection to
include the superior pancreaticoduodenal nodes and a skele-
tonization of the vessels in the porta hepatis. If the nodal dis-
section is compromised by the presence of the common bile
duct, then this should be resected. In addition, a segment IVb
and V resection of the liver or extended resection of the liver
should be included, as dictated by the location of the tumor as
well as surrounding inflammation and scar tissue.
key points
Gallbladder cancer will be found in 1 per 100 cholecystec-
tomy specimens (incidence 1.2 cases per 100,000 population
per year).
● 75% to 98% association with cholelithiasis.
● A long obstruction of the mid-common bile duct
is gallbladder cancer until proven otherwise.
● Radiologic investigation of gallbladder cancer:
Ultrasound
MRCP
CT
ERCP/PTC if jaundiced
● Surgical management:
Stage I (T1N0M0): Simple cholecystectomy alone
Stage II (T2N0M0): Radical cholecystectomy
Stage III (T3N0M0) ± hepatic invasion <2 cm:
Radical cholecystectomy
Stage IV (T4N0M0) ± liver invasion >2 cm
– No dissemination: extended hepatectomy
– Widespread dissemination: no surgical option
references
1. Gourgiotis S, Kocher HM, Solaini L, et al. Gallbladder cancer. Am J Surg
2008;196(2):252–64.
2. Kato S, Nakagawa T, Kobayashi H, Arai E, Isetani K. Septum formation
of the common hepatic duct associated with an anomalous junction of
the pancreaticobiliary ductal system and gallbladder cancer: report of a
case. Surgery Today 1994;24(6):534–7.
3. Blalock AA. A statistical study of 888 cases of biliary tract disease. Johns
Hopkins Hosp Bull 1924;35:391–409.
4. Perpetuo MD, Valdivieso M, Heilbrun LK, et al. Natural history study of
gallbladder cancer: a review of 36 years experience at M. D. Anderson
Hospital and Tumor Institute. Cancer 1978;42(1):330–5.
5. Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg
Gynecol Obstetr 1978;147(6):929–42.
6. Matsumoto Y, Fujii H, Aoyama H, et al. Surgical treatment of primary
carcinoma of the gallbladder based on the histologic analysis of
48 surgical specimens. Am J Surg 1992;163(2):239–45.
205
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
7. Bartlett DL, Fong Y, Fortner JG, Brennan MF, Blumgart LH. Long-term
results after resection for gallbladder cancer. Implications for staging
and management. Ann Surg 1996;224(5):639–46.
8. Steinert R, Nestler G, Sagynaliev E, et al. Laparoscopic cholecystectomy
and gallbladder cancer. J Surg Oncol 2006;93(8):682–9.
9. Misra MC, Guleria S. Management of cancer gallbladder found as a sur-
prise on a resected gallbladder specimen. J Surg Oncol 2006;93(8):690–8.
10. Sun CD, Zhang BY, Wu LQ, Lee WJ. Laparoscopic cholecystectomy for
treatment of unexpected early-stage gallbladder cancer. J Surg Oncol
2005;91(4):253–7.
11. Nakeeb A, Comuzzie AG, Martin L, et al. Gallstones: genetics versus
environment. Ann Surg 2002;235(6):842–9.
12. Akatsu T, Ueda M, Shimazu M, et al. Long-term survival of patients
with gallbladder cancer detected during or after laparoscopic cholecys-
tectomy. World J Surg 2005;29(9):1106–9, discussion.
13. Pawlik TM, Scoggins CR, Thomas MB, Vauthey JN. Advances in the sur-
gical management of liver malignancies. Cancer J 2004;10(2):74–87.
14. Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts,
and pancreas. Cancer 1995;75(1 Suppl):171–90.
15. Wanebo HJ, Vezeridis MP. Treatment of gallbladder cancer. Cancer Treat
Res 1994;69:97–109.
16. Cubertafond P, Gainant A, Cucchiaro G. Surgical treatment of 724 car-
cinomas of the gallbladder. Results of the French Surgical Association
Survey. Ann Surg 1994;219(3):275–80.
17. Carty NJ, Johnson CD. Carcinoma of the gallbladder: a survey of cases in
Wessex 1982–1989. J Royal Coll Surgeons Edinburgh 1991;36(4):238–41.
18. Wilkinson DS. Carcinoma of the gall-bladder: an experience and review
of the literature. Austr NZ J Surg 1995;65(10):724–7.
19. Wang SJ, Fuller CD, Kim JS, et al. Prediction model for estimating the
survival benefit of adjuvant radiotherapy for gallbladder cancer. J Clin
Oncol 2008;26(13):2112–7.
20. Ogura Y, Mizumoto R, Isaji S, et al. Radical operations for carcinoma of
the gallbladder: present status in Japan. World J Surg 1991;15(3):337–43.
21. Shirai Y, Yoshida K, Tsukada K, Muto T, Watanabe H. Radical surgery for
gallbladder carcinoma. Long-term results. Ann Surg 1992;216(5):565–8.
22. Tsukada K, Hatakeyama K, Kurosaki I, et al. Outcome of radical surgery
for carcinoma of the gallbladder according to the TNM stage. Surgery
1996;120(5):816–21.
23. Redaelli CA, Buchler MW, Schilling MK, et al. High coincidence of Mir-
izzi syndrome and gallbladder carcinoma. Surgery 1997;121(1):58–63.
24. Albores-Saavedra J, Nadji M, Henson DE. Intestinal-type adenocarci-
noma of the gallbladder. A clinicopathologic study of seven cases. Am J
Surg Pathol 1986;10(1):19–25.
25. Sumiyoshi K, Nagai E, Chijiiwa K, Nakayama F. Pathology of carcinoma
of the gallbladder. World J Surg 1991;15(3):315–21.
26. American College of Surgeons. American Joint Committee on Cancer,
Staging System of Bile Duct Cancers, 6th ed. 2003.
27. Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the gallbladder.
Histologic types, stage of disease, grade, and survival rates. Cancer
1992;70(6):1493–7.
28. Yamaguchi K, Enjoji M. Carcinoma of the gallbladder. A clinicopathology
of 103 patients and a newly proposed staging. Cancer 1988;62(7):1425–32.
29. Peerlinck ID, Irvin TT, Sarsfield PT, Harington JM. GIST (gastro-intes-
tinal stromal tumour) of the gallbladder: a case report. Acta Chir Belg
2004;104(1):107–9.
30. Park JK, Choi SH, Lee S, et al. Malignant gastrointestinal stromal tumor
of the gallbladder. J Korean Med Sci 2004 Oct;19(5):763–7.
31. Chan CP, Chang HC, Chen YL, et al. A 10-year experience of unsus-
pected gallbladder cancer after laparoscopic cholecystectomy. Int Surg
2003;88(3):175–9.
32. Yamamoto H, Hayakawa N, Kitagawa Y, et al. Unsuspected gallbladder
carcinoma after laparoscopic cholecystectomy. J Hepatobiliary Pancreat
Surg 2005;12(5):391–8.
33. Wakai T, Shirai Y, Hatakeyama K. Radical second resection provides sur-
vival benefit for patients with T2 gallbladder carcinoma first discovered
after laparoscopic cholecystectomy. World J Surg 2002 Jul;26(7):867–71.
34. Nevin JE, Moran TJ, Kay S, King R. Carcinoma of the gallbladder: stag-
ing, treatment, and prognosis. Cancer 1976;37(1):141–8.
35. Donohue JH, Nagorney DM, Grant CS, et al. Carcinoma of the gallbladder.
Does radical resection improve outcome? Arch Surg 1990;125(2):237–41.
206
36. Fong Y, Wagman L, Gonen M, et al. Evidence-based gallbladder cancer
staging: changing cancer staging by analysis of data from the National
Cancer Database. Ann Surg 2006;243(6):767–71.
37. Strom BL, Maislin G, West SL, et al. Serum CEA and CA 19-9: potential
future diagnostic or screening tests for gallbladder cancer? Int J Cancer
1990;45(5):821–4.
38. Ritts RE, Jr., Nagorney DM, Jacobsen DJ, Talbot RW, Zurawski VR, Jr.
Comparison of preoperative serum CA19-9 levels with results of diag-
nostic imaging modalities in patients undergoing laparotomy for sus-
pected pancreatic or gallbladder disease. Pancreas 1994;9(6):707–16.
39. Fong Y, Heffernan N, Blumgart LH. Gallbladder carcinoma discovered
during laparoscopic cholecystectomy: aggressive reresection is benefi-
cial. Cancer 1998;83(3):423–7.
40. Akyurek N, Irkorucu O, Salman B, et al. Unexpected gallbladder cancer
during laparoscopic cholecystectomy. J Hepatobiliary Pancreat Surg
2004;11(5):357–61.
41. Aoki T, Tsuchida A, Kasuya K, et al. Is frozen section effective for diag-
nosis of unsuspected gallbladder cancer during laparoscopic cholecys-
tectomy? Surg Endosc 2002;16(1):197–200.
42. Antonakis P, Alexakis N, Mylonaki D, et al. Incidental finding of gall-
bladder carcinoma detected during or after laparoscopic cholecystec-
tomy. Eur J Surg Oncol 2003;29(4):358–60.
43. Darmas B, Mahmud S, Abbas A, Baker AL. Is there any justification for
the routine histological examination of straightforward cholecystec-
tomy specimens? Ann R Coll Surg Engl 2007;89(3):238–41.
44. Chijiiwa K, Sumiyoshi K, Nakayama F. Impact of recent advances in
hepatobiliary imaging techniques on the preoperative diagnosis of car-
cinoma of the gallbladder. World J Surg 1991;15(3):322–7.
45. Wilbur AC, Gyi B, Renigers SA. High-field MRI of primary gallbladder
carcinoma. Gastrointest Radiol 1988;13(2):142–4.
46. Collier NA, Carr D, Hemingway A, Blumgart LH. Preoperative diagno-
sis and its effect on the treatment of carcinoma of the gallbladder. Surg
Gynecol Obstetr 1984;159(5):465ina70.
47. Schwartz LH, Coakley FV, Sun Y, Blumgart LH, Fong Y, Panicek DM. Neo-
plastic pancreaticobiliary duct obstruction: evaluation with breath-hold
MR cholangiopancreatography. Am J Roentgenol 1998;170(6):1491–5.
48. Schwartz LH, Lefkowitz RA, Panicek DM, et al. Breath-hold magnetic
resonance cholangiopancreatography in the evaluation of malignant pan-
creaticobiliary obstruction. J Comput Assist Tomogr 2003;27(3):307–14.
49. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose
positron emission tomography influences management decisions in
patients with biliary cancer. J Am Coll Surg 2008;206(1):57–65.
50. Nimura Y, Hayakawa N, Kamiya J, et al. Hepatopancreatoduodenec-
tomy for advanced carcinoma of the biliary tract. Hepato-Gastroenter-
ology 1991;38(2):170–5.
51. Sicklick JK, Choti MA. Controversies in the surgical management of
cholangiocarcinoma and gallbladder cancer. Semin Oncol 2005;32(6
Suppl 9):S112–17.
52. Gagner M, Rossi RL. Radical operations for carcinoma of the gallblad-
der: present status in North America. World J Surg 1991;15(3):344–7.
53. Shoup M, Fong Y. Surgical indications and extent of resection in gallbladder
cancer. Surgical Oncology Clinics of North America 2002;11(4):985–94.
54. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of
patients presenting initially for definitive operation with those present-
ing after prior noncurative intervention. Ann Surg 2000;232(4):557–69.
55. Tsukada K, Kurosaki I, Uchida K, et al. Lymph node spread from carci-
noma of the gallbladder. Cancer 1997;80(4):661–7.
56. Ouchi K, Owada Y, Matsuno S, Sato T. Prognostic factors in the surgical
treatment of gallbladder carcinoma. Surgery 1987;101(6):731–7.
57. Gall FP, Kockerling F, Scheele J, Schneider C, Hohenberger W. Radical
operations for carcinoma of the gallbladder: present status in Germany.
World J Surg 1991;15(3):328–36.
58. Shirai Y, Yoshida K, Tsukada K, Muto T, Watanabe H. Early carcinoma of
the gallbladder. Eur J Surg 1992;158(10):545–8.
59. Yamaguchi K, Tsuneyoshi M. Subclinical gallbladder carcinoma. Am J
Surg 1992;163(4):382–6.
60. Oertli D, Herzog U, Tondelli P. Primary carcinoma of the gallbladder: oper-
ative experience during a 16 year period. Eur J Surg 1993;159(8):415–20.
61. de A, X, Roa I, Burgos L, et al. Gallbladder cancer in Chile. A report on
54 potentially resectable tumors. Cancer 1992 Jan 1;69(1):60–5.
 TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER
62. Shirai Y, Yoshida K, Tsukada K, Muto T. Inapparent carcinoma of the
gallbladder. An appraisal of a radical second operation after simple cho-
lecystectomy. Ann Surg 1992;215(4):326–31.
63. Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of
laparoscopy and radical resection. Ann Surg 2007;245(6):893–901.
64. Kai M, Chijiiwa K, Ohuchida J, et al. A curative resection improves the
postoperative survival rate even in patients with advanced gallbladder
carcinoma. J Gastrointest Surg 2007;11(8):1025–32.
65. Jensen EH, Abraham A, Habermann EB, et al. A critical analysis of the
surgical management of early-stage gallbladder cancer in the United
States. J Gastrointest Surg 2009;13(4):722–7.
66. D’Angelica M, Dalal KM, DeMatteo RP, et al. Analysis of the extent
of resection for adenocarcinoma of the gallbladder. Ann Surg Oncol
2009;16(4):806–16.
67. Onoyama H, Yamamoto M, Tseng A, Ajiki T, Saitoh Y. Extended cholecys-
tectomy for carcinoma of the gallbladder. World J Surg 1995;19(5):758–63.
68. Duffy A, Capanu M, bou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year
experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg
Oncol 2008;98(7):485–9.
69. Lam CM, Yuen AW, Wai AC, et al. Gallbladder cancer presenting with acute
cholecystitis: a population-based study. Surg Endosc 2005;19(5):697–701.
70. Sarli L, Contini S, Sansebastiano G, et al. Does laparoscopic cholecystec-
tomy worsen the prognosis of unsuspected gallbladder cancer? Arch
Surg 2000;135(11):1340–4.
71. de A, X, Roa IS, Mora JP, et al. Laparoscopic cholecystectomy: its effect
on the prognosis of patients with gallbladder cancer. World J Surg
2004;28(6):544–7.
72. Kang CM, Choi GH, Park SH, et al. Laparoscopic cholecystectomy only
could be an appropriate treatment for selected clinical R0 gallbladder
carcinoma. Surg Endosc 2007;21(9):1582–7.
73. Kang CM, Lee WJ, Choi GH, et al. Does “clinical” R0 have validity in the
choice of simple cholecystectomy for gallbladder carcinoma? J Gastro-
intest Surg 2007;11(10):1309–16.
74. Boerma EJ. Towards an oncological resection of gall bladder cancer. Eur
J Surg Oncol 1994;20(5):537–44.
75. Drouard F, Delamarre J, Capron JP. Cutaneous seeding of gallbladder can-
cer after laparoscopic cholecystectomy. N Engl J Med 1991;325(18):1316.
76. Clair DG, Lautz DB, Brooks DC. Rapid development of umbilical
metastases after laparoscopic cholecystectomy for unsuspected gall-
bladder carcinoma. Surgery 1993;113(3):355–8.
77. Landen SM. Laparoscopic surgery and tumor seeding. Surgery
1993;114(1):131–2.
78. Fligelstone L, Rhodes M, Flook D, Puntis M, Crosby D. Tumour inocu-
lation during laparoscopy. Lancet 1993;342(8867):368–9.
79. Fong Y, Brennan MF, Turnbull A, Coit DG, Blumgart LH. Gallbladder
cancer discovered during laparoscopic surgery. Potential for iatrogenic
tumor dissemination. Arch Surg 1993;128(9):1054–6.
80. Nduka CC, Monson JRT, Menzies-Gow N, Darzi A. Abdominal wall
metastases following laparoscopy. Br J Surg 1994;81:648–52.
81. Nally C, Preshaw RM. Tumour implantation at umbilicus after laparo-
scopic cholecystectomy for unsuspected gallbladder carcinoma. Can J
Surg 1994;37(3):243–4.
82. Kim HJ, Roy T. Unexpected gallbladder cancer with cutaneous seeding
after laparoscopic cholecystectomy. Southern Med J 1994;87(8):
817–20.
83. Winston CB, Chen JW, Fong Y, Schwartz LH, Panicek DM. Recurrent
gallbladder carcinoma along laparoscopic cholecystectomy port tracks:
CT demonstration. Radiology 1999;212(2):439–44.
84. Paolucci V. Port site recurrences after laparoscopic cholecystectomy. J
Hepatobiliary Pancreat Surg 2001;8(6):535–43.
85. Giuliante F, Ardito F, Vellone M, Clemente G, Nuzzo G. Port-sites exci-
sion for gallbladder cancer incidentally found after laparoscopic chole-
cystectomy. Am J Surg 2006;191(1):114–6.
86. Fong Y, Blumgart LH, Fortner JG, Brennan MF. Pancreatic or liver resec-
tion for malignancy is safe and effective for the elderly. Ann Surg
1995;222(4):426–34.
87. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemo-
therapy useful for gallbladder carcinoma? A phase III multicenter pro-
spective randomized controlled trial in patients with resected
pancreaticobiliary carcinoma. Cancer 2002;95(8):1685–95.
88. Chao TC, Jan YY, Chen MF. Primary carcinoma of the gallbladder asso-
ciated with anomalous pancreaticobiliary ductal junction. J Clin Gas-
troenterol 1995;21(4):306–8.
89. Oswalt CE, Cruz AB, Jr. Effectiveness of chemotherapy in addition to sur-
gery in treating carcinoma of the gallbladder. Rev Surg 1977;34(6):436–8.
90. Morrow CE, Sutherland DE, Florack G, Eisenberg MM, Grage TB. Pri-
mary gallbladder carcinoma: significance of subserosal lesions and
results of aggressive surgical treatment and adjuvant chemotherapy.
Surgery 1983;94(4):709–14.
91. Todoroki T. Radiation therapy for primary gallbladder cancer. Hepato-
Gastroenterology 1997;44(17):1229–39.
92. Todoroki T, Iwasaki Y, Orii K, et al. Resection combined with intraop-
erative radiation therapy (IORT) for stage IV (TNM) gallbladder carci-
noma. World J Surg 1991;15(3):357–66.
93. Bosset JF, Mantion G, Gillet M, et al. Primary carcinoma of the gallbladder.
Adjuvant postoperative external irradiation. Cancer 1989;64(9):1843–7.
94. Hanna SS, Rider WD. Carcinoma of the gallbladder or extrahepatic bile
ducts: the role of radiotherapy. Can Med Assoc J 1978;118(1):59–61.
95. Vaittinen E. Carcinoma of the gall-bladder. A study of 390 cases diag-
nosed in Finland 1953-1967. Annales Chirurgiae et Gynaecologiae
Fenniae - Supplement 1970;168:1–81.
96. Kresl JJ, Schild SE, Henning GT, et al. Adjuvant external beam radiation
therapy with concurrent chemotherapy in the management of gallblad-
der carcinoma. Int J Radiation Oncol Biol Phys 2002;52(1):167–75.
97. Wanebo HJ, Castle WN, Fechner RE. Is carcinoma of the gallbladder a
curable lesion? Ann Surg 1982;195(5):624–31.
98. Bismuth H, Corlett MB. Intrahepatic cholangioenteric anastomosis in
carcinoma of the hilus of the liver. Surg Gynecol Obstet 1975;140:170–6.
99. Kapoor VK, Pradeep R, Haribhakti SP, Sikora SS, Kaushik SP. Early carci-
noma of the gallbladder: an elusive disease. J Surg Oncol 1996;62(4):284–7.
100. Taal BG, Audisio RA, Bleiberg H, et al. Phase II trial of mitomycin C
(MMC) in advanced gallbladder and biliary tree carcinoma. An EORTC
Gastrointestinal Tract Cancer Cooperative Group Study. Ann Oncol
1993;4(7):607–9.
101. Houry S, Schlienger M, Huguier M, et al. Gallbladder carcinoma: role of
radiation therapy. Br J Surg 1989;76(5):448–50.
102. Chijiiwa K, Tanaka M. Carcinoma of the gallbladder: an appraisal of
surgical resection. Surgery 1994;115(6):751–6.
103. Nakamura S, Sakaguchi S, Suzuki S, Muro H. Aggressive surgery for car-
cinoma of the gallbladder. Surgery 1989;106(3):467–73.
104. Fong Y, Malhotra S. Gallbladder cancer: recent advances and current
guidelines for surgical therapy. Adv Surg 2001;35:1–20.
105. Whalen GF, Bird I, Tanski W, Russell JC, Clive J. Laparoscopic cholecystec-
tomy does not demonstrably decrease survival of patients with serendipi-
tously treated gallbladder cancer. J Am Coll Surgeons 2001;192(2):189–95.
106. Todoroki T, Takahashi H, Koike N, et al. Outcomes of aggressive treat-
ment of stage IV gallbladder cancer and predictors of survival. Hepato-
Gastroenterology 1999;46(28):2114–21.
107. Paquet KJ. Appraisal of surgical resection of gallbladder carcinoma with
special reference to hepatic resection. J Hepatobiliary Pancreat Surg
1998;5(2):200–6.
108. Cucinotta E, Lorenzini C, Melita G, Iapichino G, Curro G. Incidental
gall bladder carcinoma: does the surgical approach influence the out-
come? Aust NZ J Surg 2005;75(9):795–8.
109. Hamila F, Letaief R, Khnissi M, et al. [Port site recurrence after laparo-
scopic cholecystectomy]. Tunis Med 2006;84(11):697–700.
207
22 Liver transplantation for HCC: Asian perspectives
Shin Hwang, Sung-Gyu Lee, Vanessa de Villa, and Chung Mao Lo
introduction
Hepatocellular carcinoma (HCC) is the fifth most common
and the third most deadly cancer worldwide (1). HCC is
closely associated with chronic liver disease and more than
80% of cases occur in cirrhotic livers (2). Since functional
reserve of the liver is often significantly impaired, application
of treatment modalities such as liver resection, transarterial
chemoembolization, or local ablation therapy is limited. Not
only HCC recurrence, but also progressive deterioration of
liver function decrease patient survival.
Liver transplantation (LT) is the only treatment that offers a
chance of cure for the tumor and the underlying liver cirrhosis
at the same time, although there is an additional risk of accel-
erated tumor recurrence from immunosuppression. The out-
come of LT for HCC in Western countries is encouraging, but
availability of liver grafts still remains the main limitation for
LT. Since the incidence of HCC combined with chronic liver
diseases is much higher, and organ donation from deceased
donors is much fewer in Asian countries compared to Western
countries, it is difficult to use Deceased Donor LT (DDLT) as
one of the main treatment modalities for HCC in Asia. In fact,
organ donation from deceased donors remains below five per
million per year in most Asian countries because of various
social and cultural reasons (Fig. 22.1) (3).
Because of these constraints, Living Donor LT (LDLT) is
now the main method of LT in a number of Asian countries,
and is an alternative to DDLT in every indication for LT.
Numerous technical innovations have been achieved to secure
donor safety as well as ensure patient survival. The outcomes
of LT for HCC in major Asian LT centers are acceptably favor-
able and also comparable to those seen in Western countries (3).
Patient selection criteria for HCC have also been proposed by
several major Asian LT centers based on their own data (4–7).
hepatocellular carcinoma in asia
Hepatitis B and C are the most common etiologic agents for
HCC (8). Since Hepatitis B Virus (HBV) is more prevalent in
most Asian countries, 80% of HCC occurs in areas where HBV
infection is endemic, and the geographic distribution of HCC
largely follows that of HBV infection (2). Chronic HBV infec-
tion is endemic in Asia, where an estimated 300 million indi-
viduals are infected by HBV, representing about 75% of the
world’s chronic HBV carriers (9). China has the highest age-
adjusted incidence of HCC (37.9 per 100,000 in males and
14.2 per 100,000 in females), and accounts for 50% of all cases
in the world (1,2). Unlike other Asian countries, prevalence of
HBV infection is exceptionally low in Japan, where hepatitis C
is more prevalent and similar to that seen in Europe and the
United States (8,10).
Conventional standard treatments for HCC include surgical
resection and non-surgical treatments such as chemoemboli-
208
zation, local ablation, and injection therapy. Surgical resection
has been regarded as the treatment of choice for HCC, but it
has definite limitations in both tumor resectability and patient
safety when hepatic functional reserve is markedly reduced.
Although it has been shown that liver resection can be achieved
safely in selected patients with cirrhosis (11,12), it is widely
accepted that it carries a significant risk of postoperative mor-
bidity, even in patients with Child–Pugh grade A cirrhosis.
With reasonable patient selection, liver resection is associated
with relatively low operative mortality rates, ranging in recent
studies from 0% to 4% (11–13). Long-term survival results
after surgical resection, however, are affected by tumor recur-
rence and progressive deterioration of liver function (14,15).
Non-surgical treatments often result in incomplete tumor
control and also reveal high recurrence rates when used for
advanced HCC lesions. The natural history of untreated and
non-surgically treated HCC in Asia is worse than that of simi-
lar cases in Western countries. A study from Hong Kong (16)
showed that the 1-year and 2-year survival rates of patients
with untreated HCC were 7.8% and 0.9%, respectively, whereas
a comparable study from Spain (17) showed 54% and 40%,
respectively (3).
history of lt in asia
LT in Asia started early and yet progressed slowly when com-
pared with Western countries (3). The first liver transplant in
Asia was performed in 1964 by Nakayama with a graft from a
non-heart beating donor in Chiba, Japan (18). This was only 1
year after Starzl’s first attempt in the world for human LT in
Denver, USA (19). It was a highly controversial exploit because
organ donation from a deceased person was not accepted in
Japanese culture at that time. The second transplant in Asia
was performed in 1978 in Shanghai, P.R. China (3,20). In 1984,
Chen, in Taiwan, performed the first liver transplant with
long-term survival in Asia at a time when there was still no
brain death law in that country (21). Legislation regarding
brain death was passed in Singapore (22) and Taiwan in 1987,
and subsequently in Japan and Korea (23).
In Asia, the serious scarcity of deceased donor organ dona-
tion and strong demand for LT provided a powerful driving
force for the development of LDLT as a practical alternative in
replacing DDLT. The first LDLT in Asia was performed by
Nagasue of Shimane University, Japan, in 1989 (24), only 1
year after the first attempt of LDLT by Raia in Brazil in
1988 (25). Subsequently Hong Kong, Korea, and Taiwan rap-
idly initiated pediatric LDLT programs transplanting a left lat-
eral section or a left lobe graft from a parent donor to a child.
However, the ultimate need for LDLT was in adult patients.
Transplant centers in Asia have repeatedly advanced the fron-
tier of adult-to-adult LDLT. In 1993, Makuuchi in Japan per-
formed the first successful adult LDLT using a left lobe
 LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES
Japan 0.07
Korea 1.9
Hong Kong 4.2
Singapore 4.7
Taiwan 6.6
Australia 10
United Kingdom 10.7
Canada
Germany
Portugal
Italy
France
Belgium
Austria
USA
Spain
0 5 10
Number of deceased donors per million of population
Figure 22.1 Comparison of organ donation rates from deceased donors in different countries in the East and West in 2005 (3).
graft (26). The left lobe graft, which usually comprises less
than 40% of the whole liver volume, is often too small for an
adult recipient. For successful LDLT for adult patients, graft
size is the most important factor in determining the outcome
of LDLT and is still a controversial concern for selection of the
ideal donor. The Kyoto group first reported the use of a right
lobe graft for a pediatric recipient as a result of a variance in
the donor’s arterial anatomy in 1994 (27). The first case
report (28), and subsequently the first series (29) of successful
adult LDLT, using a right lobe graft was reported from Hong
Kong in 1997.
Further technical advances in adult LDLT, including the
addition of the caudate lobe to a left lobe graft (30) and the use
of right lateral section grafts (31), were reported from Japan.
In 1999, authors proposed conservation of the middle hepatic
vein trunk to the donor, and the reconstruction of hepatic
venous drainage of the right anterior section of the liver graft
to avoid congestion injury of both the right lobe liver graft and
the donor’s remnant left lobe (32). Middle hepatic vein recon-
struction has apparently increased the success rate of the right
lobe LDLT in adult patients and widened the safety margin
and the pool of living donors. As an attempt to provide ade-
quate graft volume for an adult recipient and minimize the
risk of an individual donor, authors also performed implanta-
tion of dual grafts from two donors for one recipient in
2000 (33,34).
In Asia, where the supply of deceased donor organs remains
seriously limited and the demand for LT is persistently increas-
ing, the applicability of LDLT will continue. For successful
LDLT, the risk to the donor should be balanced by the greater
benefit to the recipient. Every effort must be taken to minimize
donor morbidities, making this procedure beneficial to the
donor and the recipient (35–38).
selection criteria of hcc and outcome
LT offers the opportunity to eliminate both tumor and under-
lying liver cirrhosis at the same time. From the viewpoints of
quality of life and tumor recurrence, any other treatment
12.8
14.4
19
20.9
22.2
22.8
24.6
25.2
35.1
15 20 25 30 35 40
modality cannot achieve such a favorable result comparable to
that of LT. However, it should be emphasized that HCC recur-
rence is the most common cause of late patient death after
LT (4,39–41). The clinical sequence of post-transplant HCC
recurrence is usually much worse than in non-transplant
patients since the response to treatment for HCC recurrence
after LT is disappointing. To date, the most effective measure
to prevent post-transplant HCC recurrence is strict selection
of transplant candidates after exclusion of patients with known
risk factors for HCC recurrence.
Eligibility guidelines for transplantation, such as the Milan
and University of California at San Francisco (UCSF) criteria,
have been adopted to reduce the post-transplant HCC recur-
rence and the wasting of donor organs (42,43). The Milan cri-
teria were originally established on the basis of pre-transplant
imaging findings but were re-evaluated on the basis of explant
liver pathology, whereas the UCSF criteria were based on
explant pathology but validated by pre-transplant imaging
findings. Each of these two sets of criteria is derived from the
experience with DDLT (Table 22.1). Application of these crite-
ria to LDLT has resulted in patient survival outcome, very
similar to that following DDLT, as shown in high-volume
multi-center cohorts from Japan and Korea (40,41). Moreover,
the prognostic powers of the Milan and UCSF criteria were
reported to be the same in both DDLT and LDLT (41).
When selecting transplant candidates, there is a real risk of
discrepancies between the pre-transplant radiological and
explant pathologic staging (4,40,41). Candidates for DDLT
should be selected after consideration of the extent of HCC at
the time of listing, and any further progression of HCC during
the waiting period. LDLT, because of its shorter waiting time,
is less affected by tumor progression, permitting more flexible
selection of transplant candidates than DDLT. A substantial
proportion of adult LDLT patients not fulfilling the Milan or
UCSF criteria has been found to survive longer than expected
after LT (4,40,41,44,45). Therefore, it seems reasonable to
attempt further reduction of unnecessary dropouts arising
from the strict application of narrow selection criteria.
209
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 22.1 Criteria for Indication of LT in the Setting of Hepatocellular Carcinoma.

Number Patient survival Patient survival
Type of of rate within rate exceeding
Center Tumor criteria donor Viral hepatitis patients criteria criteria
Asan, Korea (4) Diameter ≤5 cm; Number LDLT: 100% HBV: 93%, 221 1-year: 94.3%, 1-year: 71.9%,
of lesions ≤6; No gross HCV: 7% 3-years: 87.5%, 3-years: 37.2%,
vascular invasion 5-years: 81.6% 5-years: 20.7%
Kyoto, Japan (5) Diameter ≤5 cm; Number LDLT: 100% HBV: 34%, 125 5-years: 86.7% 5-years: 34.4%
of lesions ≤10; PIVKA-II HCV: 53%
≤400 mAU/mL
Tokyo, Japan (6) Diameter ≤5 cm; Number LDLT: 100% HCV: 62% 78 Recurrence-free Recurrence-free
of lesion ≤5 3-years: 94% 3-years: 50%
Hangzhou, Total diameter ≤8 cm; or Not defined HBV: 100% 195 1-year: 92.8%, 1-years: 49.9%,
P.R. China (7) total diameter >8 cm 3-years: 70.7%, 3-years: 27.0%,
and histopathologic 5-years: 70.7% 5-years: 18.9%
grades I and II, and AFP
≤400 ng/mL
Milan, Italy (42) Diameter ≤5 cm if single DDLT: 100% HBV: 23%, 48 4-years: 85% 4-years: 50%
lesion; or Diameter HCV: 67%
≤3 cm if multiple lesions
and number of
lesions ≤3
UCSF, USA (47) Diameter ≤6.5 cm if single DDLT: 93%, HBV: 23%, 168 Recurrence-free Recurrence-free
lesion; or Diameter LDLT: 7% HCV: 65% 1-year: 98.6%, 1-year: 80.4%,
≤4.5 cm if 2 lesions with Recurrence-free Recurrence-free
total diameter ≤8 cm 5-years: 96.7% 5-years: 59.5%
Abbreviations: AFP, alpha-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; LDLT, living donor liver transplantation; PIVKA-II, prothrombin induced
by vitamin K absence II; UCSF, University of California at San Francisco.

The golden standard to date for selection of HCC patients
for DDLT and LDLT are the Milan criteria, while the UCSF
criteria are regarded as acceptable alternative guidelines. The
UCSF criteria, which expand the maximal tumor size to 6.5 cm
for a single HCC lesion, produce survival rates comparable to
those of the Milan criteria. However, the study populations in
the original studies evaluating these two criteria do not seem
to be large enough, introducing the possibility of bias from
small numbers of patients with recurrent tumors (42,46). The
prognostic power of these criteria appears sufficient, but their
discriminatory power for those HCC patients who do not
meet these criteria is not sufficiently high (4). Many high-
volume LT center series or multi-center studies revealed that
long-term patient survival rates look uniformly favorable
when extent of HCC met the indication criteria, but the recur-
rence rates showed great differences among indication criteria
(Fig. 22.2). Currently proposed criteria for indication of LT are
summarized in Table 22.1 (4–7,42,47). Considering that these
proposed expanded criteria also showed favorable outcomes
in recent studies (4–7), it is probable that the Milan criteria are
becoming outdated. However, the question is which criteria
should be the new golden standard instead of the Milan
criteria (48).
It is reported that hepatitis C is a significant predictor of
tumor recurrence and impaired survival after LT in patients
with HCC (49), implicating that there may be a benefit in the
expansion of the Milan criteria for HCC in the non-hepatitis C
population. The clinical sequence of HCC in patients with
HBV infection has been reported to be favorable compared to
that in patients with hepatitis C virus infection because HBV
infection is more effectively controllable than hepatitis C
infection after LT (50,51).
Uniquely, some major LT centers in Korea and Japan chal-
lenged the Milan criteria, accepting a much higher number of
nodules (five or more) (4–6,52). On the other hand, a number
of major LT centers in the United States and Europe have
mainly focused on enhanced criteria regarding the tumor
diameter (more than 5 cm) (47,53–55).
LT is also indicated for small HCC in Child–Turcotte–Pugh
(CTP) class B or C cirrhosis, or CTP class A with portal hyper-
tension (42,56–59). However, the optimal treatment strategy
for patients with small single HCC, cirrhosis with preserved
liver function, and absence of portal hypertension is not yet
established. No prospective randomized study has been
reported which compares liver resection and LT for small HCC
in cirrhotic patients who could be eligible for both treatment
modalities. Authors have reported the results of liver resection
in 100 cirrhotic patients with single, less than 3 cm-sized HCC
who would have been eligible for primary LT, comparing
with a group of 17 patients who underwent LT for HCC with
similar tumor stage during diagnosis and preserved liver
function (60). These results showed that 37 of 39 HCC recur-
rences initially occurred in the liver after resection, but only
one recurrence occurred in lung after LT. Overall patient sur-
vival was not proven to be statistically different, but disease-
free survival was significantly different between the two groups
(Fig. 22.3). The influence of these encouraging results of LT for
HCC may be reflected on the proportion of liver recipients

210
 LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES

1.0 1.0

Beyond Asan
0.8 0.8
Proportion of recurrence

Proportion of recurrence
0.6 Beyond UCSF 0.6

Beyond Milan,
0.4 0.4 within Asan
Beyond Milan,
within UCSF
Within Milan
0.2 0.2

Within Milan
0.0 0.0
0 12 24 36 48 60 0 12 24 36 48 60
Posttransplant months Posttransplant months
(A) (B)
Figure 22.2 Comparison of the hepatocellular carcinoma recurrence curves between the Milan and UCSF criteria (A) and between the Milan and Asan criteria (B) (4).

1.0 1.0
LT
0.9 0.9
0.8 0.8
LT
Proportion of survival

Proportion of survival
0.7 0.7
0.6 0.6
0.5 0.5
Hepatectomy
0.4 0.4 Hepatectomy
0.3 0.3
0.2 0.2
0.1 P = 0.27 0.1 P = 0.047
0 0
0 20 40 60 80 100 120 140 0 20 40 60 80 100 120 140
Postoperative months Postoperative months
(A) (B)
Figure 22.3 Comparison of the overall patient survival (A) and recurrence-free survival (B) between the patients who undergone hepatic resection and liver trans-
plantation for hepatocellular carcinoma (HCC) <3 cm-sized, single nodule with Child–Turcotte–Pugh class A cirrhosis (60).

undergoing LT per year in Asia (Fig. 22.4). Hepatic resection is
still a good treatment modality for selected patients because of
lower cost and no requirement for donor organs. However, if a
donor is available, primary LT can be considered as a preferred
treatment modality for single small HCC of CTP class A cir-
rhosis in the presence of portal hypertension, because LT may
provide excellent disease-free survival and maintenance of
normal quality of life (60).
pretransplant treatment for hcc
Pretransplant neoadjuvant therapy has been often attempted
to the HCC patients waiting for LT by the way of percutaneous
ablation or transarterial chemoembolization (61–63). In
patients enrolled for DDLT, pretransplant neoadjuvant ther-
apy is important since the waiting period is usually too long to
leave the patient without any treatment, and downstaging of
advanced tumors may allow expansion of the current criteria
without adversely affecting survival. However, the effect of
downstaging is not strongly supported from the data of a con-
siderable number of clinical studies (64–67). In reality, the
response to neoadjuvant therapy may be potentially influ-
enced by the selection effect for tumors with better biological
behavior. Such a selection bias also influences post-transplant
outcome (68–70).
Salvage LT has been performed for recurrent HCC or dete-
rioration of liver function after primary liver resection. From
the viewpoint of pre-transplant treatment, prior liver resec-
tion has two roles: primary treatment and bridging to LT. Con-
sidering the incidence of deceased donors and high proportion
of LDLT, many of prior liver resection may be intended for
primary curative treatment rather than bridge treatment.
There are two important points to be taken into account
before performing salvage LT (71). The first is the technical
feasibility of LT, especially for LDLT. The surgical condition of
patients with recurrent HCC after prior liver resection is not
very different to that of patients who underwent non-surgical
treatment, except that adhesion and anatomical distortion
exist within the abdomen, which could be overcome by techni-
cal skill (71). Some authors claim that every combination of
prior hepatectomy and living donor graft is feasible for patients

211
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
1,200
1,000
Number of operations
800
600
400
200
0
1994 1995 1996
Figure 22.4 Annual proportions of liver transplants for hepatocellular carcinoma (HCC) in Asia (excluding mainland China) (3).
undergoing salvage LDLT. The second is the main indication
for salvage LT, in which there is still no consensus on eligibility
criteria. Authors also suggest that the survival outcome of sal-
vage LDLT, based on explant tumor staging, was equivalent to
that of primary LDLT, and it may be reasonable that primary
and salvage LDLT share the same indication criteria for HCC.
For salvage LDLT, determination of the timing of LT is of prac-
tical importance. There are proposals to perform LDLT as
early as the situation permits in order to avoid tumor progres-
sion, but it is unclear whether patients who had early HCC
recurrence after liver resection are adequate candidates for sal-
vage LT. If early recurrence is associated with a well-advanced
tumor or unfavorable pathology, the patient may not benefit
from salvage LT because there is a very high probability of
post-transplant HCC recurrence. In contrast, if early recur-
rence is related to incomplete local control of small HCC
lesions, the patient may be a candidate for salvage LT. Patients
with a longer interval between prior liver resection and salvage
LDLT show more favorable survival than those with a shorter
interval. A thorough pre-transplant HCC workup should be
performed because extra-hepatic recurrence was not uncom-
mon in patients with recurrent HCC after resection (37,72,73).
For salvage DDLT, there are two important reports revealing
contradictory results. Belghiti and colleagues (74) compared
18 patients who underwent secondary LT following liver resec-
tion with 70 undergoing primary LT and assessed post-
operative outcomes and long-term survival. They concluded
that in selected patients, liver resection prior to LT does not
increase morbidity or impair long-term survival following
primary LT, and, accordingly, liver resection prior to LT can be
integrated into the treatment strategy for HCC. On the other
hand, Adam and colleagues (75) compared the results of
secondary LT for tumor recurrence following resection of
initially transplantable HCC in 17 patients with cirrhosis with
those of primary LT in 195 patients. They reported that LT
after liver resection was associated with a higher operative
mortality, an increased risk of recurrence, and a poorer
outcome compared with primary LT.
212
HCC Non-HCC
1997 1998 1999 2000 2001 2002 2003 2004 2005
Year
treatment for recurrent hcc after lt
The clinical sequence of post-transplant HCC recurrence is
usually much worse than in non-transplant patients, since the
response to treatment for HCC recurrence after LT is disap-
pointing (Fig. 22.5). Strict recurrence surveillance for early
timely detection for recurrence is recommended. Thus, annual
risk-based adjustment of follow-up intervals should be estab-
lished. Early detection and aggressive treatment for post-
transplant HCC recurrence can result in prolongation of
patient survival in a considerable proportion of patients (76,77).
Such a survival gain may rationalize vigorous post-transplant
surveillance for HCC recurrence.
It is reported that organ transplant recipients given mam-
malian target of rapamycin (mTOR) inhibitor have reduced
incidence of recurrent or de novo post-transplant malig-
nancies (78). Kneteman and colleagues (79) performed DDLT
on 40 patients using sirolimus-based immunosuppression that
minimized exposure to calcineurin inhibitors and steroid.
Tumor-free 4-year survival was 81.1% and the tumor recur-
rence rate was less than 5.3% in 19 recipients with tumors that
satisfied the Milan criteria and were 76.8% and 19% for patients
with extended criteria tumors. From these results, Wall (80)
noted that the results obtained with HCC satisfying the Milan
criteria were good, although not essentially different from those
obtained by others using standard immunosuppressive
therapy (81–83), whereas the results with extended criteria
tumors were excellent, strongly suggesting mTOR inhibitor
therapy inhibited tumor growth. Elsharkawi and colleagues (84)
reported a DDLT case in whom three HCC pulmonary metas-
tases underwent complete regression after conversion from
cyclosporine and azathioprine to sirolimus and mycophenolate
mofetil and who remained tumor-free 18 months later.
The recent demonstration of survival benefits for HCC
patients treated with the oral agent sorafenib is encouraging
progress in the development of molecularly targeted antican-
cer agents in HCC (85,86). Several new targeted agents have
been developed and are under clinical trial in patients under-
going non-surgical treatment, resection, or LT at present. In
 LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES
1.0
0.8
Proportion of survival
0.6
0.4 DDLT
0.2
LDLT
0.0
0 12 24 36
Months
Figure 22.5 Cumulative survival curves after the first detection of hepatocel-
lular carcinoma recurrence in DDLT and LDLT groups. There is no statisti-
cally significant difference between these two groups (41).
contrast to previous cytotoxic agents, most targeted agents do
not induce regression of tumors but stabilize disease progres-
sion. Sorafenib is the first drug proven to prolong survival in
advanced stage patients, but the survival benefit is still rela-
tively short. Therefore, future trials should be conducted
regarding the combination of sorafenib with other pre-existing
treatment modalities or new targeted agents, especially in the
potential role of assisting in a bridge to LT (35,87).
conclusion
The high prevalence of HCC and subsequent high incidence of
HCC in the situation of very low organ donation rate in Asia
lead to making a unique pattern of indication and strategy in
the application of LT. HCC has begun to be a main indication
of LT, especially in the form of LDLT. Effective promotion of
deceased organ donation is essential in every Asian country.
Although LDLT has become the main form of LT in Asia,
donor safety should always be emphasized. The selection indi-
cation of LT for HCC is likely to be expanded further, but it
should be prudently adopted after qualified risk–benefit anal-
yses. Application for small HCC in patients with preserved
liver function has also been an expanded indication after grad-
ual improvements in peri-operative mortality. As before, new
innovative surgical techniques will emerge to solve currently
intractable technical problems. Emergence of new effective
treatment modalities for HCC recurrence will expand the
selection criteria further without compromising disease recur-
rence rate. The practice of LT in Asia will continue to evolve
further, giving more benefits to patients with HCC.
references
1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer
J Clin 2005; 55: 74–108.
2. McGlynn KA, London WT. Epidemiology and natural history of hepato-
cellular carcinoma. Best Pract Res Clin Gastroenterol 2005; 19: 3–23.
3. de Villa V, Lo CM. Liver transplantation for hepatocellular carcinoma in
Asia. Oncologist 2007; 12: 1321–31.
4. Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living
donor liver transplantation for hepatocellular carcinoma at one large-
volume center. Liver Transpl 2008; 14: 935–45.
5. Ito T, Takada Y, Ueda M, et al. Expansion of selection criteria for patients
with hepatocellular carcinoma in living donor liver transplantation. Liver
Transpl 2007; 13: 1637–44.
6. Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation
for hepatocellular carcinoma: Tokyo University Series. Dig Dis 2007;
25: 310–12.
7. Zheng SS, Xu X, Wu J, et al. Liver transplantation for hepatocellular carci-
noma: Hangzhou experiences. Transplantation 2008; 85: 1726–32.
8. Raza SA, Clifford GM, Franceschi S. Worldwide variation in the relative
importance of hepatitis B and hepatitis C viruses in hepatocellular carci-
noma: a systematic review. Br J Cancer 2007; 96: 1127–34.
9. Lesmana LA, Leung NW, Mahachai V, et al. Hepatitis B: Overview of the
burden of disease in the Asia-Pacific region. Liver Int 2006; 26(Suppl 2): 3–10.
10. El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin
Gastroenterol 2002; 35(Suppl 2): S72–8.
11. Fan ST, Lai ECS, Lo CM, et al. Hospital mortality of major hepatectomy
for hepatocellular carcinoma associated with cirrhosis. Arch Surg 1995;
130: 198–203.
12. Lee SG, Hwang S. How I do it: assessment of hepatic functional reserve for
indication of hepatic resection. J Hepatobiliary Pancreat Surg 2005;
12: 38–43.
13. Poon RTP, Fan ST, Lo CM, et al: Long term survival and pattern of recur-
rence after resection of small hepatocellular carcinoma in patients with
preserved liver function. Implications for a strategy of salvage transplan-
tation. Ann Surg 2002; 235: 373–82.
14. Bigourdan JM, Jaeck D, Meyer N, et al: Small hepatocellular carcinoma in
Child A cirrhotic patients: hepatic resection versus transplantation. Liver
Transpl 2003; 9: 513–20.
15. Margarit C, Escartin A, Castells L, et al. Resection for hepatocellular carci-
noma is a good option in Child-Turcotte-Pugh class A patients with cir-
rhosis who are eligible for liver transplantation. Liver Transpl 2005;
11: 1242–51.
16. Yeung YP, Lo CM, Liu CL, et al. Natural history of untreated nonsurgical
hepatocellular carcinoma. Am J Gastroenterol 2005; 100: 1995–2004.
17. Llovet JM, Bustamante J, Castells A, et al. Natural history of untreated
nonsurgical hepatocellular carcinoma: rationale for the design and evalu-
ation of therapeutic trials. Hepatology 1999; 29: 62–7.
18. Shimada M, Fujii M, Morine Y, et al. Living-donor liver transplantation:
present status and future perspective. J Med Invest 2005; 52: 22–32.
19. Starzl TE, Marchioro TL, Vonkaulla KN, et al. Homotransplantation of
the liver in humans. Surg Gynecol Obstet 1963; 117: 659–76.
20. Huang J. Ethical and legislative perspectives on liver transplantation in the
People’s Republic of China. Liver Transpl 2007; 13: 193–6.
21. Chen C, Wang K, Lee M, et al. Liver transplantation for Wilson’s disease:
report of the first successful liver transplant in Taiwan. Jap J Transplant
1987; 22: 178–84.
22. Shum E, Chern A. Amendment of the Human Organ Transplant Act. Ann
Acad Med Singapore 2006; 35: 428–32.
23. de Villa VH, Lo CM, Chen CL. Ethics and rationale of living-donor liver
transplantation in Asia. Transplantation 2003; 75(Suppl 3): S2–5.
24. Nagasue N, Kohno H, Matsuo S, et al. Segmental (partial) liver transplan-
tation from a living donor. Transplant Proc 1992; 24: 1958–9.
25. Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet
1989; 2: 497.
26. Hashikura Y, Makuuchi M, Kawasaki S, et al. Successful living-related par-
tial liver transplantation to an adult patient. Lancet 1994; 343: 1233–4.
27. Yamaoka Y, Washida M, Honda K, et al. Liver transplantation using a right
lobe graft from a living related donor. Transplantation 1994; 57: 1127–30.
28. Lo CM, Fan ST, Liu CL, et al. Extending the limit on the size of adult
recipient in living donor liver transplantation using extended right lobe
graft. Transplantation 1997; 63: 1524–8.
29. Lo CM, Fan ST, Liu CL, et al. Adult-to-adult living donor liver transplan-
tation using extended right lobe grafts. Ann Surg 1997; 226: 261–9.
30. Miyagawa S, Hashikura Y, Miwa S, et al. Concomitant caudate lobe resec-
tion as an option for donor hepatectomy in adult living related liver trans-
plantation. Transplantation 1998; 66: 661–3.
31. Sugawara Y, Makuuchi M, Takayama T, et al. Liver transplantation using a
right lateral sector graft from a living donor to her granddaughter.
Hepatogastroenterology 2001; 48: 261–3.
213
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
32. Lee SG, Lee YJ, Park KM, et al. Anterior segment congestion of a right liver
lobe graft in living donor liver transplantation and its strategy to prevent
congestion. J Korean Soc Transplant 1999; 13: 213–9.
33. Lee S, Hwang S, Park K, et al. An adult-to-adult living donor liver trans-
plant using dual left lobe grafts. Surgery 2001; 129: 647–50.
34. Lee SG. Asian contribution to living donor liver transplantation. Gastro-
enterol Hepatol 2006; 21: 572–4.
35. Hwang S, Lee SG, Lee YJ, et al. Lessons learned from 1,000 living donor
liver transplantations in a single center: how to make living donations
safe. Liver Transpl 2006; 12: 920–7.
36. Lo CM. Complications and long-term outcome of living liver donors: a
survey of 1,508 cases in five Asian centers. Transplantation 2003; 75: S12–5.
37. Akabayashi A, Slingsby BT, Fujita M. The first donor death after living-
related liver transplantation in Japan. Transplantation 2004; 77: 634.
38. Hsu HT, Hwang SL, Lee PH, Chen SC. Impact of liver donation on quality of
life and physical and psychological distress. Transplant Proc 2006; 38: 2102–5.
39. Kaihara S, Kiuchi T, Ueda M, et al. Living-donor liver transplantation for
hepatocellular carcinoma. Transplantation 2003; 75: S37–40.
40. Todo S, Furukawa H, and the Japanese Study Group on Organ Transplan-
tation. Living donor liver transplantation for adult patients with hepato-
cellular carcinoma: experience in Japan. Ann Surg 2004; 240: 451–9.
41. Hwang S, Lee SG, Joh JW, et al. Liver transplantation for adult patients with
hepatocellular carcinoma in Korea: comparison between cadaveric donor
and living donor liver transplantations. Liver Transpl 2005; 11: 1265–72.
42. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treat-
ment of small hepatocellular carcinomas in patients with cirrhosis. N
Engl J Med 1996; 334: 693–9.
43. Marsh JW, Dvorchik I, Bonham CA, Iwatsuki S. Is the pathologic TNM
staging system for patients with hepatoma predictive of outcome? Cancer
2000; 88: 538–43.
44. Gondolesi GE, Roayaie S, Munoz L, et al. Adult living donor liver trans-
plantation for patients with hepatocellular carcinoma: extending UNOS
priority criteria. Ann Surg 2004; 239: 142–9.
45. Takada Y, Ueda M, Ito T, et al. Living donor liver transplantation as a
second-line therapeutic strategy for patients with hepatocellular carci-
noma. Liver Transpl 2006; 12: 912–9.
46. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular
carcinoma: expansion of the tumor size limits does not adversely impact
survival. Hepatology 2001; 33: 1394–403.
47. Yao FY, Xiao L, Bass NM, et al. Liver transplantation for hepatocellular
carcinoma: validation of the UCSF-expanded criteria based on preopera-
tive imaging. Am J Transplant 2007; 7: 2587–96.
48. Weber M, Clavien PA. Hepatocellular carcinoma and liver transplanta-
tion: entering the area after the Milan and University of California at San
Francisco criteria? Liver Transpl 2008; 14: 911–4.
49. Bozorgzadeh A, Orloff M, Abt P, et al. Survival outcomes in liver trans-
plantation for hepatocellular carcinoma, comparing impact of hepatitis C
versus other etiology of cirrhosis. Liver Transpl 2007; 13: 807–13.
50. Sasaki Y, Yamada T, Tanaka H, et al. Risk of recurrence in a long-term
follow-up after surgery in 417 patients with hepatitis B- or hepatitis
C-related hepatocellular carcinoma. Ann Surg 2006; 244: 771–80.
51. Hwang S, Lee SG, Ahn CS, et al. Prevention of hepatitis B recurrence after
living donor liver transplantation: primary high-dose hepatitis B immu-
noglobulin monotherapy and rescue antiviral therapy. Liver Transpl 2008;
14:770–8.
52. Soejima Y, Taketomi A, Yoshizumi T, et al. Extended indication for living
donor liver transplantation in patients with hepatocellular carcinoma.
Transplantation 2007; 83: 893–9.
53. Duffy JP, Varadanian A, Benjamin E, et al. Liver transplantation criteria
for hepatocellular carcinoma should be expanded: a 22-year experience
with 467 patients at UCLA. Ann Surg 2007; 246: 502–11.
54. Onaca N, Davis GL, Goldstein RM, et al. Expanded criteria for liver trans-
plantation in patients with hepatocellular carcinoma: a report from the
International Registry of Hepatic Tumors in Liver Transplantation. Liver
Transpl 2007; 13: 391–9.
55. Jonas S, Mittler J, Pascher A, et al. Living donor liver transplantation of the
right lobe for hepatocellular carcinoma in cirrhosis in a European center.
Liver Transpl 2007; 13: 896–903.
214
56. Llovet JM, Bruix J, Gores GJ. Surgical resection versus transplantation for
early hepatocellular carcinoma: clues for the best strategy. Hepatology
2000; 31: 1019–21.
57. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepa-
tocellular carcinoma. Hepatology 2002; 35: 519–24.
58. Bigourdan JM, Jaeck D, Meyer N, et al. Small hepatocellular carcinoma in
Child A cirrhotic patients: hepatic resection versus transplantation. Liver
Transpl 2003; 9: 513–20.
59. Margarit C, Escartin A, Castells L, et al. Resection for hepatocellular carci-
noma is a good option in Child-Turcotte-Pugh class A patients with cir-
rhosis who are eligible for liver transplantation. Liver Transpl 2005;
11: 1242–51.
60. Moon DB, Lee SG, Hwang S. Liver transplantation for hepatocellular car-
cinoma: single nodule with Child-Pugh class A sized less than 3 cm. Dig
Dis 2007; 25: 320–8.
61. Soderdahl G, Backman L, Isoniemi H, et al. A prospective, randomized,
multi-centre trial of systemic adjuvant chemotherapy versus no addi-
tional treatment in liver transplantation for hepatocellular carcinoma.
Transpl Int 2006; 19: 288–94.
62. Porrett PM, Peterman H, Rosen M, et al. Lack of benefit of pre-transplant
locoregional hepatic therapy for hepatocellular cancer in the current
MELD era. Liver Transpl 2006; 12: 665–73.
63. Decaens T, Roudot-Thoraval F, Bresson-Hadni S, et al. Impact of pre-
transplantation transarterial chemoembolization on survival and recur-
rence after liver transplantation for hepatocellular carcinoma. Liver
Transpl 2005; 11: 767–75.
64. Lubienski A. Hepatocellular carcinoma: interventional bridging to liver
transplantation. Transplantation 2005; 80(Suppl 1): S113–S119.
65. Perez Saborido B, Meneu JC, Moreno E, et al. Is transarterial chemoembo-
lization necessary before liver transplantation for hepatocellular carci-
noma? Am J Surg 2005; 190: 383–7.
66. Decaens T, Roudot-Thoraval F, Bresson-Hadni S, et al. Impact of pre-
transplantation transarterial chemoembolization on survival and recur-
rence after liver transplantation for hepatocellular carcinoma. Liver
Transpl 2005; 11: 767–75.
67. Obed A, Beham A, Pullmann K, et al. Patients without hepatocellular car-
cinoma progression after transarterial chemoembolization benefit from
liver transplantation. World J Gastroenterol 2007; 13: 761–7.
68. Yao FY, Hirose R, LaBerge JM, et al. A prospective study on downstaging
of hepatocellular carcinoma prior to liver transplantation. Liver Transpl
2005; 11: 1505–14.
69. Millonig G, Graziadei IW, Freund MC, et al. Response to preoperative
chemoembolization correlates with outcome after liver transplantation in
patients with hepatocellular carcinoma. Liver Transpl 2007; 13: 272–9.
70. Otto G, Herber S, Heise M, et al. Response to transarterial chemoemboli-
zation as a biological selection criterion for liver transplantation in hepa-
tocellular carcinoma. Liver Transpl 2006; 12: 1260–7.
71. Hwang S, Lee SG, Moon DB, et al. Salvage living donor liver transplanta-
tion after prior liver resection for hepatocellular carcinoma. Liver Transpl
2007; 13: 741–6.
72. Tanaka H, Kubo S, Tsukamoto T, et al. Recurrence rate and transplant-
ability after liver resection in patients with hepatocellular carcinoma who
initially met transplantation criteria. Transplant Proc 2005; 37: 1254–6.
73. Poon RT, Fan ST, Lo CM, et al. Long-term survival and pattern of recur-
rence after resection of small hepatocellular carcinoma in patients with
preserved liver function: implications for a strategy of salvage transplan-
tation. Ann Surg 2002; 235: 373–82.
74. Belghiti J, Cortes A, Abdalla EK, et al. Resection prior to liver resection for
hepatocellular carcinoma. Ann Surg 2003; 238: 885–93.
75. Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to trans-
plantation for hepatocellular carcinoma on cirrhosis. Ann Surg 2003;
238: 508–19.
76. Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular car-
cinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;
10: 534–40.
77. Schwartz M, Konstadoulakis M, Roayaie S. Recurrence of hepatocellular
carcinoma after liver transplantation: is immunosuppression a factor?
Liver Transpl 2005; 11:494–6.
 LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES
78. Monaco AP. The role of mTOR inhibitors in the management of post-
transplant malignancy. Transplantation 2009; 87: 157–63.
79. Kneteman NM, Oberholzer J, Al Saghier M, et al. Sirolimus based immu-
nosuppression for liver transplantation in the presence of extended crite-
ria for hepatocellular carcinoma. Liver Transpl 2004; 10: 1301–11.
80. Wall WJ. Hepatocellular cancer, transplantation, and sirolimus. Liver
Transpl 2004; 10: 1312–4.
81. De Carlis L, Giacomoni A, Pirotta V, et al. Surgical treatment of hepatocel-
lular cancer in the era of hepatic transplantation. J Am Coll Surg 2003;
196: 887–97.
82. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular car-
cinoma: comparison of the proposed UCSF criteria with the Milan criteria
and the Pittsburgh modified TMN criteria. Liver Transpl 2002; 8: 765–74.
83. Herrero JI, Sangro B, Quiroga J, et al. Influence of tumor characteristics
on the outcome of liver transplantation among patients with liver cirrho-
sis and hepatocellular carcinoma. Liver Transpl 2001; 7: 631–6.
84. Elsharkawi M, Staib L, Henne-Bruns D, et al. Complete remission of post-
transplant lung metastases from hepatocellular carcinoma under therapy
with sirolimus and mycophenolate mofetil. Transplantation 2005; 77: 855–7.
85. Thomas M. Molecular targeted therapy for hepatocellular carcinoma. J
Gastroenterol 2009; 44(Suppl 19): 136–41.
86. Wang Z, Zhou J, Fan J, et al. Effect of rapamycin alone and in combination
with sorafenib in an orthotopic model of human hepatocellular carci-
noma. Clin Cancer Res 2008; 14: 5124–30.
87. Lee HC. Systemic chemotherapy of hepatocellular carcinoma–Korean
experience. Oncology 2008; 75(Suppl 1): 114–8.
215
23 Non-surgical treatment of hepatocellular carcinoma
Ghassan K. Abou-Alfa and Karen T. Brown
introduction
Hepatocellular carcinoma (HCC) is the fifth most common
cancer worldwide (1). Added to its worldwide prevalence,
there is a continued rising incidence of HCC in the western
hemisphere (2). More than 80% of patients present with
advanced or unresectable disease, and the recurrence rates
after surgical resection is as high as 50% (3).
Effective therapies for advanced HCC remain an immediate
need. In the field of local therapies for locally advanced dis-
ease, extensive work has been done in regard to the feasibility
and effectiveness of different ablative modalities, with several
issues still in debate.
In the more advanced and metastatic disease settings, recent
data showed an improvement in survival in advanced HCC
with sorafenib. This landmark study not only helped in defin-
ing a standard of care for advanced HCC, but also generated
several clinical questions among whom to treat, and how to
account for the cirrhosis and underlying liver dysfunction.
Second line therapies and future clinical trials are prime time
discussions.
local regional therapies
While surgical treatment remains the best hope for cure in
patients with primary HCC cancer, many patients are not can-
didates for resection or transplantation at the time of presen-
tation. This may be due to the extent or distribution of disease,
underlying liver function, or the general medical condition of
the patient. Although transplantation is essentially curative,
patients spend time on a transplant list awaiting a donor
organ. During this period they are at risk for progression.
Patients who undergo surgical resection have a relatively high
risk of developing recurrent disease in the remaining liver (4).
Thus, local regional therapies, including trans-arterial emboli-
zation and percutaneous chemical or thermal ablation play a
significant role in the care of these patients.
Arterial Embolization
The basic physiologic principle that makes hepatic intra-arte-
rial therapies for HCC feasible is the dual blood supply to the
liver. The portal vein provides over 75% of blood flow to the
hepatic parenchyma, and provides the primary trophic blood
supply, although in cirrhotic patients with portal hypertension
there is a shift toward more dependence upon arterial blood
flow. Conversely, studies performed in the early 1950s estab-
lished that the primary blood supply to liver tumors was from
the hepatic artery (5). Thus malignant tumors may be targeted
by delivering treatments intra-arterially; theoretically treat-
ments administered in this fashion would have little effect on
the hepatic parenchyma and would result in fewer systemic
side effects. Intra-arterial infusion therapies are usually carried
out using permanently implanted ports or pumps and are
216
beyond the scope of this chapter. There are currently three
main categories of percutaneously administered intra-arterial
therapy: bland embolization, chemo-embolization, and radio-
embolization. Recently drug-eluting microspheres that can
be loaded with chemotherapeutic agents have been used for
treating HCC as well.
Chemo-embolization and Bland Embolization
In last 30 years many papers have been published describing
myriad techniques for performing hepatic arterial embolo-
therapy. Chemotherapeutic agents mixed with lipiodol and
injected into the artery supplying the tumor, referred to as
Trans-catheter Arterial Chemo-Embolization, or TACE, has
been extensively studied and used, despite the lack of convinc-
ing pharmacokinetic data favoring this method. Studies clearly
demonstrating high and prolonged concentration of chemo-
therapeutic agents within tumor were performed using mito-
mycin C, doxorubicin, and aclarubicin dissolved in hydrocarbon
solvents and then in lipiodol (6), or using a lipophilic agent (7),
methods which are not clinically used. When the chemothera-
peutic agent is dissolved in water and then mixed with lipiodol
and administered as an emulsion, concentration of drug in the
tumor is immediately high, but low at 6 hours, 1 day, and
7 days (3). In a study by Raoul et al. (8) doxorubicin was given
to patients intra-arterially either alone as an infusion, or emul-
sified with lipiodol, or with lipiodol and gelatin sponge. There
was no significant difference in total amount of doxorubicin
released into the circulating blood, but patients in whom gela-
tin sponge was used had less release within the first hour of
treatment. In a prospective randomized clinical study per-
formed to evaluate the effect of lipiodol when added to intra-
arterial cis-platinum and doxorubicin, there was no difference
in response to treatment between the groups given only intra-
arterial chemotherapy compared to those who received che-
motherapy emulsified with lipiodol (9). Another study
evaluated intra-arterial doxorubicin versus doxorubicin with
lipiodol, and found no difference in the area under the con-
centration–time curve, or terminal half life, and no difference
in pharmacokinetic profile or systemic toxicity using the same
dose schedule but administering the doxorubicin intrave-
nously (10). Pharmacokinetic data supporting the use of
intra-arterial chemotherapy, or chemotherapy plus lipiodol
administered as an emulsion, as commonly used today,
remains debatable.
What has been demonstrated, in both pharmacokinetic and
clinical studies (7,11), is the benefit derived from the addition
of an embolic agent, such as Gelfoam, for chemo-embolization.
This has led some authors to postulate that the primary
tumoricidal effect of embolotherapy might result from isch-
emia induced by the embolization rather than the chemo-
therapy or lipiodol. Two well-known randomized trials of
 NON-SURGICAL TREATMENT OF HEPATOCELLULAR CARCINOMA

chemo-embolization which provide level 1b evidence have
shown an improvement in survival compared to best sup-
portive care (13,14). The study by Llovett et al. randomized
patients into three arms: bland embolization, also referred to
as hepatic arterial embolization (HAE), TACE, and best sup-
portive care (13). Although demonstrating a convincing sur-
vival benefit from TACE, it is unfortunate that the study was
stopped before enough patients had been accrued to the HAE
arm to permit any statement to be made about bland emboli-
zation, in particular with respect to no treatment. When the
trial was stopped, there was no significant difference in sur-
vival between the bland and chemo-embolization groups,
despite the fact that Gelfoam pledgets were used as the
embolic agent in the bland group. It is known that more prox-
imal vessel occlusion within the liver leads to almost immedi-
ate development of flow distal to the occlusion via collateral
vessels, as demonstrated by Michels in 1953 (15). Bland arte-
rial embolization results in ischemic cell death, therefore the
goal must be to cause terminal vessel blockade. The Gelfoam
pledgets used in this trial result in more proximal vessel occlu-
sion. The fact that there was no significant difference in sur-
vival between the chemo-embolization group and the group
embolized with Gelfoam pledgets alone is thus noteworthy.
Bland embolization using small particles known to cause ter-
minal vessel blockade is the primary method of intra-arterial
therapy at some institutions, and level llb evidence as sup-
ported by the data of Maluccio et al. (16). The results of bland
embolization are essentially immediate, and significant tumor
necrosis can be demonstrated by imaging within hours of the
procedure (Fig. 23.1A–C). This is a particularly useful feature
in patients who present with significant tumor burden where
further progression may render them untreatable. This is also
effective for treating tumor thrombus within the portal vein
(Fig. 23.2A and B). Bland particle embolization can provide
prompt control of disease. Little is written about the response
time line in patients treated with TACE. TACE is not per-
formed to “stasis” and the primary effect is considered to be
chemotherapy related. Proponents of this method of treat-
ment often point out that the intent is not to induce necrosis.
These facts lead one to suspect that maximum response to
treatment might not be immediately seen post-embolization.
The bland embolization or chemo-embolization debate has
been going on for quite some time now. Proponents of TACE
continue to assert that this treatment results in deposition of

(A) (B) (C)

Figure 23.1 (A) Pre-treatment CT (arterial phase) in patient with multi-focal HCC. (B) Non-treatment CT performed 12 hours after left hepatic and phrenic
artery particle (bland) embolization. Note retained contrast material and small “gas bubbles” in treated tumor. (C) Post-treatment CT (arterial phase) demonstrat-
ing imaging findings consistent with necrosis of treated tumor corresponding to treated tumor that had retained contrast and “gas bubbles” on immediate post-
embolization CT scan.

(A) (B)

Figure 23.2 (A) Pre-treatment CT in patient with large HCC in right liver with tumor thrombus extending into portal vein (B) post-treatment CT 6 weeks after
bland embolization demonstrating imaging findings of necrosis of tumor within liver and portal vein.

217
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
high concentrations of chemotherapy within the tumor that
stays there for prolonged period of time and, rightly, point out
that this method is the only one that has been proven to extend
survival in the Llovett and Lo randomized trials mentioned
previously (13,14). Excellent results (level IIa evidence) fol-
lowing chemo-embolization have been reported from Japan
on 8510 patients treated between 1994 and 2001, with 1-, 3-,
and 5-year survival of 82%, 47%, and 26% (17). About 74% of
the patients had positive hepatitis C serology. Patients were
excluded if they had evidence of nodal disease or distant
metastases, and only 4% of patients had more than second-
order portal vein involvement; however, almost half of the
patients were Child class B or C. Llovett et al. (13) reported the
probability of survival following chemo-embolization in their
group of 40 patients, the majority of whom had positive hepa-
titis C serology, to be 82%, 63%, and 29% at 1, 2, and 3 years,
respectively, while Lo et al. reported survivals of 57%, 31%,
and 26% at 1, 2, and 3 years, respectively, in their study of
40 patients; 90% of whom were hepatitis B serology positive.
The cumulative survival rates at 1, 2, and 3 years in a recent
report on triple drug chemo-embolization by Buijs et al. (18)
who treated 190 patients were 58%, 39%, and 29%. In this
level IIb evidence study 40% of patients were hepatitis C serol-
ogy positive whereas 21% had positive hepatitis B serology.
Finally, in a large series of patients treated with bland emboli-
zation, Maluccio et al. (16) reported 1-, 2-, and 3-year survival
in 159 patients who were without extra-hepatic disease or por-
tal vein involvement by tumor to be 84%, 66%, and 51%; all of
these patients were treated without the addition of chemo-
therapy or lipiodol to the embolic agent.
What seems clear from this data is that arterial embolother-
apy is an effective method of treating HCC in an effort to
prolong the patient’s survival. This has been proven in
randomized studies comparing chemo-embolization to
supportive care (13,14). Comparable, or better, survival results
can be obtained with bland embolization, as demonstrated by
Maluccio et al. (16).
Drug-Eluting Microspheres
Currently available drug-eluting beads, or DEBs, are preformed
microspheres available in diameters ranging from 40 to 1200
µm. These spheres are deformable and made from a macro-
mere derived from Polyvinyl Alcohol (PVA). They are typically
loaded with doxorubicin when used to treat HCC, using 150 mg
per treatment. The pharmacokinetic profile of the DEBs is sig-
nificantly different than that which is seen with conventional
TACE, with level IIb evidence that the peak drug concentration
in the serum is an order of magnitude lower for DEBs and the
area under the curve (AUC) is significantly lower as well (19).
Objective response by EASL criteria has been reported in 70%
to 80% of patients (19–21) and 1- and 2-year survival of 92.5%
and 88.9% have been reported in a level IIa study of 27 patients
with large or multi-focal tumors (19).
Radio-embolization
Yttrium 90 is a pure β emitter that can be loaded in glass or
resin microspheres and delivered to the tumor intra-arterially.
Only the glass microspheres are approved by the Food and
218
Drug Administration (FDA) for use in treating HCC. Within
the tumor vasculature these microspheres can deliver high
dose radiation to the tumor. The microspheres can be deliv-
ered selectively to the anatomic segment or segments that con-
tain the tumor or, in the case of multi-focal disease, can be
administered in a lobar distribution. Unlike TACE or bland
embolization, prior to treatment with 90Y patients must
undergo planning angiography to evaluate vascular and tumor
anatomy and blood flow dynamics. Non-hepatic branches in
the territory to be treated that may result in gastrointestinal
blood flow are occluded with coil embolization and finally a
technetium 99 macroaggregated albumin scan is performed
both to test for the presence of gastrointestinal blood flow and
to estimate the percent of injected material that is shunted to
the pulmonary vasculature. Radiation dose to the lungs of
30 Gy for a single administration or >50 Gy accumulated in
multiple administrations, as well as any detectable GI blood
flow not correctable by vessel occlusion precludes treatment
with intra-arterial 90Y. Recent level IIb data for 90Y glass micro-
spheres used to treat 140 patients with HCC by Atassi et al.
reported a 68% response rate by EASL criteria. Median sur-
vival for Okuda stage I or II was 800 days versus 368 days and
for Child A or B + C was 800 days versus 258 days (22). Level
IIa evidence supports the use of radio-embolization for down-
staging HCC to other methods of treatment. In a group of
35 patients who were not transplant candidates, Kulik et al.
reported that 66% were downstaged to transplant, resection,
or ablation and the median survival for the entire group was
800 days (23). Although 90Y has been shown to be an effective
method for treating HCC, grade 3 or 4 liver toxicity is seen in
up to 1/3 of low risk patients. Radio-embolization is expensive
and more complicated to administer than either bland or
chemo-embolization. The possibility that radiation-related
hepatic fibrosis superimposed on the patients underlying liver
disease may result in compromised hepatic function several
years after treatment remains unknown.
Percutaneous Chemical or Thermal Ablation
Since the 1980s, Percutaneous Ethanol Injection Therapy
(PEIT) has been widely used to treat patients with HCC (24–27).
There is level IIa evidence that this method is effective, partic-
ularly when used to treat small tumors <3 to 5 cm (28). In the
late 1990s there was a flurry of interest in using acetic acid
injection to treat HCC. Despite encouraging results showing
significant decrease in local recurrence and increase in survival
after acetic acid injection when compared to ethanol, this
agent was never in widespread use (29). Chemical ablation has
been used primarily to treat patients with three or fewer
tumors less than 3 to 5 cm. Even the smallest lesions injected
with ethanol typically required several treatment sessions,
although methods of treating even large tumors in one session
have been described (30,31).
In the late 1990s percutaneous methods of thermal ablation,
particularly Radiofrequency Ablation (RFA), became avail-
able. In 1999, Livraghi et al. published a study of 86 patients
who received either RFA or PEIT “randomized” by the distance
the patient lived from the hospital (32). This study, which
should be considered either Ib or IIa evidence, concluded that
 NON-SURGICAL TREATMENT OF HEPATOCELLULAR CARCINOMA
“RF ablation results in a higher rate of complete necrosis and
requires fewer treatment sessions than percutaneous ethanol
injection. However the complication rate is higher with RF
ablation than with PEIT. RF ablation is the treatment of choice
for most patients with HCC.” Providing level lb evidence of
the effectiveness of RFA, in 2003 Lencioni et al. reported a sta-
tistically significant difference in local recurrence-free survival
in a randomized trial of 102 patients who underwent either
RFA or PEIT, with no significant difference in complication
rate (33). Thermal ablation has moved to the forefront of
treatment for patients with HCC (34) although PEIT is still
used for lesions that are unsuitable for thermal ablation, usu-
ally because of their location.
The concept of combining radiofrequency ablation with
embolization as a means of achieving a more complete abla-
tion, and perhaps shortening treatment time has been
explored. Better results might be expected when embolization
is performed first, since the embolization procedure devascu-
larizes the tumor, eliminating much of the “heat sink” and
potentially improving the efficiency of the deposited energy.
In 2000, Rossi et al. showed that HCC tumors 3.5 to 8.5 cm in
diameter could be ablated in one or two sessions after occlu-
sion of the tumor blood supply with a balloon or gelatin
sponge (35). In 2002, Yamakado et al. performed chemo-
embolization followed by RFA in 64 patients with tumors as
large as 12 cm and reported complete necrosis by imaging of
all lesions regardless of size with only two instances of local
recurrence (36). In a case–control retrospective study pub-
lished in 2005 Maluccio et al. provided level III evidence that
there was no statistically in survival in a group of 40 patients
who underwent surgical resection, when compared to signifi-
cant difference a group of 33 patients treated with bland
embolization followed by either PEIT or RFA in tumors up to
7 cm in size (37). The latest level 1b evidence for the effective-
ness of combined therapy emerged in 2008 when Cheng et al.
a published a randomized-controlled trial of TACE–RFA,
TACE alone or RFA alone in 291 patients with HCC larger
than 3 cm (38). This paper reported statistically significant
improved overall survival in patients treated with TACE–RFA
compared to either method alone. The significance persisted
when patients were stratified into those with one tumor or
more than one tumor. Combining embolization with an abla-
tive method seems to make sense when treating HCC. Per-
forming the embolization prior to the ablation has the
advantage of accurately defining number and size of tumors as
well as making the tumors much more conspicuous for target-
ing with CT when the ablation is performed within 24 to
48 hours.
systemic therapies
Historical Background
Chemotherapy has been studied extensively in HCC. Despite
reported responses ranging between 10% and 20%, no study
has shown an impact on survival. Doxorubicin has been stud-
ied extensively and there is still no agreement about its use in
advanced HCC, with response rates ranging between 0% (39)
and 79% (40). Despite the poor or debatable outcome of most
of these trials, doxorubicin became the default standard for
treatment, and a control arm for several comparative trials test-
ing either other single agents or combination regimens (41).
PIAF (cisPlatin, Interferon, Adriamycin,
and 5-Fluorouracil)
Given the disappointing results of single agent doxorubicin
and other single agent therapies, combination regimens have
also been investigated. A combination of cisplatin, interferon,
doxorubicin, and 5-fluorouracil (PIAF) has demonstrated
promising activity in a phase II study. This regimen yielded a
response rate of 26% and a median survival of 9 months (42).
Of note, 13 patients (26%) who had a partial response, 9
underwent surgery, and 4 (9%) were found to have had a com-
plete pathologic response to chemotherapy. These data were
encouraging enough to consider evaluating PIAF versus doxo-
rubicin as part of a large randomized phase III study that failed
to show any survival advantage for PIAF (43). More impor-
tantly, the data of the phase II study of PIAF raised the possi-
bility of using the combination in the neoadjuvant setting.
This approach would be recommended in that specific setting
of medically fit patients with good liver function in whom
tumor cytoreduction is necessary to permit respectability
(Level of evidence IIa, category C).
Anti-angiogenic Therapies
HCC is a highly vascular solid tumor, and a vascular endothe-
lial growth factor (VEGF) has been shown to promote HCC
development and metastasis in preclinical models (44).
Sorafenib is a novel molecular targeted agents that inhibits
both pro-angiogenic (VEGFR-1, -2, -3; PDGFR-β) and tumor-
igenic (RET, Flt-3, c-Kit) receptor tyrosine kinases (RTKs).
Sorafenib also inhibits the serine or threonine kinase
Raf-1 in vitro (45). A phase II trial of sorafenib evaluating
response in patients with advanced HCC showed 33.6% of
patients to have stable disease (≥16 weeks) commensurate
with a median time-to-progression (TTP) of 4.2 months and
the median overall survival of all patients was 9.2 months (46).
The reported stable disease was commensurate with an inter-
esting observation of central tumor necrosis was found in
many patients in the study (Fig. 23.3). A sub-analysis evaluat-
ing the correlation between tumor necrosis and response was
performed (47). The ratio of tumor necrosis and volume
(N/T) was significantly associated with response, with
responders having greater increase in the ratio between necro-
sis and tumor volume relative to baseline, as compared to non-
responders (p = 0.02), This data stresses the need for radiologic
techniques other than RECIST to evaluate HCC response such
as dynamic imaging. For practical reasons, it is recommended
that patients on soarfenib be followed with triphasic CT scans
or MRI and any decision to continue or stop therapy should be
based on a multiple factors including patient clinical evalua-
tion, imaging studies, and serum markers (where applicable).
(Level of evidence III, category C).
This phase II study led to the development of a large double-
blinded, randomized phase III trial evaluating single agent
sorafenib versus placebo in patients with advanced HCC and
no more than Child–Pugh A cirrhosis (48). The trial demon-
strated an improvement in survival of 10.7 months in the
219
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 23.3 Baseline and serial follow-up scans demonstrate tumor necrosis in a hepatocellular carcinoma patient.
sorafenib group versus 7.9 months in the placebo group (p <
0.001, HR = 0.69). The study led to the approval of sorafenib
by the FDA for the treatment of unresectable HCC (49) and
thus sorafenib became the standard of care in this setting
(Level of evidence Ib, category A). The drug-related grade 3–4
toxicity profile included diarrhea (8%) and hand foot syn-
drome (8%). Despite the infrequency of bleeding events
(<1%), one should still use caution in this regard considering
the anti-angiogenic nature of sorafenib.
Treating Patients with Advanced Cirrhosis
The exciting results of the phase III study apply mainly to
patients with Child–Pugh A score, similar to the population
evaluated in the study. The safety and efficacy of sorafenib in
patients with Child–Pugh B or C cirrhosis is still however
being evaluated. In the phase II study evaluating sorafenib in
HCC (50), 28% of patients had Child–Pugh B cirrhosis. In
28 patients from which pharmacokinetic samples were
obtained, AUC (0–8) (mg h/L) was comparable between the
Child–Pugh A (25.4) and Child–Pugh B (30.3) patients.
Cmax (mg/L) were 4.9 and 6 for Child–Pugh A and B patients,
respectively, with similar drug-related side effects profiles.
However, Child–Pugh B patients had worsening of their liver
function at a more frequent rate. A transient increase of serum
bilirubin was reported in 40% of the patients with Child–Pugh
B compared to 18% of Child–Pugh A patients. It is unclear and
tough if this elevation in bilirubin is drug related or disease
progression. Sorafenib acts as a substrate for UGT1A1, and the
study did not collect direct bilirubin measurements, so it
remains unclear if this total bilirubin may also be due to an
inhibitory effect of UGT1A1 and decreased bilirubin gluc-
uronidation.
Another study evaluating sorafenib in patients with liver
dysfunction may help in giving certain guidance on the use of
sorafenib in patients with liver cirrhosis (51). The most com-
monly reported Drug-Limiting Toxicity (DLT) among patients
with elevated bilirubin at baseline was further elevation of
bilirubin. In the lack of any further data, one may consider the
recommended doses of sorafenib reported in this study:
400 mg PO twice per day for bilirubin up to 1.5 x upper limit
220
of normal (ULN); 200 mg PO twice per day (or 400 mg PO
daily) for bilirubin 1.5 to 3 × ULN; and to avoid sorafenib for
bilirubin above 3 × ULN (Level of evidence IIa, category C).
Nonetheless the safety of sorafenib in patients with HCC and
advanced cirrhosis needs to be further studied.
Future Developments
In the advanced disease setting, the next step will be to evalu-
ate other novel therapies or combinations of different agents
looking for further improvement in survival.
Bevacizumab, another potent anti-angiogenic agent, has
been studied extensively in patients with advanced HCC (52,53).
In one of the two studies of 28 patients, 4 had to discontinue
therapy because of serious adverse events, including 1 transient
ischemic attack and 3 serious esophageal bleeding events, which
led to a modification of the study to identify and manage
esophageal varices prior to enrollment (54). Bevacizumab has
also been studied in combination with chemotherapy (55–57)
and other biologic agents.
The most promising bevacizumab doublet data are in com-
bination with erlotinib (58). Patients with HCC and CLIP ≥ 3
were treated with bevacizumab and erlotinib. Based on the
intent-to-treat analysis, 7 of 34 patients had radiographic
responses and 27 (79.4%) had stability of disease for as long as
8 weeks. Median progression-free survival (PFS) was 9 months
and median overall survival (OS) 19 months. Grade 3 and 4
fatigue and hypertension were each reported in 15% of the
cases and similar grade gastrointestinal bleeds were reported
in 9% of the cases. The positive outcome of this study supports
the biologic relevance of this combination of anti-angiogenic
therapy and tyrosine kinase inhibitor in HCC and should be
explored further.
Sunitinib, another multi-targeted tyrosine kinase inhibitor,
has also been tested in HCC (59). Of 26 patients treated with
sunitinib at 37.5 mg daily dose, 10 (38.5%) showed stability of
disease, with a median PFS of 4.1 months. Another study
showed similarly promising results at the dose of 50 mg, with
median TTP of 21 weeks and median OS of 45 weeks (60).
Sorafenib has been evaluated in combination with doxo-
rubicin as part of a randomized double-blinded phase II
 NON-SURGICAL TREATMENT OF HEPATOCELLULAR CARCINOMA
study of doxorubicin plus sorafenib compared to doxorubicin
plus placebo in chemotherapy-naïve HCC patients (61). The
primary endpoint, median time to progression, was
9 months for the doxorubicin plus sorafenib arm and
5 months for the doxorubicin plus placebo arm. An explor-
atory comparison of OS between the two arms showed a sig-
nificant difference of 13.7 months in favor of doxorubicin
plus sorafenib versus 6.5 months for doxorubicin plus pla-
cebo (p = 0.0049, HR = 0.45). The toxicity profile was simi-
lar between the two arms of the study and with toxicities
commonly seen with single agent doxorubicin and sorafenib.
Grade 3–4 toxicities included fatigue (15%) and neutrope-
nia (50%) in both arms. Sorafenib-related toxicity included
grade 3–4 diarrhea (11%) and grade 3–4 hand–foot syn-
drome (9%) in the combination arm. There was more left
ventricular dysfunction in the doxorubicin plus sorafenib
arm, having been reported in 19% of the cases (all grades)
with 2% grade 3–4. The questionable synergy between
sorafenib and doxorubicin will be best answered in the cur-
rently underway large randomized trial evaluating the com-
bination versus sorafenib alone.
Other clinical scenarios where sorafenib has the potential of
being evaluated are surgical adjuvant setting, peri-trans-arterial
chemo-embolization of embolization, and pre-transplant.
In a study aimed at defining angiogenic activity in tumors
subjected to Trans-Arterial Embolization (TAE) by evaluating
the Tumor Microvessel Density (MVD) in an animal model (62),
it was found that tumors treated with TAE showed varying
degrees of central necrosis with residual viable tumor cells in
the periphery. Tumor MVD in animals treated with TAE was
significantly higher than that in the control group
(23.6 vs. 17.5; p = 0.001). The animals treated with TAE showed
a statistically significant increase in VEGF levels compared
with the control group. The use of an anti-angiogenic therapy
like sorafenib seems plausible to curb this angiogenic drive. A
study evaluating sorafenib in the adjuvant setting is underway.
Post-TACE is also underway.
In an attempt to reduce on the dropout rate on transplant
lists (63), a stabilizing agent like sorafenib seems plausible. How-
ever, the potential bleeding concern from an anti-angiogenic
agent remains an issue that needs to be studied further.
conclusion
HCC remains prevalent worldwide and is showing a steady
rise in incidence in the western hemisphere. A high number of
patients are in need for either local or systemic therapies.
When disease is limited to the liver, a local-regional method of
treatment such as embolization or ablation should be the ini-
tial treatment. In some cases, combining these methods of
treatment or using them sequentially is appropriate. Sorafenib
is the first systemic treatment to demonstrate a survival advan-
tage in a large, randomized, controlled phase III study and is
now approved by the FDA for patients with unresectable HCC.
Future studies are to look into improving the outcome with
sorafenib further by combining with other systemic therapies
or local therapies. Other uses of systemic therapies, that is,
adjuvant therapy, are also under investigation.
references
1. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden:
Globocan 2000. Int J Cancer 2001; 94: 153–6.
2. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in
the United States. N Engl J Med 1999 Mar 11; 340(10): 745–50.
3. Thomas MB, O’Beirne JP, Furuse J, Chan AT, Abou-Alfa G, Johnson P.
Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy,
targeted therapy and immunotherapy. Ann Surg Oncol 2008 Apr; 15(4):
1008–14.
4. Poon R T-P, Fan S-T, lo C-M, et al. Intrahepatic recurrence after curative
resection of Hepatocellular carcinoma: long-Term results of treatment &
prognostic factors. Ann Surg 1999; 229(2): 216–22.
5. Breedis C, Young G. Blood supply of neoplasms of the liver. Am J Pathol
1954; 30: 969–85.
6. Konno T. Targeting cancer chemotherapeutic agents by use of lipiodol
contrast medium. Cancer 1990; 66: 1897–903.
7. Egawa H, Maki A, Mori K, et al. Effects of intra-arterial chemotherapy
with a new lipophilic anticancer agent, Estradiol-Chlorambucil (KM2210),
dissolved in lipiodol on experimental liver tumors in rats. J Surg Oncol
1990; 44: 109–14.
8. Raoul JL, Heresbach D, Bretagne JF, et al. Chemoembolization of hepato-
cellular carcinomas. A study of biodistribution and pharmacokinetics of
doxorubicin. Cancer 1992; 70(3): 585–90
9. Carr BI, Iwatsuki S, Baron R, et al. Intrahepatic arterial cisplatinum and
doxorubicin with or without lipiodol for advanced hepatocellular carci-
noma (HCC): a prospective randomized study. Proc Annu Meet Am Soc
Clin Oncol 1993; 12: A668.
10. Johnson PJ, Kalayci C, Dobbs N, et al. Pharmacokinetics and toxicity of
intraarterial Adriamycin for hepatocellular carcinoma: effect of coadmin-
istration of lipiodol. Hepatology 1991; 13: 120–7.
11. Nakao N, Kamino K, Miura K, et al. Recurrent hepatocellular carcinoma
after partial hepatectomy: value of treatment with transcatheter chemo-
embolization. AJR 1991; 156: 1177–9.
12. Ngan H, Lai C, Fan S, et al. Transcatheter arterial chemoembolization in
inoperable hepatocellular carcinoma: four year follow-up. J Vasc Interv
Radiol 1996; 7: 419–5.
13. Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoem-
bolization versus symptomatic treatment in patients with unresectable
hepatocellular carcinoma: a randomized controlled trial. Lancet 2002;
359: 1734–9.
14. Lo C-M, Ngan H, Tso W-K, et al. Randomized controlled trial of transar-
terial lipiodol chemoembolization for unresectable hepatocellular carci-
noma. Hepatology 2002; 35(5): 1164–71.
15. Michels NA. Collateral arterial pathways to the liver after ligation of the
hepatic artery and removal of the coeliac axis. Cancer 1953; 6: 708.
16. Maluccio MA, Covey AC, Ben Porat L, et al. Transcatheter arterial embo-
lization with only particles for the treatment of unresectable hepatocel-
lular carcinoma. J Vasc Interv Radiol 2008; 19: 862–9.
17. Takayasu K, Arii S, Ikai I, et al. Prospective cohort study of transarterial
chemoembolization for unresectable hepatocellular carcinoma in
8510 patients. Gastroenterology 2006; 131: 461–9.
18. Buijs M, Vossen JA, Frangakis C, et al. Nonresectable hepatocellular carci-
noma: Long-term toxicity in patients treated with transarterial chemo-
embolization – single-center experience. Radiology 2008; 249(1): 346–54.
19. Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular
carcinoma with drug eluting beads: efficacy and doxorubicin pharmaco-
kinetics. J Hepatol 2007; 46: 474–81.
20. Poon RTP, Tso WK, Pang RWC, et al. A phase I/II trial of chemoemboliza-
tion for hepatocellular carcinoma using a novel intra-arterial drug-eluting
bead. Clin Gastroenterol Hepatol 2007; 5: 1100–8.
21. Malagari K, Chatzimichael K, Alexopoulou E, et al. Transarterial chemo-
embolization of unresectable hepatocellular carcinoma with drug eluting
beads: results of an open-label study of 62 patients. Cardiovasc Intervent
Radiol 2008; 31: 269–80.
22. Atassi B, Lewandowski RJ, Kulik L, et al. Treatment of unresectable hepa-
tocellular carcinoma using intra-arterial Y90 (TheraSphere®): long-term
follow-up. Presented at the Society of Interventional Radiology Annual
Meeting 2006, Toronto, ON, Canada.
221
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
23. Kulik L, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (Thera-
Sphere®) treatment of unresectable hepatocellular carcinoma: downstag-
ing to resection, RF ablation and bridge to transplantation. J Surg Oncol
2006; 94: 572–86.
24. Livraghi T, Salmi A, Bolondi L, et al. Small hepatocellular carcinoma:
percutaneous alcohol injection: results in 23 patients. Radiology 1988;
168: 313–7.
25. Ebara M, Ohto M, Sugiura N, et al. Percutaneous ethanol injection for the
treatment of small hepatocellular carcinoma: study of 95 patients. J Gas-
troenterol Hepatol 1990; 5: 616–26.
26. Giorgio A, Tarantino L, Francica G, et al. Percutaneous ethanol injection
under sonographic guidance of hepatocellular carcinoma in compen-
sated and decompensated cirrhotic patients. J Ultrasound Med 1992; 11:
587–95.
27. Shiina S, Imamura M, Omata M. Percutaneous ethanol injection therapy
(PEIT) for malignant liver neoplasms. Sem Intervent Radiol 1997; 14(3):
295–302.
28. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cir-
rhosis in 746 patients: long-term results of percutaneous ethanol injec-
tion. Radiology 1995; 197: 101–8.
29. Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Prospective randomized con-
trolled trial comparing percutaneous acetic acid injection and ethanol injec-
tion for small hepatocellular carcinoma. Hepatology 1998; 27(1): 67–72.
30. Livraghi T, Lazzaroni S, Pellicano S, et al. Percutaneous ethanol injection
of hepatic tumors: single-session therapy with general anesthesia. AJR
1993; 161: 1065–9.
31. Giorgio A, Tarantino L, Francica, et al. One-shot percutaneous ethanol
injection of liver tumors under general anesthesia: preliminary data on
efficacy and complications. Cardiovasc Intervent Radiol 1996; 19: 27–31.
32. Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular carci-
noma: treatment with radiofrequency ablation versus ethanol injection.
Radiology 1999; 210: 655–61.
33. Lencioni RA, Allgaier H-P, Cioni D, et al. Small Hepatocellular carcinoma
in cirrhosis: randomized comparison of radio-frequency thermal abla-
tion versus percutaneous ethanol injection. Radiology 2003; 228: 235–40.
34. Raut CP, Izzo F, Marra P, et al. Significant long-term survival after radio-
frequency ablation of unresectable hepatocellular carcinoma in patients
with cirrhosis. Ann Surg Oncol 22005; 128: 616–28.
35. Rossi S, Garbagnati F, Lencioni R, et al. Percutaneous radio-frequency
thermal ablation of nonresectable hepatocellular carcinoma after occlu-
sion of tumor blood supply. Radiology 2000; 217: 119–26.
36. Yamakada K, Nakatsuka A, Ohmori S, et al. Radiofrequency ablation
combined with chemoembolization in hepatocellular carcinoma: treat-
ment response based on tumor size and morphology. J Vasc Interv Radiol
2002; 13: 1225–32.
37. Maluccio M, Covey AM, Gandhi R, et al. Comparison of survival rates
after bland arterial embolization & ablation versus surgical resection for
treating solitary hepatocellular carcinoma up to 7cm. J Vasc Interv Radiol
2005; 16: 955–61.
38. Cheng B-Q, Jia C-Q, Liu C-T, et al. Chemoembolization combined with
radiofrequency ablation for patients with hepatocellular carcinoma larger
than 3 cm: a randomized controlled trial. JAMA 2008; 299(14): 1669–77.
39. Barbare JC, Ballet F, Petit J, et al. Hepatocellular carcinoma with cirrho-
sis: treatment with doxorubicin. Phase II evaluation. Bull Cancer 1984;
71(5): 442–5.
40. Olweny CL, Med M, Toya T, et al. Treatment of hepatocellular carcinoma
with adriamycin. Preliminary communication. Cancer 1975; 36: 1250–7.
41. Simonetti RG, Liberati A, Angiolini C, et al. Treatment of hepatocellular
carcinoma: a systematic review of randomized controlled trials. Ann
Oncol 1997; 8: 117–36.
42. Leung TW, Patt YZ, Lau WY, et al. Complete pathological remission is
possible with systemic combination chemotherapy for inoperable hepa-
tocellular carcinoma. Clin Cancer Res 1999 Jul; 5(7):1676–81,.
43. Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin
versus cisplatin/interferon α-2b/doxorubicin/fluorouracil (PIAF) combi-
nation chemotherapy for unresectable hepatocellular carcinoma. J Natl
Cancer Inst 2005; 97: 1532–8.
222
44. Yoshiji H, Kuriyama S, Yoshii J, et al. Halting the interaction between vas-
cular endothelial growth factor and its receptors attenuates liver carcino-
genesis in mice. Hepatology 39:1517–24, 2004.
45. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spec-
trum oral anti-tumor activity and targets the Raf/MEK/ERK pathway and
receptor tyrosine kinases involved in tumor progression and angiogenesis.
Cancer Res 2004; 64: 7099–109.
46. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in
patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 1–8.
47. Abou-Alfa GK, Zhao B, Capanu M, et al. Tumor Necrosis as a Correlate
for Response in Subgroup of Patients with Advanced Hepatocellular Car-
cinoma (HCC) Treated with Sorafenib. Stockholm: ESMO, 2008.
48. Llovet JM, Ricci S, Mazzaferro V, et al.; SHARP Investigators Study Group.
Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul
24; 359(4): 378–90.
49. http://www.fda.gov/CDER/Offices/OODP/whatsnew/sorafenib.htm
50. Abou-Alfa GK, Amadori D, Santoro A, et al. Is sorafenib (S) safe and
effective in patients (pts) with hepatocellular carcinoma (HCC) and
Child-Pugh B (CPB) cirrhosis? J Clin Oncol 2008 (May 20 suppl; abstr
4518); 26.
51. Miller A, Murry DJ, Owzar K, et al. Pharmacokinetic (PK) and phase I
study of sorafenib (S) for solid tumors and hematologic malignancies in
patients with hepatic or renal dysfunction (HD or RD): CALGB 60301. J
Clin Oncol 2007; ASCO Annual Meeting Proceedings Part I. Vol 25, No.
18S (June 20 Suppl): 3538.
52. Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical
and biologic effects of bevacizumab in unresectable hepatocellular carci-
noma. J Clin Oncol 2008; 26: 2992–8.
53. Malka D, Dromain C, Farace F, et al. Bevacizumab in patients (pts) with
advanced hepatocellular carcinoma (HCC): preliminary results of a phase
II study with circulating endothelial cell (CEC) monitoring. J Clin Oncol
2007; ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20
Suppl): 4570
54. Schwartz JD, Schwartz M, Goldman J, et al. Bevacizumab in hepatocellu-
lar carcinoma (HCC) for patients without metastasis and without invasion
of the portal vein. 2005 Gastrointestinal Cancer Symposium, No. 134.
55. Zhu AX, Blaskowsky LS, Ryan DP, et al. Phase II study of gemcitabine and
oxaliplatin in combination with bevacizumab in patients with advanced
hepatocellular carcinoma. J Clin Oncol 2006; 24: 1898–903.
56. Sun W, Haller DG, Mykulowycz K, et al. Combination of capecitabine,
oxaliplatin with bevacizumab in treatment of advanced hepatocellular
carcinoma (HCC): a phase II study. J Clin Oncol 2007; ASCO Annual
Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Suppl): 4574.
57. Hsu C, Yang T, Hsu C, et al. Modified-dose capecitabine + bevacizumab
for the treatment of advanced/metastatic hepatocellular carcinoma
(HCC): a phase II, single-arm study. J Clin Oncol 2007; ASCO Annual
Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Suppl): 15190.
58. Thomas MB, Morris JS, Chadha R, et al. Phase II trial of the combination
of bevacizumab and erlotinib in patients who have advanced hepatocel-
lular carcinoma. J Clin Oncol 2009; 27: 843–50.
59. Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and potential bio-
markers of sunitinib monotherapy in advanced hepatocellular carcinoma:
a phase II study. J Clin Oncol 2009; 27: 3027–35.
60. Faivre S, Raymond E, Boucher E, et al. Safety and efficacy of sunitinib in
patients with advanced hepatocellular carcinoma: an open-label, multi-
centre, phase II study. Lancet Oncol 2009; 10: 743–4.
61. Abou-Alfa GK, Johnson P, Knox J, et al. Final results from a phase II
(PhII), randomized, double-blind study of sorafenib plus doxorubicin
(S+D) versus placebo plus doxorubicin (P+D) in patients (pts) with
advanced hepatocellular carcinoma (AHCC). 2008 Gastrointestinal Can-
cers Symposium, No. 128
62. Gupta S, Kobayashi S, Phongkitkarun S, et al. Effect of transcatheter
hepatic arterial embolization on angiogenesis in an animal model. Invest
Radiol 2006 Jun; 41(6): 516–21.
63. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treat-
ment for early hepatocellular carcinoma: resection versus transplantation.
Hepatology 1999; 30: 1434–40.
24 Resection of intrahepatic cholangiocarcinoma
Junichi Arita, Norihiro Kokudo, and Masatoshi Makuuchi
Intrahepatic cholangiocarcinoma (ICC) is a rare (1,2) and
poorly understood biliary malignancy that is increasing in
incidence and therefore, in importance. The literature con-
cerning this disease is mostly limited to retrospective reviews
of patients from specialized hepatobiliary centers; moreover,
only a few case series have included 50 or more patients (3–6).
Surgical resection has offered the only chance of cure in
patients since the earliest era (7). However, no consensus or
guidelines have been established on the optimum procedure in
accordance with the stage of the disease. This article is a review
of the current knowledge on intrahepatic cholangiocarci-
noma, especially from the viewpoint of experienced liver sur-
geons who treat it.
terminology and classification
The term “cholangiocarcinoma” originally referred to primary
tumors of the intrahepatic bile ducts, but not extrahepatic bile
ducts (8); however, in its current usage, it includes intrahepatic,
perihilar, and distal extrahepatic tumors of the bile ducts (9,10).
Therefore, use of the sole word “cholangiocarcinoma” as a dis-
ease category is confusing and not recommended. ICC is a car-
cinoma arising from the mucosa of the intrahepatic bile ducts.
The separation between “intrahepatic” and “extrahepatic” bile
ducts occurs at the second-order branches of the biliary tree
according to the Japanese classification (11), and extrahepatic
bile ducts includes the hilar and common bile duct. ICC
accounts for approximately 10% of all carcinomas arising from
the biliary system (12). In addition to the above-mentioned
confusion, “peripheral cholangiocarcinoma” and “cholangio-
cellular carcinoma” are used almost synonymously with ICC.
Attempts have been made to morphologically classify ICC.
The most popular classification, advocated by the Liver Cancer
Study Group of Japan, is the mass-forming type, periductal-
infiltrating type, and intraductal-growth type (11) (Fig. 24.1).
The mass-forming type of ICC (MF-ICC) is a localized nodu-
lar tumor in the liver parenchyma, with a distinct border and
primarily grows expansively, although it sometimes shows
hilar invasion (3,13). The periductal-infiltrating type of ICC
invades the connective tissue within Glisson’s sheath in an
infiltrative rather than expansive fashion. The intraductal-
growth type of ICC (IG-ICC) is characterized by papillary or
nodular growth within the lumen of the bile ducts. Some of
these tumors exhibit superficial mucosal spread with minimal
changes on radiological images, while others may occlude the
intrahepatic bile duct to induce macroscopic bile duct dilata-
tion (13). Among the three morphologic types, MF-ICC is the
most prevalent, so that much of the description in the follow-
ing sections refers to this type of the tumor.
Originally, MF-ICC was thought to be a distinct category
with a poorer prognosis compared with the other types (3,14).
However, it has been elucidated that IG-ICC is associated with
a better prognosis than the other types (15–20). The reason for
the better prognosis of the latter type of ICC is that this type
can be detected in the early stages based on positive radiologic
signs or by the detection of liver dysfunction because of biliary
obstruction. IG-ICC is often diagnosed before tumor exten-
sion beyond the bile ducts and patients with this type of ICC
present with smaller tumor sizes than patients with the other
types of ICC (20).
epidemiology and risk factors
Over 80% of patients with ICC are reported from the devel-
oping countries of Asia and Africa, and moreover half are
from China (21). ICC accounts for only 1% of all liver malig-
nancies in the United States (22), whereas the reported pro-
portion from Japan is much higher at around 4% (23). The
incidence and mortality have been reported to be increasing
in most countries where wide disease surveillance has been
undertaken (24,25). Several risk factors for ICC have been
suggested, however, in most patients with ICC, no such risk
factors can be identified (26). Conditions pre-disposing to
ICC include infestation with parasitic liver flukes, such as
Opisthorchis viverrini and Clonorchis sinensis (27,28); expo-
sure to Thorotrast (29); hepatitis C virus infection (30–33);
smoking (27,33); and HIV infection (32). Some common
diseases co-existing with ICC have been reported, including
primary sclerosing cholangitis and associated ulcerative coli-
tis (26,34), choledochal cyst, Caroli’s syndrome (35), con-
genital hepatic fibrosis, alcoholic liver disease, and diabetes
mellitus (32,33). There are three reports from the United
States and Denmark of the results of surveys of large popula-
tions conducted to determine the risk factors of ICC (32,33,36).
Common risk factors identified in at least two of these were
cholangitis, gallbladder stones, choledocholithiasis, alcoholic
liver disease, non-specific cirrhosis, hepatitis C virus infec-
tion, diabetes mellitus, inflammatory bowel disease, and
smoking (32,33,36). Interestingly, although correlation with
hepatitis C virus infection has often been reported, involve-
ment of hepatitis B virus infection has never been reported.
pre-operative diagnosis
Because previous surveys of ICC have failed to define high-
risk groups (37), unlike the case for hepatocellular carcinoma,
early detection of ICC patients remains difficult. Moreover,
absence of early symptoms in most patients with ICC leads to
delays in diagnosis. Some of the possible symptoms associated
with ICC include abdominal pain, anemia, and weight
loss (38). In contrast to patients with extrahepatic bile duct
carcinoma, only 0% to 28% of patients with ICC present with
obstructive jaundice (5,6,38).
There are no definite tumor markers for ICC, although
carcinoembryonic antigen (CEA) and carbohydrate antigen
223
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
(A)
(C)
Figure 24.1 Morphologic classification of intrahepatic cholangiocarcinoma according to Liver Cancer Study Group of Japan. (A) Mass-forming type. (B) Periductal-
infiltrating type. (C) Intraductal-growth type. Source : From Ref. 11.
19–9 (CA19–9) are frequently elevated and so used for both
helping to confirm the diagnosis and post-operative monitoring
for tumor recurrence. The sensitivity and specificity of CA19–9
for the diagnosis of ICC have been reported to be in the range
of 70% to over 90% in patients with primary sclerosing cholan-
gitis, using various cut-off points (39–42), although a much
lower sensitivity (53%) was reported in a population without
primary sclerosing cholangitis (43). Low sensitivities for the
diagnosis of ICC have also been reported for other serum
markers that are sometimes used to identify extrahepatic bile
duct carcinoma, for example, the serum levels of liver trans-
aminases, alkaline phosphatase, and total bilirubin (5).
Because ICCs are essentially adenocarcinomas, they often
exhibit imaging findings similar to those of metastatic liver
tumors from carcinomas of the gastrointestinal tract. Typically,
the tumors are partially spherical in shape, with an irregular sur-
face, and are almost hypovascular, with peripheral enhancement
on contrast-enhanced CT, MRI, and ultrasound (44–46). Gas-
troscopy, colonoscopy, CT with optional positron emission
tomography (PET) of the thorax and abdomen should be done
to differentiate ICCs from metastatic tumors originating from
the gastrointestinal tract. Percutaneous tumor biopsy is not rec-
ommended if surgery is considered, because it may cause tumor
seeding and complicate the surgical procedure (47). The diag-
nostic ability of newer imaging modalities, including FDG-PET,
for ICC still remains under debate. One study reported high SUV
values in all of the 10 cases examined (48), and another reported
that the diagnostic accuracy of PET for lymph node metastasis
from this type of tumor was 86%; figures that were higher than
those reported for CT or MRI; also, higher SUV values were
reported to be correlated with a poorer prognosis (49).
surgical strategy
As with hepatocellular carcinoma, the counterpart of ICC as a
primary liver cancer, the only treatment that may offer a
224
(B)
chance of long survival in patients with ICC is surgery. In the
natural history of unresected ICC, the median survival after
diagnosis is less than 1 year (50,51) and most patients present
at an advanced stage when they are no longer suitable candi-
dates for curative resection. A study from the United States
reported that complete tumor resection was possible in only
29 of 44 patients who were considered for curative resection (5).
The prognosis after palliative resection is poor, with median
reported survivals of between 2 and 3 months (50,51).
No consensus has been established with regard to the criteria
for surgery, because of the small number of patients in each
reported series. However, based on the literature, it would seem
that surgery should be offered to all patients with potentially
resectable ICC, regardless of tumor stage. Some have claimed
that positive lymph node metastasis detected on examination
of frozen sections at laparotomy is a contraindication for tumor
resection (3), whereas two reports have recommended surgery
for patients with lymph node metastasis, given a solitary hepatic
lesion (52) or less than two lymph node metastases (53). Sur-
gery affords no survival benefit in patients with ICC with any
extent of distant metastasis (15). Although multiple hepatic
lesions have been shown to be correlated with a poor prognosis
(6,54–56), the indication for surgery in relation to the number
of tumors remains unclear at present.
There is also no established consensus with regard to the
optimal surgical procedure for patients with ICC. A positive
surgical margin has been shown to be associated with a poor
prognosis (3,5,6,54,55) and tumor invasion along Glisson’s
sheath is often observed (57,58), therefore extended anatomi-
cal hepatic resections would seem to be a more rational surgi-
cal procedure as compared with non-anatomical limited
hepatic resections. However, the superiority of such a proce-
dure has not yet been demonstrated. A recent study reported
that under certain conditions, tumor resection with a minimal
surgical margin may be reasonable (59). In patients with ICC
 RESECTION OF INTRAHEPATIC CHOLANGIOCARCINOMA

100

90

80

70

Survival rate (%)

60

50

40
N0 1,028
30

20
N1 495
10

0
0 12 24 36 48 60 72 84 96 108 120 132 144
Survival period (month)
Figure 24.2 Impact of lymph node metastasis on the overall survival rate of patients with ICC who underwent tumor resection. N0 indicates patients without
lymph node metastasis and N1 indicates those with lymph node metastasis. Source : From Ref. 11.

Table 24.1 Outcome After Liver Resection for Intrahepatic Cholangiocarcinoma in Literature
1-year 3-year 5-year Median
First author Year Country n survival, % survival, % survival, % survival, mo
Kawarada (68) 1990 Japan 11 34 34 –
Cherqui (47) 1995 France 14 – – – 14
Schlinkert (66) 1992 USA 6 – – 33 –
Yamamoto (31) 1992 Japan 10 59.3 44.4 44.4 –
Pichlmayr (63) 1995 Germany 32 – – – 12.8
Nakeeb (9) 1996 USA 9 – – 44 22
Jan (67) 1996 China 41 53.7 36.6 26.8 12
Casavilla (54) 1997 USA 34 64 34 26 –
Madariaga (55) 1998 USA 34 67 40 35 19
Chen (38) 1999 Taiwan 138 33 17 14 –
Valverde (65) 1999 France 30 86 22 – 28
Inoue (3) 2000 Japan 52 63 36 36 –
Okabayashi (4) 2001 Japan 60 68 35 29 –
Weber (56) 2001 USA 33 – – – 37.4
DeOliveira (5) 2001 USA 44 – – 40 23
Shimada (59) 2007 Japan 47 – 45 40 –
Paik (6) 2008 Korea 97 74.9 51.8 31.1 –

with apparent invasion of the major portal pedicles or major
hepatic veins, major hepatic resection should be considered.
The decision on the appropriate surgical procedure must be
made with reference to the functional liver reserve; an algo-
rithm suggested by Makuuchi and colleagues (60) has been
widely adopted for this purpose. Pre-operative portal vein
embolization should be considered when the optimal surgical
procedure is impossible based on the functional liver
reserve (61). Some reports have recommended extrahepatic
bile duct resection for MF-ICC, because the majority of this
type of ICC shows biliary invasion (14,57,62).
The reported incidence, from studies including at least
30 patients, of lymph node metastasis in surgically treated
patients with ICC is as high as 18% to 40% (3,54,55,63–65).
Patients with lymph node metastasis have a poor prognosis; a
nation-wide surveillance conducted in Japan (n = 495)
revealed 1-, 3-, and 5-year survival rates of 52.4%, 23.1%, and
15.6%, respectively (Fig. 24.2) (23). The prognostic benefit of
lymph node dissection remains controversial. Some authors
have demonstrated its usefulness in cases where the tumor is
solitary (52,53) and when a limited number of lymph nodes
are metastatic (53). On the other hand, Shimada and col-
leagues (16) contradicted the survival benefit of lymph node
dissection, because it was often seen in patients treated with-
out lymph node dissection that recurrent lymph node metas-
tasis occurred not at the hilar site but at distant sites.
prognosis after surgery
The prognosis after surgery in patients with ICC is slightly
worse than that seen in patients with hepatocellular carcinoma.

225
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

100

90

80

70

Survival rate (%) 60

50

40

30
3,499
20

10

0
0 12 24 36 48 60 72 84 96 108 120 132 144
Survival period (month)
Figure 24.3 Overall survival rates of all patients with ICC who underwent tumor resection. Source : From Ref. 11.

Table 24.2 Prognostic Factors After Surgery for Intrahepatic Cholangiocarcinoma

Lymph Vascular Positive Tumor Multiple Bilobar
First author Year n node invasion margin size tumors disease Others
Nakeeb (9) 1996 9 – – U – – – –
Jan (67) 1996 41 – U U, M – – Lymphatic invasion
Chou (69) 1997 27 U – – – – – –
Casavilla (54) 1997 54 U, M U U, M – U, M U TNM stage
Madariaga (55) 1998 34 U, M U – U U, M U –
Valverde (65) 1999 30 U – – – U – –
Inoue (3) 2000 52 U, M U, M U, M – – – Left lobe
Weber (56) 2001 33 – U, M U – U – –
DeOliveira (5) 2001 44 U – U, M – – – –
Paik (6) 2008 97 U – U, M U U, M – Morphologic type
U, significant by univariate analysis for overall survival; M, significant by multivariate analysis for overall survival.

According to a nation-wide survey conducted in Japan, the 1-,
3-, and 5-year survival rates in 1626 patients who underwent
tumor resection for ICC were 70.5%, 43.8%, and 32.7%,
respectively (Fig. 24.3) (23). The results of surgical treatment
for ICC, most cases of which are accounted for by MF-ICC, are
summarized in (Table 24.1 (3–6,9,31,38,47,54–56,59,63,65–
68). Median survival time ranged from 12 to 37 months, and the
5-year survival rate ranged from 14% to 44%; the wide range
was probably caused by the small number of patients included
in the studies. According to some studies, the pre-operative
mortality rates ranged between 2% and 5%. The most common
site of recurrence was the liver, followed in frequency by lungs,
bones, peritoneum, adrenal glands, and kidneys (54,56). The
prognostic factors in patients undergoing surgery for ICC pro-
posed in the literature are listed in (Table 24.2 (3,5,6,9,54–
56,65,67,69). The indicators of poorer prognosis proposed in
these multiple reports include positive lymph node metastasis,
positive surgical margin, multiple hepatic lesions, presence of
vascular invasion, and a large tumor size. While a large tumor
size and bilobar tumor location were identified as prognostic
factors by univariate analysis in a number of studies, these could
not be confirmed as prognostic factors by multivariate analysis.
Despite these suggested prognostic factors, the contraindica-
tions to surgery have not yet been fully elucidated.
adjuvant therapy
Because the prognosis after tumor resection alone is far from
satisfaction, adjuvant therapy may be considered in some
patients. There have been only a few reports of long-term sur-
vival with such therapy among patients with ICC (70,71).
Moreover, there have been no reported randomized prospec-
tive trials of adjuvant therapy in these patients, although the
CRUK BILCAP study of surgery versus surgery plus adjuvant
gemcitabine continues to recruit in the United Kingdom.
There have also been only a few anecdotal reports of chemo-
therapy for patients with recurrent or unresectable ICC, using
5-FU, cisplatin, epirubicin, gemcitabine, capecitabine, and
cetuximab (72–76). Further therapeutic trials are therefore
warranted using recently developed treatment modalities or
those that are developed in the future, including radiotherapy,
immunotherapy, and chemotherapy with or without mole-
cule-targeted drugs.

226
 RESECTION OF INTRAHEPATIC CHOLANGIOCARCINOMA
references
1. SEER Cancer Statistics Review 1973–2005 [database on the Internet]. U.S.
National Institute of Health. [cited 2009/02/08]. Available from: http://
www.seer.cancer.gov/
2. Cancer Information Service [database on the Internet]. National Cancer
Center. [cited 2009/02/08]. Available from: http://ganjoho.jp/
3. Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prog-
nostic factors in the surgical treatment of mass-forming type cholangio-
carcinoma. Surgery 2000; 127: 498–505.
4. Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for
mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative
and postoperative variables. Cancer 2001; 92: 2374–83.
5. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarci-
noma: thirty-one-year experience with 564 patients at a single institution.
Ann Surg 2007; 245: 755–62.
6. Paik KY, Jung JC, Heo JS, et al. What prognostic factors are important for
resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 2008;
23: 766–70.
7. Hammill CW, Wong LL. Intrahepatic cholangiocarcinoma: a malignancy
of increasing importance. J Am Coll Surg 2008; 207: 594–603.
8. Kokudo N, Makuuchi M. Extent of resection and outcome after curative
resection for intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am
2002; 11: 969–83.
9. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of
intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224: 463–73;
discussion 73–5.
10. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J
Med 1999; 341: 1368–78.
11. Liver Cancer Study Group of Japan. The General Rules for the Clinical and
Pathological Study of Primary Liver Cancer, 5th ed. Tokyo: Kanehara, 2008.
12. Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in under-
standing a deadly old disease. J Hepatol 2006; 45: 856–67.
13. Sano T, Kamiya J, Nagino M, et al. Macroscopic classification and preop-
erative diagnosis of intrahepatic cholangiocarcinoma in Japan. J Hepato-
biliary Pancreat Surg 1999; 6: 101–7.
14. Yamanaka N, Okamoto E, Ando T, et al. Clinicopathologic spectrum of
resected extraductal mass-forming intrahepatic cholangiocarcinoma.
Cancer 1995; 76: 2449–56.
15. Isaji S, Kawarada Y, Taoka H, et al. Clinicopathological features and out-
come of hepatic resection for intrahepatic cholangiocarcinoma in Japan.
J Hepatobiliary Pancreat Surg 1999; 6: 108–16.
16. Shimada M, Yamashita Y, Aishima S, et al. Value of lymph node dissection
during resection of intrahepatic cholangiocarcinoma. Br J Surg 2001;
88: 1463–6.
17. Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intra-
hepatic cholangiocarcinoma and clinicopathological factors influencing
survival. Br J Surg 2002; 89:1525–31.
18. Suh KS, Chang SH, Lee HJ, et al. Clinical outcomes and apomucin expres-
sion of intrahepatic cholangiocarcinoma according to gross morphology.
J Am Coll Surg 2002; 195: 782–9.
19. Tajima Y, Kuroki T, Fukuda K, et al. An intraductal papillary component
is associated with prolonged survival after hepatic resection for intrahe-
patic cholangiocarcinoma. Br J Surg 2004; 91: 99–104.
20. Yeh CN, Jan YY, Yeh TS, et al. Hepatic resection of the intraductal papil-
lary type of peripheral cholangiocarcinoma. Ann Surg Oncol 2004;
11: 606–11.
21. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer
J Clin 2005; 55: 74–108.
22. Martin R, Jarnagin W. Intrahepatic cholangiocarcinoma. Current man-
agement. Minerva Chir 2003; 58: 469–78.
23. Liver Cancer Study Group of Japan. National Surveillance of Primary
Liver Cancer in Japan, 17th Report. Kyoto: Media Planning, 2006.
24. Patel T. Worldwide trends in mortality from biliary tract malignancies.
BMC Cancer 2002; 2: 10.
25. Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic
cholangiocarcinoma in the United States: a true increase? J Hepatol 2004;
40: 472–7.
26. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol
1999; 10 (Suppl 4): 308–11.
27. Parkin DM, Srivatanakul P, Khlat M, et al. Liver cancer in Thailand. I. A
case-control study of cholangiocarcinoma. Int J Cancer 1991; 48: 323–8.
28. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma.
Br J Surg 2002; 89: 962–70.
29. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and
treatment of cholangiocarcinoma: consensus document. Gut 2002; 51
Suppl 6: VI1-9.
30. Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and
hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a
case-control study in Italy. Cancer Causes Control 2001; 12: 959–64.
31. Yamamoto S, Kubo S, Hai S, et al. Hepatitis C virus infection as a likely
etiology of intrahepatic cholangiocarcinoma. Cancer Sci 2004; 95: 592–5.
32. Shaib YH, El-Serag HB, Nooka AK, et al. Risk factors for intrahepatic and
extrahepatic cholangiocarcinoma: a hospital-based case-control study.
Am J Gastroenterol 2007; 102: 1016–21.
33. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic
and extrahepatic cholangiocarcinoma in the United States: a population-
based case-control study. Clin Gastroenterol Hepatol 2007; 5: 1221–8.
34. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malig-
nancies in primary sclerosing cholangitis. J Hepatol 2002; 36: 321–7.
35. Dayton MT, Longmire WP, Jr., Tompkins RK. Caroli’s disease: a premalig-
nant condition? Am J Surg 1983; 145: 41–8.
36. Welzel TM, Mellemkjaer L, Gloria G, et al. Risk factors for intrahepatic
cholangiocarcinoma in a low-risk population: a nationwide case-control
study. Int J Cancer 2007; 120: 638–41.
37. Yamanaka N, Takaya Y, Oriyama T, et al. Hepatoprotective effect of a non-
selective endothelin receptor antagonist (TAK-044) in the transplanted
liver. J Surg Res 1997; 70: 156–60.
38. Chen MF, Jan YY, Jeng LB, et al. Intrahepatic cholangiocarcinoma in Tai-
wan. J Hepatobiliary Pancreat Surg 1999; 6: 136–41.
39. Nichols JC, Gores GJ, LaRusso NF, et al. Diagnostic role of serum CA 19–9
for cholangiocarcinoma in patients with primary sclerosing cholangitis.
Mayo Clin Proc 1993; 68: 874–9.
40. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients
with primary sclerosing cholangitis: a multicenter case-control study.
Hepatology 2000; 31: 7–11.
41. Levy C, Lymp J, Angulo P, et al. The value of serum CA 19-9 in predicting
cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig
Dis Sci 2005; 50: 1734–40.
42. Charatcharoenwitthaya P, Enders FB, Halling KC, et al. Utility of serum
tumor markers, imaging, and biliary cytology for detecting cholangiocar-
cinoma in primary sclerosing cholangitis. Hepatology 2008; 48: 1106–17.
43. Patel AH, Harnois DM, Klee GG, et al. The utility of CA 19-9 in the diag-
noses of cholangiocarcinoma in patients without primary sclerosing
cholangitis. Am J Gastroenterol 2000; 95: 204–7.
44. Miura F, Okazumi S, Takayama W, et al. Hemodynamics of intrahepatic
cholangiocarcinoma: evaluation with single-level dynamic CT during
hepatic arteriography. Abdom Imaging 2004; 29: 467–71.
45. Kim SJ, Lee JM, Han JK, et al. Peripheral mass-forming cholangiocarci-
noma in cirrhotic liver. AJR 2007; 189: 1428–34.
46. Chen LD, Xu HX, Xie XY, et al. Enhancement patterns of intrahepatic
cholangiocarcinoma: comparison between contrast-enhanced ultrasound
and contrast-enhanced CT. Br J Radiol 2008; 81: 881–9.
47. Cherqui D, Tantawi B, Alon R, et al. Intrahepatic cholangiocarcinoma.
Results of aggressive surgical management. Arch Surg 1995; 130:
1073–8.
48. Kim YJ, Yun M, Lee WJ, et al. Usefulness of 18F-FDG PET in intrahepatic
cholangiocarcinoma. Eur J Nucl Med Mol Imaging 2003; 30: 1467–72.
49. Seo S, Hatano E, Higashi T, et al. Fluorine-18 fluorodeoxyglucose positron
emission tomography predicts lymph node metastasis, P-glycoprotein
expression, and recurrence after resection in mass-forming intrahepatic
cholangiocarcinoma. Surgery 2008; 143: 769–77.
50. Chu KM, Fan ST. Intrahepatic cholangiocarcinoma in Hong Kong. J Hep-
atobiliary Pancreat Surg 1999; 6: 149–53.
51. Kim HJ, Yun SS, Jung KH, et al. Intrahepatic cholangiocarcinoma in
Korea. J Hepatobiliary Pancreat Surg 1999; 6: 142–8.
52. Uenishi T, Kubo S, Yamazaki O, et al. Indications for surgical treatment of
intrahepatic cholangiocarcinoma with lymph node metastases. J Hepato-
biliary Pancreat Surg 2008; 15: 417–22.
227
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
53. Nakagawa T, Kamiyama T, Kurauchi N, et al. Number of lymph node
metastases is a significant prognostic factor in intrahepatic cholangiocar-
cinoma. World J Surg 2005; 29: 728–33.
54. Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and transplan-
tation for peripheral cholangiocarcinoma. J Am Coll Surg 1997; 185:
429–36.
55. Madariaga JR, Iwatsuki S, Todo S, et al. Liver resection for hilar and
peripheral cholangiocarcinomas: a study of 62 cases. Ann Surg 1998;
227: 70–9.
56. Weber SM, Jarnagin WR, Klimstra D, et al. Intrahepatic cholangiocarci-
noma: resectability, recurrence pattern, and outcomes. J Am Coll Surg
2001; 193: 384–91.
57. Sasaki A, Aramaki M, Kawano K, et al. Intrahepatic peripheral cholangio-
carcinoma: mode of spread and choice of surgical treatment. Br J Surg
1998; 85: 1206–9.
58. Shirabe K, Shimada M, Harimoto N, et al. Intrahepatic cholangiocarci-
noma: its mode of spreading and therapeutic modalities. Surgery 2002;
131: S159–64.
59. Shimada K, Sano T, Sakamoto Y, et al. Clinical impact of the surgical mar-
gin status in hepatectomy for solitary mass-forming type intrahepatic
cholangiocarcinoma without lymph node metastases. J Surg Oncol 2007;
96: 160–5.
60. Makuuchi M, Kosuge T, Takayama T, et al. Surgery for small liver cancers.
Semin Surg Oncol 1993; 9: 298–304.
61. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver vol-
ume and hepatic functional reserve as a guide to decision-making
in resectional surgery for hepatic tumors. Hepatology 1997; 26:
1176–81.
62. Suzuki S, Sakaguchi T, Yokoi Y, et al. Clinicopathological prognostic fac-
tors and impact of surgical treatment of mass-forming intrahepatic chol-
angiocarcinoma. World J Surg 2002; 26: 687–93.
63. Pichlmayr R, Lamesch P, Weimann A, et al. Surgical treatment of cholan-
giocellular carcinoma. World J Surg 1995; 19: 83–8.
64. Chu KM, Lai EC, Al-Hadeedi S, et al. Intrahepatic cholangiocarcinoma.
World J Surg 1997; 21: 301–5; discussion 5–6.
228
65. Valverde A, Bonhomme N, Farges O, et al. Resection of intrahepatic chol-
angiocarcinoma: a Western experience. J Hepatobiliary Pancreat Surg
1999; 6: 122–7.
66. Schlinkert RT, Nagorney DM, Van Heerden JA, et al. Intrahepatic cholan-
giocarcinoma: clinical aspects, pathology and treatment. HPB Surg 1992;
5: 95–101; discussion –2.
67. Jan YY, Jeng LB, Hwang TL, et al. Factors influencing survival after hepa-
tectomy for peripheral cholangiocarcinoma. Hepatogastroenterology
1996; 43: 614–9.
68. Kawarada Y, Yamagiwa K, Das BC. Analysis of the relationships between
clinicopathologic factors and survival time in intrahepatic cholangiocar-
cinoma. Am J Surg 2002; 183: 679–85.
69. Chou FF, Sheen-Chen SM, Chen YS, et al. Surgical treatment of cholan-
giocarcinoma. Hepatogastroenterology 1997; 44: 760–5.
70. Izumi R, Shimizu K, Kiriyama M, et al. Long-term survival of peripheral
intrahepatic cholangiocarcinoma with distant metastasis. Am J Gastroen-
terol 1995; 90: 505–7.
71. Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann
Oncol 2005; 16 (Suppl 2): ii93–6.
72. Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine
in patients with advanced biliary cancer: a phase II trial. J Clin Oncol
2005; 23: 2332–8.
73. Park SH, Park YH, Lee JN, et al. Phase II study of epirubicin, cisplatin, and
capecitabine for advanced biliary tract adenocarcinoma. Cancer 2006;
106: 361–5.
74. Paule B, Herelle MO, Rage E, et al. Cetuximab plus gemcitabine-oxalipla-
tin (GEMOX) in patients with refractory advanced intrahepatic cholan-
giocarcinomas. Oncology 2007; 72: 105–10.
75. Kim MJ, Oh DY, Lee SH, et al. Gemcitabine-based versus fluoropyrimidine-
based chemotherapy with or without platinum in unresectable biliary
tract cancer: a retrospective study. BMC Cancer 2008; 8: 374.
76. Takezako Y, Okusaka T, Ueno H, et al. Phase II study of cisplatin, epirubi-
cin and continuous infusion of 5-fluorouracil in patients with advanced
intrahepatic cholangiocellular carcinoma (ICC). Hepatogastroenterology
2008; 55: 1380–4.
25 Transplantation for hilar cholangiocarcinoma
Julie K. Heimbach, Charles B. Rosen, and David M. Nagorney
background
Cholangiocarcinoma (CCA) is a malignancy arising from the
bile duct epithelium which has a very poor prognosis. The
incidence in the United States is approximately 1.2 in 100,000,
though it is far higher in Eastern Europe and Asia, and it
appears to be increasing worldwide (1–3). Although CCA can
occur anywhere along the intra- or extra-hepatic bile ducts,
the most common location is at the hilar region, involving the
confluence of the right and left ducts (60%) (4,5). While most
patients develop CCA de novo, risk factors for the develop-
ment of CCA relate to chronic inflammation of the biliary
tree. In Western countries CCA is most often associated with
Primary Sclerosing Cholangitis (PSC), though other risk factors
include choledochal cysts, hepaticolithiasis, and parasitic infec-
tions including Clonorchis sinensis and Opisthorchis viverrini.
The prevalence of CCA in patients with PSC is 5% to 15% (6).
Establishing a timely diagnosis of hilar CCA is challenging.
The tumor is a desmoplastic lesion which typically grows
along the bile duct rather than in a radial diameter which lim-
its early detection by cross-sectional imaging. Endoscopic
brushing and biopsy are often negative even in of the presence
well-established disease, and the tropism for bile producing
growth in a longitudinal fashion often leads to the lack of a
mass lesion, even in the face of biliary obstruction (7). Eventu-
ally, tumor growth becomes independent of bile and mass
lesions develop, which are demonstrable by cross sectional
imaging. Direct cholangiography (endoscopic retrograde
cholangiography and percutaneous transhepatic cholangio-
gram) best characterizes the site, extent, and configuration of
ductal CCA. However, the use of imaging modalities, includ-
ing high-resolution CT and MRI, are also important for the
diagnosis of CCA by providing additional information regard-
ing adjacent structures which differentiate CCA from benign
counterparts. While contrast-enhanced MRI and magnetic
resonance cholangio-pancreatography have improved the
diagnostic sensitivity and specificity of imaging, due to the
biologic principles of the tumor, early diagnosis remains a sig-
nificant problem (8–10). A promising technique in obtaining a
tissue diagnosis may be the use of Spyglass cholangioscopy,
which allows biopsy if bile duct lesions under direct endo-
scopic visualization. Although this technique may prove to be
useful for diagnostic purposes, it will not enhance accuracy of
pre-operative tumor staging (11).
Thus far, no molecular markers in bile have proven reliable in
establishing a more timely diagnosis. The serum marker CA
19–9 has not been shown to be accurate enough for screening.
However, for patients with PSC and a malignant appearing stric-
ture, serum CA 19–9 >130 U/mL has a sensitivity of 79% and a
specificity of 98% (12). Conventional cytology has a sensitivity of
only 20% to 40%, though the specificity is 100% (13). The limi-
tation of conventional cytology is the paucicellular nature of a
desmoplastic tumor which leads to the inability to obtain an
adequate number of cells to make a definitive diagnosis. Fluores-
cent in situ hybridization (FISH) is a cytologic technique which
allows for the detection of aneuploidy in epithelial cells. In par-
ticular, FISH polysomy (two or more chromosomes duplicated)
identifies another 20% of patients with CCA missed by conven-
tional cytology while maintaining a specificity of 100% (13).
Despite the use of advances cytologic techniques, the ability to
make a timely and accurate diagnosis remains sub-optimal.
The primary therapy for hilar CCA is surgical resection.
There is no effective systemic therapy, though radiation may
provide palliation and in exceptional cases, prolonged sur-
vival. Outcomes for resection of CCA are limited by the inabil-
ity to obtain an accurate early diagnosis as many patients
present with unresectable lesions. An R0 resection is possible
in 70% to 80% of attempted resections and in most series,
5-year survival is approximately 25% to 30% (14–19). Recent
resectional approaches for CCA have included techniques
such as pre-operative portal vein embolization to induce
hypertrophy in the anticipated-remaining hepatic remnant for
prevention of liver failure and techniques of vascular reconstruc-
tion to expand the potential for R0 resectability. Yokoyama et al.
have described an extensive experience with pre-operative portal
vein embolization (PVE) in 240 patients, in which selective arte-
rial embolization has been used to improve response to PVE
(20). Though the authors report a decrease in operative mortal-
ity from 21.9% to most recently (after 2001) 1.6% following
PVE, they do not describe the impact of PVE on long-term sur-
vival following resection for CCA. A large series from Johns Hop-
kins also published in 2008 review the outcomes of 564 patients
with CCA (50% hilar CCA) and reports on predictors of
improved outcome following resection (21). Favorable prognos-
tic factors included patients resected in a more recent time period
(after 1995), negative margins, well-differentiated tumors, and
negative lymph nodes. For patients with hilar CCA, the median
survival was 30 months with 30% 5-year survival. Three other
recent single-center series have been reported in the last year and
all report similar survival outcomes of 30% to 40% at 5 years and
included the use of extended hepatic resection with portal vein
reconstruction (22–24). When analysis is restricted to only to
those patients with negative resection margins with or without
portal vein reconstruction, a 5-year survival of 45% was reported
by Hemming et al. (24). Similar improved outcomes with
advanced techniques have also been reported by Neuhas et al.
(25). All of these data are single-center non-randomized reports
with outcomes compared to historical controls.
neoadjuvant chemoradiotherapy followed
by liver transplantation
Liver transplantation (OLT) was initially proposed as the ideal
solution to the problem of achieving a complete resection.
229
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Complete hepatectomy followed by transplantation addressed
all relevant margins of resection—hepatic, vascular, and
ductal—and provided equivalent, if not more complete
regional lymphadenectomy. Unfortunately, early experience
with OLT was dismal, as recipients demonstrated a high recur-
rence rate and very poor survival (26–33). Moreover, the initial
application of OLT for CCA did not discriminate between
intra-hepatic and extra-hepatic origin. Currently OLT alone is
contra-indicated in patients with CCA However, based on the
observation that radiation provided effective palliation, and in
some cases prolonged survival, a neoadjuvant protocol com-
bining External Beam Radiotherapy (EBRT) and brachyther-
apy with 5-FU and oral capecitabine followed by OLT was
started at the Mayo Clinic in 1993 (34). At the same time, a
similar protocol was started in Nebraska employing higher
dose of brachytherapy without EBRT (35).
The Mayo Clinic protocol is restricted to patients with unre-
sectable, non-metastatic hilar CCA. Diagnosis is established by
a positive endoscopic biopsy or brushings, in the presence of a
mass lesion (<3 cm in radial diameter), polysomy at multiple
chromosomes by FISH and CA 19–9 >100, in the presence of
a radiographically malignant stricture. Patients with resectable
disease undergo resection, but those with bilobar segmental
ductal extension which precludes R0 resection; patients with
bilobar hilar vascular encasement or those with underlying
PSC are considered for the protocol. Patients are staged by
cross-sectional imaging and endoscopic ultra-sound prior to
enrollment, and are excluded if they have evidence of meta-
static disease, have undergone prior attempted resection with
violation of the tumor plane or percutaneous (or transluminal
biopsy) of the primary lesion or have medical contra-indications
precluding OLT.
Enrolled patients receive EBRT administered with a target
dose of 4500 cGY in 30 fractions delivered over a 3-week
period, with 5-FU given in 500 mg/m2 daily bolus for 3 days at
the initiation of EBRT (see Fig. 25.1). Two to three weeks after
completion of EBRT, a transluminal boost of radiation is
delivered using transcatheter iridum192 seeds with target dose
of 2000 to 3000 cGy. Patients remain on oral capecitabine
Hilar cholangiocarcinoma
Mayo clinic protocol
Selected patients with unresectable hilar
cholangiocarcinoma (began in 1993)
Neoadjuvant radiation and chemotherapy
External beam radiotherapy with bolus 5-FU
Brachytherapy with protracted capcitabine
Staging operation to rule-out metastases or local
extension of tumor precluding complete resection
of tumor
Orthotopic liver transplantation
Figure 25.1 Combined chemoradiotherapy followed by liver transplantation
protocol for patients with unresectable hilar CCA.
230
while awaiting transplantation. Prior to undergoing trans-
plantation, which is performed either with a deceased donor
or living donor allograft, patients undergo formal operative
staging (either open or more recently, using hand-assisted lap-
aroscopy) with routine sampling of common hepatic artery
and peri-choledochal lymph nodes in addition to biopsy of
any other suspicious nodules.
Our initial experience with neoadjuvant chemoradiother-
apy followed by transplantation was encouraging (36,37) and
was followed by a comparison of all 38 patients undergoing
OLT for unresectable hilar CCA from 1993 to 2002 versus all
patients who underwent resection of hilar CCA at the same
institution during the same time period (14). A comparison
between liver transplantation with neoadjuvant therapy and
resection is imperfect because the OLT protocol was restricted
to patients with unresectable disease. Nevertheless, transplan-
tation provided superior outcomes, with 82% 5-year survival
versus 21% 5-year survival after resection. In this study, a sur-
vival benefit for transplantation versus resection was seen both
in patients with PSC and in those with de novo CCA. Our
most recent published survival data from December of
2006 includes 65 patients with a mean follow-up of 32 months.
Patient survival was 91% at 1 year and 76% at 5 years (38). To
date, 167 patients have enrolled in this protocol. There have
been 111 patients who have undergone OLT with 1- and 5-year
survival of 96% and 72%, respectively (see Figs. 25.2 and 25.3).
Though patient survival following the combined protocol
for treatment of hilar CCA is similar to other indications for
liver transplantation, the toxicity of the neoadjuvant therapy is
significant. Common complications include cholangitis, liver
abscess, duodenal ulceration, malnutrition, liver decompensa-
tion, and disease progression (14,36–38). Approximately 20%
of patients have evidence of metastatic disease at operative
staging and are therefore not eligible for OLT (see Fig. 25.2).
Additionally, despite the aggressive pre-treatment protocol, 11
of 65 (17%) in the most recent published analysis still devel-
oped disease recurrence following liver transplantation (38). A
retrospective analysis of these 11 patients who developed dis-
ease recurrence determined that older patients, those with
Cholangiocarcinoma treatment protocol
results (September 1, 2008)
167 patients
12 deaths/disease progression
Irradiation
+ 5-FU 2 transplanted elsewhere
10 receiving neoadjuvant therapy
143 staging 27 (19%) staged positive
operation 2 awaiting transplantation
2 transplanted elsewhere
1 death
75 decease donor
111 liver
35 living donor
transplantation
1 domino donor
Figure 25.2 Results of a combined chemoradiotherapy followed by liver trans-
plantation protocol for hilar CCA.
 TRANSPLANTATION FOR HILAR CHOLANGIOCARCINOMA
larger tumors, a prior cholecystectomy, and those with an
increased CA 19–9 at transplant (though not at enrollment) to
be at an increased risk of recurrence, with a median time to
recurrence of 22 months. Those with unfavorable tumor char-
acteristics, such as residual tumor >2 cm in the explanted liver
and perineural invasion were also at an increased risk of recur-
rence. In this series, three patients developed local-regional
recurrence while eight had distant metastasis.
Recently, Becker et al. analyzed the United Network for Organ
Sharing/Organ Procurement and Transplantation Network
(UNOS/OPTN) database for patients with CCA who under-
went transplant from 1987 to 2005 (39). There were 280 patients
who had a diagnosis of CCA either at listing, at discharge, or
both, though it is not known whether the patients received neo-
adjuvant therapy, pre-transplant staging, or any standardized
inclusion criteria. Survival for patients who underwent OLT
from 1994 to 2005 with a listing diagnosis of CCA (n = 102)
experienced a 5-year actuarial survival of 68%. Given these
patients underwent OLT in an era when CCA was a known
contra-indication to OLT, it is presumed that most of these
patients received neoadjuvant therapy, though this assumption
is uncertain. Those transplanted in the same era without a pre-
transplant diagnosis of CCA (presumably incidental CCA and
therefore without neoadjuvant therapy, n = 77) remained with a
5-year survival of 20%, which is similar to the historically poor
survival associated with OLT for CCA. The conclusion of this
multi-center analysis is that transplant for early stage hilar CCA
(unresectable or arising in the setting of PSC) is beneficial based
on the survival rate of 68% for those with a known diagnosis of
CCA, though the study is hindered by the lack of essential
details, such as the use of neoadjuvant therapies.
With the potential for broader application of the combined
neoadjuvant chemo-radiotherapy and OLT protocol, attention
must be focused on the recognition and management of antic-
ipated complications following this aggressive treatment. In
addition to pre-operative morbidity such as cholangitis and
duodenal ulceration, intra-operative challenges attributable to
the neoadjuvant therapy include severe inflammatory changes
and dense fibrosis leading to difficulty in identifying and
Patient survival after transplantation
1993–2008
96 ± 2% n = 111
100
90 83 ± 4%
80 72 ± 6%
70
60
50
40
30
20
10
0 the protocol across multiple centers, the key principles, such as
0 1 2 3 4 5
Years after transplantation
Figure 25.3 Kaplan–Meier analysis of survival for patients undergoing trans-
plantation after completion of neoadjuvant therapy at Mayo Clinic.
separating hilar structures. Late effects of tissue injury from
radiation therapy, which may be broadly considered a result of
fibrosis and chronic ischemic injury, are also of concern. A
recent retrospective analysis of 68 patients who underwent
neoadjuvant chemoradiotherapy followed by OLT showed
increased incidence of late vascular strictures (arterial and
portal vein) when compared to controls undergoing OLT for
other indications (40). The late vascular complication rate was
40%, though patient and graft survival did not differ between
the groups. In most patients, these complications were man-
ageable with a percutaneous endovascular approach. The key
findings from this analysis are that arterial interposition grafts
should be used to replace the irradiated native artery in all
cases of deceased donor transplantation. Additionally, late
strictures of the portal vein (and non-replaced arteries as in
the case of a living donor transplant) should be anticipated
and may be amenable to endovascular interventions.
organ allocation
The findings from the Mayo Clinic and Nebraska protocols as
well as the historical data for OLT without adjuvant therapy
were carefully considered by the Model for End Stage Liver Dis-
ease (MELD) Exception Study Group, which was assembled to
consider standardization of diagnoses which commonly led to
MELD exception scores (41). The conclusion of this group was
to recommend national standardization of MELD score excep-
tions for patients with early stage, unresectable hilar CCA pro-
vided they are enrolled in an approved protocol which includes
neoadjuvant therapy, and standard inclusion (i.e., diagnostic),
and exclusion criteria. The group proposed an allocation policy
applied nationally similar to that currently granted for HCC,
which is based on a 10% risk of mortality subject to readjust-
ment every three months. Currently, organ allocation in the
United States for hilar CCA, as well as other diagnoses which
require MELD exception, varies considerably by each region. It
is possible that a national policy for MELD exceptions for com-
mon diagnoses may be considered in the future.
conclusions
Excellent outcomes can be achieved with neoadjuvant chemo-
radiotherapy followed by OLT for selected patients with early
stage hilar CCA. Obtaining a timely diagnosis remains a key
challenge regardless of whether resection or transplantation is
being considered. As with hepatocellular carcinoma, it is nec-
essary to determine the risk for disease progression following
neoadjuvant therapy for patients awaiting transplantation.
Given the severe donor organ shortage, continued analysis of
outcomes in order to identify patients not likely to gain benefit
from this aggressive protocol is necessary. In light of the results
achievable with the combined neoadjuvant chemoradiother-
apy protocol, however, a standardized approach to organ allo-
cation which is applied nationally, as for HCC, is necessary
and will hopefully be forthcoming. Finally, with application of
multi-disciplinary approach, pre-transplant staging to ensure
inclusion of only those without metastasis, replacement of
irradiated vessels when possible as well as monitoring for post-
operative vascular complications, must be highlighted.
231
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
key points
1. The diagnosis of hilar CCA remains a challenge
(level II evidence).
2. Based on non-randomized analysis (level II evi-
dence), neoadjuvant chemoradiotherapy followed
by liver transplantation for patients with early stage
unresectable hilar CCA offers excellent survival.
3. Percutaneous, open, or transgastric biopsy of the
primary tumor should not be performed due to
the risk of tumor seeding into the peritoneal cavity
(level II).
4. Radiation injury may lead to hepatic artery throm-
bosis and late vascular strictures. Native hepatic
arteries should be replaced by arterial conduits in
deceased donor transplantation to reduce early
thrombosis. Late strictures may be amenable to
endovascular treatment (level III).
5. Toxicity of the neoadjuvant therapy is signifi-
cant, and a multi-disciplinary approach including
commitment from radiology, radiation oncology,
medical oncology, hepatology, and hepatobiliary/
transplantation surgery is necessary.
references
1. Shaib Y, el-Serag HB. The epidemiology of cholangiocarcinoma. Semin
Liver Dis 2004; 24: 115–25.
2. Sripa B, Pairojkul C. Cholangiocarcinoma: lessons from Thailand. Curr
Opin Gastro 2008; 24: 349–56.
3. Maggs JR, Chapman RW. An update on primary sclerosing cholangitis.
Curr Opin Gastro 2008, 24: 377–83.
4. Bismuth H, Castaing D. Hepatobiliary malignancy. London: Edward
Arnold, 1994.
5. De Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J
Med 1999; 341: 1368–79.
6. Knan Sa, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and
treatment of cholangiocarcinoma: consensus document. Gut 2002; 51
(Suppl 6): VI 1–9.
7. Gores GJ, Nagorney DM, Rosen CB. Cholangiocarcinoma: is transplanta-
tion an option? For whom? J Hepatol 2007; 47: 454–75.
8. Manfredi R, Barbaro B, Masselli G, et al. Magnetic resonance imaging of
cholangiocarcinoma. Semin Liv Dis 2004; 24(2): 155–64.
9. Braga HJ, Imam K, Bluemke DA. MR imaging of intrahepatic cholangio-
carcinoma: use of ferumoxides for lesion localization and extension. AJR
2001; 177: 111–14.
10. Yeh TS, Jan YY, Tseng JH, et al. Malignant perihilar biliary obstruction:
magnetic resonance cholangiopancreaticographic findings. Am J Gastro
2000; 95: 432–40.
11. Chen YK, Pleaskow DK. SpyGlass single-operator peroral cholangiopan-
creatoscopy system for the diagnosis and therapy of bile-duct disorder: a
clinical feasibility study. Gastrointest Endosc 2007; 65(6): 832–41.
12. Levy C, Lymp J, Angulo P, et al. The value of serum Ca 19-9 in predicting
cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig
Dis Sci 2005; 50: 1734–40.
13. Moreno Luna LE, Kipp B, Halling et al. Advanced cytologic techniques for
the detection of malignant pancreatobiliary strictures. Gastroenterology
2006; 131: 1064–72.
14. Rea D, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadju-
vant chemoradiation is more effective than resection for hilar cholangio-
carcinoma. Ann Surg 2005; 3: 451–61.
15. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of
intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224: 463–73;
discussion 473–5.
232
16. Pichlmayr R, Weimann A, Klempnauer J, et al. Surgical treatment in proximal
bile duct cancer. A single-center experience. Ann Surg 1996; 224: 628–38.
17. Kosuge T, Yamamoto J, Shimada K, et al. Improved surgical results for
hilar cholangiocarcinoma with procedures including major hepatic resec-
tion. Ann Surg 1999; 230: 663–71.
18. Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for
cholangiocarcinoma. Arch Surg 2001; 234: 270–6.
19. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and out-
come in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001; 234:
507–17; discussion 517–9.
20. Yokoyama Y, Nagina M, Nishio H, et al. Recent advances in the treatment
of hilar cholangiocarcinoma: portal vein embolization. J Hepatobiliary
Pancreat Surg 2007; 14: 447–54.
21. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma
thirty-one-year experience with 564 patients at a single institution. Ann
Surg 2007; 5: 755–62.
22. Miyazaki M, Kato A, Ito H, et al. Combined vascular resection in operative
resection for hilar cholangiocarcinoma: does it work or not? Surgery
2007: 5: 581–8.
23. Hasegawa S, Ikai I, Fujii H, et al. Surgical resection of hilar cholangiocar-
cinoma: analysis of survival and postoperative complications. World J
Surg 2007; 31: 1256–63.
24. Hemming AW, Kim RD, Mekeel KL, et al. Portal vein resection for hilar
cholangiocarcinoma. Am Surg 2006; 72: 599–605.
25. Neuhaus P, Joans S. Surgery for hilar cholangiocarcinoma—the German
experience. J Hepatobiliary Pancreat Surg 2000; 7(2):142–7.
26. Goldstein RM, Stone M, Tillery GW, et al. Is liver transplantation indicated
for cholangiocarcinoma? Am J Surg 1993; 166: 768–71; discussion 771–2.
27. Jonas S, Kling N, Guckelberger O, et al. Orthotopic liver transplantation
after extended bile duct resection as treatment of hilar cholangiocarci-
noma. First long-terms results. Transpl Int 1998; 11 (Suppl 1): S206–8.
28. Loinaz C, Abradelo M, Gomez R, et al. Liver transplantation and inciden-
tal primary liver tumors. Transplant Proc 1998; 30: 3301–2.
29. Iwatsuki S, Todo S, Marsh JW, et al. Treatment of hilar cholangiocarci-
noma (Klatskin Tumors) with hepatic resection or transplantation. J Am
Coll Surg 1998;187: 358–64.
30. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarci-
noma: results in 207 patients. Transplantation 2000; 69: 1633–7.
31. Shimoda M, Farmer DG, Colquhoun SD, et al. Liver transplantation for
cholangiocellular carcinoma: analysis of a single-center experience and
review of the literature. Liver Transpl 2001; 12: 1023–33.
32. Robles R, Figueras J, Turrion VA, et al. Liver transplantation for hilar cholan-
giocarcinoma: Spanish experience. Transpl Proceedings 2003; 35: 1821–2.
33. Ghali P, Marotta PJ, Yoshida EM, et al. Liver transplantation for incidental
cholangiocarcinoma: analysis of the Canadian experience. Liver Transpl
2005; 11: 1412–6.
34. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival
after orthotopic liver transplantation plus adjuvant chemoirradiation for
cholangiocarcinoma. Liver Transpl 2000; 6: 309–16.
35. Sudan D, DeRoover A, Chinnakotia S, et al. Radiochemotherapy and
transplantation allow long-term survival for nonresectable hilar cholan-
giocarcinoma. Am J Transpl 2002; 2: 774–9.
36. Hasson Z, Gores GJ, Rosen CB, et al. Preliminary experience with liver
transplantation in selected patients with unresectable hilar cholangiocar-
cinoma. Surg Oncol Clin N Am 2002; 11: 909–21.
37. Heimbach JK, Gores GJ, Haddock MG, et al. Liver transplantation for unre-
sectable perihilar cholangiocarcinoma. Semin Liver Dis 2004; 24(2): 201–7.
38. Heimbach JK, Gores GJ, Haddock MG, et al. Predictors of disease recur-
rence following neoadjuvant chemoradiotherapy and liver transplanta-
tion for unresectable perihilar cholangiocarcinoma. Transplantation
2006; 12: 1703–7.
39. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for
280 patients with cholangiocarcinoma treated with liver transplantation
over an 18-year period. J Gastrointest Surg 2008; 12(1): 117–22.
40. Mantel HTJ, Rosen CB, Heimbach JK, et al. Vascular complications after
orthotopic liver transplantation after neoadjuvant therapy for hilar chol-
angiocarcinoma. Liver Transpl 2007; 12: 1372–81.
41. Gores GJ, Gish RG, Sudan D, et al. MELD Exception Study Group. Model
for end-stage liver disease (MELD) exception for cholangiocarcinoma or
biliary dysplasia. Liver Transpl 2006; 12: S95–7.
26 Rare vascular liver tumors
Jan P. Lerut, Eliano Bonaccorsi-Riani, Giuseppe Orlando, Vincent Karam,
René Adam, and the ELITA–ELTR Registry a
introduction
Vascular hepatic tumors form a continuum going from the
completely benign hemangioma (HA) to the very aggressive
hemangiosarcoma (HAS). Sometimes due to their difficult
differential diagnosis and the rarity of the more malignant
varieties, and also to the limited worldwide experience with
liver resection and transplantation (LT) for these tumors, these
vascular lesions are often neglected or misdiagnosed and their
therapeutic management algorithm is unclear.
The rarity of malignant vascular liver lesions is well demon-
strated by the data of the European Liver Transplant Registry
(ELTR). During the period January 1988 to June 2007, 12%
(8278) of all European LT were performed because of hepato-
biliary tumors, but of these, only 125 (0.1%) were done
because of malignant vascular diseases.
In this chapter hepatic epithelioid hemangioendothelioma
(HEHE), infantile hemangioendothelioma (HIHE), and hem-
angiosarcoma (HAS) will be discussed, based on a recent lit-
erature review and of the experience gathered by the audited
ELITA–ELTR during the period 1988 to 2004 (1). The infor-
mation obtained from both sources allows a more clear insight
into diagnosis and treatment of these rare liver diseases.
For the sake of completeness, benign Nodular Regenerative
Hyperplasia (NRH) is also included in this chapter because of
its vascular etiopathogenesis. Hemangioma and lymphangi-
oma are discussed in a separate chapter dealing with benign
liver tumors.
hepatic epithelioid
hemangioendothelioma ₍hehe₎
HEHE is a rare (<1 per million population), low-grade malig-
nancy which has a malignant behavior potential between HA
and HAS (2). This vascular tumor was first recognized in 1982
by Weiss and Enzinger in soft tissues, later on in the head and
neck region, then in bones and finally in many other organs,
such as lungs and bronchi. Liver involvement occurs most
often as a primary tumor. HEHE is more frequent in young
adult women; with a peak incidence during the fourth decade.
This tumor has been rarely reported in children less than
15 years old. No definitive etiological factor has been clearly
identified (2).
Macroscopically, HEHE appears as multifocal fibrous masses
(Fig. 26.1A and B). Microscopically, HEHE is characterized by
pleiomorphic cells, both of medium and of large size, that are
epithelioid in appearance and that spread within sinusoids and
small veins at the periphery of the lesion, whereas the center is
fibrous and studded with elongated tumor cells, sometimes
a
The European Liver Transplant Registry is a service of the European Liver and Intestinal Transplant Association (ELITA); see www.eltr.org.
with intracellular vascular lumens containing red blood cells
(Fig. 26.2A and B). In contrast to HAS, the hepatic acinar land-
marks are better preserved. HEHE originates from endothelial
cells which explains positive immunohistochemistry (IHC) for
factor VIII-related antigen and for the endothelial markers
CD31 and CD34. Ultrastructural examination also shows char-
acteristic features of endothelial cells, such as a basal lamina,
pinocytic vesicles, and Weibel–Palade bodies (2–4).
The clinical manifestations of HEHE are unspecific, varying
from totally asymptomatic to hepatic failure (Table 26.1). The
malignant potential of HEHE often remains unclear in each
individual patient. Based on the analysis of the ELITA–ELTR
study, the most frequent symptoms are non-specific upper
abdominal or epigastric discomfort or pain, weakness, general
malaise, and jaundice. About 20% of patients are asymptom-
atic and 10% present with pulmonary symptoms (Table 26.1).
Hepato-splenomegaly (50%) and weight loss (20%) are the
most frequent clinical signs; portal hypertension may be
caused by tumor compression or venous infiltration (3–6).
Anicteric cholestasis and cytolytic activity are frequently
present (60% and 40%, respectively). Serum tumor markers
are normal in the absence of accompanying liver disease.
Radiological investigation identifies two different patterns
of HEHE: the early peripheral and nodular, usually bilobar
type (peripheral pattern), and the later confluent type (diffuse
pattern) with eventual invasion of the greater vessels
(Fig. 26.3A). Focal calcifications are present in 20% of tumors.
Angiography reveals only moderate vascularization with
displacement of marginal vessels (Fig. 26.3B and C).
Scintigraphic and FDG–PET imaging plays an important
role in the staging of the disease, especially in view of later LT
and also in view of the early detection of recurrent disease (7–8).
Complete assessment of these patients is mandatory to
exclude other, especially thoracic, disease localization. In
doubtful cases thorascopic lung and/or pleural biopsy should
be performed in order to exclude the often frequent thoracic
involvement.
Definitive diagnosis, frequently based on a high degree of
suspicion, can be made by associating radiological and clinical
features, such as occurrence in a young adult (usually female),
the contrast between numerous intrahepatic (often calcified)
tumors, the overall condition of the patient, and finally the
longstanding clinical history. The diagnosis can only be con-
firmed by pathological examination of appropriate, surgically
obtained biopsy material.
The treatment algorithm of HEHE was till recently far from
standardization. The literature review, including 13 very small
233
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A) (B)
Figure 26.1 Intraoperative view of 7.6 kg heavy HEHE responsible for IVC syndrome and supine dyspnea (A). Characteristic gross appearance of a HEHE
hepatectomy specimen showing multiple fibrous masses with zoning phenomenon (B).

(A) (B)
Figure 26.2 Histological features of HEHE at the periphery (A) and in the center (B) of the lesion. Source: C. Sempoux, Dept. of Pathology.

(≥5 pts) series and three reviews, lacks detailed data analysis,
Table 26.1 Clinical presentation of HEHE in the and most importantly, long-term follow-up. The published
ELITA–ELTR series experience does not allow comparison of results of untreated
and of surgically and medically treated patients. The place of
Age 39 ± 15 years
(range 0.4–65) – 2 children
LT has especially been questioned in view of well-documented
spontaneous resolution, long-term survival, the high inci-
Gender 43 F and 16 M
dence of extra-hepatic disease (up to 45%) (Table 26.2), the
Symptoms
lack of predictive clinical or histological criteria, and finally
Upper abdominal pain/ 59%
discomfort the high incidence (up to 33%) of, sometimes even very late,
Weakness/fatigue 20% recurrent allograft disease (6).
Asymptomatic 19% The largest institutional series, coming from Pittsburgh and
Anorexia 15% containing 16 patients, showed that LT offers 5-year overall
Nausea 14% and disease-free survival rates of 71% and 60%, respectively
Dyspnea 10% (9). The Mehrabi review indicates that the treatment of choice
Signs of HEHE is total hepatic resection (3). In this literature review,
Hepatomegaly 49% the 5-year survival rates of LT, partial liver resection (reported
Weight loss 20% in only very few patients), local or systemic chemo- and radio-
Jaundice 10% therapy (CHTH) and treatment abstention were 55%, 75%,
Ascites 9% 30%, and 0%, respectively. Partial liver resection is not a logi-
Hemangioma 9% cal treatment because HEHE is nearly always a multinodular
Portal hypertension 7%
and bilobar disease. Indeed the examination of the total hepa-
Hepatopulmonary syndrome 2%
tectomy specimens analyzed in the ELITA–ELTR study showed

234
 RARE VASCULAR LIVER TUMORS

(A) (B) (C)

Figure 26.3 CT-scan of HEHE showing the initial peripheral nodular (A) and the later confluent patterns of the disease (B). Angiography confirming the avascular
nature and vascular displacement (C).

49% of pts) is the only parameter which significantly influ-

Table 26.2 Histological presentation of HEHE in the
ences outcome after LT. Mitotic index and cellular pleiomor-
ELITA–ELTR series
phism are other major histological prognostic criteria
Bilobar involvement 96% reflecting more aggressive tumor behavior (10). Their influ-
Number nodules >15 86% ence on patient survival could not be analyzed in the ELITA–
Microvascular involvement 44.4% ELTR study due to the impossibility of obtaining central
Macrovascular involvement 9.4% pathology recording. The recently published UNOS data
Hilar lymph node 33% (18/54p) 4/18 pts (22%)
reporting 128 patients with a median follow-up of 24 months
positivity patients only positive on IHC
go in the same direction; 1- and 5-year patient survival rates
4/10 pts with extrahepatic EHE
localization were lymph node were 80% and 64%, respectively (11).
positive Recurrent disease after (partial and total) hepatectomy
Extrahepatic localization 17% (10 pts) should be treated aggressively as prolonged, sometimes even
Lung 4 disease-free, survival can be achieved (1,3). The role of re-LT
Mediastinum 1 in the treatment of recurrent allograft disease is unclear as
Peritoneum 1 only one single case has been reported (5).
Spleen It is conceivable that in view of the high incidences of extrahe-
Femoral vein 1 patic disease localization, and of recurrence in- and outside the
Brain and bone 1 allograft (22% in the ELITA–ELTR study) (Table 26.3), a more
Omentum 1
radical approach combining total hepatectomy and anti-
angiogenic therapy, such as use of VEGF-antibodies, α-interferon
bilobar disease in 96% of cases; 86% of the specimen con- and rapamycin could be of value in the treatment of
tained more than 15 tumor nodules (Table 26.2). Moreover, HEHE (1,12). Rapamycin is of particular interest in this context
several reports documented disease recurrence, or LT because as this drug is nowadays frequently used not only as a renal spar-
of recurrent HEHE after partial resection; fortunately, ing but also as an anti-tumoral immunosuppressive drug in
pre-transplant liver surgery doesn’t seem to impair survival liver transplant recipients. Such an approach, combined with a
after LT (6). better study of the molecular and genetic markers based on
The assessment of non-surgical treatments, such as radio- tumor biology, will be of great assistance in further improving
therapy, local tumor destruction, hormonotherapy, systemic or outcome, monitoring efficacy of emerging neo- and adjuvant
locoregional CHTH, trans-arterial embolization, and chemo- treatments and in recognizing the aggressive subtypes of
embolization, is even more difficult because of the lack of uni- HEHE (3,5,13–15).
form treatment modalities and of long-term follow-up (3).
The ELITA–ELTR study is the largest worldwide, detailed hepatic infantile hemangioendothelioma
long-term study in relation to HEHE (1). This study collected ₍hihe₎
59 European patients from 32 centers. The follow-up from HIHE, the most common mesenchymal tumor of the liver in
diagnosis is 104 ± 72 months (median of 93 months) and from infants (<3 years), is always diagnosed nearly during the first
LT 83 ± 55 months (median of 79 months). 6 months of life. The tumor is also more frequent in females
The study validated the place of LT in the treatment of this and presents with (a)symptomatic hepato-splenomegaly, fail-
disease and 5 and 10 years post-transplant survival rates are ure to thrive, congestive cardiac failure (15%) due to intratu-
83% and 74%, respectively, with 5 and 10 years recurrence-free moral arteriovenous shunting, cutaneous hemangiomas
survival rates of 82% and 64%, respectively (Fig. 26.4A and B). (20–40%), consumptive coagulopathy due to Kasabac–Merritt
This study confirms that medical and/or surgical pre-LT treat- syndrome, and medically resistant hypothyroidism (2,16). In
ment (present in 30% of pts), invasion of regional lymph node the majority of the cases, HIHE appears to be a histological
(present in 33% of pts) and of (limited) extrahepatic disease benign tumor that may regress spontaneously in 5% to 10% of
(present in 17% of pts) are not formal contraindications to LT. cases; however its outcome is usually much poorer because of
Combined micro- and macrovascular invasion (present in its severe complications (2,16–18).

235
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

HIHE can occur either as a single tumor (Fig. 26.5A) or it
can be multifocal and diffuse (Fig. 26.5B). The lesions are soft,
spongy, red-tan nodules, sometimes more firm and grey-
white or brown with areas of necrosis and hemorrhage. His-
tology identifies two types of HIHE. Type 1 the most frequent
is made of intercommunicating small vascular channels lined
by a single layer of regular endothelial cells (Fig. 26.5C). There
may be areas of cavernous changes and extramedullary hema-
topoiesis is often found. Type 2 HIHE, a more pleiomorphic
HIHE with nuclear atypia, multi-layering, and papillary pro-
jections (Fig. 26.5D), is now considered as a form of HAS.
IHC examination is of importance in relation to the differen-
tiation of HIHE from hepatic vascular malformations associated
with capillary proliferation; immunoreactivity for GLUT-1
can be of help for the diagnosis of HIHE (19). The difficulty
with these tumors lies in the fact that HIHE may harbor foci
of HAS. Data from the ELITA–ELTR showed that children
with HIHE present with a rapid deterioration of their condi-
tion or presenting with acute liver failure and/or Budd–Chiari
syndrome, indeed also presented with (foci of) HAS (see
further).
HEHE can be differentiated from HIHE as both have differ-
ent, age-related, clinical, and pathological features. The natural
history of HIHE is variable, but up to two thirds of symptomatic
patients die of tumor complications, for example, cardiac
failure. Treatment modalities of HIHE vary from medical

Patient survival after liver transplantation for epithelioid hemangioendothelioma: 59 patients

100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10
Survival %
1 yr 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs 8 yrs 9 yrs 10 yrs
93% 86% 85% 83% 83% 80% 75% 72% 72% 72%

Number of exposed patients

Total 1 yrs 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs 8 yrs 9 yrs 10 yrs
59 55 51 46 41 36 31 26 18 14 13

Disease free survival after liver transplantation for epithelioid hemangioendothelioma: 52 patients
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10
Survival %
1 yr 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs 8 yrs 9 yrs 10 yrs
90% 87% 85% 85% 82% 79% 76% 68% 64% 64%

Number of exposed patients

Total 1 yr 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs 8 yrs 9 yrs 10 yrs
52 47 45 40 36 31 27 23 16 11 11

Figure 26.4 Overall patient survival of HEHE after liver transplantation in the ELITA-ELTR study (A). Recurrent-free survival in the same patient cohort of
59 patients (B).

236
 RARE VASCULAR LIVER TUMORS

anti-angiogenic therapies using or combining high dose steroids, all primary liver tumors. Peak age of incidence is in the sixth
interferon, CHTH or radiotherapy, other interventional radio- and seventh decades of life, with a male to female ratio of 3/1.
logical or surgical therapies (2,16–18). Recently the Boston HAS has rarely been reported in children and, if so, is regarded
group presented a clearly defined algorithm for the treatment of as a distinct entity (2,21).
this paediatric condition. Partial hepatectomy is indicated if HAS has received much recent attention because of its fre-
lesions are confined to one liver lobe; diffuse HIHE disease, quent association with several environmental carcinogens,
resistant to steroid therapy, should be treated using LT (20). such as thorotrast, vinyl chloride, monomer, radium, pesti-
cides, external radiation, cyclophosphamide, arsenical com-
hepatic hemangiosarcoma ₍has₎ pounds, use of androgenic/anabolic steroids and iron overload,
Although relatively rare, HAS is the most common primary such as seen in hemochromatosis (2). A clear etiological cause
sarcoma occurring in the liver. It may account for up to 2% of of HAS is however not found in 70% of patients.
The diagnosis, especially of diffuse HAS, can be extremely
difficult. Liver biopsy has been reported as dangerous and
Table 26.3 Recurrence of HEHE after liver transplantation non-diagnostic (22). Macroscopically, the HAS appears as ill-
in the ELITA–ELTR series defined spongic hemorrhagic nodule(s) that involve(s) the
Tumor recurrence in 14 (23.7%) patients: 5 patients still alive whole liver. HAS can present four different types of growth
Delay post- 45 ± 35 mo 49 mo (range 6–98) patterns: multiple nodular, large dominant mass, mixed pat-
transplantation terns of multiple nodules and dominant mass, and more rarely
Lung 5 AWD 59 (ChTh), diffusely infiltrating macro-nodular tumor (Fig. 26.6). At the
84 (Res) mo time of diagnosis, extra-hepatic metastases are present in 20%
DWD 23,41,73 mo to 40% of patients; the most common sites of metastases are
Liver 5 AWD 112 mo (Res, RF, lung, spleen, bone, and adrenals (2,21).
ChTh) 211 and 212 mo The most characteristic histological pattern of HAS is a
DWD 15,73 (Res, ChTh), sinusoidal and tectorial growth of malignant endothelial spin-
79 mo (Burkitt) dle cells on the surface of liver cell plates leading to their atro-
Liver and omentum 1 DWD 9 mo
phy, and associated with formation of larger vascular channels
Liver and bone 1 DWD 4 mo (ChTh)
and cavernous spaces with papillary projections into
Not precised 2 DWD 19, 20 mo
their lumen (Fig. 26.7A–C). Tumoral cells have bizarre and

(A) (B)

(C) (D)
Figure 26.5 Macro- and microscopic features of HIHE. The lesion can be either solitary (A) or multiple (B). Type 1 HIHE is made of multiple vascular channels
with a single layer of regular endothelial cells (C) whereas in type 2 HIHE more atypia are observed (D). Source: S. Gosseye, Dept. of Pathology.

237
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

hyperchromatic nuclei with numerous mitoses and they edema, acute Budd–Chiari syndrome, acute abdomen due to
exhibit IHC positivity for endothelial markers (Factor VIII, tumor rupture, and thrombocytopenia may follow. In contrast to
CD31, and CD 34). HAS differs from HEHE by the fact that it HEHE, evolution of these patients is much more rapid and worse.
has more atypical cells and it is much more destructive with All patients in the ELITA–ELTR study died due to tumor
obliteration of the normal liver (21). Histological diagnosis on recurrence after a median of 6 months (Fig. 26.8). Similarly,
adequate tissue sampling is of utmost importance in order to very poor results were reported recently by the Cincinnati
avoid futile, especially surgical interventions. transplant tumor registry in six patients and by the Memorial
Although the diagnosis of HAS is nowadays easier following Sloan-Kettering group in five patients (23,24). Embryonal sar-
the introduction of nuclear magnetic imaging, the diagnosis coma is the only liver sarcoma that can nowadays be treated
still frequently remains difficult. This difficulty is exemplified successfully by (partial or more seldom necessary) hepatec-
in the ELITA–ELTR study collecting 22 patients of whom 6 tomy (23). Both European and American experiences confirm
were children. Correct pre-LT histological diagnosis of HAS that HAS is an absolute contra-indication to LT. In cases of
was only made in one-third of 16 biopsied patients, and half of difficult differential diagnosis between HIHE/HEHE and HAS,
22 patients were transplanted because of HIHE or HEHE. At it is wise to respect a waiting period of 6 months on the trans-
the time of LT, 15% of patients already had distant metastases plant list in order to avoid wasting scarce organ resources.
All four HAS presenting as acute Budd–Chiari syndrome were Indeed the aggressive evolution of the liver tumor during this
seen in children with a supposed diagnosis of HIHE (Table 26.4). time span will allow the establishment of the correct diagnosis.
Pathologic examination of the hepatectomy specimen showed The outcome for patients with HAS will only be improved by
massive and diffuse bilobar involvement in all cases. the development of a more effective interdisciplinary onco-
Biochemical abnormalities in HAS are non-specific; serum logical approach (24).
alkaline phosphatase is elevated in 70% of patients and tumor
markers are negative in the absence of accompanying liver dis-
ease. In the early stages HAS may present with hepato-
splenomegaly, ascites, jaundice, signs of portal hypertension, Table 26.4 Indication for LT in 22 HAS patients of the
weight loss, and muscle wasting; later on, pain, peripheral ELITA–ELTR series
35.3 ± 22.6 years
Age Children 4.4 years (1–12)
14 males and 8 females
Gender Six children <15 years
Invalidating tumor 15
(9 HEHE–6 HAS)
Unclear diagnosis of liver 5
failure (22%)
Cryptogenic cirrhosis 1
Focal nodular hyperplasia 1
Hemochromatosis 1
Subacute failure 1
Budd–Chiari syndromea 1
Solitary hepatocellular cancer 1
Budd–Chiari syndrome,b 3
HEHE 2
HAS 1
HAS 1
a
Budd–Chiari syndrome: 18%.
b
All children.
Figure 26.6 CT-scan of HAS showing a diffuse nodular infiltration of the liver.

(A) (B) (C)

Figure 26.7 HAS. Macroscopy showing a diffuse spongy tumoral mass (A); microscopy showing the development of cavitary space (B) because of the sinusoidal
progressive growing of tumoral cells destroying the liver cell plates (C). Source: J. Rahier, Dept. of Pathology.

238
 RARE VASCULAR LIVER TUMORS
nodular regenerative hyperplasia ₍nrh₎
NRH of the liver is a rare condition that is most often presents
with the stigmata of portal hypertension and its sequelae (25).
Its prevalence is estimated between 0.70% and 2.6% in autopsy
series. NRH is the major cause of non-cirrhotic portal hyper-
tension. Current theories favor a primary vasculopathy with
alterations in blood flow as the causative agent. It is supposed
that the presence of a portal venopathy (occlusion or terminal
portal venules) with or without accompanying hepatic arterial
disorders causes diffuse microvascular transformation, finally
leading to NRH. Vasculopathy results in ischemia leading to
atrophy with compensatory hyperplasia in adjacent unaffected
areas. When a critical proportion of the portal venules is
affected, portal hypertension ensues. NRH is characterized by
the formation of usually small, up to 1 cm, non-fibrotic paren-
chymal nodules. This absence of fibrosis allows the establish-
ment of the differential diagnosis with micronodular cirrhosis.
Histologically, the regenerative nodules are composed by large
hyperplastic hepatocytes which compress the adjacent liver
cell plates that then become atrophic (Fig. 26.9A), a feature
nicely underlined by reticulin stain (Fig. 26.9B). Hemodynamic
Survival function
1.0
0.8
Cum survival
0.6
0.4
0.2
0.0
0 5 10 15 20
Postoperative months
Figure 26.8 Overall patient survival of HAS after liver transplantation in the
ELITA–ELTR study.
(A)
Figure 26.9 Microscopic features of NRH on a HE section (A) and reticulin stain (B). Source: C. Sempoux, Dept. of Pathology.
investigation shows pre-sinusoidal portal hypertension in
association with a patent portal vein.
Various systemic diseases are known to occur in association
with NRH, such as primary biliary cirrhosis, Budd–Chiari
syndrome, hemorraghic hereditary teleangiectasia or Rendu–
Osler–Weber disease, lympho- and myeloproliferative disor-
ders, collagen-vascular diseases, congenital and acquired
hepatic macrovascular abnormalities, as well as exposure to
toxins, such as azathioprine and some chemotherapeutic
agents. Familial cases of NRH occurring without underlying
or associated systemic disease have been described (26). These
forms have a poor clinical course and are often associated with
progressive renal failure.
In relation to LT, it should be noted that recurrent allograft
NRH has been reported, that NRH has been reported as a
complication of chronic immunosuppression using azathio-
prine, leading even to re-LT, and NRH has been described in
the context of living donor liver transplantation using small-
for-size grafts. Also, NRH and obliterative portal venopathy
have been documented in recipients transplanted for biliary
tract disease complicated with severe non-cirrhotic portal
hypertension (27–29).
Six patients with NRH have been reported to the ELTR. Four
had favorable outcomes; two died in 20 and 42 months, respec-
tively, post-transplantation due to cardiac failure. Three
patients had to be treated prior to transplantation because of
bleeding esophageal varices; three presented with cholestatic
cirrhosis. One patient had a previous kidney transplant. Four
larger series and some case reports describing successful LT for
this condition have been reported in literature (26,30).
conclusion
Due to their scarcity, difficulties in diagnosis, as well as lack of
consensus around treatment of vascular tumors of the liver,
there is no universally accepted standard of care for these
patients. The recent review of the literature and of the audited
25 European Liver Transplant Registry data have permitted some
clarification of the therapeutic algorithms for these lesions.
One should always have a high degree of suspicion in relation
to these lesions which may have an extremely divergent clinical
(B)
239
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
course. Aggressive diagnostic work-up, using adequate tissue
sampling is mandatory especially in order to differentiate the
potentially curable HEHE or HIHE from the incurable HAS.
HEHE should be treated aggressively by LT. Indeed these
lesions represent an excellent indication for LT allowing long-
term (disease-free) survival even in the presence of (limited)
extrahepatic disease localization at the time of transplanta-
tion. Combining LT and anti-angiogenic drugs during the
post-transplant follow-up could be of interest to further
improve the outcomes. HIHE has a highly variable disease
outcome ranging from spontaneous disease regressions to
fatal outcomes. Diffuse HIHE resistant to steroid therapy
should be treated using LT. The appearance of acute liver fail-
ure and/or Budd–Chiari syndrome may be an indicator toward
the development of HAS. The outlook for HAS remains
extremely dismal to whatever therapy is applied. In HAS, LT is
absolutely contra-indicated due to the very rapid and aggres-
sive disease recurrence.
In case of unclear diagnosis, futile liver transplantation can
be avoided placing the patient on the waiting list for a mini-
mum period of 6 months. This time span confers two advan-
tages; first, it does not interfere with the outcome of liver
transplantation in case of HIHE or HEHE, and second, it
allows observation of the natural, always fatal, evolution of
HAS. Severe, symptomatic, non-cirrhotic portal hypertension
caused by nodular regenerative hyperplasia can also be cured
by liver transplantation if the therapeutic armamentarium
fails to control its severe complications.
appendix
Recommended grading of categories of evidence
Ia: evidence from meta-analysis of randomized
controlled trials
Ib: evidence from at least one randomized controlled
trial
IIa: evidence from at least one controlled study
without randomization
IIb: evidence from at least one other type of quasi-
experimental study
III: evidence from non-experimental descriptive
studies, such as comparative studies, correlation
studies and case–control studies
IV: evidence from expert committee reports or
opinions and/or clinical experience of respected
authorities
Recommended strengths of management recommendation
A. directly based on category I evidence
B. directly based on category II evidence or
extrapolated recommendation from category I
evidence
C. directly based on category III evidence or
extrapolated recommendation from category I or
II evidence
D. directly based on category IV evidence or
extrapolated recommendation from category I, II,
or III evidence
240
references
1. Lerut JP, Orlando G, Adam R, et al. The place of liver transplantation in
the treatment of hepatic epitheloid hemangioendothelioma: report of the
European liver transplant registry. Ann Surg 2007; 246: 949–57.
2. Ishak K, Goodman Z, Stocker J. Tumors of the liver and intrahepatic bile
ducts. Atlas of Tumor Pathology. Third series, fascicle 31 edn. Washington:
Armed Forces Institute of Pathology, 1999: 282–307.
3. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithe-
lioid hemangioendothelioma: a comprehensive review of the literature
with emphasis on the surgical therapy. Cancer 2006; 107: 2108–21.
4. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma
of the liver: a clinicopathologic study of 137 cases. Cancer 1999; 85: 562–82.
5. Demetris AJ, Minervini M, Raikow RB, et al. Hepatic epithelioid haeman-
gioendothelioma – biological questions based on pattern of recurrence in an
allograft and tumor immunophenotype. Am J Surg Pathol 1997; 21: 263–70.
6. Lerut JP, Orlando G, Sempoux C, et al. Hepatic haemangioendothelioma
in adults: excellent outcome following liver transplantation. Transpl Int
2004; 17: 202–07.
7. Nguyen BD. Epithelioid haemangioendothelioma of the liver with F-18
FDG PET imaging. Clin Nucl Med 2004; 29: 828–30.
8. Lin E, Agoff N. Recurrent hepatic epithelioid hemangioendothelioma:
detection by FDG PET/CT. Clin Nucl Med. 2007; 32: 949–51.
9. Madariaga JR, Marino IR, Karavia DD, et al. Long-term results after liver
transplantation for primary hepatic epithelioid haemangioendothelioma.
Ann Surg Oncol 1995; 2: 483–87.
10. Kelleher MB, Iwatsuki S, Sheahan Dg. Epitheloid haemangioendotheli-
oma of the liver. Clinicopathological correlation of 10 cases treated by
orthotopic liver transplantation. Am J Surg Pathol 1988; 89: 999–1008.
11. Rodriguez JA, Becker NS, O’Mahony CA, Goss JA, Aloia TA. Long-term
outcomes following liver transplantation for hepatic hemangioendothe-
lioma: the UNOS experience from 1987 to 2005. J Gastrointest Surg 2008;
12: 110–6.
12. Kayler LK, Merion RM, Arenas JD, et al. Epithelioid hemangioendotheli-
oma of the liver disseminated to the peritoneum treated with liver trans-
plantation and interferon alpha-2B. Transplantation 2002; 74: 128–30.
13. Theurillat JP, Vavricka SR, Went P, et al. Morphologic changes and altered
gene expression in an epithelioid hemangioendothelioma during a ten-
year course of disease. Pathol Res Pract 2003; 199: 165–70.
14. Calabrò L, Di Giacomo AM, Altomonte M, et al. Primary hepatic epithe-
lioid hemangioendothelioma progressively responsive to interferon-
alpha: is there room for novel anti-angiogenetic treatments? J Exp Clin
Cancer Res 2007; 26: 145–50.
15. Miller MA, Sandler AD. Elevated plasma vascular endothelial growth fac-
tor levels in 2 patients with hemangioendothelioma. J Pediatr Surg 2005;
40: 17–9.
16. Lopez-Terrada DL, Finegold MJ. Liver tumors. In: Walker AW, Durie PR,
Hamilton JR, Walker-Smith JA, Watkins J, eds. Pediatric Gastrointestinal
Disease: Pathophysiology, Diagnosis, Management, 5th edn. St. Louis: CV
Mosby, 2008: 911–26.
17. Selby DM, Stocker J Th, Waclawiw MA, et al. Infantile hemangioendothe-
lioma of the liver. Hepatology 1994; 20: 39–45.
18. Daller JA, Bueno J, Gutierrez J, et al. Hepatic hemangioendothelioma: clini-
cal experience and management strategy. J Pediatr Surg 1999; 34: 98–106.
19. Mo JQ, Dimashkieh HH, Bove KE. GLUT1 endothelial reactivity distin-
guishes hepatic infantile hemangioma from congenital hepatic vascular
malformation with associated capillary proliferation. Hum Pathol 2004;
35: 200–9.
20. Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hemangio-
mas: subtype classification and development of a clinical practice algo-
rithm and registry. J Pediatr Surg 2007; 42: 62–8.
21. Maluf D, Cotterell A, Clark B, et al. Hepatic angiosarcoma and liver trans-
plantation: case report and literature review. Transplant Proc 2005; 37:
2195–99.
22. Saleh HA, Tao LC. Hepatic angiosarcoma:aspiration biopsy cytology and
immunocytochemical contribution. Diagn Cytopathol 1998; 18: 208–11.
23. Husted TL, Neff G, Thomas MJ, Gross TG, et al. Liver transplantation for
primary or metastatic sarcoma to the liver. Am J Transplant 2006; 6: 392–7.
24. Weitz J, Klimstra DS, Cymes K, et al. Management of primary liver sarco-
mas. Cancer 2007; 109: 1391–6.
 RARE VASCULAR LIVER TUMORS
25. Wanless IR. Micronodular transformation (nodular regenerative hyperpla-
sia) of the liver. A report of 64 cases among 2500 autopsies and a new clas-
sification of benign hepatocellular nodules. Hepatology 1990; 11: 787–97.
26. Dumortier J, Boillot O, Chevallier M, et al. Familial occurrence of nodular
regenerative hyperplasia of the liver: a report on three families. Gut 1999;
45: 289–94.
27. Breen DP, Marinaki AM, Arenas M, et al. Pharmacogenetic association
with adverse drug reactions to azathioprine immunosuppressive therapy
following liver transplantation. Liver Transpl 2005; 11: 826–33.
28. Gane E, Portmann B, Saxena R, et al. Nodular regenerative hyperplasia
of the liver graft after liver transplantation. Hepatology 1994; 20:
88–94.
29. Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic observations
and histopathologic recognition of the portal hyperperfusion or small-
for-size syndrome. Am J Surg Pathol 2006; 30: 986–93.
30. Krasinskas AM, Eghtesad B, Kamath PS, et al. Liver transplantation for
severe intrahepatic noncirrhotic portal hypertension. Liver Transpl 2005;
11: 627–34.
241
27 Management of recurrent pyogenic cholangitis
W. Y. Lau and C. K. Leow
introduction
While practicing in Hong Kong in 1930, Digby drew attention
to a condition which was subsequently known as recurrent
pyogenic cholangitis by reporting on eight cases of “common
duct stones of liver origin” (1). The term Recurrent Pyogenic
Cholangitis (RPC) was used by Cook et al. in 1954 when they
reported their experience with the condition in a series of
90 patients (2). The synonyms associated with this condition
include Asiatic cholangiohepatitis, oriental cholangiohepatitis,
Hong Kong Disease (3), Chinese biliary obstruction syn-
drome (4), and primary cholangitis (5). This condition is
commonly seen in Chinese living in Canton and Hong Kong
but is not restricted to the Chinese in the Orient since it also
occurs in Chinese immigrants in Malaysia, Singapore, North
America, and Australia (6–8). RPC is also common in Japanese
in Japan and Taiwanese in Taiwan. Although rare, RPC has also
been reported to afflict occidentals (9,10).
pathogenesis
In RPC the gallstones found within the biliary system are cal-
cium bilirubinate stones or pigmented calcium stones. Cal-
cium bilirubinate stones are prevalent in Asia and are very rare
in Europe and the United States. In addition to the presence of
these friable concretions of various shapes and sizes within the
biliary tree, the bile is often muddy in consistency and contains
numerous fine particles of calcium bilirubinate. Biochemical
analysis of these stones revealed a bilirubin content of 40.2%
to 57.1% and a cholesterol content of 2.9% to 25.6%. This dif-
fers greatly from cholesterol stones, which are common in
Europe and the United States, which contain >96% of
cholesterol in pure cholesterol stone, and >71.3% in mixed
cholesterol stone but the bilirubin content is only 0.02% to
5.0% (11). The peculiarity of the formation of calcium biliru-
binate stones in RPC has been ascribed to the high incidence
of bile being infected with Escherichia coli (E. coli). In man, the
major portion of bilirubin is excreted in bile as bilirubin gluc-
uronide. In the presence of β-glucuronidase, bilirubin gluc-
uronide is hydrolyzed into free bilirubin and glucuronic acid.
Normally, calcium is secreted into bile and when it combines
with the carboxyl radical of free bilirubin, insoluble calcium
bilirubinate is formed. Normal bile is free of β-glucuronidase
activity, whereas bile infected with E. coli has intense
β-glucuronidase activity. Bile calcium content increases in the
presence of biliary tract inflammation and this coupled with
the increased hydrolysis of bilirubin glucuronide by the
β-glucuronidase from E. coli gives rise to the multiple stones
formation classically seen in RPC (11). There are two types of
pigmented stones, black, and brown. The infected type seen in
RPC is the brown pigment stone.
The postulated port of entry for the micro-organisms of
bowel origin is via the portal vein from an attack of enteric
242
infection. In the acute stage of RPC, Ong reported that 39.5%
of the studied cases had a positive portal blood culture, while
the positive supraduodenal lymph node culture rate was
38.1% (12). The rate of infected bile in patients with pig-
mented stone compared to those with cholesterol stone is cor-
respondingly much higher in the former. In comparing
patients with pigmented stones against those with cholesterol
stones, Maki demonstrated that 88.3% of the bile in patients
with pigmented stone was infected and E. coli was isolated
from all cases. This compared to 43.5% in patients with cho-
lesterol stone and of these only 70% of cases had E. coli
isolated (13). However, bacteria excreted into the bile within a
non-obstructed biliary system will not usually give rise to
infection and an attack of cholangitis. Thus obstruction by
parasites, such as Clonorchis sinensis (Fig. 27.1) and Ascaris
lumbricoides can initiate the sequence of events which eventu-
ally lead to the formation of intrahepatic pigment stones (2).
Furthermore, the egg or carcass of the parasite can act as a
nidus for the deposition of calcium bilirubinate (13). How-
ever, only a proportion of patients with RPC have positive ova
in stools indicating parasitic infestation, while in some patients
the remains of parasites can be identified within the stones
recovered (12,13). Clonorchis infection does not occur in the
Sarawak state of West Malaysia due to the absence of the snail,
Bithynia, which is the first intermediate host in the life cycle of
Clonorchis sinensis (12). Yet RPC is common among the Chi-
nese and the indigenous race, the Dyaks. Thus parasitic infes-
tation is only one of the etiological factors for RPC. Maki
suggested that the migration of roundworms through the
ampulla of Vater leads to papillitis and secondary dyskinesia of
the Common Bile Duct (CBD). This leads to increased intra-
hepatic ductal pressure, dilatation of the CBD and poor drain-
age of the biliary system (13). A poorly draining biliary system
contributing to the formation of intrahepatic stones and colo-
nization of the bile by bacteria was experimentally shown in
rabbits by Ong in 1962. Rabbits who had the CBD constricted
by a linen thread prior to a single intraportal injection of an
E. coli suspension developed ductal dilatation and stone for-
mation in the CBD and intrahepatic ducts. On culture, the bile
from the gallbladder and bile ducts was positive for E. coli (12).
In the mid 1950s in Japan, the proportion of pigmented to
cholesterol stones found in professionals was almost equal.
However, almost 90% of the gallstones found in farmers were
of pigmented calcium stone. As the farmers were economically
less well off, they could only afford a diet which was deficient
in fat and protein. It was postulated that the deficient diet may
be a factor for the development of pigmented stone (13).
Matsushiro et al. have demonstrated that a diet low in protein
and fat leads to lower levels of glucaro-1:4-lactone, a powerful
inhibitor of β-glucuronidase, in bile (14). The reduced level of
glucaro-1:4-lactone in bile thus permits increased hydrolysis
 MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS
(A) (B)
Figure 27.1 (A) Magnified view of Clonorchis sinensis (×12.5). (B) Numerous Clonorchis removed from the CBD of one patient.
of bilirubin glucuronide to free bilirubin and glucuronic acid
by the bacterial β-glucuronidase present in infected bile. The
free bilirubin then conjugates with calcium in the bile to form
the typical calcium bilirubinate stones of RPC. In Hong Kong,
RPC is no longer seen in the younger generation born and
bred in modern-day Hong Kong. Young patients, in their 30s,
who present to our institution with RPC are invariably immi-
grants from China. We suspect that the much better social and
economic conditions of modern-day Hong Kong have played
a role in eradicating the condition (15). The reduced incidence
of gastroenteritis, the inabilility of the enteric organism, which
gained entry via the portal blood, to establish itself within the
liver parenchyma due to better host defense from an improved
high protein, low carbohydrate diet and possibly the fact that
less Chinese herbal medicine is being consumed by the mod-
ern generation of youngsters may all have contributed to the
demise of this condition.
pathology
Macroscopically, due to the repeated attacks of biliary sepsis, it
is common to find adhesions between the liver surface and the
surrounding parietal peritoneum, especially the diaphrag-
matic surface, at operation. The liver surface is scarred and
prominent dilated ducts may be obvious. The affected lobe of
the liver, usually the left, is normally atrophic with compensa-
tory hypertrophy of the remaining lobe. On palpation, the
stones within the dilated biliary ducts are easily palpable.
Occasionally, the underlying lobe can be so destroyed by the
repeated attacks of cholangiohepatitis that what remains is a
cavernous biliary sac with minimal surrounding liver paren-
chyma (Fig. 27.2). Within the sac is a soup of biliary mud and
stones. The brown pigment stones are soft stones which crum-
ble when squeezed between fingers or forceps. The size varia-
tion goes from fine grains to stones of 4 to 5cm in diameter.
The stones are irregular, can take up the shape of the biliary
duct or become faceted when the stones are packed (Fig. 27.3).
Apart from the stones, the bile duct is filled with biliary mud.
This is a broth of mucus, altered bile products, microcalculi,
desquamated epithelium, parasites, and pus.
The pathological hallmark of RPC is the steadily progressive,
recurrent cholangiohepatitis with periportal fibrosis. Histo-
logically, in the early acute stage of an attack of cholangiohep-
atitis, it is similar to that of bacterial cholangitis associated
with cholecystitis and calculus obstruction seen in the Western
world (16), while the histological picture of the acute, chronic,
and advanced stage of the disease is not dissimilar to that seen
in sclerosing cholangitis (17). In the early lesions the lumen of
the small biliary ducts is filled with pus, with rapid extension
into the surrounding tissue. There is marked dissociation of
the liver cells by polymorphonuclear infiltration of the sinu-
soids together with Kupffer cell hyperplasia. In the lobules
around the affected duct there is a varying degree of cellular
necrosis. Resolution of the underlying inflammation leads to
dense round-cell infiltration, which is then replaced by fibrous
tissue. In the larger intrahepatic ducts, the duct wall becomes
inflamed, ulcerated, and destroyed together with the forma-
tion of cholangitic abscesses. Resolution results in intense
fibrosis which accounts for the undue prominence of the duct
wall seen on sectioning a liver affected by RPC. During the
acute episode, these larger ducts can become irregular in cali-
ber and short segments of relative stricture can occur at inter-
vals along the duct. The duct proximal to the stenosis dilates.
243
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 27.2 A totally destroyed left liver lobe consisting of a cavernous biliary
sac with negligible liver parenchymal tissue (f = falciform ligament).
Recurrent attacks of infection and resolution lead to perma-
nent damage of the duct wall and the ducts remain dilated. The
relative stricture then becomes a true localized stricture. These
strictures are most frequently encountered at the site of ductal
confluence. One of the main concerns of these inflammatory
strictures is malignant transformation into cholangiocarci-
noma. Ohta et al., from their autopsy studies, suggested that
repeated inflammatory damage to the ductal epithelium from
the attacks of cholangitis can lead to atypical epithelial hyper-
plasia, dysplasia, and eventually cholangiocarcinoma (18).
The left lobe of the liver is preferentially affected. The exact
reason for this is unknown. One possible explanation may be
the selective distribution of portal blood within the liver. Two
studies suggested that the left lobe of the liver receives blood
from the colon and the left lobe will be the first port of call for
enteric organisms such as E. coli which have entered the portal
venous system (19,20). Colonization of the bile with E. coli will
lead to the production of β-glucuronidase in the biliary sys-
tem. Another explanation is that the more oblique course of
the left hepatic duct results in poorer drainage of the left ductal
system as compared to the right hepatic duct, thus leading to
increased incidence of stone formation. If stones are found
in the right hepatic duct, almost invariably stones are found in
the left duct. In one study of 115 patients with hepatolithiasis,
the ratio of stones found in the left and right hepatic ducts was
6:1 (5). The stones form in the dilated ducts proximal to the
stricture site. These strictures can be multiple and bilobar in
distribution and commonly occur at the origin of the right
and left hepatic ducts. Stones within the common bile duct are
usually lodged at the supraduodenal portion of the duct or at
the ampulla. At ERCP, a patulous ampulla of Vater (probably a
result of repeated passage of stones) is not an uncommon
finding in patients with RPC.
The bile in patients with hepatolithiasis is usually infected
with enteric organisms. The two most common organisms iso-
lated are E. coli and Klebsiella species. The overall positive bile
culture rate has been reported to be as high as 87% and the
incidence of positive culture in patients requiring surgical
244
Figure 27.3 Large number of pigment stones removed from one patient
with RPC.
intervention and those which settled on conservative measures
is similar (90% vs. 85%) (21).
The gallbladders in these patients are usually thin-walled,
large, and distended. The majority of them do not contain gall-
stones. While the incidence of CBD stones and biliary mud
varied from 60% to 90%, the incidence of associated gallstones
in the gallbladder was only 15% to 40% (4,7). Macroscopically,
the gallbladder looks normal but histological examination
invariably shows features compatible with low-grade chronic
cholecystitis. Along the gastrohepatic omentum gross lymph-
adenitis with enlarged lymph nodes is commonly encountered.
clinical presentation
Patients with RPC tend to be younger (third and fourth
decade) than those affected by cholesterol stone disease, which
is much more prevalent in older women, in the Western world.
Although the condition does not have particular sex preva-
lence, those afflicted are almost invariably from the lower
socio-economic classes. The usual presentation consists of the
classical Charcot’s triad of abdominal pain, fever (with or
without chills and rigors), and jaundice which signifies an
attack of cholangitis. The patient may not notice the jaundice
but a history of tea-colored urine is usual. The jaundice is usu-
ally not severe since cholangitis secondary to a completely
obstructed biliary system will rapidly progress to acute sup-
purative obstructive cholangitis with septicemia. In addition
to the triad of symptoms, these patients also develop mental
confusion and shock, which is referred to as Reynaud’s pentad.
The epigastric or right upper quadrant pain is usually described
as a constant and gnawing or cutting (12) pain, which may
radiate to the back. Vomiting is not a constant feature. Patients
have spiking fever, not unlike that seen with an underlying
abscess or collection, which normally resolves rapidly when
the conservative treatment has been effective.
On examination, the patient looks unwell and restless with
a tinge of jaundice. The associated jaundice is typically mild
and clinically can be just discernible. Abdominal examination
may reveal the telltale signs of surgical scars from previous
 MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS
operations. Tenderness with varying degree of guarding is
noted in the epigastrium or right upper quadrant. A tender
hepatomegaly may be present. Marked tenderness may imply
the presence of an underlying abscess. Deterioration in the
abdominal signs (increasing and generalized tenderness) and/
or the development of worsening hemodynamic parameters
(persistent hypotension, tachycardia, poor urine output
despite adequate resuscitation) argues for emergency surgical
intervention to decompress the biliary system.
Those patients who present or develop shock have a flushed
facie, warm periphery, bounding peripheral pulse, and hypo-
tension. The massive vasodilatation and reduced cardiac con-
tractility secondary to the endotoxemia adequately explain the
state of shock.
investigations
Both the hematological and biochemical tests do not differen-
tiate patients with RPC from those with other causes of biliary
obstruction and infection. Full blood count will reveal an
underlying leucocytosis with neutrophilia and mild thrombo-
cytopenia in some patients. A number of patients will also
have a concomitant mild derangement of the clotting profile
with a prolonged prothrombin time. The deranged liver func-
tion test is compatible with an obstructive picture with a mod-
erately raised level of bilirubin and a high serum alkaline
phosphatase level. The level of γ-glutamyltranspeptidase is
elevated. The slightly elevated alanine transaminase level in
some patients is a reflection of the parenchymal damage sec-
ondary to the underlying infection within the biliary system.
Other than showing the presence of pneumobilia, in some
cases a plain abdominal radiograph is not helpful. The calcium
bilirubinate stones are radiolucent because of the low calcium
and high bilirubin content. The least expensive and most help-
ful investigation is ultrasonography (USG). It can demonstrate
the presence of stones within the dilated intrahepatic and
common bile ducts, the presence or absence of an underlying
liver abscess and occasionally the presence of a solid liver mass
secondary to malignancy complicating a benign stricture. Also
it can reveal the presence or absence of gallstone(s) within the
gallbladder. Intra- and extrahepatic ductal stones are present
in the majority of patients, but cholelithiasis is much less com-
mon and is seen in the minority cases. Although intrahepatic
stones normally cast sonic shadows on USG, the presence of
air within the bile ducts (either spontaneously or secondary to
previous biliary drainage procedures) can give rise to highly
reflective echoes with posterior shadows, thus confusing and
misleading the radiologist in diagnosing the presence of stones
within the bile ducts. In about 3% of RPC, pneumobilia is
present (22). In some cases the amorphous and small stones
can form a cast of the biliary tree and, under such circum-
stances, highly reflective echoes and posterior acoustic shad-
owing on USG may be absent. It may then be difficult to
identify dilated bile ducts and the ducts can appear as soft tis-
sue masses on USG (7).
USG images and its interpretations are operator dependent.
Computed tomography (CT) removes this bias and can pro-
vide images of the dilated intra- and extrahepatic ducts, even
if they are filled with sludge or pus. On CT scanning these
filling defects are of higher attenuation than bile, but have a
lower attenuation than contrast-enhanced liver paren-
chyma (23). Although uncommon, the amorphous stones
which completely fill the ducts, and which are isodense with
the hepatic parenchyma could be missed on CT. Unlike USG,
there is no difficulty in distinguishing pneumobilia from
stones on CT and visualization of the extrahepatic ducts is not
limited by overlying bowel gas.
USG and CT do not provide sufficient details of the ductal
anatomy. Cholangiography, in the form of Endoscopic Retro-
grade Cholangiopancreatography (ERCP) and/or Percutane-
ous Transhepatic Cholangiography (PTC), is essential for the
detail delineation of the entire biliary tract. Older methods of
delineating the biliary tracts, such as oral cholecystography
and intravenous cholangiography are no longer used because
they provide suboptimal visualization of the ductal system. In
addition to the potential complication of allergic reaction to
the contrast injected, there is no place for intravenous cholan-
giography in the presence of biliary obstruction or cholangitis.
Our first line of investigation is ERCP since it is both diagnos-
tic and therapeutic. The typical cholangiogram will show
dilated extrahepatic ducts in more than half the cases. The
intrahepatic ducts have the classical “truncated tree” pattern
where the “tree” has been trimmed back to its “main branches”.
The terminal end of these “branches” is tapered, resembling an
arrow or a spear head (Fig. 27.4). It is more common to see a
dilated left ductal system containing calculi than an affected
right system. There may be an accompanying relative or true
stricture distal to the dilated ducts. When a stone or stricture
prevents the filling of the intrahepatic ducts, or when it is tech-
nically impossible to perform an ERCP due to previous
biliary–enteric bypass surgery, PTC under USG guidance is
performed. As a result of the stones and stricture(s), the biliary
anatomy can be very complicated. Once an obstructed biliary
duct is punctured during PTC, the obstructed system must be
drained to avoid cholangitis and/or bile leak. Underfilling dur-
ing cholangiography can lead to missed segmental ducts. More
importantly, the paucity of intrahepatic ducts shown on chol-
angiograms should prompt the surgeon to count the number
of segmental ducts present in order not to miss the diagnosis
of undrained segment(s). Cholangiography complements
USG and CT and their findings should be considered as a
whole and not in isolation.
We have shown that Magnetic Resonance (MR) cholangiog-
raphy is comparable to ERCP in diagnosing choledocholithia-
sis (24). Apart from being non-invasive, MR cholangiography
can delineate biliary strictures which may be difficult to show
or missed on ERCP due to technical reasons (Fig. 27.5). In a
recent study by Park et al. MR cholangiography has been
shown to be better than ERCP/PTC (25). Occasionally, a
radioisotope scan is performed to demonstrate the presence of
undrained or hypo-functioning liver segments.
The radiographic features of certain conditions can simulate
RPC. Sclerosing cholangitis can lead to biliary tract strictures.
However, these are usually more peripherally located and there
is a lack of the marked proximal dilatation and stones seen in
RPC. Although the common bile duct is massively dilated in
choledochal cysts, in most cases, there is an abrupt transition
245
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 27.4 Typical truncated biliary tree appearance together with the arrow
or spear head sign (arrow) on ERCP. A large stone(s) in the left duct.
Figure 27.5 MR Cholangiogram demonstrating a stricture (arrow) at the con-
fluence of the right and left hepatic ducts.
to normal or slightly dilated proximal ducts (26). Patients with
Caroli disease (cavernous ectasia of the biliary tract) have
dilated intrahepatic ducts and calculi but the extrahepatic
ducts are disproportionately small (27). The condition is often
associated with renal cystic disease (28) which, on CT, helps to
distinguish it from RPC.
In almost all cases, given the clinical and investigation find-
ings, the diagnosis of RPC is seldom in doubt. The investigations
246
merely help to define the extent and severity of the underlying
disease and guide the management plan.
acute management
RPC patients have repeated attacks of acute cholangitis which
would settle on conservative measures in the majority of cases.
The need for urgent therapeutic interventional procedures
only applies to a minority of cases, such as those with signs of
peritonitis secondary to perforated gangrenous gallbladder,
ruptured liver abscess, or those with septicemic shock despite
conservative measures. The role of definitive procedures for
most patients who settled on conservative measures depends
on the frequency and severity of each attack, presence of bili-
ary strictures (which may be malignant) and the presence of
any existing co-morbid medical conditions.
The initial approach to any acute attack is to control the
underlying infection with the commencement of intravenous
fluid infusion, antibiotic treatment after blood culture, pre-
scription of adequate analgesia and keeping the patient nil per
oral. Our standard first line antibiotic regimen is cefuroxime.
Metronidazole is sometimes prescribed to cover the anaerobe
Bacteroides fragilis, which is present in a minor proportion of
patients who have had previous biliary tract surgery and/or
complicated anatomy due to stones and strictures. An urgent
ultrasound scan of the liver is performed to identify the extent
of lithiasis within the biliary tree, the presence of a liver mass
which can be an abscess or an underlying cholangiocarcinoma.
Those patients who fail to respond or have evidence of a severe
attack of cholangitis with or without shock undergo an urgent
ERCP. The smallest amount of contrast feasible is used during
ERCP as increased biliary pressure from excessive contrast
injection will result in cholangio-venous reflux, which can lead
to septicemia. No attempt is made to perform a full cholangio-
gram or to remove all calculi from the biliary system. In the
procedure, the system is decompressed with a nasobiliary
drain. Only when the patient’s condition has improved and
stabilized would a check cholangiogram with endoscopic
removal of stones be performed. If part of the biliary tree can-
not be decompressed adequately because of an obstructing
distal stone or stricture, then endoscopic drainage alone may
not be adequate and successful. As such, percutaneous tran-
shepatic biliary drainage of the obstructed biliary ducts will be
of use. However, these drainage tubes are small and can be eas-
ily blocked by the tenacious biliary mud. If a liver abscess is
present, the abscess is drained percutaneously under ultra-
sound guidance.
The patient is monitored closely after admission for signs of
deterioration. Those responding to the conservative treatment
will have a reduction in abdominal pain, a fall in temperature
toward normal and the disappearance of tachycardia over the
first 24 to 48 hours. If there is no obvious improvement after
48 hours, the possibility of undrained biliary system or indi-
vidual liver segments due to impacted stones or underlying
strictures must be considered and the need for urgent surgical
intervention entertained. At any time during conservative
management, the presence of increasing abdominal pain cou-
pled with shock and peritoneal signs mandate urgent surgical
treatment.
 MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS
Those patients who are present in shock must be actively
resuscitated. Those who respond quickly can be treated con-
servatively, while those who fail must undergo therapeutic
intervention. It is unclear why conservative measures work for
some but not others. In a series of 88 RPC patients presenting
with acute cholangitis, 17% required therapeutic intervention
for septicemic shock. A pulse rate greater than 100/min and a
platelet count of more than 150 × 109/l within 24 hours of pre-
sentation were the only two independent factors that predicted
the need for therapeutic intervention (21).
The sole aim of an urgent therapeutic intervention during
an acute attack is to decompress the obstructed biliary system.
Non-operative interventional procedures using the endo-
scopic or percutaneous routes are preferred to open surgical
route (29). Occasionally, open surgery is required to deal with
peritonitis as a result of gangrenous cholecystitis or ruptured
liver abscess. The most expedient means to decompress the
CBD is insertion of a large T-tube. No attempt is made to per-
form definitive surgery. When the usually enlarged and thick-
walled CBD is opened, thick-infected biliary mud and bile will
be gushed out. The biliary mud and friable bilirubinate stones
are scooped out. Following a gentle saline flush of the CBD, a
bougie is passed down the CBD into the duodenum to check
for patency of the lower end of the CBD. The way an impacted
stone in the lower end, which cannot be removed during CBD
exploration, is dealt with depends on whether there is a con-
comitant attack of pancreatitis. In the absence of acute pancre-
atitis, the stone can be dealt with percutaneously via the T-tube
tract when the acute episode is over. In the presence of acute
pancreatitis, a transduodenal sphincteroplasty is performed to
remove the stone. An alternative is the use of electrohydraulic
lithotripsy to fragment the impacted stone, thus avoiding a
transduodenal sphincteroplasty (30).
The patency of the right and left hepatic ducts is checked to
ensure there is free flow of bile into the CHD and CBD. Any
strictures found are dilated with graduated sounds to release
the infected bile and mud dammed up behind the stricture(s).
Gentle irrigation of the hepatic ducts with saline is performed.
Irrigation or flushing at high pressure via a syringe must be
resisted as this can initiate or aggravate a septicemic state.
When bile flow from both hepatic ducts is established, a large
bore T-tube is placed, the choledochotomy closed with catgut
and the operation is terminated. The T-tube not only decom-
presses the system but also affords a percutaneous route for
endoscopic intervention when the patient has recovered.
Large palpable liver abscesses are drained intraoperatively.
Multiple small abscesses will respond to appropriate antibiot-
ics after the biliary system is decompressed. A cholecystectomy
is performed only when it is grossly distended or there is evi-
dence of cystic duct obstruction, empyema or gangrene of the
gallbladder. During the emergency CBD exploration, an oth-
erwise non-inflamed gallbladder, with or without stone(s) in
situ, is left behind because of the added risk of performing a
cholecystectomy in an ill patient.
definitive management
The definitive management of RPC is to use a multidisci-
plinary approach (31), aiming to remove all biliary stones, to
establish adequate drainage to the biliary system, and to resect
non-functioning liver segments which harbor bacteria and
serve as foci of infection. If properly performed, definitive
interventional procedures decrease the episodes and severity
of future attacks of cholangitis. In some patients cure
is possible.
minimal access approach
Once the acute episode has settled, more definitive treatment
via the endoscope or under radiological guidance can be per-
formed. Those treated initially by nasobiliary drainage have a
check cholangiogram to delineate the extent of lithiasis and
the existence of ductal stricture(s). Stones within the CBD and
CHD can be removed with a dormia basket and large stones
can be crushed with the mechanical lithotripter or fragmented
by laser prior to their removal. For those RPC patients with
stones confined to the CBD, endoscopic sphincterotomy with
stone extraction only is safe and effective. The medium-term
result of endoscopic sphincterotomy is comparable to surgical
sphincteroplasty. In 118 patients who underwent endoscopic
treatment, 95.8% remained symptom-free after a median
follow-up of 2.3 years (8), compared to 83.4% who had a good
outcome after surgical sphincteroplasty at a mean follow-up of
7.3 years (32). In the absence of ductal strictures, small intra-
hepatic calculi not retrieved by ERCP can be shattered by
Extracorporeal Shock Wave Lithotripsy (ESWL) and the frag-
ments allowed to fall into the bowel through a widely patent
sphincteroplasty.
Intrahepatic calculi within dilated biliary ducts usually lie
proximal to a site of relative or true stricture. The stricture can
be dilated sufficiently to allow complete removal of the stones
endoscopically (Fig. 27.6). When the stricture is confined to
one lobe of the liver which is atrophic, and the contralateral
liver lobe is normal or relatively unaffected, hepatic resection
should be performed unless the patient is medically unfit to
undergo liver resection. In the presence of multiple strictures,
a more conservative approach with repeated dilatation can be
successful in achieving stone clearance and control of disease.
Balloon dilatation of intrahepatic biliary strictures prior to
stone removal has been reported to be highly successful. The
immediate overall success rate of complete stone clearance
with balloon dilatation in 57 patients was 94.5% (33). Long
segmental strictures which are likely to restenose can be
successfully stented. The main complications of dilatation
therapy include septicemia, hemobilia, mild diarrhea, and
restenosis. The cumulative probability of stricture recurrence
after dilatation is 4% at 2 years and 8% at 3 years (33). The true
long-term patency rate following dilatation alone is still
unknown since benign strictures surgically treated can recur
10 or more years later, as partial obstructions can remain com-
pletely asymptomatic for long periods. Apart from the prob-
lem of restricturing, it is difficult to rule out the presence of a
malignant stricture with certainty.
In patients with a Percutaneous Transhepatic Biliary Drainage
(PTBD) catheter in situ, the tract can be dilated to allow dor-
mia basket stone retrieval under fluoroscopic screening or to
allow passage of a flexible twin channel choledochoscope.
Under direct vision the stone(s) can be fragmented using the
247
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
(A)
(C)
Figure 27.6 (A) ERCP demonstrating the presence of stones proximal to a relative stricture (arrow) in the left hepatic duct, (B) the stricture is dilated with a bal-
loon prior to stone retrieval, and (C) the dilated left duct is cleared of stones.
electrohydraulic lithotripter and the fragments removed with a
basket. Intrahepatic strictures can be dilated or stented. Instilla-
tion of stone dissolving agents directly into the affected biliary
duct has been advocated by some, but we do not practise this
approach as it is often painful, time-consuming, ineffective,
and can lead to ascending cholangitis and sepsis. In patients
where the initial endoscopic approach has failed, the estab-
lished percutaneous route can be combined with endoscopy
subsequently to achieve stone clearance or stricture dilatation.
In those patients who received acute surgical intervention
and T-tube decompression of the biliary system, the tract is
allowed to mature. After 6 weeks, any stones present can be
removed through the tract with a choledochoscope or under
radiological control.
definitive surgery
Since RPC can and does affect the biliary tract at different sites
with varying degrees of severity, the aim of the surgery is to
provide adequate biliary drainage for bile and debris. This
encompasses stone extraction, stricturoplasty or excision of
248
(B)
stricture, resecting non-functioning liver segments and creat-
ing a bilio–enteric bypass with a permanent percutaneous
access loop to the biliary tract to allow subsequent access to the
biliary system for stone extraction and dilatation of stricture(s).
Before embarking on definitive surgery, it is mandatory to
have a complete knowledge of the location of calculi and
stricture(s), and the uni- or bilobar extent of disease with or
without concomitant liver atrophy.
In the presence of predominantly extrahepatic disease, sim-
ple exploration of the common bile duct with intraoperative
choledochoscopy will suffice. In the absence of extrahepatic
ductal stricture, the incisions used for the exploration of the
CBD and hepatic ducts will depend on the location of the
stones (Fig. 27.7A–D). We routinely remove the gallbladder in
these patients since, histologically, it shows underlying evi-
dence of low grade inflammation. Furthermore, if the sphinc-
ter of Oddi has been previously destroyed, the gallbladder will
permanently be in a collapsed state. The placement of a large
T-tube following the exploration will allow post-operative
imaging of the biliary tracts and any residual stones found can
 MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS
(A) (B)
(C) (D)
Figure 27.7 (A) Longitudinal incision for the exploration of CBD only,
(B) separate incisions for exploration of the CBD and the hepatic ducts, (C)
incision for the combined exploration of the CBD and one of the hepatic
ducts (left side is shown), (D) horizontal incision over the hepaticojejunos-
tomy (---- = incision).
be easily removed under radiological control or with a flexible
choledochoscope. When there is stenosis of the ampulla of
Vater or distal CBD, or impacted stone(s) in the lower CBD, a
transduodenal sphincteroplasty is performed. In patients who
have had multiple operations on the CBD, the standard
approach can be difficult. Under such circumstances, Ong
et al. have described an extraperitoneal approach to the duo-
denum, which is located by its anterior position to the right
kidney. A transduodenal sphincteroplasty is performed and
the CBD is explored from below (34,35). However, this
approach is seldom necessary as the result of endoscopic
sphincterotomy has been shown to be comparable (8).
In the presence of extra- and intrahepatic calculi, stone
extraction can be difficult if they are impacted, situated behind
relative or true ductal strictures or, present within angulated
ducts, such as the right posterior or left medial segmental
ducts. Although direct hepatotomy can be performed to
remove the stones, it can be very bloody if the stones are deep-
seated. Following the removal of all the stones within the CBD
and CHD, after a choledochoscopic examination to rule out
any strictures in the right and left hepatic ducts, the right and
left ducts are flushed with saline. The right and left lobes of the
liver are gently massaged in-between the flushing. This maneu-
vre normally helps to discharge more biliary mud and small
stones from the intrahepatic ducts. Once the effluent is rela-
tively clear, a repeat choledochoscopy is performed. Any resid-
ual stones can be retrieved with a dormia basket. Segmental
ductal stricture is dilated prior to stone retrieval. Any impacted
or large stones can be shattered with the electrohydraulic lith-
otripter introduced through the working channel of the flexi-
ble choledochoscope. It is not always possible to clear the
intrahepatic ducts of stones completely. Once the large stones
and strictures are dealt with, small stones or fragments can be
left to “fall out”, provided an adequate biliary drainage proce-
dure has been performed.
The thick, dilated CBD/CHD with an inelastic wall behaves
more like a cavernous sac which does not drain adequately,
even in the presence of a sphinteroplasty. Although it is rea-
sonable to perform a supraduodenal choledochoduodenos-
tomy as a biliary drainage procedure, this has the disadvantage
that patients may develop “sump syndrome”, developing
symptoms of pain and fever, which is thought to be a result of
debris being lodged in the diseased distal CBD. While the
sump syndrome can be treated by performing an endoscopic
sphincterotomy, supraduodenal choledochoduodenostomy is
contra-indicated in the presence of a proximal biliary tract
stricture or when the CBD is not wide enough. Under such
circumstances, we routinely perform an end-to-side hepatico-
jejunostomy with a retrocolic Roux-en-Y loop. This provides a
widely patent anastomosis for biliary drainage and for small
stones to fall freely into the loop of bowel. Furthermore, the
closed end of the Roux loop can provide a permanent access
route to the biliary tract.
With the hepaticojejunostomy it is crucial that the access
loop is short and has a straight course from the anterolateral
abdominal wall to the anastomosis. A poorly constructed jeju-
nal loop with redundant length makes subsequent choledo-
choscopy and access to the intrahepatic ducts difficult. The
access loop can either be placed intraperitoneally, to be
accessed percutaneously under ultrasound guidance, or it can
be placed under the skin as a hepaticocutaneous jejunostomy.
We prefer to leave the loop intraperitoneally. In those cases
where immediate access to the biliary tract is not necessary,
the end of the loop is tacked to the peritoneal surface of the
anterolateral abdominal wall with catgut. The staples from the
GIA stapler used to transect the jejunum during Roux loop
formation or the ligaclips placed around the blind end of the
loop at the end of the operation allow the interventional radi-
ologist subsequently to identify and access the loop percutane-
ously. Once the loop is punctured, the tract can be gradually
dilated to admit a twin channel choledochoscope for endo-
scopic manipulation (15). For those cases where access to the
biliary tract is required soon after the operation, a 24 Fr cath-
eter is introduced through the anterolateral abdominal wall
into the access loop at the end of the operation. The tract is
allowed to mature for 4 to 6 weeks before instrumentation.
Hepaticocutaneous jejunostomy has been used by others (36).
Although the biliary tract can be accessed sooner through the
cutaneous stoma compared to our technique, the cutaneous
stoma is not without its complication. Fifteen percent of
patients with hepaticocutaneous jejunostomy, performed
either with the cutaneous stoma formed at the initial operation
249
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
or subsequently created from its subcutaneous site, did experi-
ence complications. These complications include wound
infection of the closed stoma wound, development of cutane-
ous fistula after stoma closure, difficulty in reconstructing the
stoma for subsequent use and development of parajejunos-
tomy hernia. Repeated therapeutic intervention of the biliary
tract is inevitable due to the chronic relapsing nature of the
condition. The formation of a hepaticojejunostomy with an
access loop is a satisfactory and adequate way to manage fur-
ther attacks of stones, strictures and cholangitic attacks. On a
median follow-up time of 27 months, symptoms recurred
only in 12 patients (29%). Only one patient required a reop-
eration for stricture while the others were adequately treated
through the access jejunal loop (36).
RPC predisposes to the formation of inflammatory, non-
iatrogenic strictures in the biliary tract. Strictures in the sub-
segmental and peripheral ducts are difficult to treat.
Fortunately, obstruction of these minor ducts does not pro-
duce jaundice and the cholangitic attacks may pass unnoticed
and the infection subsides without any intervention. However,
strictures in the major bile ducts do lead to unrelenting chol-
angitis, stones and liver abscess formation, septicemic epi-
sodes, and death. Over a 10-year period, we treated 57 patients
with major bile duct strictures (37). Forty-four of the 60 stric-
tures involved the left hepatic duct (23) or the left lateral seg-
mental ducts (21). Strictures in the CBD or CHD can be
treated by the formation of a choledochojejunostomy or a
hepaticojejunostomy. Stricture involving the confluence of the
hepatic ducts can be treated by hepatotomy and Y–V plasty,
but the procedure is technically difficult and bleeding, bile
leakage and restenosis are potential serious complica-
tions (5,38). We have stopped performing Y–V plasty for such
strictures due to our poor results. Instead, we treat such stric-
tures by performing bilateral hepaticojejunostomy. In a rela-
tively normal left lobe of the liver with a left duct stricture at its
origin, a left duct approach as described by Hepp and
Couinaud (39) for a side-to-side anastomosis between the left
duct and a Roux loop can be performed without the need for
a left hepatectomy. The biliary drainage procedures performed
for these inflammatory strictures are occasionally combined
with liver resection, or liver resection alone is performed to
deal with these strictures.
Before embarking on hepatic resection, the severity of symp-
toms, status of the remaining biliary tract, parenchymal func-
tional reserve, and alternative procedures have to be considered.
Hepatic resection is only performed for those with recurrent,
troublesome and localized severe disease. Disease can be con-
fined to the left lateral segment which is atrophic and contains
large number of calculi within cavernous bile ducts. In more
extensive disease, the medial segment of the left lobe can also
be affected due to a tight stricture in the left hepatic duct.
Hepatectomy is performed to remove not only the source of
symptoms and sepsis, but also the underlying stricture which
has the potential to turn malignant. Liver resection for right-
sided disease is unusual. By the time resection is necessary, the
right lobe is usually destroyed, with compensatory left lobe
hypertrophy. Consequently, a right hepatectomy should lead
to little functional disturbance. In one series of 172 patients
250
with hepatolithiasis, liver resection was necessary in 37% of
patients, of which left lateral segmentectomy and left hepatec-
tomy accounted for most of the resections (90.5%). Right
hepatectomy was only performed in one patient (40). Trouble-
some adhesions between the diseased liver and the diaphragm
and adjacent viscera can make liver resection difficult. Severe
adhesions and fibrosis around the left hepatic vein and the
inferior vena cava can make dissection in the region difficult
and severe bleeding from these structures due to injudicious
dissection can be a problem. The overall operative mortality in
hepatic resection for hepatolithiasis is low (<2%), but the
morbidity, such as wound infection, subphrenic collections,
and biliary fistulae, from operating on an underlying septic
condition is correspondingly high (approximately 30%).
complications
In RPC the biliary mud and stones within the common bile
duct can lead to acute pancreatitis. In 1971, Ong et al. reported
that approximately half of all patients with acute pancreatitis,
in Hong Kong, were associated with RPC (41). Another report
claims that about 20% of RPC patients had high serum amy-
lase levels but were clinically asymptomatic (42). In some
patients, the big common bile duct stones can lead to the for-
mation of a choledochoduodenal fistula.
Liver abscesses complicating RPC can present with rupture
into the peritoneal cavity or adjacent viscera. A left lobe liver
abscess can rupture into the pericardial cavity and cause car-
diac tamponade (43), while a right lobe abscess can lead to the
formation of a pleurobiliary or bronchobiliary fistula (44). A
chronic abscess can, on clinical and radiological grounds, be
indistinguishable from an underlying cholangiocarcinoma.
The final diagnosis can only be certain after histological exam-
ination of the resected specimen.
Cholangiocarcinoma complicating RPC has been reported.
The higher incidence of cholangiocarcinoma in areas where
RPC is also prevalent has been attributed to the presence of
Clonorchis sinensis infestation (45). In a necropsy study of 50
cases of cholangiocarcinoma, 92% of the cases were associated
with clonorchiasis and intrahepatic stones were found in 20%
of the cases (45). In a huge series of 1105 cases of hepatolithia-
sis studied over the period 1978 to 1990, Chen et al. (46)
reported that the incidence of cholangiocarcinoma in these
patients increased from 2.4% (between 1978 and 1987) to
13.7% (between 1988 and 1990), despite a decreasing inci-
dence of clonorchiasis in the population.
Thrombophlebitis of the branches of the portal vein due to
the underlying periductal inflammation can lead to portal
venous thrombosis with an enlarged spleen (6). Occasionally,
septic emboli to the pulmonary tree can lead to the develop-
ment of lung abscesses and significant pulmonary hyperten-
sion (6,47).
Despite multiple operations, RPC patients with long-stand-
ing severe disease can develop secondary biliary cirrhosis and
liver failure (48). When cirrhosis sets in, portal hypertension
and bleeding esophageal varices ensue, thus making further
corrective surgery for the underlying stricture(s) more hazard-
ous. In these patients the only available option is liver
transplantation.
 MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS
conclusions
As the name implies, RPC runs a recurrent and unrelenting
course with variable frequencies of attacks of cholangitis.
Medical therapy is ineffective and surgical treatment is not
entirely satisfactory. Despite surgery, stones and strictures can
return. In Hong Kong and Taiwan, the peak age incidence of
RPC has changed over the years from the third to the fifth
decade in the 1950s and 1970s to the seventh decade in the
early 1990s (49). This is due to an increasing proportion of
patients who have survived previous surgery, only to have RPC
recur again in later life. In Hong Kong, young patients in their
third and fourth decade of life who present to us with RPC are
invariably immigrants from mainland China. RPC is a dying
disease in Hong Kong, but is still common in China. Although
there are various theories on the pathogenesis of RPC, we
believe the condition is closely linked to the level of social and
economic conditions of a community. Surgery merely deals
with the consequences of the condition, but does not address
its roots. With better living conditions and public hygiene,
perhaps RPC can be eradicated in this millennium. Until then,
a judicious choice of a mixture of treatment, both medical and
surgical, is necessary to achieve a satisfactory and long-lasting
solution to a recurrent inflammatory condition.
key points
● Calculi are predominantly calcium bilirubinate.
● Probably secondary to E. coli infection of bile.
● Presentation:
Third and fourth decade
Recurrent attacks of cholangitis
Obstructive jaundice
Preferentially affects left lobe.
● Investigations:
Plain abdominal radiography (AXR)
CT
ERCP B1 PTC.
● Complications:
Acute pancreatitis
Liver abscess
Cholangiocarcinoma
Portal thrombophlebitis
Secondary biliary cirrhosis.
references
1. Digby KH. Common-duct stones of liver origin. Br J Surg 1930; 17: 578–91.
2. Cook J, Hou PC, Ho HC, et al. Recurrent pyogenic cholangitis. Br J Surg
1954; 42: 188–203.
3. Mage S, Morel AS. Surgical experience with cholangiohepatitis (Hong
Kong Disease) in Canton Chinese. Ann Surg 1965; 162: 187–90.
4. Harrison-Levy A. The biliary obstruction syndrome of the Chinese. Br J
Surg 1962; 49: 674–85.
5. Choi TK, Wong J, Ong GB. The surgical management of primary intrahe-
patic stones. Br J Surg 1982; 69: 86–90.
6. Chou ST, Chan CW. Recurrent pyogenic cholangitis: a necropsy study.
Pathology 1980; 12: 415–28.
7. Federle MP, Cello JP, Laing FC, et al. Recurrent pyogenic cholangitis in
Asian immigrants. Use of ultrasonography, computed tomography, and
cholangiography. Radiology 1982; 143: 151–6.
8. Lam SK. A study of endoscopic sphincterotomy in recurrent pyogenic
cholangitis. Br J Surg 1984; 71: 262–6.
9. Wilson MK, Stephen MS, Mathur M, et al. Recurrent pyogenic cholangitis
or ‘oriental cholangiohepatitis’ in occidentals: case reports of four
patients. Aust N Z J Surg 1996; 66: 649–52.
10. Menu Y, Lorphelin JM, Scherrer A, et al. Sonographic and computed
tomographic evaluation of intrahepatic calculi. AJR 1985; 145: 579–83.
11. Maki T. Pathogenesis of calcium bilirubinate gallstone: role of E. coli,
β-glucuronidase and coagulation by inorganic ions, polyelectrolytes and
agitation. Ann Surg 1966; 164: 90–100.
12. Ong GB. A study of recurrent pyogenic cholangitis. Arch Surg 1962;
84: 63–89.
13. Maki T. Cholelithiasis in the Japanese. Arch Surg 1961; 82: 599–612.
14. Matsushiro T, Suzuki N, Sato T, et al. Effects of diet on glucaric acid con-
centration in bile and the formation of calcium bilirubinate gallstones.
Gastroenterology 1977; 72: 630–3.
15. Leow CK, Lau WY. Biliary access procedure in the management of orien-
tal cholangiohepatitis. Am Surg 1998; 64: 99.
16. Flinn WR, Olson DF, Oyasu R, et al. Biliary bacteria and hepatic histologic
changes in gallstone disease. Ann Surg 1977; 185: 593–7.
17. Thorpe MEC, Scheuer PJ, Sherlock S. Primary sclerosing cholangitis, the
biliary tree and ulcerative cholangitis. Gut 1967; 8: 435–48.
18. Ohta G, Nakanuma Y, Terada T. Pathology of hepatolithiasis: cholangitis
and cholangiocarcinoma. Prog Clin Biol Res 1984; 152: 91–113.
19. Copher GH, Dick BM. ‘Streamline’ phenomena in portal vein and selec-
tive distribution of portal blood in liver. Arch Surg 1928; 17: 408–19.
20. Hahn PF, Donald WD, Grier RC Jr. Physiological bilaterality of the portal
circulation; streamline flow of blood into liver as shown by radioactive
phosphorus. Am J Physiol 1945; 143: 105–7.
21. Fan ST, Lai ECS, Mok FPT, et al. Acute cholangitis secondary to hepatoli-
thiasis. Arch Surg 1991; 126: 1027–31.
22. Wastie ML, Cunningham IGE. Roentgenologic findings in recurrent pyo-
genic cholangitis. AJR 1973; 119: 71–7.
23. Itai Y, Araki T, Furui S, et al. Computed tomography and ultrasound in the
diagnosis of intrahepatic calculi. Radiology 1980; 136: 399–405.
24. Chan YL, Chan ACW, Lam WWM, et al. Choledocholithiasis: comparison
of MR cholangiography and endoscopic retrograde cholangiography.
Radiology 1996; 200: 85–9.
25. Park MS, Yu JS, Kim KW, et al. Recurrent pyogenic cholangitis: compari-
son between MR cholangiography and direct cholangiography. Radiology
2001; 220: 677–82.
26. Araki T, Itai Y, Tasaka A. CT of choledochal cyst. AJR 1980; 135: 729–34.
27. Kaiser JA, Mall JC, Salmen BJ, et al. Diagnosis of Caroli disease by com-
puted tomography: report of two cases. Radiology 1979; 132: 661–4.
28. Mujahed Z, Glenn F, Evans JA. Communicating cavernous ectasia of the
intrahepatic ducts (Caroli’s disease). AJR 1971; 113: 21–6.
29. A0Lillemoe KD. Surgical treatment of biliary tract infection. Am Surg
2000; 66: 138–44.
30. Fan ST. Transduodenal sphincteroplasty for impacted stone made unnec-
essary by electrohydraulic lithotripsy. Surg Gynecol Obstet 1989;
169: 363–4.
31. A0Cosenza CA, Durazo F, Stain SC, et al. Current management of recur-
rent pyogenic cholangitis. Am Surg 1999; 68: 939–43.
32. Choi TK, Wong J, Lam KH et al. Late result of sphincteroplasty in the
treatment of primary cholangitis. Arch Surg 1981; 116: 1173–5.
33. Jeng KS, Yang FS, Ohta I, et al. Dilatation of intrahepatic biliary strictures
in patients with hepatolithiasis. World J Surg 1990; 14: 587–93.
34. Ong GB, Kwong KH, Cheng FCY. Extraperitoneal transduodenal choled-
ocho-duodenostomy for removal of overlooked common bile duct stones.
Aust N Z J Surg 1970; 40: 166–70.
35. Choi TK, Lee NW, Wong J, et al. Extraperitoneal sphincteroplasty for
residual stones: an update. Ann Surg 1982; 196: 26–9.
36. Fan ST, Mok F, Zheng SS, et al. Appraisal of hepaticocutaneous jejunos-
tomy in the management of hepatolithiasis. Am J Surg 1993; 165: 332–5.
37. Lau WY, Chan KL, Li AKC. Surgical treatment of inflammatory strictures
of the major bile ducts. Asian J Surg 1990; 13: 51–4.
38. Lau WY, Fan ST, Yip WC, et al. Surgical management of strictures of the
major bile ducts in recurrent pyogenic cholangitis. Br J Surg 1987;
74: 1100–2.
39. Hepp J, Couinaud C. L’abord et l’utilisation du canal hepatique gauche dans
les reparations de la voie biliaire principale. Presse Med 1956; 64: 947–8.
251
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
40. Fan ST, Lai ECS, Wong J. Hepatic resection for hepatolithiasis. Arch Surg
1993; 128: 1070–4.
41. Ong GB, Adiseshiah M, Leong CH. Acute pancreatitis associated with
recurrent pyogenic cholangitis. Br J Surg 1971; 58: 891–4.
42. Wong J, Choi TK. Recurrent pyogenic cholangitis. Prog Clin Biol Res
1984; 152: 175–92.
43. Choi TK, Wong J. Recurrent pyogenic cholangitis. In: Schwartz SI, Ellis H,
Husser WC, eds. Maingot’s Abdominal Operations. Volume 2, 9th edn.
New Jersey: Prentice-Hall International, 1990: 1519–31.
44. Wei WI, Choi TK, Wong J, et al. Bronchobiliary fistula due to stones in the
biliary tree: report of two cases. World J Surg 1982; 6: 782–5.
252
45. Chou ST, Chan CW. Mucin-producing cholangiocarcinoma: an autopsy
study in Hong Kong. Pathology 1976; 8: 321–8.
46. Chen MF, Jan YY, Wang CS, et al. A reappraisal of cholangiocarcinoma in
patient with hepatolithiasis. Cancer 1993; 71: 2461–5.
47. Lai KS, McFadzean AJS, Young RTT. Microemboli pulmonary hyperten-
sion in pyogenic cholangitis. Br Med J 1968; 1: 22–4.
48. Jeng KS, Shih SC, Chiang HJ, et al. Secondary biliary cirrhosis. A limit-
ing factor in the treatment of hepatolithiasis. Arch Surg 1989; 124:
1301–5.
49. Fan ST, Choi TK, Lo CM, et al. Treatment of hepatolithiasis: improvement
of result by a systemic approach. Surgery 1991; 109: 474–80.
28 Liver abscess: amebic, pyogenic, and fungal
Purvi Y. Parikh and Henry A. Pitt
introduction
Hepatic abscess is an uncommon disorder that continues to be a
challenge to identify and treat. The three major types of hepatic
abscesses are (i) pyogenic, most often polymicrobial, due to
aerobic and anaerobic bacteria, (ii) amebic, due to Entamoeba
histolytica, and (iii) fungal, principally due to Candida species.
Pyogenic hepatic abscesses are seen most commonly in temper-
ate climates, and in the United States they account for approxi-
mately 80% of the cases. Amebic abscesses account for about
10% of U.S. patients but are relatively more common in semi-
tropical and tropical climates (1). Fungal abscesses are seen in
10% of U.S. cases and are increasing in frequency secondary to
more immunocompromised patients as well as those having
invasive hepatic procedures with prolonged antibiotic expo-
sure (2,3). This chapter focuses on the pathogens, diagnosis, and
current management of liver abscesses.
amebic abscess
Amebic liver abscess was not recognized as a separate entity
until the nineteenth century. Several European investigators
had suggested a relationship between dysentery and liver
abscess; however, in 1875 Feder Losch discovered that
Entamoeba histolytica was the causal agent. In 1890, Sir William
Osler described the first North American case of amebic liver
abscess when he found amoeba in a patient’s liver and stool
sample (4). Open surgical drainage was the treatment of choice
of amebic abscess until the 1930s, when aspiration and emetine
became the standard of therapy. During this time, mortality
decreased remarkedly from 57% to 14% by using therapeutic
aspiration combined with amebicidal therapy (5). Further
advancement in management happened with the introduction
of serologic tests, improved radiologic imaging, and new
amebicidal agents.
Epidemiology
Amebiasis is a widespread parasitic disease that affects people
in developed and underdeveloped countries in tropical cli-
mates. Mexico, India, East and South Africa as well as Central
and South America have the highest epidemic activity of
E. histolytica (6). Worldwide, an estimated 500 million people
are carriers of E. histolytica, and 50 million people worldwide
develop amebic colitis or amebic liver abscesses resulting in
50,000 to 100,000 deaths each year (7). High-risk groups in the
United States include immigrants, tourists who travel to
endemic areas, institutionalized people, and the homosexual
population. Amebic liver abscess is much more common in
men, with a male to female ratio of 10:1. Low socio-economic
status and unsanitary conditions are significant risk factors.
Other associated risk factors include patients with heavy alco-
hol consumption, impaired immunity, malnutrition, and
chronic infections (8).
Pathogenesis
Infection occurs after fecal–oral transmission of E. histolytica,
which exists in either an immobile cyst form or the invasive tro-
phozoite form. The main sources of infection are from asymp-
tomatic carriers who transmit the cysts from water to vegetables
contaminated with feces, food contaminated by fertilizers, or
the hands of infected food handlers (9). The cystic form is swal-
lowed and passes unaffected through the stomach into the intes-
tine where the outer cyst wall is then digested by pancreatic
enzymes. The trophozoite form is released into the intestine
where it lives and multiplies. In most patients, the trophozoite
asymptomatically colonizes the intestine, but some patients may
develop amebic dysentery. The trophozoite invades through the
intestinal mucosa, enters the mesenteric venules and lymphat-
ics, travels to hepatic venules by the portal vein, and aggregates
in the liver parenchyma (7). Accumulation of enough trophozo-
ites leads to thrombosis, and necrosis and formation of an
abscess. The outer rim of the abscess wall is infested by E. histo-
lytica. The liquefied hepatic parenchyma has the appearance of
“anchovy paste” (10). More than 80% of patients with amebic
liver abscess have excess alcohol intake and thus a vulnerable
liver to Entamoeba (11). Higher rates of tissue invasion are
found in patients with Human Immunodeficiency Virus (HIV),
splenectomy, and corticosteroid administration.
Diagnosis
The clinical presentation of amebic liver abscess is significantly
different from pyogenic (Table 28.1). More than 90% of cases
occur in men who usually live in or have a travel history to an
endemic area in the last 2 to 5 months (5). Typical symptoms
include fever, chills, anorexia, right upper quadrant pain,
abdominal tenderness, and hepatomegaly with point tender-
ness over the liver or subcostal region. Diaphragmatic involve-
ment causes right-sided pleural pain or pain referred to the
shoulder (12). Patients with amebic liver abscess rarely have
concurrent amebic dysentery, but 10% to 35% of patients have
gastrointestinal symptoms that include nausea, vomiting,
abdominal cramping, or distention (12). Jaundice, septic
shock or a palpable mass may rarely be seen.
Patients with an amebic liver abscess usually have a mild leu-
kocytosis without eosinophilia (8). Mild anemia with moder-
ate elevation of alkaline phosphatase and other liver function
tests also may be present. The most common abnormality is an
increased prothrombin time (12,13). Young males who are
alcoholics may have normal or increased hemoglobin. If con-
current colitis is present, the wet mount prep will contain tro-
phozoites 70% of the time if three separate stool samples are
examined (11). If the patient has no colitis and a solitary liver
abscess, stool samples are positive in 40% to 50% of cases (6).
The definitive diagnosis of amebic liver abscess is by the
detection of E. histolytica trophozoites in the abscess and by
253
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

finding serum antibodies to the amoeba. Serum antibodies are
positive in 85% of patients with invasive colitis, and 99% of
patients with liver abscesses (14). However, in endemic coun-
tries positive serologies can also be found in asymptomatic
carriers. Biopsies of the abscess wall also can reveal trophozo-
ites with periodic acid-Schiff stain (11).
Chest radiographs typically show elevation of the right
dome of the diaphragm, pleural effusion, and atelectasis. A
plain abdominal film will usually show an enlarged hepatic
shadow and may demonstrate air in the biliary tree if a com-
munication to the pleural cavity or hollow viscous is present.
However, ultrasound (US), computed tomography (CT), and
magnetic resonance imaging (MRI) are all excellent at detect-
ing and characterizing hepatic abscesses (13). Ultrasonogra-
phy is simple, inexpensive, and quick to perform with a
diagnostic accuracy of 90% (15). In an acute setting, CT scan
does not add to the diagnostic accuracy of US unless it is
needed for evaluation of rupture of abscesses. However, the
CT scan does show better delineation of other organs in rela-
tionship with the liver (13). MRI is not superior to CT for
diagnosis of amebic liver abscess. A nuclear hepatic scan with
gallium may differentiate a “cold” amebic abscess from a
“hot” pyogenic abscess because of the presence of neutro-
phils (16). Performing a diagnostic aspiration is usually
unnecessary if there is a high clinical suspicion of an amebic
liver abscess (13).
Treatment
Treatment for uncomplicated amebic liver abscess is gener-
ally amecidal drugs. Selective patients may require further
treatment such as aspiration and percutaneous or surgical
drainage because diagnosis is questionable or when com-
plications occur. The mainstay of therapy is metronidazole
that is highly effective against both intestinal and extraint-
estinal infection. The standard dose is 500 mg IV q6 hr
with oral administration of 750 mg q8 hr for a total of 7 to
10 days (6). Most patients have rapid clinical improvement
in 72 hours, and 90% are cured with metronidazole.
Patients who have a persistent abscess and do not respond
to metronidazole within 5 days may require the addition of
chloroquine (17). Approximately 10% of patients have a
recurrence of their abscesses if the intestinal colonization is
not treated (18).
The majority of patients do not require percutaneous aspi-
ration of the amebic abscess because they respond to amebi-
cidal therapy. Blessmann and colleagues reported that
therapeutic aspiration had minor benefit and was insufficient
to justify routine needle aspirations (19). A 2009 Cochrane
Review also found that simple aspiration of uncomplicated
amebic liver abscesses did not help patients (20). However,
simple aspiration may be beneficial in patients with failure to
respond to drug therapy within 5 to 7 days. Aspiration should
also be considered in patients with abscesses greater than
5 cm in size because of the risk of rupture or in patients with
abscesses in the left hepatic lobe that have increased frequency
of peritoneal leak or rupture into the pericardium and a
higher mortality (Fig. 28.1) (21). Aspiration may be indicated
if a pyogenic cause needs to be ruled out or for treatment of
pulmonary, peritoneal, and pericardial complications. The
procedure can be performed safely with US- or CT-guided
aspiration. The fluid of an amebic abscess is odorless, and
Gram stain and cultures are negative. Amoeba are recovered

Table 28.1 Comparison of Amebic and Pyogenic Abscess

Features Amebic abscess Pyogenic abscess
Age (mean) 20–40 years >50 years
Male: female ratio >10:1 1:1
1
Abscess number 1 in ≥80% ≥1 in 50%
Travel/emigration Yes No
history 2
Diabetes mellitus Uncommon Common
Alcohol abuse Common Common 8
3
Jaundice Uncommon Common
Pruritus Uncommon Common
Abdominal pain Common Uncommon A B
Diarrhea Common Uncommon 9
Elevated bilirubin Uncommon Common 4
Elevated alkaline Common Common
phosphate
Elevated Uncommon Common
transaminase 7
Positive blood No Yes
5 6
culture
Positive amebic Yes No
Figure 28.1 Paths of extension of amebic liver abscesses located within (A) the
serology
right hepatic (labels 1–7) and (B) the left hepatic lobe (8,9).

254
 LIVER ABSCESS: AMEBIC, PYOGENIC, AND FUNGAL
in 33% to 90% of aspirates with a higher yield in patients with
wall scrapings (13).
Open surgical drainage of amebic liver abscess is rarely per-
formed because most patients respond to amecidal drug ther-
apy with or without aspiration. Most experts recommend
avoidance of open surgical drainage because of concern about
secondary bacterial colonization; however, they agree that sur-
gical drainage is often necessary in patients with rupture into
the peritoneal cavity, the pleura, lung or pericardium. Thus,
open surgical drainage is reserved for patients with complica-
tions from rupture, failure to respond to medical therapy, and
inadequate aspiration.
Outcomes
Complications of amebic liver abscesses occur secondary to
rupture of the abscess into the peritoneum, pleural cavity, or
pericardium. Ruptured amebic liver abscesses occur in 2% to
17% of patients with mortality between 12% and 50% (18).
Free rupture into the peritoneal cavity is rare and occurs in
patients with poor nutrition or with simultaneous amebic
colitis. Peritonitis may occur secondary to rupture or second-
ary to necrotizing or perforated amebic colitis. Most often,
the ruptured liver abscess adheres to the diaphragm or omen-
tum that tends to wall it off. Thoracic amebiasis causing
empyema, bronchohepatic fistulas, and pleuropulmonary
diseases is the most common complication followed by peri-
cardial amebiasis manifested by acute pericarditis with tam-
ponade (6). When tamponade develops, aspiration of the
pericardium, drainage of the liver abscess and anti-amebic
drugs are indicated (18). Severely ill patients with sepsis sec-
ondary to amebiasis also may develop cerebral amebiasis and
experience seizures (6).
The overall mortality rates of patients with amebic liver
abscess are from 0% to 18%, and high mortality rates suggest
delayed diagnosis, secondary bacterial infection or complica-
tions (11). Factors that are associated with a poor prognosis
are jaundice, advanced age, encephalopathy, decreased albu-
min, large abscess cavity, or complications such as rupture into
the peritoneum or pericardium (22). Patients will have clinical
improvements with amecidal therapy much more rapidly than
radiologic resolution. Complete radiologic resolution may
take up to 9 months. Follow-up imaging studies in patients
with resolution of symptoms after treatment for amebic liver
abscess is advised.
pyogenic liver abscess
Liver abscess was recognized in ancient times, and the first
description is credited to Hippocrates in 4000 BC. No new
information was identified until the landmark paper by
Ochsner and Debakey in 1938 (23). They described the dis-
ease as having a 62% survival rate for patients undergoing
surgical drainage. With improvements in antibiotics, the
combination of surgical drainage and antibiotics became the
standard of care. In 1953, McFadzean and associates first
reported percutaneous drainage (24). By the mid-1980s, the
development of US and CT scans led to numerous reports of
patients successfully treated by percutaneous drainage and
antibiotics (25,26).
Epidemiology
Pyogenic liver abscess is the most common form of liver
abscess accounting for approximately 80% of all liver abscesses
in the United States (1). The disease process has significantly
increased over the past 30 years, presenting in about 15 cases
per 100,000 admissions. Seeto and Rocky reported an incidence
nearly double that of earlier reports (22 per 100,000) due to a
more aggressive management approach to hepatobiliary and
pancreatic diseases (27). The predominant etiology of pyo-
genic liver abscess has changed from an intra-abdominal sep-
tic source to a biliary origin with more reports of cryptogenic
liver abscesses in recent years. Advanced imaging techniques,
improved antibiotics, and numerous treatment modalities
have decreased morbidity and mortality.
Pathogenesis
The liver is a sterile organ that has Kupffer cells that filter out
microorganisms. Abscesses form when the normal liver fails to
clear the organisms, and the infection causes parenchymal
necrosis. Potential sources of these microorganisms are (i)
biliary, secondary to ascending cholangitis or biliary malig-
nancy, (ii) portal, pyemia secondary to appendicitis, diverticu-
litis, or other intra-abdominal source, (iii) arterial, from
generalized septicemia, (iv) direct extension, (v) trauma, and
(vi) cryptogenic (Table 28.2).
Ascending infection of the biliary tree causing obstruction
now accounts for 35% to 40% of all pyogenic liver abscesses (1).
The etiology of the biliary obstruction has some geographic
differences. In Western countries, 40% of pyogenic liver
abscesses have underlying malignant disease (28). In Asian
countries, hepatolithiasis and associated biliary strictures
predominate as the cause of pyogenic liver abscess (29).
Percutaneous or endoscopic manipulation or stenting can
introduce infection into the biliary tree causing cholangitis,
which has the propensity to cause pyogenic liver abscess. Other
causes include Caroli’s disease, invasion of the biliary tree by
parasites and/or a previous biliary-enteric anastomosis.
In the past, the most common source of pyogenic liver abscess
was appendicitis. In Ochsner’s study, appendicitis accounted for
43% of all abscesses seeded via the portal vein (23). Today, even
though intestinal pathology is responsible for 20% of all pyo-
genic liver abscesses, appendicitis accounts for only 2% of all
pyogenic liver abscesses. Diverticulitis and perforated colon
cancers remain more common causes of pyogenic liver abscesses.
Hematogenous spread of infection from sources like endo-
carditis, dental abscess, and intravenous drug abuse are exam-
ples of generalized septicemia that may lead to a pyogenic liver
abscess. Transarterial embolization or ablative therapies for
liver tumors are also associated with liver abscess formation
(30,31). Direct extension of empyema of the gallbladder, per-
forated gastric or duodenal ulcers, and subphrenic abscess also
may cause a pyogenic liver abscess.
Liver trauma from penetrating or blunt injury may cause
parenchymal necrosis, hemorrhage, or intrahepatic biloma that
may become infected and develop into pyogenic liver abscess
(32). Hepatic artery thrombosis after liver transplantation or
ligation after a pancreatobiliary operation may lead to a liver
abscess especially following obstructive jaundice. In some
255
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

patients, no identifiable cause of pyogenic liver abscess can be Streptococci viridians. An abscess secondary to biliary tract dis-
found; they are labeled cryptogenic abscesses and occur in 10% ease or originating from a gastrointestinal source is more likely
to 55% of patients (33,34). Cryptogenic abscess tend to be soli- to be polymicrobial with aerobic and anaerobic organisms.
tary, monomicrobial, and associated with diabetes, immuno- Bacteroides is the most common isolated anaerobic organism,
suppression, or malignancy. Cryptogenic abscesses usually have followed by Fusobacterium (10). The increased use of indwell-
a normal bilirubin and no duct dilation on imaging (27). ing biliary stents has resulted in an increased incidence of
Klebsiella, streptococcal, staphylococcal, and pseudomonal
Microbiology species in liver abscesses (28). Fifteen percent of patients have
With the various routes of infection, identification of micro- a negative culture that may be attributed to poor anaerobic
organisms recovered from blood culture or aspiration of pus culture technique or the use of broad-spectrum antibiotics
from the pyogenic liver abscess is imperative for treatment. prior to abscess drainage. This factor also is thought to be
Patients with cryptogenic liver abscess are more like to have responsible for the increased incidence of fungal abscesses (6).
negative blood cultures. However, liver abscesses from biliary In patients with Acquired Immune Deficiency Syndrome
tract disorders are more likely to have positive cultures from (AIDS) the most common infecting organism for hepatic
blood and pus. The most common organisms cultured are abscesses is Mycobacterium tuberculosis (36).
Escherichia coli and Klebsiella pneumoniae (Table 28.3) (35).
Other frequently encountered aerobes include enterococci and Diagnosis
The clinical presentation of pyogenic liver abscess is non-
specific and includes malaise, nausea, anorexia, weight loss,
Table 28.2 Most Frequent Causes of Pyogenic Liver Abscess headaches, and myalgias. These symptoms may be present for
many weeks before the appearance of more specific symptoms
Hepatobiliary
such as fever, chills and abdominal pain in the right upper
Benign
Choledocholithiasis
quadrant (RUQ) (Table 28.1). The classic triad of fever, jaun-
Hepatolithiasis dice, and RUQ tenderness is present in less than 10% patients.
Biliary-enteric anastomosis Diarrhea also occurs in 10% of patients (37). On physical
Endoscopic biliary procedure examination, some patients may also have a tender and enlarged
Percutaneous biliary procedures abdomen. Abscesses adjacent to the diaphragm may cause
Malignant pleuritic chest pain, cough, and dyspnea. Septic shock may be
Biliary present in patients with cholangitis or peritonitis after rupture
Gallbladder into the peritoneal cavity. Laboratory investigations demon-
Ampulla strate leukocytosis (70% to 90%), hyperbilirubinemia (50% to
Head of pancreas 67%), and elevated alkaline phosphatase (80%) in a majority of
Portal patients. Many patients may also have anemia, hypoalbumin-
Benign emia, and prolonged prothrombin time (34,37,38). Patients
Diverticulitis with pyogenic abscesses are also more likely than those with an
Anorectal abscess
amebic abscess to have diabetes mellitus.
Pelvic abscess
Post-operative abscess
Intestinal perforation
Table 28.3 Spectrum of Microorganisms That Cause
Pancreatic abscess
Appendicitis Pyogenic Liver Abscess
Inflammatory bowel disease Gram-positive aerobes
Malignant Streptococcus milleri
Colon cancer Staphylococcus aureus
Gastric cancer Enterococcus spp.
Arterial Others
Endocarditis Gram-Negative Aerobes
Ear, throat, nose infection Escherichia coli
Dental infection Klebsiella pneumoniae
Pseudomonas aeruginosa
Direct extension
Proteus spp.
Empyema of the gallbladder
Enterobacter cloacae
Perforated ulcer
Citrobacter freundii
Traumatic Others
Benign Gram-positive anaerobes
Open or closed abdominal trauma Clostridium spp.
Transarterial embolization Peptostreptococcus spp.
Percutaneous ethanol injection Gram-negative anaerobes
Ablation Bacteroides spp.
Cryptogenic Fusobacterium spp.

256
 LIVER ABSCESS: AMEBIC, PYOGENIC, AND FUNGAL

Imaging studies are essential in establishing the diagnosis of Treatment

hepatic abscess. Plain films of the abdomen and chest show
abnormalities in 50% of patients (39). The films will show right-
sided atelectasis, pleural effusion, and hemi-diaphragm on chest
x-ray and hepatomegaly, possible portal venous gas, and occas-
sional air/fluid levels. Ultrasound and CT scans have a greater
sensitivity in visualizing the liver abscess and providing image-
guided therapy. The US has a sensitivity as high as 75% to 95%;
however, US has difficulty detecting multiple abscesses or those
on the dome of the right lobe (27). A CT scan is more accurate
than US in differentiating liver lesions from abscesses and visual-
izing multiple abscesses throughout the liver (Fig. 28.2). CT also
has a sensitivity of 95%, but the advantage of abdominal CT
scans is that they may help to identify other intra-abdominal
pathology and abscesses as small as 0.5 cm (27). Magnetic reso-
nance imaging is also very accurate but has no advantage over
ultrasounds or CT scans in the diagnosis of pyogenic liver abscess.
The principles of treatment for liver pyogenic liver abscesses
are to start appropriate antibiotics, drain the pus, and treat the
underlying cause, if identified. Although antibiotics alone may
be curative, these patients have a higher risk of recurrence and
complications such as abscess rupture. Ultrasound and CT
scans have allowed for earlier diagnosis and facilitated treat-
ment by percutaneous aspiration and drainage (Fig. 28.2). The
combination of antibiotic therapy and percutaneous drainage
has become the first line treatment for most pyogenic liver
abscesses (Table 28.4).
Initial antibiotic therapy should be started to cover gram-
negative and gram-positive aerobes and anaerobes. Multiple
single antibiotics such as pipacillin/tazobactam, ticarcillin/cla-
vulanate, imipenem/cilastin, or meropenem may be started
initially if a biliary source is suspected. Alternative therapies
including a third-generation cephalosporin or a fluroquinolone

(A) (B)

(C) (D)
Figure 28.2 (A) CT demonstrating pyogenic abscess with air/fluid level in segment VI of the liver. (B) CT scan showing residual abscess after initial percutaneous
drainage. (C) Further percutaneous drainage catheters. (D) CT demonstrating resolution of abscess.

257
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Table 28.4 Comparison of Liver Abscess: Diagnosis
and Treatment
Liver abscess Diagnosis Treatment
Amebic Clinical Suspicion Amebicidal therapy
US or CT scan Lumenal agent
Positive amebic serology Drainage of
complicated
abscess
Pyogenic Clinical Suspicion Systemic antibiotics
US or CT scan Drainage of abscess
± Aspiration
Fungal Immunocompromised Systemic antifungal
patient
US or CT scan Drainage of abscess
± Aspiration Systemic antibiotics
for polymicrobial
abscess
Abbreviations: CT, computed tomography; US, ultrasound.
with metronidazole may be administered if the bowel is thought
to be the source. Parenteral administration of antibiotics for
the first 10 to 14 days followed by oral agents for a total of 4 to
6 weeks is the classic recommendation. However, recent studies
suggest that only 2 weeks of antibiotic therapy may be required
(40). A combination of an aminoglycoside with either an
extended spectrum beta-lactam, such as piperacillin, or a third
generation cephalosporin is preferred for patients with K. pneu-
moniae liver abscesses (41). Multiple abscesses <1.5 cm in size
and no other surgical disease may be treated with antibiotics
alone. However, patients with multiple small abscesses usually
have biliary tract disease and require biliary drainage. Matoba
and coworkes recently reported that when percutaneous drain-
age cannot be performed and intravenous administration of
antibiotics are ineffective, intermittent hepatic artery infusion
therapy may be a useful alternative (42).
Clinicians have questioned when the primary treatment for
pyogenic liver abscesses should be aspiration alone or place-
ment of a percutaneous catheter for drainage. Giorgio and
associates treated 115 patients with percutaneous needle aspi-
ration with a 98% success rate (43). Half the patients required
only one aspiration whereas the remainder needed two to
three aspirations. In 2004, C.H. Yu and associates also found
that aspiration and catheter drainage had a similar mortality,
success rate, and hospital stay (44). On the other hand, Rajak
and associates performed a prospective randomized controlled
trial comparing aspiration and catheter drainage showing a
100% success rate for catheter drainage compared to only 60%
for aspiration (45). In summary, needle aspiration is less inva-
sive and avoids all of the complications associated with cathe-
ter care. However, recurrence rates and the requirement for
surgical intervention may be increased for patients who
undergo aspiration alone.
Although highly successful, percutaneous catheter drainage fails
in approximately 10% of patients. Incomplete or unsuccessful
drainage may result from the catheter being too small, highly vis-
cous material, malposition of the catheter, or premature removal
of the catheter. Furthermore, contradictions of percutaneous
drainage requiring surgical drainage include patients with (i) large
258
or multiple abscess, (ii) abscesses of unknown etiology, (iii) ascites,
(iv) a known intra-abdominal source that requires surgery, and
(v) abscesses that require transpleural drainage (1).
Operative intervention is recommended when complica-
tions occur following percutaneous catheter drainage or fail-
ure of non-operative treatment. Open abdominal surgical
exploration involves localization of the abscess, identification
of additional lesions via ultrasound, evacuation of the abscess,
insertion a large-bore drainage tube, and treatment of the
inciting pathology (Fig. 28.3). Post-operative lavage of the cav-
ity through the drainage tube has been shown to be advanta-
geous. The role of hepatic resection for the treatment of
pyogenic liver abscesses remains controversial. Chou and asso-
ciates published a series of 483 patients with pyogenic liver
abscesses where 27 patients had a liver resection with 1 death
(3.7%) (46). They concluded that when single or multiple liver
abscesses have caused severe hepatic destruction, resection
should be considered. Patients with significant liver atrophy
and multiple pyogenic liver abscesses secondary to a long term
biliary obstruction from hepatolithiasis or intrahepatic biliary
stricture may also be best treated by hepatic resection (46).
Outcomes
Pyogenic liver abscess may be fatal if left untreated. Forty percent
of patients with pyogenic liver abscesses develop complications
that include pleural effusions, empyema, pneumonia, and gener-
alized sepsis. Pyogenic liver abscesses may also cause hemobilia
and hepatic vein thrombosis. Deaths in patients with pyogenic
liver abscesses have been attributed to the intra-peritoneal rup-
ture of the abscess. In one analysis, the causative bacteria in 72%
of the cases of failed medical treatment were S. milleri and
K. pneumoniae (47). Bacteremia, disseminated intravascular
coagulopathy (DIC), septic pulmonary emboli, and acute renal
failure are common complications of liver abscesses.
Since the introduction of broad-spectrum antibiotics and the
advancements in image-guided drainage, the mortality from pyo-
genic liver abscess has drastically decreased. However, the mortal-
ity in patients with multiple abscesses remains higher than in
those with a solitary abscess. Liver abscesses are now diagnosed
earlier and may be treated non-operatively thus reducing the
mortality to less than 20% (46). Seeto and Rockey showed in their
series a mortality of only 2% (27). Risk factors for mortality
include septic shock, jaundice, hypoalbuminemia, malignancy,
disseminated intravascular coagulopathy, APACHE II score >10,
multiple abscesses, and intra-peritoneal rupture (48).
fungal liver abscesses
Bacteria and parasites cause the vast majority of hepatic
abscesses; however, fungal liver abscesses account for about
10% of hepatic abscesses (2,3). Most monomicrobial fungal
abscesses occur in immunocompromised patients including
patients receiving chemotherapy and patients with HIV infec-
tions. Patients with biliary malignancies, indwelling stents, and
frequent courses of antibiotics tend to develop a polymicrobial
fungal abscess in conjunction with pyogenic abscesses. Candida
albicans and other Candida species are the predominate
organism in about 80% of cases (3). Aspergillus, Cryptococcus
and mixed infections make up the remaining fungal pathogens.
 LIVER ABSCESS: AMEBIC, PYOGENIC, AND FUNGAL
Ultrasonic
probe
Site of unilocular
abscess
Deep multiloculated
abscess
Gallbladder
Liver
Anaerobic
culture
Normal liver parenchyma
Abscess
(A)
Figure 28.3 (A) Intra-operative ultrasound, aspiration, and anaerobic culture of abscess, and liver incision for pyogenic abscess. (B) Aerobic culture, manual dis-
ruption of loculations, and irrigation of the pyogenic abscess. Source: Reproduced from Ref. (51).
Treatment
Fungal liver abscesses are treated with intravenous antifungal
therapy as well as drainage of the abscess by simple aspiration,
percutaneous drainage or open surgical drainage (Table 28.4).
Caspofungin is the agent of choice for these patients (49,50).
Patients with mixed bacterial and fungal abscesses should also
be treated with appropriate systemic antibiotics for the isolated
bacteria. An adequate course of caspofungin should be employed
as an earlier analysis suggested that inadequate treatment with
amphoteracin B was associated with a high mortality.
Outcomes
Very few patients develop pure fungal abscesses. Most patients
have polymicrobial fungal and bacterial abscesses. The overall
mortality rate is 50% because patients who do not receive anti-
fungal therapy in early stage develop systemic fungemia (12).
In addition, the underlying disease in the majority of these
patients is associated with a high mortality. Moreover, the
majority of these abscesses are multiple. As a result, patient
survival is not influenced by different drainage procedures.
references
1. Pitt HA. Surgical management of hepatic abscess. World J Surg 1990;
14:498–504.
2. Simpfendorfer CH, Henderson JM. Hepatic abscess. In: Cameron J, ed.
Current Surgical Therapy, 9th edn. Philadelphia, PA: Elsevier-Mosby,
2008: 317–21.
3. Lipsett PA, Huang CJ, Lillemoe KD, et al. Fungal hepatic abscess: charac-
terization and management. J Gastrointestinal Surg 1997; 1:78–84.
4. Martinez BM. Historical introduction. In: Martinez-Palomo A, ed. Amebiasis.
Human Parasitic Diseases, Vol. 2. Amsterdam, Holland: Elsevier; 1986: 1–9.
5. Hughes MA, Petri WA Jr. Amebic liver abscess. Infect Dis Clin N Am 2000;
14: 565–82.
Aerobic
culture
T-extension
Loculations
within
abscess
Liver
Antibiotic
containing
saline
solution
(B)
6. Wells CD, Aruqedas M. Amebic liver abscess. S Med J 2004; 97: 673–82.
7. Santi-Rocca J, Rigothier MC, Guillen N. Host-microbe interactions and
defense mechanisms in the development of amoebic liver abscesses. Clin
Microbiol Rev 2009; 22: 65–75.
8. Tanyuksel M, Petri WA. Laboratory diagnosis of amebiasis. Clin Micro-
biol Rev 2003; 16:713–29.
9. Salles JM, Moraes LM, Salles MC. Hepatic amebiasis. Braz J Infect Dis
2003; 7:96–110.
10. Leslie DB, Dunn DL. Hepatic abscess. In: Cameron J, ed. Current Surgical
Therapy, 8th edn. Philadelphia, PA: Elsevier Mosby; 2004: 298–303.
11. Petri WA Jr, Singh U. Diagnosis and management of amebiasis. Clin Infect
Dis 1999; 29: 1117–25.
12. Haque R, Huston CD, Hughes M, et al. Current concepts: amebiasis. N
Engl J Med. 2003; 48: 1565–73.
13. Barnes S, Lillemoe K. Liver abscess and hydatid cyst disease. In: Zinner M,
Schwartz S, Ellis H, Ashley S, McFadden D, ed. Maingot’s Abdominal
Operations, 10th edn. Stamford, CT: Appleton & Lange; 1997: 1513–45.
14. Haque R, Mollah NU, Ali IKM, et al. Diagnosis of amebic liver abscess and
intestinal infection with the techLab Entamoeba histolytica II antigen
detection and antibody tests. J Clin Microbiol 2000; 38: 3235–9.
15. Sepulveda B, Manzo NTG. Clinical manifestations and diagnosis of ame-
biasis. In: Martinez-Palomeo A, ed. Amebiasis: Human Parasitic Diseases,
No. 2 Amsterdam: Elsevier, 1986; 169–87.
16. Stanley SL Jr. Amebiasis. Lancet 2003; 361: 1025–34.
17. Lodhi S, Sarwari AR, Muzammil M, et al. Features distinguishing amoebic
from pyogenic liver abscess: a review of 577 adult cases. Trop Med Int
Health 2004; 9: 718–23.
18. Thomas PG, Ravindra KV. Amebiasis and biliary infection. In: Blumgart
LH, Fong Y, ed. Surgery of the Liver and Biliary Tract, 3rd edn. London:
WB Saunders; 2001: 1147–65.
19. Blessmann J, Binh HD, Hung DM, et al. Treatment of amebic liver abscess
with metronidazole alone or in combination with ultrasound-guided
needle aspiration: a comparative, prospective and randomized study. Trop
Med Int Health 2003; 8: 1030–4.
20. Chavez-Tapia NC, Hernandez-Calleros J, Tellez-Avia FI, et al. Image-
guided percutaneous procedure plus metronidazole versus metronidazole
alone for uncomplicated amoebic liver abscess (Review). The Cochrane
Library 2009 Issue 2.
259
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
21. Weinke T, Grobusch MP, Buthoff W. Amebic liver abscess: rare need for
percutaneous treatment modalities. Eur J Med Res 2002; 7:25–9.
22. Sharma MP, Dasarthy S, Verma N, et al. Prognostic markers in amebic
liver abscess: a prospective study. Am J Gastro 1996; 91: 2584–8.
23. Ochsner A. Pyogenic abscess of the liver. Am J Surg 1938; 40: 292–353.
24. McFadzean AJS, Chang EPS, Wong CL. Solitary abscess of the liver treated
by closed aspiration and antibiotics: a report of the 14 consecutive cases
with recovery. Br J Surg 1953; 41: 141–52.
25. Bertel C. Treatment of pyogenic hepatic abscess: surgical versus percuta-
neous drainage. Arch Surg 1986; 121: 554–8.
26. Gerzof SG, Johnson WC, Robbins AH, et al. Intrahepatic pyogenic abscess:
Treatment by percutaneous drainage. Am J Surg 1985; 149: 487–94.
27. Seeto R, Rockey D. Pyogenic liver abscess: changes in etiology, manage-
ment and outcomes. Medicine 1996; 75: 99–113.
28. Huang CJ, Pitt HA, Lipsett PA, et al. Pyogenic liver abscess: changing
trends over 42 years. Ann Surg 1996; 223: 600–9.
29. Kurland JE, Brann OS. Pyogenic and amebic liver abscesses. Curr Gastro
Rep 2004; 6: 273–9.
30. Chen C, Chen PJ, Yang PM, et al. Clinical and microbiological features of
liver abscess after transarterial embolization for hepatocellular carci-
noma. Am J Gastro 1997; 92: 2257–9.
31. de Baère T, Roche A, Amenabar JM, et al. Liver abscess formation after
local treatment of liver tumors. Hepatology 1996; 23: 1436–40.
32. Strong RW. Pyogenic liver abscess. In: Blumgart LH, ed. Surgery of the
Liver, Biliary Tract and Pancreas, 4th edn. Philadelphia: Saunders/Elsevier,
2007; 1: 927–33.
33. Christians KK, Pitt HA. Hepatic abscess and cystic disease of the liver. In:
Zinner M, Ashley S, ed. Maingot’s Abdominal Operations, 11th edn.
Stamford, CT: Appleton & Lange 2007; 757–81.
34. Chu KM, Fan ST, Lai ECS, et al. Pyogenic liver abscess: an audit of experi-
ence over the past decade. Arch Surg 1996; 131: 148–52.
35. Alvarez Pèrez J, Gonzáles JJ, Baldonedo RF. Clinical course, treatment and
multivariate analysis of risk factors for pyogenic liver abscess. Am J Surg
2001; 181: 177–86.
36. Pope IM, Poston GJ. Pyogenic liver abscess. In: Blumgart LH, Fong Y, ed.
Surgery of the Liver and Biliary Tract, 3rd edn. London: WB Saunders,
2001: 1135–45.
260
37. Branum GD, Tyson GS, Branum MA, et al. Hepatic abscess: changes in
etiology, diagnosis and management. Ann Surg 1990; 212: 655–62.
38. Leslie DB, Dunn DL. Hepatic abscess. In: Cameron J, ed. Current
Surgical Therapy, 8th edn. Philadelphia, PA: Elsevier Mosby 2004;
298–303.
39. Saini S. Imaging of the hepatobiliary tract. New Engl J Med 1997;
336:1889–94.
40. Ng FH, Wong WM, Wong BC, et al. Sequential intravenous/oral antibiot-
ics vs. continuous intravenous antibiotics in the treatment of pyogenic
liver abscess. Aliment Pharmacol Ther 2002; 16: 1083–90.
41. Lederman ER, Crum NF. Pyogenic liver abscess with a focus in Klebsiella
pneumoniae as a primary pathogen: an emerging disease with unique
clinical characteristics. Am J Gastro 2005; 100: 322–31.
42. Matoba M, Tonami H, Kuginuki M, et al. Intermittent hepatic artery
antibiotic infusion for pyogenic hepatic abscess. Acta Radiol 2004; 45:
13–17.
43. Giorgio A, Tarantino L, Mariniello N, et al. Pyogenic liver abscess: 13 years
of experience in percutaneous needle aspiration with US guidance. Radi-
ology 1995, 195: 122–4.
44. Ch Yu S, Hg Lo R, Kan PS, et al. Single and multiple pyogenic liver abscess:
treatment with needle aspiration. Clin Radiol 1997; 52: 912–6.
45. Rajak C, Gupta S, Jain S, et al. Percutaneous treatment of liver abscess:
needle aspiration vs. cathetar drainage. AJR 1998; 170: 1035–9.
46. Chou FF, Sheen-Chen SM, Chen YS, et al. Single and multiple pyogenic
liver abscesses: clinical course, etiology and results of treatment. World J
Surg 1997, 21: 384–9.
47. Lublin M, Bartlett DL, Danforth DN, et al. Hepatic abscesses in patients
with chronic granulomatous disease. Ann Surg 2002; 235: 383–91.
48. Christein JD, Kendrick ML, Que FG. What affects mortality after the
operative management of hepatic abscess? HPB 2006; 8:175–8.
49. Lai CH, Chen HP, Chen TL. Candidal liver abscesses and cholecystitis in a
37-year-old patient without underlying malignancy. World J Gastro 2005;
11: 1725–7.
50. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidia-
sis. Clin Infect Dis 2004; 38: 161–89.
51. Cameron JL, et al. Liver abscess. In: Atlas of Surgery. Philadelphia, PA: BC
Decker; 1990.
29 Benign solid tumors of the adult liver
Mark Duxbury and O. James Garden
introduction
As diagnostic radiological imaging techniques have improved
and become more widely applied, benign solid lesions of the
liver have become an increasingly common incidental finding.
These lesions are often detected in asymptomatic patients
without significant liver disease and there may be an increas-
ing trend to resect such lesions with the introduction of lapa-
roscopic liver surgery, an issue that remains contentious (1–3).
Although the etiology of these lesions is not well understood,
benign liver lesions can be classified according to their cellular
origin (Table 29.1).
Benign solid liver lesions can arise from hepatocytes, biliary
epithelium, surrounding mesenchymal structures, or mixtures
thereof. Some of these lesions are sufficiently rare that they can
be regarded as medical curiosities, although they may present
genuine diagnostic and management challenges. A compre-
hensive understanding of the clinical and pathological features
of benign solid liver lesions will facilitate differential diagnosis
and allow rational management.
The principal issues to be resolved in the management of
this group of patients are
1. Confirmation that the lesion is benign.
2. Determining whether the lesion requires surgical
treatment.
Detailed history addressing relevant risk factors and relevant
clinical examination will guide further investigation. While
commonly asymptomatic, benign liver lesions may present as
surgical emergencies with acute local or systemic symptoms
and signs due to hemorrhage, rupture, vascular thrombosis, or
necrosis. Commonly, patients present with symptoms that are
unrelated to an incidentally detected liver lesion. These
patients frequently require further assessment to exclude an
alternative cause for their symptoms. Particular aspects of the
history may increase the pre-investigation probability of a par-
ticular diagnosis, for example, pain, weight loss—malignancy;
known gallstones—biliary colic; previous cancer—metastasis;
primary sclerosing cholangitis or ulcerative colitis—
intrahepatic cholangiocarcinoma; oral contraceptive use: ade-
noma; cirrhosis, viral hepatitis, inborn errors of metabolism:
hepatocellular carcinoma.
While liver biochemistry is usually normal, this finding can
be helpful in supporting the diagnosis of a benign lesion.
Abnormal results may reflect a complication such as hemor-
rhage, infarction, or the presence of neoplasia. Systemic phe-
nomena, more commonly associated with hepatic malignancies,
are exceptional with benign liver lesions.
Advances in imaging have meant an increasing majority of
benign liver lesions are diagnosed solely on radiological fea-
tures, particularly in the case of hemangiomata, focal nodular
hyperplasia, and confounding focal fatty change. Percutaneous
biopsy or surgical resection may be helpful in cases of diagnos-
tic uncertainty, symptomatic lesions, or potentially premalig-
nant conditions. Our institutional practice is to reserve biopsy
for non-surgical candidates and only in cases where the biopsy
result will influence subsequent management (recommenda-
tion strength: D). The role of percutaneous needle biopsy
remains controversial, potential problems including bleeding
from vascular lesions and a risk of tumor seeding. Needle
biopsy and cytology are also subject to sampling errors which
can lead to misdiagnosis.
Current challenges for clinicians managing this group of
patients include
● Establishing the diagnosis of a radiologically detected
solid liver lesion with a satisfactory degree of cer-
tainty, a persisting problem being the differentiation
of FNH from adenoma and confirming the nature of
focal lesions in the cirrhotic liver.
● Managing patients with lesions identified inciden-
tally at operation
● Managing patients following complete or partial
resection of a lesion
● Managing patients with an incidental histological
diagnosis following resection or biopsy
● Determining optimal follow-up of these patients
based on the natural history of these lesions
In a recent clinical database review, surgery for benign dis-
ease accounted for 5% of patients undergoing resectional liver
surgery (4). Advances in preoperative assessment, perioperative
care, anesthesia, and surgical technique, including the increas-
ing application of minimally invasive laparoscopic approaches,
have the potential to decrease the morbidity and mortality rates
associated with resectional liver surgery (5,6). A recent European
study reported 87 patients treated laparoscopically with zero
mortality and a low-postoperative complication rate (5%) (7).
These improvements have altered the analysis of clinical risk
versus benefit required when managing a patient with a diag-
nosis of a solid benign liver lesion but should not increase the
prevalence of unnecessary liver resection.
imaging
Ultrasound (US) is often helpful in confirming an intrahe-
patic mass and will differentiate most cystic from solid paren-
chymal lesions. However, axial imaging in the form of
contrast-enhanced computerized tomography (CT) or mag-
netic resonance imaging (MRI) is usually required for ade-
quate lesion characterization. Recently developed MRI
contrast agents (superparamagnetic iron oxide, SPIO; gado-
benate dimeglumine, Gd-BOPTA) have improved the ability
to differentiate between solid benign lesions on MRI.
Improvements in these modalities mean that angiography is
261
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

form of hemangioendothelioma with intermediate malignant

Table 29.1 A Classification of Benign Solid Tumors of the
potential has been reported (9).
Adult Liver
Hemangiomata are of mesenchymal origin and probably
Hepatocellular origin represent a congenital, hamartomatous proliferation of vas-
Hepatocellular adenoma cular endothelial cells. Approximately 90% are solitary and
Hepatocellular adenomatosis structurally, 80% are cavernous hemangiomata, the reminder
Hepatocellular hyperplasia: being capillary hemangiomata (10). Over 90% of hemangio-
Focal nodular hyperplasia
mata are less than 5 cm in diameter, which can occasionally
Nodular regenerative hyperplasia
Regenerative nodule
make radiological characterization difficult. Current evidence
Dysplastic nodules indicates that hemangiomata have no malignant potential.
Cholangiocellular origin
Biliary hamartoma capillary hemangioma
Biliary adenoma In comparison to the more common cavernous form, capillary
Biliary cystadenoma hemangiomata are generally smaller in size and are more fre-
Congenital hepatic fibrosis quently multiple. These smaller lesions are a common inciden-
Mesenchymal origin tal finding in an asymptomatic patient. Once the diagnosis is
Vascular established, no further treatment is required (recommenda-
Hemangioma tion strength: D).
Adult hemangioendothelioma
Peliosis hepatis cavernous hemangioma
Hereditary hemorrhagic telangiectasia Pathology
Lymphangioma Cavernous hemangiomata occur in up to 8% of autopsy stud-
Adipose ies. These lesions are the second most common solid hepatic
Focal fatty changes tumor (10). Cavernous hemangiomata occur principally in
Lipoma
women (F:M = 5:1) and are more common in the right liver.
Angiomyolipoma
Myelolipoma
Large peripheral lesions may become pedunculated. The
Smooth muscle mean age at diagnosis is 50 years with most being detected
Leiomyoma between the third and fifth decade. Their prevalence is greatest
Fibroma in those with higher parity (11,12). Although there is no proven
Mesothelioma association with oral contraceptive use, the relationship
Mixed epithelial and mesenchymal remains controversial.
Mesenchymal hamartoma Hemangiomata are generally asymptomatic until they reach
Teratoma diameters of over 10 cm. Symptoms include non-specific
Inflammatory pseudotumor abdominal pain, pressure symptoms, and fever. Pain may be
Heterotopic tissue due to capsular stretching by larger lesions. Jaundice and rup-
Adrenal rests ture are rare. Cavernous hemangiomata may reach massive
Pancreatic heterotopia proportions, with reported lesions reaching several kilograms
in weight. Giant hemangiomata are defined as those measuring
5 cm and above in diameter (13) and are multiple in 10% of
now less commonly a part of initial patient assessment. Posi- cases (10).
tron emission tomography (PET) is undergoing further eval- Hepatic cavernous hemangiomata may be associated with
uation as a diagnostic adjunct and laparoscopy is used similar lesions in other organs (14). Other associated condi-
increasingly to allow direct visualization of liver lesions and tions, for example, liver cysts, gallbladder disease, gastroduode-
can be enhanced by intraoperative US. Nuclear medicine nal ulcers, or hiatus hernia are reported in 42% (15). In the rare
techniques such as single positron emission computerized Kasabach–Meritt syndrome intravascular coagulopathy may
tomography (SPECT) and tagged RBC scans, although less progress to systemic fibrinolysis and thrombocytopenia. The
commonly applied, may facilitate differentiation of heman- condition has a reported mortality rate of 20% to 30% (16).
gioma from hepatocellular carcinoma. 99mTc-sulfur colloid Macroscopically, cavernous hemangiomata appear purplish
scanning may help differentiate focal nodular hyperplasia in color and may collapse on sectioning. A plane can generally
from hepatocellular adenoma. be identified between the hemangioma and surrounding liver
parenchyma. Thrombosis, fibrosis, and calcification are com-
hemangioma ₍adult₎ mon features (Fig. 29.1). Cavernous hemangiomata may
Hemangiomata are the most common benign solid tumor of undergo complete fibrous transformation. Hemorrhage is
the liver. In terms of focal liver lesions they are second only to remarkably rare and rupture exceptional. This lesion probably
simple cysts in frequency. Autopsy studies have shown a preva- represents a congenital hamartoma with endothelium-lined
lence of up to 20% (8). Adult hemangioma differs in both spaces and fibrous septa being typical microscopic features.
presentation and histology from infantile hemangioendothe- Lesions enlarge through ectasia rather than hypertrophy or
lioma, which is considered elsewhere. An extremely rare adult hyperplasia.

262
 BENIGN SOLID TUMORS OF THE ADULT LIVER
Figure 29.1 Typical macroscopic appearances of hemangioma on sectioning
of resection specimen.
Imaging Features
Hemangiomata are usually hyperechoic on US, although US is
often inadequate for differentiating between solid liver lesions.
Color-flow Doppler shows peripheral vessel filling. Axial
imaging with CT or MRI is usually sufficient to confirm the
diagnosis. The principle challenge in managing small (<3 cm)
hemangiomata is differentiating them from other lesions, par-
ticularly in cases with atypical enhancement and significant
arterio-venous shunting.
Lesions tend to be hypodense on non-contrast CT and show
peripheral followed by central enhancement. Isoenhancement
with the arteries is typical. Delayed scans show persisting con-
trast enhancement and features such as corkscrewing and “cot-
ton wool” appearance reflect the abnormal vessels within the
lesion. Globular enhancement isodense with the aorta has
been shown to be 67% sensitive and 100% specific in differen-
tiating hemangiomata from metastases (17).
Hemangiomata are hypointense on T1-weighted sequences.
They appear very bright on T2-weighted sequences (the “light
bulb sign”). Peripheral nodular enhancement on dynamic
gadolinium-enhanced images and a non-intact ring appear-
ance immediately after contrast with centripetal enhancement
(maximal at 90s) are typical. Hemangiomata do not take up
SPIO or manganese dipyridoxyl ethylenediamine diacetate
(bis)phosphate (Mn-DPDP) as they do not contain Kupffer
cells or hepatocytes. 99mTc-SPECT is effective in assessing hem-
angiomata but appears inferior to MRI (18).
Management
Biopsy of hemangiomata is generally contraindicated given
the risk of hemorrhage and samples obtained from hemangio-
mata may resemble fibrosis. Resection may be justified rarely
for symptomatic lesions and in cases where the diagnosis can-
not be established despite investigation. Surgical resection or
enucleation remains the principal effective therapies (19). Use
of liver transplantation has been reported for unresectable dis-
ease in association with Kasabach–Merritt (20). The use of
arterial ligation and embolization has not been widely
accepted, except as a temporizing measure to facilitate transfer
of an emergency patient. The application of radiotherapy and
corticosteroids is also reported but is not well supported
by evidence.
focal nodular hyperplasia ₍fnh₎
and fnh-like lesions
Pathology
FNH occurs in up to 3% of the population and is the second
most common solid benign liver lesion after hemangioma (21,22).
Ninety percent of patients are females in their second and
third decades, although cases have been reported in males.
Less than 10% of FNH is symptomatic and, in contrast to
hepatocellular adenomata, hemorrhage and rupture are
rare (23). Presence of hemorrhage raises the possibility that a
hepatocellular adenoma has been misdiagnosed as FNH. The
incidence of FNH is increasing, although this increase appears
unrelated to oral contraceptive introduction. The effects of
female sex hormones on the natural history of FNH remain
controversial. However, discontinuing oral contraceptive use
may be associated with a decrease in size of FNH (24,25).
There is insufficient evidence to recommend avoiding preg-
nancy in the presence of FNH.
FNH usually forms a firm lobulated lesion in otherwise nor-
mal liver (Fig. 29.2) and is more common in the right liver (26).
Lesions are typically well circumscribed but lack a definite
capsule. Differentiating FNH from other focal liver lesions,
particularly hepatocellular adenoma, remains a challenge. The
“classical” finding of a central scar (Fig. 29.3) may be absent in
approximately 40% of FNH cases (27).
Twenty percent of patients exhibit multifocal FNH and up
to 20% of FNH coexist with hemangiomata (28). FNH and
adenomata may also coexist. A histological diagnosis of FNH
does not mean coexisting lesions will also be FNH. Further-
more, co-existing malignancy is reported in 6% of patients
with an indeterminate presumed benign liver lesion (29).
NH has a microscopic appearance similar to that of cirrho-
sis, exhibiting regenerative nodules. Normal hepatocytes with
intervening connective tissue septa and bile ductules are typi-
cal. FNH is thought to be a hyperplastic response to abnormal
vascularization, rather than a neoplastic process and is not
regarded as having malignant potential (23). Moderate lym-
phocytic infiltration and mild cholestasis are common. It is
unusual for FNH to undergo rapid changes in size and this
should call the diagnosis into question. Calcification is a less
common finding, occurring in approximately 1.4% of
cases (30), and should alert the clinician to the possibility of
fibrolamellar hepatocellular carcinoma.
Telangiectatic FNH
Telangiectatic FNH (TFNH) accounts for 10% to 15% of FNH
cases and usually presents with multiple soft nodules without
a central scar (31). Intra-lesion bleeding is more common in
TFNH than in FNH. TFNH lesions commonly exhibit high
levels of angiopoietin 2 gene expression (32). Although the
origin of TFNH remains controversial, it is regarded by some
as a neoplastic lesion and may in fact represent a variant of HA
rather than a subtype of FNH.
263
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 29.2 Characteristic lobulated appearance of focal nodular hyperplasia.
FNH-Like lesions
FNH-like lesions have close histological similarity to FNH.
Although due to a variety of processes, the common etiologi-
cal factor appears to be abnormal liver vascularity, specifically
increased arterial flow and decreased venous flow. Investiga-
tors have noted that FNH and hepatic adenomata occur more
often in patients who have coexisting vascular tumors, portal
venous thrombosis or occlusion, and those with significant
portohepatic venous shunts (33,34). Other conditions associ-
ated with FNH-like lesions include Budd–Chiari syndrome,
hereditary hemorrhagic telangectasia, and congenital hepatic
fibrosis. FNH-like lesions have a tendency to increase in num-
ber or size, unlike “classical” FNH.
Imaging Features
Radiological diagnosis of FNH can be challenging and a mul-
timodality approach is often required. CT has a reported 82%
sensitivity and 97% specificity (35). A well-defined hypervas-
cular lesion with a single central artery and spoke wheel
centrifugal vessel filling is typical. FNH and FNH-like lesions
are hyperintense T1-weighted MRI and hypointense on
T2-weighted series. Strong arterial enhancement is often
observed. MRI has a reported sensitivity of 70% and a specific-
ity of 98% (36). In a recent study, differentiation between HA
and FNH was not possible on the basis of precontrast or
dynamic phase images alone. However, images acquired 1 to
3 hours after gadobenate dimeglumine enhancement, allowed
differentiation between FNH and HA/adenomatosis with a
specificity, PPV, NPV, and overall accuracy of 96.9%, 100%,
100%, 96.4%, and 98.3%, respectively (37).
Management
Management of patients with FNH and FNH-like lesions
depends on the level of certainty of diagnosis. Once the diag-
nosis of FNH is established with confidence, no further inter-
vention is required. In cases of diagnostic uncertainty,
laparoscopic or open biopsy may be helpful and may be pref-
erable to percutaneous needle biopsy. Although observation
may be more appropriate for some patients, resection or
264
Figure 29.3 Classical central scar of focal nodular hyperplasia.
enucleation is preferred in most cases if surgery can be
achieved safely (recommendation strength: D).
hepatocellular adenoma
Pathology
Hepatocellular adenoma is usually identified as a solitary lesion in
an otherwise normal liver. Adenomata are well defined but lack a
capsule. Approximately 90% occur in women, most being diag-
nosed in the third to fifth decade. The lesions occur more com-
monly in the right liver. Adenomata are significantly less common
than both hemangiomata and FNH. Ninety percent of patients
report oral contraceptive use. The incidence is 3–4/100,000/year if
oral contraceptive use has exceeded 2 years and their diagnosis has
increased following the introduction of the oral contraceptive (38).
Higher dose and longer duration of oral contraceptive use appear
to promote adenoma development. Anabolic steroid use is also a
risk factor for the development of a hepatocellular adenoma.
Patients may present with pain due to hemorrhage into or rup-
ture of an adenoma. The risk of bleeding is increased in larger
and rapidly growing adenomata, and in patients using OCP,
particularly when use is prolonged (39).
Hepatocellular adenomata are associated with abnormalities
of carbohydrate metabolism. Adenomata are observed more
frequently in glycogen storage disease type 1 (glucose-6-
phosphatase deficiency), type 3 (glycogen debrancher defi-
ciency), galactosemia, and iron overload. In these patients,
adenomata develop at an earlier age and tend to show a male
preponderance (2:1) (40,41).
Sectioning reveals a yellow or pale brown tumor with sur-
rounding normal tissue and a variable degree of encapsulation
(Fig. 29.4). There may be evidence of hemorrhage (Fig. 29.5).
Adenomata are generally uniform masses consisting of benign-
appearing hepatocytes without ducts or portal triads. Hepato-
cytes are pale due to increased levels of glycogen or fat. Venous
lakes (peliosis hepatis, vide infra) may be present. Initially,
Kupffer cells were thought to be absent from adenomata but
molecular techniques have confirmed their presence in these
lesions. However, adenomata generally do not sequester
99m
Tc-sulfur colloid which is taken up preferentially by Kupffer
 BENIGN SOLID TUMORS OF THE ADULT LIVER
(A)
Figure 29.4 (A) Intraoperative image of pedunculated peripheral hepatocellular adenoma. (B) Section through resected hepatocellular adenoma.
Figure 29.5 Recent hemorrhage into hepatocellular adenoma.
cells. Adenomata fall into three molecular pathological sub-
groups: (1) those with inactivated hepatocyte nuclear factor
1-alpha (HNF-1alpha, chromosome 12q)-, (2) those with beta-
catenin activation, and (3) those with inflammatory changes.
These subtypes reportedly display differing characteristics
on MRI (42).
Imaging Features
Hepatocellular adenomata are usually heterogeneous in
appearance on US. CT appearances are iso/hypodense pre-
contrast with variable enhancement. There may be evidence of
recent hemorrhage or infarction.
MRI demonstrates a well-defined fatty lesion which is iso/
hyperintense on T1 sequences and mildly hyperintense on T2
MRI. Gadolinium-enhanced studies show hypervascularity in
the arterial phase. Enhancement is often heterogeneous. Angi-
ography demonstrates a peripherally supplied hypervascular
lesion with areas of hypovascularity due to hemorrhage or
infarction. Isotope scanning may help differentiate hepatocel-
lular adenoma from FNH, an adenoma appearing as a filling
defect (“black hole sign”).
(B)
PET appears to be useful in differentiating benign from malig-
nant liver lesions (43) and 11C-acetate PET may have additional
benefit in detecting HCC. In a study by Ho et al., benign tumors,
such as adenomata and hemangiomata, were not 11C-acetate-avid.
FNH showed only mild 11C-acetate uptake (44).
Management
In cases of acute hemorrhage, resuscitation may be combined
with hepatic arterial embolization or laparotomy and packing
to facilitate transfer to a specialist center. Formal hepatic resec-
tion represents optimal treatment for this group of acute
patients, although this may be deferred in a stable patient with
confined hemorrhage (recommendation strength: D).
Discontinuing oral contraceptive use is probably advisable
since there have been reports of lesion regression on their ces-
sation, although there is little compelling evidence to support
this position for all patients (recommendation strength: D).
Although adenomata may regress following discontinuation
of the oral contraceptive (45,46), malignant transformation
has also been reported despite its discontinuation and in con-
traceptive-naive patients (47).
Adenomata are currently thought to be premalignant with
an approximate transformation rate of 10% (48). Transforma-
tion should be suspected in adenomata that increase in size,
particularly in conjunction with increasing alpha-fetoprotein
levels. The risk of malignant transformation is higher in males
and in patients with large lesions.
Difficulties in differentiating adenomata from FNH or HCC
are commonly encountered in young female patients. Because
of the abnormal vasculature typical of these lesions, biopsy is
associated with a significant risk of hemorrhage and is gener-
ally contraindicated. In summary, if a focal liver lesion is
suspected to be an adenoma, surgical resection should be
considered, especially for symptomatic or large (5 cm or more
in diameter) adenomata, provided resection can be accom-
plished safely (49) (recommendation strength: C).
hepatocellular adenomatosis
Pathology
Hepatocellular adenomatosis is a rare condition, first recog-
nized by Flejou et al. in 1985 (40). The condition is defined
265
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
arbitrarily as the presence of 10 or more adenomata (50). Ade-
nomatosis appears to be a different pathological entity from
the solitary adenoma, having a more equal sex distribution
and no association with oral contraceptive use (48). Hepato-
cellular adenomatosis is associated with maturity-onset diabe-
tes of the young (MODY). Adenomatous hyperplasia is often
observed between lesions. Intervening cells are smaller with
cytoplasm that appears lighter than normal. Mutations in the
transcription factor 1 gene (TCF1) occur in MODY (the most
common form, termed MODY3) and biallelic inactivation of
TCF1 has been reported in hepatic adenomas. In contrast,
TCF1 inactivation is not a feature of FNH.
Management
Patients with hepatic adenomatosis and a TCF1 mutation
should be monitored for future onset of diabetes mellitus, if
not already diagnosed. Family members of patients with the
TCF1 mutation should be considered for genetic screening for
such mutations or liver imaging. Liver adenomatosis also car-
ries a risk of malignant transformation, similar to that of the
solitary adenoma. Close follow-up in asymptomatic patients
with regular liver imaging and serum alpha-fetoprotein esti-
mation is advised to monitor for the potential complications
of hemorrhage and malignant transformation (recommenda-
tion strength: D). In rare situations, orthotopic liver trans-
plantation has been employed to treat extensive disease that
progresses to liver failure, for malignancy, or for unresectable
solitary lesions (51,52).
Regenerative Changes
Regenerative Nodules
The cirrhotic liver is defined by the presence of fibrosis and
nodules, which include regenerative nodules, dysplastic nod-
ules, and hepatocellular carcinoma. Terms such as macrore-
generative nodule and adenomatous hyperplasia have been
superseded by a new classification of regenerative nodule, with
or without low- or high-grade dysplasia (Terminology of nod-
ular hepatocellular lesions, International Working Party (53)).
Currently, agreed nomenclature envisages a progression of
carcinogenesis from regenerative nodule to low-grade dysplas-
tic nodule to high-grade dysplastic nodule to small then large
hepatocellular carcinoma. Macroscopically, regenerative and
dysplastic nodules appear similar although they may differ in
color. In addition to the cirrhotic liver, these lesions may
develop in the context of Budd–Chiari syndrome. These
lesions are generally 0.8 to 3 cm in diameter. Dysplastic nod-
ules may show signs of nuclear atypia, increased cytoplasmic
fat or glycogen, and focally decreased reticulin staining is com-
mon. Differentiating dysplastic nodules from hepatocellular
carcinoma by imaging or histopathology remains problematic.
Imaging Features and Management
US features are variable. CT may show high attenuation on
pre-contrast CT with low attenuation on arterial phase
although regenerative nodules in the context of Budd–Chiari
are often hypervascular and multiple.
MRI: T1 variable, T2 low intensity. Reliable differentiation
of regenerative nodules from dysplastic nodules is beyond the
266
capacity of current MRI technology (54), although high-grade
dysplastic nodules may increase in size, display high intensity
on T1-weighted MRI, and show increased vascularity (55).
Any nodule within the cirrhotic liver that increases in size,
shows altered signal or increased enhancement warrants cor-
relation with alpha-fetoprotein and early serial imaging and
should be regarded as suspicious for hepatocellular carcinoma
(recommendation strength: D).
Nodular Regenerative Hyperplasia
This often asymptomatic condition usually affects patients
over 50 years of age and is reported to occur in 2% autopsy
livers (56,57). The etiology of NRH remains unclear, although
it is associated with a range of lymphoproliferative and rheu-
matological disorders and may occur post-transplantation.
Associations with a range of therapeutic drugs are reported.
NRH is a benign diffuse nodular transformation and differs
from the regenerative nodules found in cirrhosis and FNH.
The hepatic parenchyma is entirely replaced by nodules
between 0.1 and 4 cm in diameter. Hepatocyte hyperplasia
separated by atrophic parenchyma with reticulin collapse and
sinusoidal dilatation is typical. The diagnosis should be con-
sidered in patients with portal hypertension and mild liver
function abnormalities without cirrhosis on liver biopsy. Por-
tal hypertension and cholestasis may occur due to intrahepatic
compression. Laparoscopic or open biopsy is usually required
for diagnosis but NRH may be difficult to differentiate from
hepatocellular adenoma, which forms a discrete lesion as
opposed to the diffuse changes of NRH, on isolated biopsy.
Needle biopsy may also not uncommonly yield normal liver
tissue.
Imaging Features and Management
Imaging is often non-specific or normal, although NRH may
cause pseudotumor formation. The lesions appear hypo/
isoechoic on US and display variable enhancement on CT.
Lesions appear hyperintense on T1-weighted MRI and iso/
hypointense on T2-weighted sequences.
NRH may rarely undergo malignant transformation and
monitoring is therefore recommended (recommendation
strength: D). Treatment involves the management of associ-
ated portal hypertension. NRH may result in liver failure that
may necessitate liver transplantation.
Biliary Hamartoma (Von Meyenburg complex)
Biliary hamartomata are benign developmental abnormalities
of the liver. Although biliary hamartomata occur in over 5% of
the population, they are principally of clinical interest due to
the frequency of their submission for intraoperative frozen
section to differentiate them from metastases. They are usually
less than 5 mm in diameter and multiple lesions are common.
Imaging Features and Management
Such lesions are often not apparent on preoperative imaging
because of their size and US features are non-specific. CT usu-
ally shows a hypodense lesion without contrast enhancement.
MR features are hypointense on T1-weighted images and
strongly hyperintense on T2-weighted MRI. MRI contrast
 BENIGN SOLID TUMORS OF THE ADULT LIVER
enhancement is variable although rim enhancement may
occur due to compression of adjacent parenchyma. Micro-
scopic features include bile ductules with enlarged lumina,
inflammatory infiltrate, and fibrosis. Association with adult
polycystic disease has been reported. No treatment is required
(recommendation strength: D).
Biliary Adenoma
This benign cholangioma is a generally well defined and often
subcapsular lesion, usually less than 1 cm in diameter. Microscop-
ically a proliferation of non-cystic biliary structures with fibrous
stroma is observed. The presence of mucin, but not bile, is typical.
Although histological differentiation from hamartomata may be
challenging, the practical significance of this is limited.
Imaging Features and Management
Early nodular enhancement, which is prolonged is usual on CT.
Bile duct adenomata have no malignant potential but may
require excisional biopsy to allow differentiation from the bile
duct proliferations found in FNH as well as from some poorly
differentiated adenocarcinoma of the biliary tract type. Once
diagnosed no treatment is required (recommendation
strength: D).
congenital hepatic fibrosis
This rare autosomal recessive fibropolycystic condition results
from malformation of the ductal plate and may lie on a con-
tinuum with Caroli’s disease, the latter involving larger ducts,
in contrast to CHF. This is a multisystem disorder (58), the
kidneys being most commonly affected (usually autosomal
recessive polycystic kidney disease). CHF is associated with
overexpression of transforming growth factor-beta1 and
thrombospondin-1 (59). Presentation is usually in adoles-
cence, although presentations in the neonatal period and late
adulthood are reported. Intrahepatic portal hypertension is
typical, but patients may present a cholangitic or mixed pic-
ture. Focal solid liver lesions are reported (60,61). The diagno-
sis can be often established on axial imaging (62). Management
of the manifestations of portal hypertension is the mainstay
of treatment.
Focal Fatty Variants
Steatosis of the liver is usually a diffuse process but fat distri-
bution may be heterogeneous leading to a focal lesion. The
diagnosis should be apparent from imaging alone and particu-
larly MRI.
Focal Fatty Sparing
This diagnosis is usually made radiologically and is most com-
monly encountered in the posterior aspect of segment 4. These
lesions are hypoechoic on US and hyperdense on CT. Hypoin-
tensity on T1-weighted MRI is usual. Focal fatty sparing is of
no pathological or surgical significance other than requiring
differentiation from other focal liver lesions.
Focal Fatty Change
This abnormality of parenchymal fat distribution usually
occurs adjacent to the falciform ligament and may be associated
with obesity, diabetes, alcoholism, steroids, total parenteral
nutrition, chemotherapy, and antiretroviral therapy.
Imaging Features and Management
These fatty lesions are hyperechoic on US and hypodense on
CT. Their fat content results in a hyperintense appearance on
T1-weighted MRI. Radiological diagnosis usually suffices. If
multiple areas of focal fatty change occur, pseudotumoral ste-
atosis may result which can be mistaken for other tumors, and
may require confirmatory biopsy.
Angiomyolipoma
This rare tumor consisting of fat, epithelioid, and smooth mus-
cle cells with thick-walled blood vessels and may occur in asso-
ciation with tuberous sclerosis. Ten percent of patients with
tuberous sclerosis and renal angiolipomata have either angio-
myolipomata or lipomata (63). Women are predominantly
affected. While these lesions often become large and may cause
compressive effects requiring resection, malignant transforma-
tion has been reported, although this is extremely rare (64).
Imaging Features and Management
The reliability of diagnostic imaging is impaired by the variable
proportion of fat (10–90%) and other constituents the angio-
myolipomata contain. Lesions with low-fat content may mimic
hepatocellular carcinoma. US examination usually demonstrates
a hyperechoic lesion. The lesion is hypodense with arterial
enhancement and central opacification on CT. Macroaneurysms
may be observed. On MRI, the T1-weighted signal is high. Fat
suppressed MR may help confirm the diagnosis.
Management consists of observation with resection reserved
for patients with symptomatic lesions (recommendation
strength: D).
Lipoma
Hepatic lipomata are less common than angiomyolipomata.
Lipomata are generally well defined and homogenous.
Imaging Features and Management
CT shows a hypodense, non-enhancing lesion. MRI features
are hyperintense on T1-weighted series and moderately hyper-
intense on T2-weighted series. Decreased signal with fat sup-
pression is typical. These lesions consist of well-differentiated
adipose tissue and require no treatment (recommendation
strength: D).
pseudolipoma
These unusual lesions consist of well-differentiated subcapsu-
lar adipose tissue and may occur if an adherent fatty structure
becomes detached and incorporated into the liver paren-
chyma. Pseudolipomata may require differentiation form
metastasis, although they require no specific treatment.
Peliosis Hepatis
Peliosis hepatis refers to the development of multiple abnor-
mal vascular channels with secondary fibrosis. This condition
is associated with anabolic steroid use as well as with tubercu-
losis and, in some cases, other tumors.
267
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Imaging Features and Management
The lesion is usually well defined. Arterial enhancement is
observed on CT. Peliosis hepatis is hyperintense on T2-weighted
MRI and contrast enhancement is observed. Management pri-
orities include withdrawal of potential causative agents and
treatment of primary/secondary infection. Malignant trans-
formation is not a feature of peliosis hepatis.
Hereditary Hemorrhagic Telangiectasia
Hepatic involvement in HHT is recognized (65) and presents
as a spectrum from small telangiectasia to large volume lesions,
which may be associated with arteriovenous shunting. These
lesions are usually asymptomatic and do not generally warrant
treatment, although hepato-hepatic fistulas can induce high-
output cardiac failure and hepato-portal fistulas may induce
portal hypertension (66).
Heterotopic Tissue
A choristoma, formed by the abnormal development of tissue
of a type not normally found at that site, is an uncommon
cause of a focal liver lesion. Intrahepatic heterotopic tissue for-
mation can often be diagnosed radiologically but may require
resection or biopsy for definitive diagnosis. Adrenal tissue
tends to occur in the subcapsular region and may mimic ade-
noma. Heterotopic pancreatic tissue is an occasional finding.
The origin of these lesions is uncertain although they are
probably congenital. Acquired splenic choristoma formation
can occur post-splenectomy through autotransplantation of
splenic tissue. Nuclear medicine is specific in diagnosing this
abnormality. In each of these cases, once the diagnosis of het-
erotopic tissue is established, no specific treatment is required
(recommendation strength: D).
Inflammatory Pseudotumor
These inflammatory myofibroblastic lesions may exhibit radio-
logical features suggestive of neoplasia. A male preponderance
is reported and the average age at diagnosis is 35 years (67). The
history is often suggestive of an infective etiology. Pseudotumor
formation may occur secondary to thrombosis or infarction,
may represent an immune reaction, or may occur as an abscess
resolves.
Imaging Features and Management
The lesion is typically well defined, hyper, or hypoechoic on US
hypodense on CT and hyperintense on T2-weighted MRI. Angi-
ography usually confirms a hypervascular lesion. In some cases,
pseudotumors can be structurally diffuse and locally destruc-
tive. Histopathological examination reveals myofibroblasts,
immunocytes, and fibrous tissue. These lesions usually resolve
spontaneously and are generally managed non-operatively,
although resection may be indicated in some cases to prevent
reactivation of infection (recommendation strength: D).
Miscellaneous Rare Benign Solid Liver Lesions
These lesions are individually very uncommon but as a group
represent a significant proportion of benign solid liver lesions.
Mesenchymal hamartomas are probably congenital, usually
occur in infants but are reported in adults. Histologically a
268
myxoid background with cellular mesenchymal components,
hepatocytes, bile ducts, and cystic changes are characteristic.
Liver function may be compromised through enlargement and
resection may be required. Other rare tumors include myx-
oma, mesothelioma, leiomyoma, and fibroma. Benign tera-
toma of the liver is reported although this generally occurs in
the pediatric population.
key points
● Benign liver tumors are increasingly detected due
to greater use of improved diagnostic imaging
● There may be an increasing trend to resect benign
lesions with the introduction of laparoscopic
surgery
● Successful management of patients with benign
liver lesions requires accurate diagnosis and an
understanding of the natural history
● Most patients with benign liver tumors do not
have associated liver disease
● Benign liver tumors rarely require surgery although,
when necessary, centralized expert management
minimizes associated morbidity and mortality
● Inappropriate investigation can lead to morbidity
and compromises definitive treatment
● Hemangioma is the most common solid benign
liver tumor
● Hepatocellular adenomata are rare but are associ-
ated with significant complications, are viewed as
premalignant and generally warrant resection
● Hepatocellular adenomata are associated with oral
contraceptive use. While controversial, no estab-
lished links exist for hemangiomata or focal nodu-
lar hyperplasia
● A focal lesion in a cirrhotic liver should be regarded
as malignant until proven otherwise
● Progressive symptoms, an enlarging tumor, com-
plications or raising tumor markers are relative
indications for resection
appendix
Recommended Grading of Categories of Evidence
Ia: evidence from meta-analysis of randomized
controlled trials
Ib: evidence from at least one randomized controlled
trial
IIa: evidence from at least one controlled study
without randomization
IIb: evidence from at least one other type of quasi-
experimental study
III: evidence from non-experimental descriptive
studies, such as comparative studies, correlation
studies and case–control studies
IV: evidence from expert committee reports or
opinions and/or clinical experience of respected
authorities
 BENIGN SOLID TUMORS OF THE ADULT LIVER
Recommended Strengths of Management Recommendation
A: directly based on category I evidence
B: directly based on category II evidence or
extrapolated recommendation from category I
evidence
C: directly based on category III evidence or
extrapolated recommendation from category I
or II evidence
D: directly based on category IV evidence or
extrapolated recommendation from category I,
II, or III evidence
references
1. Morino M, Morra I, Rosso E, Miglietta C, Garrone C. Laparoscopic vs open
hepatic resection: a comparative study. Surg Endosc 2003; 17(12): 1914–8.
2. Koffron AJ, Auffenberg G, Kung R, Abecassis M. Evaluation of 300 mini-
mally invasive liver resections at a single institution: less is more. Ann
Surg 2007; 246(3): 385–92.
3. Koffron A, Geller D, Gamblin TC, Abecassis M. Laparoscopic liver sur-
gery: Shifting the management of liver tumors. Hepatology 2006; 44(6):
1694–1700.
4. Dimick JB, Cowan JA Jr., Knol JA, Upchurch GR Jr. Hepatic resection in
the United States: indications, outcomes, and hospital procedural vol-
umes from a nationally representative database. Arch Surg 2003; 138(2):
185–91.
5. Buell JF, Thomas MT, Rudich S, et al. Experience with more than 500 min-
imally invasive hepatic procedures. Ann Surg 2008; 248(3): 475–86.
6. Polignano FM, Quyn AJ, de Figueiredo RS, et al. Laparoscopic versus open
liver segmentectomy: prospective, case-matched, intention-to-treat anal-
ysis of clinical outcomes and cost effectiveness. Surg Endosc 2008; 22(12):
2564–70.
7. Descottes B, Glineur D, Lachachi F, et al. Laparoscopic liver resection of
benign liver tumors. Surg Endosc 2003; 17(1): 23–30.
8. Karhunen PJ. Benign hepatic tumours and tumour like conditions in
men. J Clin Pathol 1986; 39(2): 183–8.
9. Frider B, Bruno A, Selser J, et al. Kasabach-Merrit syndrome and adult
hepatic epithelioid hemangioendothelioma an unusual association. J
Hepatol 2005; 42(2): 282–3.
10. Ishak KG, Rabin L. Benign tumors of the liver. Med Clin North Am 1975;
59(4): 995–1013.
11. Sewell JH, Weiss K. Spontaneous rupture of hemangioma of the liver. A
review of the literature and presentation of illustrative case. Arch Surg
1961; 83: 729–33.
12. Schwartz SI, Husser WC. Cavernous hemangioma of the liver. A single
institution report of 16 resections. Ann Surg 1987; 205(5): 456–465.
13. Adam YG, Huvos AG, Fortner JG. Giant hemangiomas of the liver. Ann
Surg 1970; 172(2): 239–245.
14. Erdogan B, Sen O, Aydin VM, et al. Multi-organ cavernous hemangiomas:
case report. Neurol Res 2003; 25(1): 92–94.
15. Farges O, Daradkeh S, Bismuth H. Cavernous hemangiomas of the liver:
are there any indications for resection? World J Surg 1995; 19(1): 19–24.
16. el Dessouky M, Azmy AF, Raine PA, Young DG. Kasabach-Merritt syn-
drome. J Pediatr Surg 1988; 23(2): 109–11.
17. Leslie DF, Johnson CD, Johnson CM, Ilstrup DM, Harmsen WS. Distinc-
tion between cavernous hemangiomas of the liver and hepatic metastases
on CT: value of contrast enhancement patterns. AJR 1995; 164(3): 625–9.
18. Krause T, Hauenstein K, Studier-Fischer B, Schuemichen C, Moser E.
Improved evaluation of technetium–99m-red blood cell SPECT in hem-
angioma of the liver. J Nucl Med 1993; 34(3): 375–80.
19. Lerner SM, Hiatt JR, Salamandra J, et al. Giant cavernous liver hemangio-
mas: effect of operative approach on outcome. Arch Surg 2004; 139(8):
818–21.
20. Longeville JH, de la HP, Dolan P, et al. Treatment of a giant haemangioma
of the liver with Kasabach-Merritt syndrome by orthotopic liver trans-
plant a case report. HPB Surg 1997; 10(3): 159–62.
21. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular
hyperplasia of the liver. Hepatology 1985; 5(6): 1194–200.
22. Karhunen PJ, Penttila A, Liesto K, Mannikko A, Mottonen MM. Occur-
rence of benign hepatocellular tumors in alcoholic men. Acta Pathol
Microbiol Immunol Scand [A] 1986; 94(2): 141–7.
23. Reddy KR, Kligerman S, Levi J, et al. Benign and solid tumors of the liver:
relationship to sex, age, size of tumors, and outcome. Am Surg 2001;
67(2): 173–8.
24. Cote C. Regression of focal nodular hyperplasia of the liver after oral con-
traceptive discontinuation. Clin Nucl Med 1997; 22(9): 587–90.
25. Pain JA, Gimson AE, Williams R, Howard ER. Focal nodular hyperplasia
of the liver: results of treatment and options in management. Gut 1991;
32(5): 524–7.
26. Nguyen BN, Flejou JF, Terris B, Belghiti J, Degott C. Focal nodular hyper-
plasia of the liver: a comprehensive pathologic study of 305 lesions and
recognition of new histologic forms. Am J Surg Pathol 1999; 23(12):
1441–54.
27. Kerlin P, Davis GL, McGill DB, et al. Hepatic adenoma and focal nodular
hyperplasia: clinical, pathologic, and radiologic features. Gastroenterol-
ogy 1983; 84(5 Pt 1): 994–1002.
28. Vilgrain V, Uzan F, Brancatelli G, et al. Prevalence of hepatic hemangioma
in patients with focal nodular hyperplasia: MR imaging analysis. Radiol-
ogy 2003; 229(1): 75–79.
29. Belghiti J, Pateron D, Panis Y, et al. Resection of presumed benign liver
tumours. Br J Surg 1993; 80(3): 380–383.
30. Caseiro-Alves F, Zins M, Mahfouz A-E, et al. Calcification in focal nodular
hyperplasia: a new problem for differentiation from fibrolamellar hepato-
cellular carcinoma. Radiology 1996; 198(3): 889–892.
31. Bioulac-Sage P, Rebouissou S, Sa CA et al. Clinical, morphologic, and
molecular features defining so-called telangiectatic focal nodular hyper-
plasias of the liver. Gastroenterology 2005; 128(5): 1211–1218.
32. Bioulac-Sage P, Rebouissou S, Sa CA, et al. Clinical, morphologic, and
molecular features defining so-called telangiectatic focal nodular hyper-
plasias of the liver. Gastroenterology 2005; 128(5): 1211–1218.
33. Ishak KG. Benign tumors and pseudotumors of the liver. Appl Pathol
1988; 6(2): 82–104.
34. Grazioli L, Federle MP, Ichikawa T, et al. Liver adenomatosis: clinical, his-
topathologic, and imaging findings in 15 patients. Radiology 2000;
216(2): 395–402.
35. Weimann A, Ringe B, Klempnauer J, et al. Benign liver tumors: differential
diagnosis and indications for surgery. World J Surg 1997; 21(9): 983–990.
36. Cherqui D, Rahmouni A, Charlotte F, et al. Management of focal nodular
hyperplasia and hepatocellular adenoma in young women: a series of
41 patients with clinical, radiological, and pathological correlations. Hep-
atology 1995; 22(6): 1674–1681.
37. Grazioli L, Morana G, Kirchin MA, Schneider G. Accurate differentiation
of focal nodular hyperplasia from hepatic adenoma at gadobenate dime-
glumine-enhanced MR imaging: prospective study. Radiology 2005;
236(1): 166–177.
38. Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between
benign hepatomas and oral contraceptives. Lancet 1973; 2(7835): 926–929.
39. Mays ET, Christopherson W. Hepatic tumors induced by sex steroids.
Semin Liver Dis 1984; 4(2): 147–157.
40. Flejou JF, Barge J, Menu Y, et al. Liver adenomatosis. An entity distinct
from liver adenoma? Gastroenterology 1985; 89(5): 1132–1138.
41. Ronald M, Woodfield J, McCall J, Koea J. Hepatic adenomas in male
patients. HPB (Oxford) 2004; 6(1): 25–27.
42. Laumonier H, Bioulac-Sage P, Laurent C, et al. Hepatocellular adenomas:
magnetic resonance imaging features as a function of molecular patho-
logical classification. Hepatology 2008; 48(3): 808–818.
43. Delbeke D, Martin WH, Sandler MP, et al. Evaluation of benign vs malig-
nant hepatic lesions with positron emission tomography. Arch Surg 1998;
133(5): 510–515.
44. Ho CL, Yu SC, Yeung DW. 11C-acetate PET imaging in hepatocellular car-
cinoma and other liver masses. J Nucl Med 2003; 44(2): 213–221.
45. Tesluk H, Lawrie J. Hepatocellular adenoma. Its transformation to carci-
noma in a user of oral contraceptives. Arch Pathol Lab Med 1981; 105(6):
296–299.
269
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
46. Steinbrecher UP, Lisbona R, Huang SN, Mishkin S. Complete regression
of hepatocellular adenoma after withdrawal of oral contraceptives. Dig
Dis Sci 1981; 26(11): 1045–1050.
47. Colovic R, Grubor N, Micev M, Radak V. Hepatocellular adenoma with
malignant alteration. Hepatogastroenterology 2007; 54(74): 386–388.
48. Barthelmes L, Tait IS. Liver cell adenoma and liver cell adenomatosis. HPB
(Oxford) 2005; 7(3): 186–196.
49. Cho SW, Marsh JW, Steel J, et al. Surgical management of hepatocellular
adenoma: take it or leave it? Ann Surg Oncol 2008; 15(10): 2795–2803.
50. Chiche L, Dao T, Salame E, et al. Liver adenomatosis: reappraisal, diagno-
sis, and surgical management: eight new cases and review of the literature.
Ann Surg 2000; 231(1): 74–81.
51. Weimann A, Ringe B, Klempnauer J, et al. Benign liver tumors: differential
diagnosis and indications for surgery. World J Surg 1997; 21(9): 983–990.
52. Tepetes K, Selby R, Webb M, et al. Orthotopic liver transplantation for
benign hepatic neoplasms. Arch Surg 1995; 130(2): 153–156.
53. Terminology of nodular hepatocellular lesions. International Working
Party. Hepatology 1995; 22(3): 983–993.
54. Efremidis SC, Hytiroglou P. The multistep process of hepatocarcinogen-
esis in cirrhosis with imaging correlation. Eur Radiol 2002; 12(4):
753–764.
55. Earls JP, Theise ND, Weinreb JC, et al. Dysplastic nodules and hepatocel-
lular carcinoma: thin-section MR imaging of explanted cirrhotic livers
with pathologic correlation. Radiology 1996; 201(1): 207–214.
56. Wanless IR. Micronodular transformation (nodular regenerative hyper-
plasia) of the liver: a report of 64 cases among 2,500 autopsies and a new
classification of benign hepatocellular nodules. Hepatology 1990; 11(5):
787–797.
270
57. Nakanuma Y. Nodular regenerative hyperplasia of the liver: retrospective
survey in autopsy series. J Clin Gastroenterol 1990; 12(4): 460–465.
58. Yonem O, Ozkayar N, Balkanci F, et al. Is congenital hepatic fibrosis a pure
liver disease? Am J Gastroenterol 2006; 101(6): 1253–1259.
59. El Youssef M, Mu Y, Huang L, Stellmach V, Crawford SE. Increased expres-
sion of transforming growth factor-beta1 and thrombospondin-1 in con-
genital hepatic fibrosis: possible role of the hepatic stellate cell. J Pediatr
Gastroenterol Nutr 1999; 28(4): 386–392.
60. Zeitoun D, Brancatelli G, Colombat M, et al. Congenital hepatic fibrosis:
CT findings in 18 adults. Radiology 2004; 231(1): 109–116.
61. Hausner RJ, Alexander RW. Localized congenital hepatic fibrosis present-
ing as an abdominal mass. Hum Pathol 1978; 9(4): 473–476.
62. Akhan O, Karaosmanoglu AD, Ergen B. Imaging findings in congenital
hepatic fibrosis. Eur J Radiol 2007; 61(1): 18–24.
63. Ros PR. Hepatic angiomyolipoma: is fat in the liver friend or foe? Abdom
Imaging 1994; 19(6): 552–553.
64. Deng YF, Lin Q, Zhang SH, et al. Malignant angiomyolipoma in the liver:
A case report with pathological and molecular analysis. Pathol Res Pract
2008; 204(12): 911–918.
65. Sabba C, Pompili M. Review article: the hepatic manifestations of heredi-
tary haemorrhagic telangiectasia. Aliment Pharmacol Ther 2008; 28(5):
523–533.
66. Buscarini E, Danesino C, Olivieri C, Lupinacci G, Zambelli A. Liver
involvement in hereditary haemorrhagic telangiectasia or Rendu-Osler-
Weber disease. Dig Liver Dis 2005; 37(9): 635–645.
67. Koea JB, Broadhurst GW, Rodgers MS, McCall JL. Inflammatory pseudo-
tumor of the liver: demographics, diagnosis, and the case for nonopera-
tive management. J Am Coll Surg 2003; 196(2): 226–235.
30 Liver trauma
Timothy G. John, Myrddin Rees, and Fenella K. Welsh
introduction
The size and location of the liver account for its high suscepti-
bility to both blunt and penetrating trauma. The type and
severity of liver injuries vary greatly and associated organ inju-
ries are common. The leading cause of death is hemorrhage,
with road traffic accidents accounting for an ever increasing
proportion of blunt liver injuries. It also presents a large target
for penetrating injuries to the trunk and these, including gun-
shot wounds, can be difficult to manage. The intimate connec-
tions between the liver capsule, the major hepatic veins, and
the retrohepatic inferior vena cava anchor the liver within the
upper abdominal cavity and most of the venous return from
the lower body flows within these thin-walled veins. Injuries to
these vulnerable, high-volume-flow “juxtahepatic” vessels
pose a uniquely challenging aspect of severe liver trauma.
Dramatic advances in the management of liver trauma have
been reported in recent years and algorithms of management
continue to evolve. The last two decades have witnessed a
major paradigm shift in the management of liver trauma, with
Non-Operative Management of Liver Injury (NOMLI) now
firmly established as the standard of care for the majority of
patients. For those undergoing surgery, the philosophy of
damage control at abbreviated laparotomy prevails and the
technique of perihepatic packing has come to serve a domi-
nant role. Multidisciplinary interventions are indispensible in
managing both the inevitable consequences of NOMLI and as
adjuncts to surgical intervention. Unsurprisingly, little or no
Grade I–II evidence exists from randomized or controlled
studies of liver trauma, and recommendations for manage-
ment are based on large descriptive studies, including multi-
institutional prospective cohort studies, and the clinical
experience of respected authorities in the field.
classification of liver trauma
The importance of a standardized method of classifying liver
trauma is fundamental to meaningful comparisons of treat-
ment outcomes. The modern system of injury grading and
standardization of care is based on the central role of comput-
erized tomography (CT) in the assessment of liver trauma.
The classification of liver injuries described by Moore and co-
workers in 1989 (1), revised in 1994 (2), has now been adopted
as the “industry standard” by the American Association for the
Surgery of Trauma (AAST) (Table 30.1).
Early attempts to validate the AAST Organ Injury Scale
(OIS) noted good correlation between operative score severity
on one hand and transfusional requirements and methods of
operative management necessitated on the other (3). Similar
conclusions were drawn from a study of 170 liver injury
patients (90% blunt trauma) where blood transfusions, surgi-
cal interventions, and liver-related morbidity and mortality all
correlated well with the grade of injury (4). However, the liver
OIS as determined by pre-operative CT can be fallible and
instances of both understaging and overstaging by CT have
been documented (3).
A recent attempt to validate the AAST OIS identified 14,919
isolated hepatic injuries, and 21,532 with associated injuries, in
the American College of Surgeons National Trauma Databank
between 2000 and 2004 (5). A significant increase in outcomes
including mortality, organ-specific operative rate, and hospital
charges were associated with increasing OIS grades.
initial assessment and diagnosis
of liver trauma
Initial management of the patient with suspected liver trauma
follows Advanced Trauma Life Support (ATLS) principles (6)
with rapid identification of life-threatening injuries and
aggressive fluid resuscitation. The importance of preventing
systemic hypothermia during resuscitation and transfer
deserve particular emphasis (7).
The concept of the “Focused Assessment for the Sono-
graphic examination of the Trauma patient” (FAST) has
gained widespread acceptance in the initial rapid screening of
the trauma patient for the presence of hemoperitoneum (8). A
landmark study of surgeon-performed FAST in 1540 patients
with blunt and penetrating truncal injuries reported high sen-
sitivity (83.3%) and specificity (99.7%) for the technique,
most pronounced following blunt injury (9). In this way, the
invasive, overly sensitive, and non- organ-specific technique of
diagnostic peritoneal lavage has become obsolete in the initial
assessment of the trauma patient with suspected liver injury.
Immediate laparotomy to control intra-abdominal bleeding
remains the standard of care in the persistently hemodynami-
cally unstable patient. The Western Trauma Association’s study
of death in the operating room following major trauma at
eight North American Level I trauma centers between 1985
and 1992 (10) reported uncontrolled hemorrhage as the
primary cause of death in 82% of patients, while delays in
transfer to the operating room and inadequate perioperative
resuscitation were implicated in half the intra-operative deaths
judged to have been preventable. Thus, shocked patients not
responding to aggressive fluid resuscitation require immediate
operation to attempt arrest of intra-abdominal hemorrhage.
Alternatively, and more controversially, it has been suggested
that selective hepatic arterial embolization may be effective in
arresting hepatic arterial bleeding in the hemodynamically
unstable patient, especially those who respond to initial fluid
resuscitation, and its role extended as an alternative to sur-
gery (11,12) (Fig. 30.1). Ciraulo and colleagues reported an
encouraging experience with “resuscitative” angioembolization
in “bridging” operative and non-operative management (13).
Seven out of 11 patients with CT-determined Grade IV–V
blunt hepatic injuries and requiring continuous resuscitation
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 30.1 AAST Liver Injury Scale (1994 Revision) (2)

Gradea Injury descriptionb
I. Hematoma Subcapsular, non-expanding, <10% surface area
Laceration Capsular tear, non-bleeding, <1 cm parenchymal depth
II. Hematoma Subcapsular, 10–50% surface area; Intra-parenchymal, <10 cm in diameter
Laceration 1–3 cm parenchymal depth, <10 cm in length
III. Hematoma Subcapsular, >50% surface area or expanding
Ruptured subcapsular or parenchymal hematoma
Intra-parenchymal hematoma >10 cm or expanding
Laceration >3 cm parenchymal depth
IV. Laceration Parenchymal disruption involving 25–75% of hepatic lobe or 1–3 Couinaud’s segments within a single lobe
V. Laceration Parenchymal disruption involving >75% of hepatic lobe or >3 Couinaud’s segments within a single lobe
Vascular Juxtahepatic venous injuries; i.e., retrohepatic vena cava / central major hepatic veins
VI. Vascular Hepatic avulsion
a
Advance one grade for multiple injuries to the same organ.
b
Based on most accurate assessment at autopsy, laparotomy, or radiological study.

hemoperitoneum (17) and demonstration of associated intra-

peritoneal and retroperitoneal injuries (Fig. 30.2). Technical
refinements such as the development of rapid spiral CT scan-
ners, protocols optimizing vascular contrast enhancement,
and CT-scanning suites adjacent to the emergency department
and equipped for critical care monitoring have established the
central role of CT in the management of all but the most
unstable cases of liver trauma (16).
Despite concerns regarding the reliability of CT in the detec-
tion of hollow vicious injuries (18), the incidence of missed
injuries following non-operative management based on clini-
cal and CT findings is reported to be as low as 0.2% (7).
Although reliable predictors of failure of non-operative man-
agement are lacking, contrast extravasations (“pooling” or a
“blush”) merits emphasis as a cardinal sign of active hemor-
rhage mandating prompt (angiographic and / or surgical)
intervention (7,15,16,19,20) (Fig. 30.3). Fang and colleagues
reported contrast pooling in eight out of 150 stable patients
treated non-operatively, six of whom (75%) developed hemo-
dynamic instability requiring liver-related laparotomy (20).

Figure 30.1 Selective hepatic angiography (right hepatic artery arising from
superior mesenteric artery) demonstrates contrast extravasation (arrows).
Angioembolization was performed.
were successfully managed by hepatic embolization as defini-
tive therapy. The “alternative” management of hemorrhage
from Grade V juxtahepatic venous lacerations by percutane-
ous hepatic venous stenting has also been reported (14).
Clearly much depends on the timing of such intervention and
the prompt availability of appropriate expertise (with an oper-
ating room on standby) (12,15).
Abdominal CT is established as the primary screening
modality for the hemodynamically stable patient with sus-
pected blunt liver trauma (16). Detailed cross-sectional imag-
ing of the abdominal organs permits precise delineation of the
type and extent of the liver injury, estimation of the volume of
Non-operative Management of Blunt Liver Trauma (NOMLI)
Non-operative management of the majority of patients pre-
senting with blunt liver injury (NOMLI) represents a major
paradigm shift in liver trauma management during the last
two decades (Fig. 30.2). Analysis of 35,510 hepatic injuries
documented in the American College of Surgeons National
Trauma Databank revealed a highly significant increase in
NOMLI from 75% to 87% between 1994 and 2003 (95.1% for
blunt liver injuries) (21). Factors heralding this change include
(i) the recognition that as many as two-thirds of patients
undergoing surgery on the basis of positive diagnostic perito-
neal lavage were found to have relatively trivial injuries during
non-therapeutic laparotomy (22–24), (ii) the improved imag-
ing with abdominal CT and less concern regarding missed
injuries (15,25), (iii) the precedents for successful non-
operative management of solid organ injuries documented in

272
 LIVER TRAUMA
Figure 30.2 Grade V blunt liver trauma associated with right renal hematoma
in a hemodynamically unstable patient responding to fluid resuscitation and
angioembolization.
the pediatric literature (26–30), (iv) a better understanding of
the pathophysiology and natural history of the injured and
healing liver (31), and (v) the availability of adjunctive inter-
ventional techniques to deal effectively with the inevitable
consequences of the non-operated liver injury (15).
High success rates with NOMLI have been reported. Pachter
and Hofstetter’s multi-center study of 404 patients in 1995
reported NOMLI in 98.5% of patients with just two liver-
related deaths (32). A collective review of 16 published series
comprising 609 adult patients with liver trauma managed
non-operatively between 1988 and 1997 reported success rates
of 84% to100%, mean hospital stays of 11.5 to 16.6 days and
mean transfusional requirements of 1 to 4 units (19). Others
confirm that NOMLI may be undertaken in 85% to 95% of all
adult patients with blunt liver trauma (15,23,24,30,33,34). It is
generally accepted that the adoption of non-operative man-
agement, in place of the pre-1990s practice of liberal operative
intervention, has heralded a substantial reduction in the mortal-
ity historically, associated with severe blunt liver injuries (7,15).
Although it remains difficult to predict in whom NOMLI
will fail, increased experience and confidence has lowered the
threshold for attempting non-operative treatment to include
all hemodynamically stable patients (i.e., systolic blood pres-
sure >90 mmHg) without the signs of peritonitis, regardless of
age, injury grade, or associated injuries (35). It should be
emphasized that it is hemodynamic status and not the grade of
liver injury which determines decision making. The patient
typically at risk of failure of NOMLI, most often because of
intra-abdominal bleeding, has been characterized as having a
high-grade liver injury and remaining dependent on ongoing-
fluid resuscitation with persisting acidosis (35).
Complications of Non-operative Management
Contamination of the peritoneal cavity with blood and bile is
an inevitable consequence of non-operative management of
the fractured liver and both localized peritoneal signs and a
Figure 30.3 Abdominal CT performed after perihepatic packing for blunt liver
trauma showing intra-parenchymal contrast extravasation (arrow). The
patient was transferred from the referring hospital and underwent day 1 re-
laparotomy because of deteriorating LFTs and evidence of the abdominal
compartment syndrome.
systemic inflammatory response may be expected. The antici-
pation and management of specific complications is integral
to the successful non-operative management of severe liver
injuries. Typically these include arterio-venous fistulas, bile
leaks, intra- or peri-hepatic abscesses, and vascular-biliary
communications (bilhemia and hemobilia). Such complica-
tions should be regarded as virtually obligatory consequences
of non-operative management (36). This re-defines the phi-
losophy of surgical abstention recognizing that delayed sur-
gery and/or interventional procedures should be deemed an
inherent part of the overall management plan rather than
treatment failure.
Carillo and colleagues reported that 32 patients out of 135
(24%) with severe blunt liver trauma managed non-operatively
during 1995 to 1997 developed such complications (15).
Strategies employed in their treatment included angioemboli-
zation (37%), CT-guided drainage of collections (31%), ERCP
(25%), and laparoscopic drainage of collections (7%). A more
recent multicenter study of 453 patients with Grades 3 to 5
blunt liver trauma managed by NOMLI at seven urban level 1
American trauma centers between 2000 and 2003 revealed 87
complications in 61 patients (13%)(37). Similarly, these com-
prised bleeding, biliary complications, abdominal compart-
ment syndrome, and infective complications, which required
86 multimodality interventions.
Hemorrhage
Ongoing or recurrent bleeding in the non-operatively man-
aged patient is typically recognized by hemodynamic instabil-
ity with a gradually declining hematocrit and the requirement
for repeated transfusions at an early stage. Angioembolization
is usually effective for the relatively small proportion of
patients who exhibit the signs of early ongoing hemorrhage or
late re-bleeding, though this is unusual beyond 3 days post-
injury (37). Liver enzyme derangement is common in the
273
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
aftermath of severe blunt liver trauma, though escalating serum
transaminases reflect ongoing hepatocellular damage and may
prompt further intervention. An algorithm for management of
delayed hemorrhage following blunt liver injury instituted by
Carillo and colleagues (15,19) is shown in Fig. 30.6.
Biliary Complications (Algorithm from Wahl et al. (38))
Clinically significant biliary complications following NOMLI
affect less than 5% of patients (7,34,39) and are typically her-
alded by elevated serum bilirubin and worsening abdominal
pain. Bile collections are amenable to percutaneous drainage
that, alone, may lead to resolution in 70% of cases (40). Biliary
decompression by ERCP, sphincterotomy, and endobiliary
stent insertion is indicated if a bile leak persists (15,41,42).
Biliary complications tend to occur at a later stage than bleed-
ing (mean 12 days post-injury (37)) and it has been suggested
that screening with HIDA scans may increase detection and
facilitate earlier intervention, especially in patients who have
undergone angioembolization (38). Bile peritonitis may
require laparotomy, although laparoscopic peritoneal washout
of the old blood and bile with drain insertion has obvious
advantages and has become mainstream therapy (15,36–38,43).
Biliary stricture formation following intra-hepatic bile duct
disruption is a less well understood aspect of the pathophysi-
ology of blunt liver injury and seems to be rare.
Disruption of the gall bladder or extra-hepatic bile ducts is
also rare and usually follows more severe trauma in associa-
tion with hepatic parenchymal or pancreatic injuries (44).
Interventional procedures are unlikely to suffice following
major central biliary injuries and surgery is usually required.
Cholecystectomy, operative cholangiography, temporary
external drainage, and delayed bilio-enteric reconstruction are
the mainstays of treatment.
Hemobilia and bilhemia are uncommon consequences of
traumatic vascular–biliary communication. Intra-hepatic
pseudoaneurysm formation is implicated in hemobilia which
is characterized by pain, deranged liver function tests, jaun-
dice, anemia, and overt gastrointestinal bleeding. Angioembo-
lization, with or without ERCP (for evacuation of blood from
the biliary tree) fulfill both diagnostic and therapeutic roles in
the management of traumatic hemobilia (15,45–48). Bilhemia
occurs because of hepatic venous-biliary disruption and is
characterized by jaundice with a massive rise in serum biliru-
bin (>2000 μmol/L) disproportionate to any abnormality of
liver enzymes. Successful resolution has been reported follow-
ing endoscopic biliary decompression, hepatic venous emboli-
zation, and/or occlusion of the fistula with selective endobiliary
tissue glue injection (49,50).
Intra-abdominal Sepsis
The prime role of CT in the diagnosis and guided drainage of
delayed intra-hepatic abscesses or perihepatic collections fol-
lowing NOMLI is well established (15), although some patients
may still require operative drainage. Abscesses typically com-
plicate liver necrosis in patients with high grade liver injury
managed non-operatively, particularly following angioembo-
lization (35), and also following hepatic artery ligation in the
operated patient where liver resection may be required (37).
274
Abdominal Compartment Syndrome
It has been recognized relatively recently that Abdominal
Compartment Syndrome (ACS) may complicate NOMLI, as
well as the better recognized scenario following laparotomy.
Intra-abdominal hypertension (pressure > 25 mmHg) com-
plicating NOMLI has been associated with high volume resus-
citative infusions of fluid and blood and in patients managed
by angioembolization in particular (51,52). Intra-abdominal
pressure monitoring, the recognition of the clinical manifesta-
tions of ACS and expedient decompression by laparotomy (35),
laparoscopy (51), or percutaneous drainage (52) are required
to drain the responsible blood and/or bile-stained
intra-abdominal fluid. Consequently, respiratory, renal, and
gastrointestinal complications are usually resolved without
necessarily compromising the tamponade effect on the
underlying liver injury.
Follow-up of Liver Injuries
In practice, sequential CT scanning is commonly performed,
particularly in those with higher grade liver injuries (53).
However, there is little evidence to support routine repetition
of scans. Cox and colleagues reviewed the outcomes of NOMLI
in 530 patients and reported a change of management (angi-
ography or percutaneous drainage) based on repeat CT find-
ings in just three cases in whom clinical signs were anyway
apparent (54).
Finally, although early mobilization may seem counterintui-
tive during NOMLI, a large retrospective study recently
reported that routine mobilization within 72 hours of admis-
sion seemed not to contribute to the risk of delayed hemor-
rhage (55).
Gunshot Wounds to the Liver—The Role
of Non-operative Management
Liver gunshot wounds (LGSWs) present unique problems
because of extensive hepatic parenchymal fragmentation together
with a high incidence of associated organ and vascular injuries.
Operative management has traditionally been regarded as man-
datory. Non-operative management of LGSWs is therefore con-
troversial and its role has tend to be restricted to very carefully
selected patients in an environment of intensive moni-
toring (35,56). The challenge of managing LGSWs non-
operatively was highlighted by Demetriades and colleagues who
reported that, of nearly 1000 patients presenting with abdominal
gunshot wounds to a level I trauma center, successful non-opera-
tive management was accomplished in just 11 out of 16 selected
cases (7% of all liver injuries or 21% of isolated liver injuries) (57).
Important pre-requisites for non-operative management of
LGSWs include: hemodynamic stability without blood trans-
fusion, minimal, localized abdominal signs, and the absence of
associated injuries which preclude adequate serial physical
examination, and abdominal CT scanning plays a key role in
this regard (58,59). Accordingly, a report from Cape Town,
South Africa, describes successful non-operative management
of LGSWs in 31 out of 33 selected patients regardless of liver
injury grade (59). A recent update from the same group cites
successful NOMLI for LGSWs in 58 out of 63 patients (92%)
without mortality (60).
 LIVER TRAUMA
Angioembolization plays an important role in this group of
patients for treatment of false aneurysms or active
bleeding (56,57). It remains to be seen whether diagnostic
laparoscopy will be increasingly adopted to identify the
isolated non-bleeding LGSW as suggested by some (61–64).
Early Decision Making During Laparotomy
Arrest of hemorrhage is the priority at initial operation and
rapid decision making is required of the surgeon who encoun-
ters major liver injury at laparotomy. Most liver injuries are
relatively minor and can be dealt with by simple maneuvers
such as bimanual compression of the adjacent parenchyma,
diathermy or suture ligation of visible bleeding points. Ongo-
ing bleeding which is not easily controlled in this way requires
temporary vascular inflow control by the Pringle maneuver,
which serves both therapeutic and diagnostic roles. Grade IV–V
injuries with hepatic venous/caval lacerations may not respond
to inflow occlusion and any attempts to mobilize the liver or
inspect the retrohepatic space may be met with profuse venous
bleeding. Consideration of perihepatic packing as the main-
stay of the Damage Control Laparotomy (DCL) should now
occur (65–67).
Perihepatic Packing
Perihepatic packing is acknowledged as one of the most
important factors in reducing the mortality following liver
trauma in recent years (7). Temporary resuscitative packing
may be distinguished from definitive therapeutic packing. The
former aims to achieve hemodynamic stability, allows the sur-
geon to regain his composure, repair other priority vascular
injuries, await more experienced surgical assistance, and/or
facilitate transfer to a major trauma or hepatobiliary center
for definitive treatment (67,68). Pack tamponade is the key
maneuver underpinning the philosophy of “surgical restraint”
and “damage control” during abbreviated laparotomy (69).
Its judicious use may pre-empt the rapid cascade of events
leading to refractory hypotension, dilutional coagulopathy,
hypothermia, acidosis, and metabolic failure. A decision can
then be taken either to attempt definitive control of bleeding
or to proceed with therapeutic packing with abdominal clo-
sure and staged reoperation. The timing of the decision to
pack is critical and the avoidance of packing as a desperate last
resort when all other measures have failed should be empha-
sized (70). Indeed, a multicenter study identified failure to
recognize the value of timely packing as the most common
scenario in which patients died from fatal exsanguinations in
the operating room (10). Furthermore, initially effective
packing may engender a false sense of security when a “pack
and peek” sequence develops and it is important to avoid the
vicious cycle of repeated packing, resuscitation, unsuccessful
attempts at definitive hemostasis, and repeated re-bleeding
into shock (71).
Perihepatic packing requires careful insertion of large, folded,
dry gauze laparotomy packs around the diaphragmatic surfaces
of liver and aims to restore its external contours (66,67)
(Fig. 30.3). Sufficient packs must be inserted to provide ade-
quate external counterpressure to achieve tamponade (without
causing abdominal compartment syndrome), most of this
external force being provided by the body wall and rib cage fol-
lowing wound closure. In this regard, Krige and colleagues
describe a “six-pack technique”(72). The patient is later
returned to the operating room for re-laparotomy and pack
removal according to the progress of metabolic recovery. The
Cape Town experience supports delay of liver pack removal
beyond 48 hours without increased risk of septic complications
or bile leaks, whereas early re-look laparotomy performed
within 24 hours was associated with re-bleeding (73).
A refinement in therapeutic perihepatic packing is the “mesh
hepatorrhaphy” technique which employs a synthetic (polyg-
lycolic acid or polygalactin) absorbable mesh and obviates the
need for re-laparotomy (74). The technique seems logical for
extensive lobar stellate lacerations, but unsurprisingly is inef-
fective in instances of juxtahepatic or caval injury and does not
seem to have achieved widespread acceptance. Similarly, the
use of a non-permeable “liver bag” following failure of con-
ventional packing has been described (75).
Refractory Bleeding Following Perihepatic Packing
Continued bleeding through the packs that ceases with the
Pringle manouevre and recurs with its release indicates hepatic
arterial bleeding. Selective hepatic artery ligation remains an
option although is regarded by some authorities as obsolete
(76,77) and of historical interest only (78). Rather, post-
operative transfer to the angiography suite for selective angio-
embolization has been identified as a major advance in this
scenario (42,79). Asensio and colleagues reported early angio-
embolization as an adjunct to surgical intervention in 23 out
of 57 survivors (40%) with grades IV–V liver trauma, and the
use of angiography in this way was identified as a significant
independent predictor of outcome associated with decreased
mortality (80).
Persistent bleeding despite inflow occlusion suggests retro-
hepatic caval or hepatic venous injury and critical decisions
must be made regarding the next level of intervention and
whether to attempt definitive control of parenchymal / vascu-
lar bleeding with or without debridement of devascularized
parenchyma (Fig. 30.4).
Definitive Surgical Procedures in Complex Liver Trauma
The latter option requires the use of one or more recognized
manouevres. Although these techniques all have their propo-
nents and detractors, they are nevertheless not mutually exclu-
sive. No controlled trials exist to provide an evidence base for the
superiority of one particular method over the other and much
depends on anecdote, local expertise, and individual experience.
Hepatotomy and Selective Vascular Ligation
Rapid exposure and selective vascular suture/ligation of deep-
seated, actively bleeding, intra-hepatic vessels under hepatic
inflow control have long been advocated as a mainstay in some
centers (7). In the series of 107 patients with Grade III–IV liver
injuries reported from New York, finger-fracture hepatotomy
technique was successful in controlling hemorrhage in no less
than 100 cases (93.5%) for a cumulative mortality of 15% (81).
It should be noted, however, that 83% of these patients had
penetrating injuries. Similarly, Beal reported the use of
275
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 30.4 Laparotomy and perihepatic packing was performed for post-
angioembolization hemodynamic instability. The patient continued to bleed
and re-laparotomy with hepatic segmentectomy 7/8 and repair of a middle
hepatic vein laceration was performed.
hepatotomy in 53 out of 121 patients (44%) with complex liver
trauma, citing success in 87% of cases (71). The popularity
of the technique in large North American trauma centers dur-
ing the 1980s is evidenced by its reported use in approximately
43% of nearly 3000 collected cases of complex hepatic
trauma (71,82,83), and in 28 out of 85 (33%), such cases
reported from Cape Town (72).
Non-anatomic Resection
In the nomenclature of non-anatomic liver resection for
trauma, Strong and colleagues emphasized that such proce-
dures are appropriately defined as either partial resections,
where devascularized liver peripheral to the fracture line is
removed, or resectional debridement, which involves limited
removal of non-viable liver bordering the injury (76). Such
atypical liver resections may be performed during the index
operation after hemostasis has been achieved, or during subse-
quent staged re-operations following therapeutic perihepatic
packing. The limited removal of non-viable tissue in this way
has gained popularity as part of the philosophy of surgical
restraint in the management of severe liver trauma, as distinct
from the more aggressive approach of definitive anatomical
hepatic resection.
Specific Manouevres for Control of Hemorrhage
from Juxtahepatic/Caval Injuries
Liver injuries involving the retrohepatic vena cava and hepatic
veins are the most difficult and deadly, and are associated with
mortality rates of 50% to 80% (81,83–86). Buckman and col-
leagues have classified two patterns of juxtahepatic injury: Type
A intra-parenchymal hepatic venous injuries, and Type B extra-
parenchymal venous wounds (86). Type A injuries are probably
more common, with predominant bleeding through the associ-
ated disrupted hepatic parenchyma and capsule. Restoration of
containment by perihepatic packing may achieve tamponade
of hemorrhage from high flow or low pressure intra-parenchy-
mal veins in such cases. Thus, Beal reported success with pack-
ing in 20 patients with Grade 5 venous injuries (71). Similarly,
Strong and colleagues observed that this manouevre, while not
276
always achieving complete hemostasis and hemodynamic sta-
bility, nevertheless permitted patient transfer and avoided early
death from exsanguinations (76).
Type B juxtahepatic injuries implicate extra-hepatic venous
avulsion with uncontained hemorrhage around the liver, and
are likely to require additional operative measures when the
severity of hemorrhage defies control by perihepatic
packing (86). Such injuries are more likely to require exposure
and direct vascular control. Total hepatic vascular isolation, with
cross-clamping of both suprahepatic and infrahepatic segments
of the IVC (87), may seem a daunting prospect to the uniniti-
ated in the face of heavy bleeding, and the hypovolaemic patient
may not tolerate trial caval occlusion without circulatory col-
lapse. Also, reperfusion with gut endotoxins may cause tachyar-
rhythmias following clamp removal. However, good results
have been reported for direct repair of penetrating juxtahepatic
IVC injuries when total vascular isolation techniques were
employed (88). Khaneja and co-workers reported operative sur-
vival in nine out of ten such patients presenting with Grade V
stab and gunshot wounds between 1988 and 1996 for an overall
survival of 70% (88). Others have reported more modest sur-
vival rates of 42% following direct venous repair (89).
The concept of atrio-caval shunting (84,85,90) seems logical
but in reality outcomes have been poor with >90% mortality
and the technique is generally regarded as obsolete (77).
Anatomical Hepatic Resection
The decision to embark upon an anatomical liver resection for
complex liver trauma must be regarded as one of the most dif-
ficult and controversial as most authorities emphasize a policy
of conservative surgery and damage limitation. Detractors of
formal resection cite prohibitive mortalities of 40% to 60%
(71,91), and observe its dwindling usage (2% to 4% incidence)
in the trauma centers of North America (7). Others recom-
mend limiting hepatic resection to the management of the rare
instance of major burst injuries with extensive lobar devital-
ization (72).
The rationale for hepatic resection is nevertheless logical in
fulfilling the dual role of eradicating both the site of hemor-
rhage and source of necrosis (Figs. 30.5–30.7). Although there
is a paucity of evidence for anatomical resection in this
scenario, the principles of surgical restraint observed in most
North American trauma centers have also been challenged by
surgeons in Japan (92) and France (93).
Data supporting an enhanced role for anatomic resection in
severe liver trauma from Brisbane comprised 37 such patients
(76). Right hepatectomy was the most commonly performed
procedure (27 cases (73%)), and Grade V juxtahepatic venous
injuries were encountered in 11 patients (30%). There were no
on-table deaths, three post-operative deaths, the overall mor-
tality was 8% and re-exploration was performed in seven
instances (three of which were for removal of post resection
packs) (76). This experience should be considered in the con-
text of a specialist hepatobiliary team with experience in elec-
tive liver resection and transplant techniques. Initial
laparotomy had previously occurred at the referring hospital
in two thirds of cases, and in this regard the life-saving role of
perihepatic packing prior to transfer was emphasized.
 LIVER TRAUMA

Figure 30.5 Hemodynamically unstable patient with severe blunt liver trauma
underwent laparotomy, common hepatic artery ligation, liver suture, perihe-
patic packing, and was transferred for definitive management. Re-laparotomy
and pack removal on day 1 revealed that active bleeding had stopped but the
gall bladder was necrotic and there was a major bile leak from the sutured
right liver laceration.

Figure 30.7 Abdominal CT performed 2 weeks later shows satisfactory hyper-

trophy of the remnant left hemiliver and no complications.

tion was still <1%, and the availability of experienced hepato-

biliary and liver transplant surgeons at this institution was
again a significant factor (95). It remains to be seen whether
such results are reproducible widely, or whether the role of
major resections in this context will remain the preserve of the
surgical virtuoso.
For deep penetrating liver injuries, including central bilobar
LGSWs, balloon tamponade is an innovation which offers the
chance of salvage (96–98).
Total hepatectomy is the ultimate strategy in desperate cir-
cumstances when hemorrhage from a shattered liver cannot be
controlled, or when a Grade VI avulsion injury renders the
liver remnant non-viable. However, the logistical and ethical
dilemmas presented by this scenario are daunting as the future
survival of the patient depends at the very least on the avail-
ability of a suitable donor organ. While an increasing number
of reports have testified to the feasibility of this approach
(99,100), the reality was illustrated by the Hannover experi-
ence in which six out of eight such patients died (101). The
authors emphasize the importance of the (early) timing of
hepatectomy, but stress that this approach can only be justified
in exceptional circumstances.

references
Figure 30.6 Formal right hepatectomy was performed and the patient made
an uncomplicated post-operative recovery.
Subsequent reports by Tsugawa and colleagues (94), and the
University of Pittsburgh group (95), support further the role
of hepatic resection in selected patients with severe liver trauma
requiring operative intervention. A mortality of 9% and
hepatic-related morbidity of 30% were achieved in the latter
series. However, the overall rate of formal major hepatic resec-
1. Moore EE, Shackford SR, Pachter HL, et al. Organ injury scaling: spleen,
liver, and kidney. J Trauma 1989; 29: 1664–6.
2. Moore EE, Cogbill TH, Jurkovich GJ, et al. Organ injury scaling: spleen
and liver (1994 revision). J Trauma 1995; 38: 323–4.
3. Croce MA, Fabian TC, Kudsk KA, et al. AAST organ injury scale: corre-
lation of CT-graded liver injuries and operative findings. J Trauma
1991; 31: 806–12.
4. Rizoli SB, Brenneman FD, Hanna SS, et al. Classification of liver trauma.
HPB Surgery 1996; 9: 235–8.
5. Tinkoff G, Esposito TJ, Reed J, et al. American Association for the Sur-
gery of Trauma Organ Injury Scale I: spleen, liver, and kidney, validation
based on the National Trauma Data Bank. J Am Coll Surg 2008;
207: 646–55.
6. Alexander RH, Proctor HJ. Advanced Trauma Life Support Program for
Physicians. 5th edn. Chicago: American College of Surgeons, 1993.

277
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
7. Pachter HL, Feliciano DV. Complex hepatic injuries. Surg Clin N Am
1996; 76: 763–82.
8. Körner M, Krötz MM, Degenhart C et al. Current role of emergency us
in patients with major trauma. Radiographics 2008; 28: 225–44.
9. Rozycki GS, Ballard RB, Feliciano DV, et al. Surgeon-performed ultra-
sound for the assessment of truncal injuries. Ann Surg1998; 228: 557–67.
10. Hoyt DB, Bulger EM, Knudson MM, et al. Death in the operating room:
an analysis of a multi-center experience. J Trauma 1994; 37: 426–32.
11. Hagiwara A, Yukioka T, Ohta S, et al. Nonsurgical management of
patients with blunt hepatic injury: efficacy of transcatheter arterial
embolization. AJR 1997; 169: 1151–6.
12. Monnin V, Sengel C, Thony F, et al. Place of arterial embolization in
severe blunt hepatic trauma: a multidisciplinary approach. Cardiovasc
Intervent Radiol 2008; 31: 875–82.
13. Ciraulo DL, Luk S, Palter M, et al. Selective hepatic arterial embolization
of grade IV and V blunt hepatic injuries: an extension of resuscitation in
the non-operative management of traumatic hepatic injuries. J Trauma
1998; 45: 353–9.
14. Denton JR, Moore EE, Coldwell DM. Multimodality treatment for
grade V hepatic injuries: perihepatic packing, arterial embolization, and
venous stenting. J Trauma 1997; 42: 964–8.
15. Carrillo EH, Spain DA, Wohltmann CD, et al. Interventional techniques
are useful adjuncts in nonoperative management of hepatic injuries. J
Trauma 1999; 46: 619–24.
16. Shanmuganathan K, Mirvis SE. CT scan evaluation of blunt hepatic
trauma. Radiol Clin N Am 1998; 36: 399–411.
17. Knudson MM, Lim RC, Oakes DD, et al. Nonoperative management of
blunt liver injuries: the need for continued surveillance. J Trauma 1990;
30: 1494–1500.
18. Shankar KR, Lloyd DA, Kitteringham L, et al. Oral contrast with com-
puted tomography in the evaluation of blunt abdominal trauma in chil-
dren. Br J Surg1999; 86: 1073–7.
19. Carrillo EH, Platz A, Miller FB, et al. Non-operative management of
blunt hepatic trauma. Br J Surg1998; 85: 461–8.
20. Fang J-F, Chen R-J, Wong Y-C, et al. Pooling of contrast material on
computed tomography mandates aggressive management of blunt
hepatic injury. Am J Surg 1998; 176: 315–9.
21. Hurtuk M, Reed RLn, Esposito TJ, et al. Trauma surgeons practice what
they preach: the NTDB story on solid organ injury management. J
Trauma 2006; 61: 243–55.
22. John TG, Greig JD, Johnstone AJ, et al. Liver trauma: a ten year experi-
ence. Br J Surg 1992; 79: 1352–6.
23. Meredith JW, Young JS, Bowling J, et al. Nonoperative management of
blunt hepatic trauma: the exception or the rule. J Trauma 1994; 36: 529–35.
24. Croce MA, Fabian TC, Menke PG, et al. Nonoperative management of
blunt hepatic trauma is the treatment of choice for hemodynamically
stable patients. Results of a prospective trial. Ann Surg 1995; 221: 744–55.
25. Brasel KJ, DeLisleC.M., Olson CJ, et al. Trends in the management of
hepatic injury. Am J Surg 1997; 174: 674–7.
26. Karp MP, Cooney DR, Pros GA, et al. The non-operative management
of pediatric hepatic trauma. J Pediatric Surg 1983; 18: 512.
27. Cywes S, Rode H, Miller AJ. Blunt liver trauma in children: non-opera-
tive management. J Pediat Surg 1985; 20: 14.
28. Oldham KT, Guice KS, Ryckman F, et al. Blunt liver injury in childhood:
evolution of therapy and current perspective. Surgery 1986; 100: 542–9.
29. Bond SJ, Eichelberger MR, Gotschall CS, et al. Nonoperative manage-
ment of blunt hepatic and splenic injury in children. Ann Surg 1996;
223: 286–9.
30. Malhotra AK, Fabian TC, Croce MA, et al. Blunt hepatic injury: a para-
digm shift from operative to nonoperative management in the 1990s.
Ann Surg 2000; 231: 804–13.
31. Richardson JD. Changes in the management of injuries to the liver and
spleen. J Am Coll Surg 2005; 200: 648–69.
32. Pachter HL, Hofstetter SR. The current status of nonoperative manage-
ment of adult blunt hepatic injuries. Am J Surg1995; 169: 442–54.
33. Farnell MB, Spencer MP, Thompson E, et al. Nonoperative management
of blunt hepatic trauma in adults. Surgery 1988; 104: 748–56.
34. Christmas AB, Wilson AK, Manning B, et al. Selective management of
blunt hepatic injuries including nonoperative management is a safe and
effective strategy. Surgery 2005; 138: 606–11.
278
35. Franklin GA, Casos SR. Current advances in the surgical approach to
abdominal trauma. Injury 2007; 37: 1143–56.
36. Carrillo EH, Richardson JD. Delayed surgery and interventional proce-
dures in complex liver injuries. J Trauma 1999; 46: 978.
37. Kozar RA, Moore FA, Cothren CC, et al. Risk factors for hepatic mor-
bidity following non-operative management. Arch Surg 2006; 141: 451–9.
38. Wahl WL, Brandt M-M, Hemmila MR, Arbabi S. Diagnosis and man-
agement of bile leaks after blunt liver injury. Surgery 2005; 138: 742–8.
39. Durham RM, Buckley J, Keegan M, et al. Management of blunt hepatic
injuries. Am J Surg1992; 164: 477–81.
40. Fingerhut A, Trunkey D. Surgical management of liver injuries in adults –
current indications and pitfalls of operative and non-operative policies:
a review. Eur J Surg 2000; 166: 676–86.
41. Harrell DJ, Vitale GC, Larson GM. Selective role for endoscopic retro-
grade cholangiopancreatography in abdominal trauma. Surg Endosc
1998; 12: 400–4.
42. Asensio JA, Demetriades D, Chahwan S, et al. Approach to the manage-
ment of complex hepatic injuries. J Trauma 2000; 48: 66–9.
43. Franklin GA, Richardson JD, Brown AL, et al. Prevention of bile perito-
nitis by laparoscopic evacuation and lavage after nonoperative treat-
ment of liver injuries. Am Surg 2007; 73: 611–6.
44. Burgess P, Fulton RL. Gallbladder and extrahepatic biliary duct injury
following abdominal trauma. Injury 1992; 23: 413–4.
45. Clancy TE, Warren RL. Endoscopic treatment of biliary colic resulting
from hemobilia after nonoperative management of blunt hepatic
injury: case report and review of the literature. J Trauma 1997; 43: 527–9.
46. Velmahos GC, Toutouzas K, Radin R, et al. High success with non-oper-
ative management of blunt hepatic trauma: the liver is a sturdy organ.
Arch Surg 2003; 138: 475–81.
47. Srivastava DN, Sharma S, Pal S, et al. Transcatheter arterial embolization
in the management of hemobilia. Abdom Imaging 2006; 31: 439–48.
48. Forlee MV, Krige JEJ, Welman CJ, et al. Hemobilia after penetrating and
blunt liver injury: treatment with selective hepatic artery embolisation.
Injury 2004; 35: 23–8.
49. Glaser K, Wetscher G, Pointner R, et al. Traumatic bilhemia. Surgery
1994; 116: 24–7.
50. Sattawattamrong Y, Janssens AR, Alleman MJA, et al. Endoscopic treat-
ment of bilhaemia following percutaneous liver biopsy. HPB 1999;
1: 33–5.
51. Chen RJ, Fang JF, Chen MF. Intra-abdominal pressure monitoring as a
guideline in the nonoperative management of blunt hepatic trauma. J
Trauma 2001; 51: 44–50.
52. Yang EY, Marder SR, Hastings G, Knudson MM. The abdominal com-
partment syndrome complicating nonoperative management of major
blunt liver injuries: recognition and treatment using multimodality
therapy. J Trauma 2002; 52: 982–6.
53. Lee SK, Carrillo EH. Advances and changes in the management of liver
injuries. Am Surg 2007; 73: 201–6.
54. Cox JC, Fabian TC, Maish GO, et al. Routine follow-up imaging is
unnecessary in the management of blunt hepatic injury. J Trauma 2005;
59: 1175–80.
55. London JA, Parry L, Galante J, et al. Safety of early mobilization of
patients with blunt solid organ injuries. Arch Surg 2008; 143: 972–6.
56. Moore EE. When is nonoperative management of a gunshot wound to
the liver appropriate. J Am Coll Surg 1999; 188: 427–8.
57. Demetriades D, Gomez H, Chahwan S, et al. Gunshot injuries to the
liver: the role of selective nonoperative management. J Am Coll Surg
1999; 188: 343–8.
58. Velmahos GC, Constantinou C, Tillou A, et al. Abdominal computed
tomographic scan for patients with gunshot wounds to the abdomen
selected for nonoperative management. J Trauma 2005; 59: 1155–61.
59. Omoshoro-Jones JAO, Nicol JA, Navsaria PH, et al. Selective non-oper-
ative management of liver gunshot injuries. Br J Surg 2005; 92: 890–5.
60. Navsaria PH, Nicol JA, Krige JEJ, et al. Selective non-operative manage-
ment of liver gunshot wounds. Ann Surg 2009; 249: 653–6.
61. Sosa JL, Markley M, Sleeman D, et al. Laparoscopy in abdominal gun-
shot wounds. Surg Laparosc Endosc 1993; 3: 417–9.
62. Ivatury RR, Simon RJ, Stahl WM. A critical evaluation of laparoscopy in
penetrating abdominal trauma. J Trauma 1993; 34: 822–8.
 LIVER TRAUMA
63. Simon RJ, Ivatury RR. Current concepts in the use of cavitary endos-
copy in the evaluation and treatment of blunt and penetrating truncal
injuries. Surg Clin N Am 1995; 75: 157–74.
64. Ditmars ML, Bongard F. Laparoscopy for triage of penetrating trauma:
the decision to explore. J Laparoendosc S 1996; 6: 285–91.
65. Feliciano DV, Mattox KL, Burch JM, et al. Packing for control of hepatic
haemorrhage. J Trauma 1986; 26: 738–43.
66. Krige JEJ. Perihepatic packing in the management of liver trauma. HPB
Surg 1991; 3: 141–4.
67. Krige JEJ, Bornman PC, Terblanche J. Therapeutic perihepatic packing
in complex liver trauma. Br J Surg 1992; 79: 43–6.
68. Watson CJE, Calne RY, Padhani AR, et al. Surgical restraint in the man-
agement of liver trauma. Br J Surg 1991; 78: 1071–5.
69. Rotondo MF, Schwab CW, McGonigal MD, et al. ‘Damage control’: an
approach for improved survival in exsanguinating penetrating abdomi-
nal injury. J Trauma 1993; 35: 375–83.
70. Garrison JR, Richardson JD, Hilakos AS, et al. Predicting the need to pack
early for severe intra-abdominal hemorrhage. J Trauma 1996; 40: 923–9.
71. Beal SL. Fatal hepatic hemorrhage: an unresolved problem in the man-
agement of complex liver injuries. J Trauma 1990; 30: 163–9.
72. Krige JEJ, Bornman PC, Terblanche J. Liver trauma in 446 patients. S Afr
J Surg1997; 35: 10–5.
73. Nicol JA, Hommes M, Primrose R, et al. Packing for control of haemor-
rhage in major liver trauma. World J Surg 2007; 31: 569–74.
74. Reed RL, Merrell RC, Meyers WC, et al. Continuing evolution in the
approach to severe liver trauma. Ann Surg 1992; 216: 524–38.
75. Sattler S, Gentilello LM. The liver bag: report of a new technique for treat-
ing severe, exsanguinating hepatic injuries. J Trauma 2004; 57: 884–6.
76. Strong RW, Lynch SV, Wall DR, et al. Anatomic resection for severe liver
trauma. Surgery 1998; 123: 251–7.
77. Krige JEJ, Nicol JA. Treating major liver injuries. SAJS 2006; 44: 128–30.
78. Mays ET. Hepatic trauma. Curr Probl Surg 1976; 13: 6–73.
79. Fang J-F, Chen R-J, Lin B-C, et al. Blunt hepatic injury: minimal inter-
vention is the policy of treatment. J Trauma 2000; 49: 722–8.
80. Asensio JA, Roldan G, Petrone P, et al. Operative management and out-
comes in 103 AAST-OIS grades IV and V complex hepatic injuries:
trauma surgeons still need to operate, but angioembolization helps. J
Trauma 2003; 54: 647–54.
81. Pachter HL, Spencer FC, Hofstetter SR, et al. Significant trends in the
treatment of hepatic trauma. Experience with 411 injuries. Ann Surg
1992; 215: 492–502.
82. Feliciano DV, Mattox KL, Jordan GL, et al. Management of 1000 consecu-
tive cases of hepatic trauma (1979–1984). Ann Surg 1986; 204: 438–42.
83. Cogbill TH, Moore EE, Jurkovich GJ, et al. Severe hepatic trauma: a multi-
center experience with 1,335 liver injuries. J Trauma 1988; 28: 1433–8.
84. Rovito PF. Atrial caval shunting in blunt hepatic vascular injury. Ann
Surg 1987; 205: 318–21.
85. Burch JM, Feliciano DV, Mattox KL. The atriocaval shunt. Facts and
fiction. Ann Surg 1988; 207: 555–68.
86. Buckman RF, Miraliakbari R, Badellino MM. Juxtahepatic venous inju-
ries: a critical review of reported management strategies. J Trauma 2000;
48(5): 978–84.
87. Bismuth H, Castaing D, Garden OJ. Major hepatic resection under total
vascular exclusion. Ann Surg 1989; 210: 13–9.
88. Khaneja SC, Pizzi WF, Barie PS, Ahmed N. Management of penetrating
juxtahepatic inferior vena cava injuries under total vascular occlusion. J
Am Coll Surg 1997; 184: 469–74.
89. Richardson JD, Franklin GA, Lukan JK, et al. Evolution in the management
of hepatic trauma: a 25 year perspective. Ann Surg 2000; 232: 324–30.
90. Chen R-J, Fang J-F, Lin B-C, et al. Surgical management of juxtahepatic
venous injuries in blunt hepatic trauma. J Trauma 1995; 38: 886–90.
91. Moore FA, Moore EE, Seagraves A. Nonresectional management of
major hepatic trauma. An evolving concept. Am J Surg 1985; 150:
725–9.
92. Kasai T, Kobayashi K. Searching for the best operative modality for
severe hepatic injuries. Surg Gynecol Obstet 1993; 77: 551–5.
93. Menegaux F, Langlois P, Chigot J-P. Severe blunt trauma of the liver: a
study of mortality factors. J Trauma 1993; 35: 865–9.
94. Tsugawa K, Koyanagi N, Hashizume M, et al. Anatomic resection for
severe blunt liver trauma in 100 patients. World J Surg 2002; 26: 544–9.
95. Polanco P, Leon S, Pineda J, et al. Hepatic resection in the management
of complex injury to the liver. J Trauma 2008; 65: 1264–70.
96. Poggetti RS, Moore EE, Moore FA, et al. Balloon tamponade for bilobar
transfixing hepatic gunshot wounds. J Trauma 1992; 33: 694–7.
97. Seligman JY, Egan M. Balloon tamponade: an alternative in the treat-
ment of liver trauma. Am Surg 1997; 63: 1022–3.
98. Demetriades D. Balloon tamponade for bleeding control in penetrating
liver injuries. J Trauma 1998; 44: 538–9.
99. Jeng LB, Hsu CH, Wang CS, et al. Emergent liver transplantation to sal-
vage a hepatic avulsion injury with a disrupted suprahepatic vena cava.
Arch Surg 1993; 128: 1075–7.
100. Demirbas A, Fragulidis GP, Karatzas T, et al. Role of liver transplanta-
tion in the management of liver trauma. Transpl Proc 1997; 29: 2848.
101. Ringe B, Pichlmayr R. Total hepatectomy and liver transplantation: a
life-saving procedure in patients with severe hepatic trauma. Br J Surg
1995; 82: 837–9.
279
31 Portal hypertension
Michael D. Johnson and J. Michael Henderson
introduction
Portal hypertension has undergone major changes in under-
standing its pathophysiology, investigation, and management
over the past 3 decades. It has moved from a dominantly surgi-
cal syndrome to a predominantly medical one, but in day-to-
day practice includes a broad group of disorders that require a
multidisciplinary team for evaluation and management. Basic
science has defined the pathophysiology, allowing the intro-
duction of pharmacologic therapies for treating many of the
complications of portal hypertension. Technology advances in
endoscopic therapies and endovascular stenting have changed
the treatment options for variceal bleeding. The coming of age
of liver transplantation has dramatically altered the manage-
ment of patients with end stage liver disease and portal hyper-
tension, and is now the dominant surgical option for suitable
patients. This chapter will address these changes and present
the evidence supporting management choices for the main
clinical presentations of portal hypertension.
etiology
Portal hypertension can be divided into prehepatic, intrahe-
patic, and posthepatic causes based on the location of obstruc-
tion to portal blood flow—Table 31.1. Most of the prehepatic
causes have a normal liver which improves overall prognosis
for this group. Portal vein thrombosis should prompt a workup
for hypercoagulable states (1). Rarely, a procedural induced
arteriovenous fistula or functional fistulae associated with
Osler Weber Rendu disease (Hereditary hemorrhagic telangi-
ectasia) (2,3), can cause portal hypertension.
Intrahepatic portal hypertension is usually secondary to cir-
rhosis with its multiple causes. The severity of the liver disease
is the most important factor in determining prognosis. Intra-
hepatic presinusoidal obstruction occurs in congenital hepatic
fibrosis and schistosomiasis, and liver function is well pre-
served. Schistosomiasis accounts for 200 million cases of por-
tal hypertension worldwide (4,5).
Posthepatic portal hypertension is rare and includes Budd–
Chiari Syndrome (BCS) and veno-occlusive disease. BCS
results from obstruction of either the hepatic veins or supra-
hepatic vena cava, and is often associated with a myeloprolif-
erative or hypercoagulable disorder. Outcome is determined
by the extent of hepatic vein involvement, the rapidity of
development, and the underlying liver function (6,7).
pathophysiology
Portal hypertension occurs when portal venous pressure rises
above the normal pressure of 8 mmHg and becomes clinically
important above 10 to 12 mmHg. The cascade of events that
follow portal flow obstruction are illustrated in Figure 31.1. As
portal pressure rises, additional dynamic factors come into
play as a result of neurohormonal changes. Vasoconstriction
280
with endothelins (8), norepinephrine, angiotensin II, vaso-
pressin whose levels are elevated in cirrhotic patients plays a
role (9). Insufficiency of local vasodilators, such as nitric oxide
and carbon monoxide has been implicated, and while levels of
Nitric Oxide Synthase (NOS) are normal, NOS activity is
depressed, partly due to increased expression of caveolin (10).
Splanchnic vasodilation and the development of portosys-
temic collateral are influenced by Vascular Endothelial Growth
Factor (VEGF) and Platelet Derived Growth Factor (PDGF).
VEGF receptor inhibition has been shown to prevent the for-
mation of portosystemic collaterals in animal models (11,12)
and reverse the adverse hemodynamic consequences of estab-
lished portal hypertension (13).
These neurohumoral changes lead to increased splanchnic
hyperemia and a hyperdynamic systemic circulation with a
low arterial blood pressure and increased cardiac output.
clinical manifestations
Variceal Bleeding
Variceal bleeding is one of the major complications of portal
hypertension requiring medical and surgical therapies (14).
Screening endoscopy in cirrhotics shows that patients with
more advanced liver disease and a lower platelet count are more
likely to have varices (15). Epidemiologic studies have shown
linear progression of varices over time (16). All patients with
cirrhosis should undergo an initial screening upper endoscopy
for varices: if none are present this should be repeated every
2 years. If present, intervention with prophylactic therapy to
prevent bleeding (primary prophylaxis) should be considered.
Ascites
Ascites is a marker of advanced liver disease that develops later
than varices. Refractory ascites which does not respond to salt
restriction and diuretics and has consistently been linked to
increased mortality (17). In addition, refractory ascites is
potentially complicated by fluid and electrolyte imbalances,
spontaneous bacterial peritonitis, and a higher incidence of
abdominal wall hernias (18).
Hypersplenism
Portal hypertension can lead to splenomegaly and hypersplen-
ism, with anemia, leukopenia, and thrombocytopenia. Blood
is sequestered and destroyed in the spleen due to morphologic
changes (19). Hypersplenism improves with decompression of
the portal hypertension and rarely is splenectomy needed. Par-
tial splenic embolization has been advocated by some (20), but
is less effective.
Pulmonary Syndromes
Hepatopulmonary syndrome (HPS) is characterized by hypox-
emia with the development of right-to-left intrapulmonary
 PORTAL HYPERTENSION
shunts and a widened alveolar-arterial oxygen gradient (21).
Treatment is with liver transplantation which usually reverses the
syndrome with survival rates similar to non-HPS cohorts (22).
Pulmonary hypertension is also seen in patients with portal
hypertension and carries a more sinister prognosis than HPS.
Unless pulmonary arterial pressure can be reduced to normal
ranges, liver transplant is contraindicated in these patients.
Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma is a common cause of death among
patients with cirrhosis and has increased in importance as
other causes of mortality have declined (23). The most com-
mon conditions leading to HCC are hepatitis B and C and
alcoholism. Screening is recommended for patients with cir-
rhosis using hepatic ultrasound. However effectiveness of this
approach has been questioned (24). Early detection of HCC in
patients with well-compensated cirrhosis who are eligible for
resection or can be prioritized for transplantation is the goal.
evaluation
The three essential components in evaluating patients with
portal hypertension are (i) assessment of liver function,
(ii) endoscopic study, and (iii) radiologic imaging.
Liver Function is assessed from clinical and laboratory
parameters. Ascites, jaundice, muscle wasting, and encepha-
lopathy are markers for advanced liver disease. Biochemical
and hematologic lab profiles include a complete blood count,
prothrombin time, serum electrolytes, and liver chemistries.
Specific markers of liver disease include hepatitis panels,
antinuclear antibody, antimitochondrial antibody, iron and
copper levels, alpha 1 antitrypsin, and alpha fetoprotein for
HCC screening. The Child-Pugh and MELD scoring systems
combine clinical and laboratory variables to determine prog-
nosis in chronic liver disease.
Endoscopy focuses on the presence, extent and size of esoph-
ageal and/or gastric varices and Portal Hypertensive Gastropa-
thy (PHG). Grading of varices, using, for example, the North
Italian Endoscopic Club (NIEC) system, risk-stratify based on
variceal size, severity of red wale markings. When combined
with Child–Pugh class, such grading can help to guide
therapy (25,26). Similar grading systems have been developed
and validated for PHG and gastric varices (27,28).
Table 31.1 Causes of Portal Hypertension
Prehepatic Portal or splenic vein trombosis
Arteriovenous fistula
Extrinsic portal vein compression
Intrahepatic Pre-sinusoidal: Schistosomiasis
Hepatic fibrosis
Sarcoidosis
Early primary biliary cirrhosis
Sinusoidal—Alcoholic liver disease
Most causes of Cirrosis
Post hepatic Hepatic vein thrombosis
Veno occlusive disease
Caval and hepatic vein webs
Source: Adapted from (77).
Radiologic Imaging includes ultrasound as a versatile, low
cost, low-risk tool for imaging of the liver parenchyma and the
portal and hepatic venous systems. The addition of Doppler
allows portal venous velocity assessment. Ultrasound can aid
to guide percutaneous liver biopsy and paracentesis, screen for
hepatocellular carcinoma, and define vessels. Computed
tomography (CT) provides better anatomic detail, especially
with newer multidetector array scanners and digital recon-
struction of images in different planes and in three dimen-
sions. Magnetic resonance imaging (MRI) is an imaging
modality that may be preferred by some over CT scan, and can
provide more information about the bile and pancreatic ducts.
Visceral angiography and hepatic venography are occasionally
indicated. The Hepatic Venous Pressure Gradient (HVPG) is
calculated by measuring the hepatic venous wedge pressure
with a balloon occlusion catheter minus the free hepatic vein
pressure. In patients treated with pharmacotherapy, it has
been shown that variceal bleeding rarely occurs when the
HVPG is below 10 mmHg and if the HVPG can be reduced
to below 12 mmHg or by 20% from baseline after an initial
variceal bleed (29,30).
management of variceal bleeding
Primary Prophylaxis
Figure 31.2 presents a management algorithm for primary
prophylaxis to prevent an initial variceal bleed. This is based
on data from multiple randomized controlled trials (Grade 1a
evidence). If small, low-risk varices or no varices are discovered
repeat endoscopy should be performed in 2 to 3 years. If small
Obstruction to portal flow
(cirrhosis/PVT/etc.)
Increased portal venous pressure
Increased production Increased production
vasoconstrictors vasodilators
Increased hepatic
vascular tone
Peripheral, ↓ BP Splanchnic
hyperemia
Increased hepatic
vascular resistance Activate neurohumoral
Na and H2O retention
Increased
Increased C.O. collateral
flow
Portal hypertension
Copyright 2007 by Saunders, an imprint of Elsevier Inc.
Figure 31.1 Pathophysiology of portal hypertension demonstrating complex
vascular and neurohormonal responses. BP, blood pressure; CO, cardiac
output; PVT, portal vein thrombosis. Source: From Ref. (97).
281
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
varices (<5 mm) are found, but there are other risk factors
(Child B/C or presence of red wale marks), non-selective beta-
blockers should be started. The presence of medium or large
esophageal varices is an indication for starting a non-
cardioselective beta-blocker (propranolol or nadolol). Treat-
ment of the latter two populations reduces the risk of first
variceal hemorrhage from 30% to 14% (31). Endoscopic
Variceal Ligation (EVL) can be used in patients that are intol-
erant to beta blocker therapy or have large high-risk varices. In
a meta-analysis of 12 studies, EVL was slightly better at pre-
venting a first variceal bleed than beta-blocker therapy with-
out any improvement in mortality (32). Beta-blocker therapy
is first-line therapy in primary prophylaxis and reduction of
the HVPG to less than 12 mmHg or by 20% from baseline is
the goal of therapy (33–36).
Acute Variceal Hemorrhage
Accurate diagnosis of acute upper GI bleeding in patients with
cirrhosis requires differentiation of variceal bleeding from
Mallory Weiss lesions, portal hypertensive gastropathy, and
peptic ulcer disease. Figure 31.3 shows a management approach
for acute variceal bleeding.
Management starts with conservative resuscitation in a closely
monitored setting with large bore IV access in the setting of
massive bleeding, recognizing that orotracheal intubation may
be required. Blood product transfusion should be individual-
ized based on hemoglobin, platelet count, INR, and overall
hemodynamic profile. Over-resuscitation should be avoided as
this may exacerbate bleeding by increasing portal venous pres-
sure. In patients known to have cirrhosis, pharmacologic ther-
apy with octreotide (Sandostatin—Novartis Pharmaceuticals)
or terlipressin (Glypressin—Ferring Pharmaceuticals), and the
Algorithm for prophylaxis of variceal bleeding
Cirrhosis
Endoscopy
No varices: f/u Varices Small varices (<5 mm)
endoscopy 2 yrs (moderate or large) f/u endoscopy 1 yr
Non-cardioselective β-blocker
(Propanolol or Nadolol)
Intolerance to β-blockers
or high-risk varices
Band ligation
Figure 31.2 Primary prophylaxis to prevent an initial variceal bleed. Manage-
ment algorithm based on variceal size. Source: From Ref. (97).
282
administration of intravenous antibiotics should precede
endoscopy (37,38) (Grade 1a evidence). Terlipressin, a long-
acting synthetic vasopressin, in a meta-analysis of seven ran-
domized controlled trials afforded a 34% relative risk reduction
in all-cause mortality compared to placebo (39). Octreotide, was
compared to terlipressin in two randomized controlled trials and
both agents were found to be similarly effective (40,41).
Endoscopy should be performed early for diagnosis and
treatment. EVL and injection sclerotherapy are effective at
controlling acute bleeding, especially when combined with
pharmacologic treatment (42). When compared to sclerother-
apy, banding is associated with a lower rate of rebleeding with
fewer complications and endoscopy sessions (43) (Grade 1b
evidence).
In the 5% to 10% of patients not responding to the above
measures, balloon tamponade may be necessary as a rescue
measure until emergency Transjugular Intrahepatic Portosys-
temic Shunt (TIPS) can be performed.
In-hospital mortality from acute variceal hemorrhage has
steadily declined over the last couple of decades to 14.5%,
thanks in large part to better resuscitation strategies, lower
rates of rebleeding, and prevention of infectious complica-
tions (44).
Prevention of Recurrent Variceal Bleed
A first variceal bleed changes the odds of subsequent bleeding.
Without specific therapy, approximately 60% of patients will
rebleed within 1 to 2 years (31,45). This emphasizes the need for
optimal strategies to prevent rebleeding and at the same time
not accelerate the rate of progression of any underlying liver dis-
ease (46). Figure 31.4 illustrates a management algorithm.
Pharmacologic and Endoscopic Therapy
The best results for prevention of rebleeding have been
obtained using a combination of pharmacologic therapy with
non-selective beta-blockers (sometimes in combination with
Suspected variceal bleed
1. Somatostatin/octreotide
2. Conservative resuscitation
3. Antibiotics
Endoscopy -Diagnostic
-Therapeutic: sclerotherapy
or ligation
Continued bleed -Balloon tamponade
or rebleed -TIPS
Copyright 2007 by Saunders, an imprint of Elsevier Inc.
Figure 31.3 Acute variceal bleed. A management algorithm for diagnosis and
management of acute variceal bleeding. Source: From Ref. (97).
 PORTAL HYPERTENSION
nitrates) and EVL (Grade 1b evidence). The latter should be
performed in 2 to 4 sessions, 7 to 10 days apart until variceal
obliteration is achieved. Combination therapy has succeeded in
lowering rebleeding rates to as low as 14% at 2 years (47). The
lowest rates of rebleeding are found in patients deemed
“responders” based on HVPG measurements as mentioned
earlier. Patients with a HVPG < 12 mmHg or a 20% decrease in
HVPG have a 10% rebleeding rate (48–50). Some have argued
that pharmacologic therapy should be tried first, with EVL added
for “non-responders.” In a meta-analysis of 12 randomized con-
trolled trials comparing TIPS to endoscopic therapy for prevent-
ing variceal rebleeding, TIPS performed better in the prevention
of rebleeding and deaths due to rebleeding, albeit with a higher
rate of encephalopathy (51) (Grade 1a evidence). However, half
of the studies used sclerotherapy alone for secondary prophy-
laxis. Subgroup analysis showed EVL was statistically equivalent
to TIPS in terms of rebleeding, mortality, and encephalopathy.
The data suggest TIPS should be used only once the combination
of pharmacologic and endoscopic therapies has failed.
Variceal Decompression
Variceal decompression, either with a radiologic shunt (TIPS)
or a surgical shunt, is indicated in patients that continue to
bleed despite adequate medical and endoscopic therapy. TIPS
has largely replaced surgical shunts both for patients with
good hepatic reserve, and as a bridge to transplantation.
Acute bleed controlled with banding
Evaluation
β-blocker and course of banding
Varices obliterated Persistent high-risk varices
or rebleeding
β-blocker -Repeat banding
-or decompress
TIPS
DSRS
End-stage liver disease
Transplant
Copyright 2007 by Saunders, an imprint of Elsevier Inc.
Figure 31.4 Prevention of recurrent variceal bleeding with cascading therapy
options. TIPS, transjugular intrahepatic portosystemic shunt; DSRS, distal
splenorenal shunt. Source: From Ref. (97).
TIPS
Since its introduction in the 1990s TIPS has undergone a
number of modifications, allowing it to become the primary
means of portal decompression with a rebleeding rate at 1 year
of about 13% (52). It is functionally an intrahepatic side-to-
side portocaval shunt which lowers the portal venous pressure
and sinusoidal pressure. Initially, the main limitation of TIPS
was stenosis, with the need for frequent surveillance and rein-
tervention in the first year (50 % to 80%). The use of polytet-
rafluoroethylene (PTFE)-covered stents has markedly reduced
the need for reintervention to <25%. Two randomized trials
demonstrated improved primary patency rates with no impact
on rate of encephalopathy or survival (53,54) (Grade 1b evi-
dence). The other main side effect of TIPS is the development
or worsening of encephalopathy which occurs in approxi-
mately 30% of patients (52). This is often amenable to medical
management or modification of the TIPS itself.
TIPS Procedure
Venous access is usually obtained through the right internal
jugular vein into the right or middle hepatic veins. The main
right portal vein is identified by a retrograde hepatic veno-
gram, and the portal venous system is entered above the bifur-
cation. After a contrast portal venogram confirms correct
positioning, the TIPS is placed with a gentle curve to the pros-
thesis to prevent kinking. It is also important to choose a stent
of the correct length, not extending too far into either the
hepatic vein or the portal vein. At the same time, the entire
hepatic vein segment should be covered to prevent the devel-
opment of a stenosis at this end. Portal venous pressures are
measured before and after the TIPS is deployed, and a comple-
tion venogram is obtained. The goal is a portal vein to right
atrial gradient of <10 mmHg. Recurrence of variceal bleeding
often heralds TIPS dysfunction and warrants recatheterization
of the shunt to assess for patency and measure the gradient.
Surgical Shunts
Surgical shunts can be classified as total, partial, or selective.
Total shunts divert all portal venous blood flow either a direct
side-to-side portocaval shunt or an H-graft shunt using a
10-mm or greater PTFE graft. Portal decompression and reso-
lution of variceal bleeding are excellent at greater than 90%;
however, encephalopathy develops in up to 45% (55). Partial
shunts use an 8 mm graft to partially decompress the portal
venous system while preserving some hepatopedal blood flow.
Prevention of variceal rebleeding remains greater than 90%
with lower rates of encephalopathy compared to total
shunts (56,57) (Grade 3 evidence). Selective shunts, such as
the Distal Splenorenal Shunt (DSRS), selectively decompress
gastroesophageal varices while maintaining portal hyperten-
sion (Fig. 31.5). These became the most widely used surgical
shunts from 1980s to 1990s. Most series demonstrated rebleed-
ing rates from 5% to7% and encephalopathy in 5% to 19%
range. An NIH-funded prospective, randomized trial (1997 to
2003) compared DSRS to TIPS in patients with Child’s class A
and B cirrhosis (58) (Grade 1b evidence). At the close of this
study (mean follow-up of 46 ± 26 months with a range 24 to
96 months), the survival rates were not different at 2 and
283
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
5 years (DSRS 81% and 62%; TIPS 88% and 61%). The overall
rebleeding rates were not significantly different (5.5% in the
DSRS group, 10.5% in the TIPS group), and the occurrence of
a first episode of any degree of encephalopathy was 50% in
each arm. The reintervention rate was significantly higher
(p < 0.001) at 82% in the TIPS group versus 11% in the DSRS
group. This study was conducted before covered stents were
available for TIPS and the use of covered stents has lowered the
shunt dysfunction rate at 1 year to 13% (53,54).
Devascularization Procedures
These series of operations were devised to decrease variceal
inflow, while preserving portal hypertension and therefore
decreasing the rate of encephalopathy. These have been used
much more extensively in the Mid and Far East on patients
with non-alcoholic liver disease with good results. In their
original series of 276 patients, Sugiura and Futagawa reported
an operative mortality of 4.3% and 2.3% rate of variceal recur-
rence (59). Various modifications have been made to the pro-
cedure that generally consists of splenectomy, devascularization
of the upper two-thirds of the greater and lesser curvature of
the stomach and 7 cm of distal thoracic esophagus, esophageal
transection and reanastomosis, and pyloroplasty (60). Outside
Japan, experience with gastroesophageal devascularization has
not been quite as impressive. In the largest series in the West-
ern hemisphere, Orozco et al. reported an operative mortality
of 22% and rebleeding rate of 10% but included patients with
Child’s class C cirrhosis (61). Encephalopathy rates have gen-
erally been less than 10% in most series. Currently, devascular-
ization procedures are most appropriate for patients with
extensive thrombosis of the portal venous system with recur-
rent variceal bleeding and preserved liver function who lack
“shuntable” veins (Grade 3 evidence).
Figure 31.5 Distal splenorenal shunt selectively decompresses gastroesopha-
geal varices while maintaining portal perfusion through the superior mesen-
teric and portal veins. Source: From Ref. (97).
284
Transplantation
Liver transplantation constitutes the ultimate “shunt” with
normalization of portal venous hemodynamics and restora-
tion of liver synthetic function. Ongoing improvements in
operative techniques and immunosuppression are responsible
for a modern 5-year patient survival rates approaching 75% (62).
The major shortcoming of transplantation remains a shortage
of available donor organs. Strategies to deal with this have
included “split liver” and living-related transplantation.
ascites
This is the most common complication of cirrhosis and portal
hypertension and is an important source of morbidity and
mortality. Figure 31.6 presents a management algorithm.
Ascites develops as a result of sinusoidal portal hypertension
and the concomitant vasodilatation within the splanchnic
circulation with an imbalance between hepatic lymph
production and return to the systemic circulation. A relative
hypovolemia is sensed by the kidneys due to reflex systemic
vasoconstriction that, in turn, activates the renin–angiotensin
system leading to sodium and water retention.
Paracentesis is used in the diagnosis and management of
ascites. For diagnosis, a Serum-Ascites Albumin Gradient
Treatment of ascites
Ascites
Mild/moderate
1. Diet, sodium restriction (2 gm/day)
2. Spironolactone (100 mg/day)
3. May add Lasix (40 mg/day)
Refractory
Persistent ascites
Large volume
paracentesis
± albumin infusion
Increased
frequency TIPS
? Transplant
Figure 31.6 Ascites. A management algorithm based on severity and response
to therapy. TIPS, transjugular intrahepatic portosystemic shunt. Source: From
Ref. (97).
 PORTAL HYPERTENSION
(SAAG) greater than 1.1 is highly suggestive of cirrhosis. Other
causes of ascites (malignancy, infection, pancreatic ascites)
usually have a SAAG less than 1.1. In the cirrhotic patient with
ascites, abdominal pain and signs of infection, paracentesis
should be performed to evaluate for possible spontaneous bac-
terial peritonitis, which carries a mortality of around 37% (63).
Diagnosis of SBP requires the presence of at least 250 polymor-
phonuclear cells per cubic millimeter of ascitic fluid (64). As
with gastroesophageal varices, a systematic approach should be
taken in the management of ascites.
The cornerstones of treatment of mild to moderate ascites
are sodium restriction, to less than 2 g/d and diuretics (65).
Spironolactone is the first-line diuretic acting as an aldosterone
antagonist. Therapy starts with 100 mg daily and can be titrated
up to a maximum dose of 400 mg daily. Furosemide can be
added to assist with natriuresis and reduction of peripheral
edema, but caution must be exercised to prevent overdiuresis.
Refractory ascites fails to respond to maximum medical
management and carries a poor prognosis. It interferes signifi-
cantly with quality of life and requires a more aggressive
approach that may include Large Volume Paracentesis (LVP),
TIPS, or transplant. LVP removes 5 or more liters of ascites,
with or without concomitant albumin infusion. A meta-
analysis of four randomized trials comparing LVP to TIPS,
showed that TIPS was superior to LVP in terms of control of
ascites and transplant-free survival but carried a higher risk of
hepatic encephalopathy (66) (Grade 1a evidence). Patients
with refractory ascites are best served with transplantation for
long-term survival.
portopulmonary syndromes
Lung dysfunction may develop for a variety of reasons in
patients with cirrhosis and portal hypertension, with the two
main clinical entities of hepatopulmonary syndrome (HPS)
and portopulmonary hypertension (PPH). (Figure 31.7 sum-
marizes key features of these two syndromes.
HPS is characterized by a defect in arterial oxygenation in the
setting of liver disease due to arteriovenous shunting in the pul-
monary vascular bed (21). HPS manifests most commonly
with dyspnea, digital clubbing, cyanosis, and hypoxemia. Diag-
nosis of this syndrome requires (1) advanced liver disease, (2)
arterial hypoxemia (PaO2 < 80 mmHg or alveolar-arterial oxy-
gen gradient > or = 15 mmHg), and (3) pulmonary vascular
dilatation (67). The precise etiology for the pulmonary vascular
changes that take place are not entirely known, but are thought
related to elevated pulmonary nitric oxide levels. Diagnosis can
Variables Hepatopulmonary
Syndrome (pO2 < 70)
Prevalence 8–20%
Pulmonary Vasodilatation
vascular changes
Contributors Liver dysfunction
portal hypertension
Transplant? Curative
Figure 31.7 Pulmonary syndromes in liver disease: characteristics and management. RVSP, right ventricular systolic pressure. Source: From Ref. (97).
be made with the use of contrast-enhanced transthoracic echo-
cardiography with agitated saline to produce microbubbles. In
the presence of the abnormally dilated pulmonary vascular bed
typical of HPS, microbubbles can be seen in the left atrium
within 3 to 6 cardiac cycles. Alternatively, a more sensitive
method involves the injection of technetium-99m-labeled
microaggregated albumin into a peripheral vein with quantita-
tive uptake in the brain. Liver transplantation is the only known
definitive treatment for HPS with a 5-year survival of 76% in
one series compared to 23% for patients not undergoing trans-
plant (22) (Grade 3 evidence). Given the progressive nature of
the disease and inferior outcome after transplant for those with
severe hypoxemia (PaO2 < 50 mmHg), patients diagnosed with
HPS should be prioritized for transplantation.
Portopulmonary hypertension is defined by the presence of
the following in the setting of portal hypertension: elevated
pulmonary artery pressures (>25 mmHg), elevated pulmo-
nary vascular resistance (>240 dyne s–1 cm–5), and pulmonary
artery occlusion pressures <15 mmHg (68). As with HPS, the
presence or severity of PPH does not seem to correlate with
the degree of liver disease or portal hypertension. The hyper-
dynamic circulation that accompanies portal hypertension
leads to increased sheer stress and vascular remodeling in the
pulmonary vasculature which, in turn, leads to elevated resis-
tance. The most common symptom is dyspnea on exertion but
fatigue, syncope, palpitations, and chest pain can also be seen.
Transthoracic echocardiography is a good initial screening test
to perform if PPH is suspected with right-heart catheteriza-
tion used to confirm the diagnosis along with its severity.
Milder cases of PPH may be reversible with liver transplant,
but severe PPH is associated with high post-transplant mortal-
ity (69) (Grade 3 evidence). Aggressive medical therapy with
prostanoids and other pulmonary vasodilators is mandatory
prior to considering patients for transplantation.
portal hypertension and the
general surgeon
Although the role of surgical shunts has diminished greatly
over the last couple of decades, general surgeons should be
familiar with the pathophysiology and surgical risks in patients
with cirrhosis and portal hypertension. Surgery in these
patients is associated with higher morbidity and mortality in a
wide range of surgical procedures (70–73) (Grade 3 evidence).
The Child–Turcotte–Pugh (CTP) scoring system has been
used to predict postoperative morbidity and mortality for 3
decades. Recently the Model for End-Stage liver Disease
Portopulmonary
Hypertension (RVSP > 40)
3–12%
Vasoconstriction
Portal hypertension
Contraindicated
285
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
(MELD) score, developed to predict TIPS outcome, and used
as the basis for the allocation of cadaveric livers for transplan-
tation, has become a useful prognostic tool for predicting
postoperative outcomes in non-transplant surgery. CTP
involves subjective grading of ascites and encephalopathy, but
the MELD score utilizes objective, continuous variables
derived from a linear regression model. Northrup et al. found
MELD score to be the only statistically significant predictor of
30-day mortality among patients undergoing a wide range of
surgical procedures (74). Likewise, in a larger retrospective
series, Teh et al. identified MELD score, age, and American
Society of Anesthesiologists (ASA) class as the only significant
predictors of mortality in multivariate analysis (75).
General surgery in patients with cirrhosis is complicated by
higher rates of usual postoperative complications, and unique
complications, such as decompensation of liver function, ascites
leak, and impaired wound healing. Weighing risk versus benefit
of operation is particularly difficult in these patients. When an
elective procedure is indicated, measures taken to lessen the
chances of perioperative complications include nutritional opti-
mization, TIPS, and aggressive management of ascites (76). Sur-
geons must also take into account the potential conversion of an
elective procedure, such as hernia repair, into an emergent pro-
cedure down the road. Emergent surgery in this patient group
has been associated with significantly higher morbidity and
mortality than in the elective setting, and may warrant accepting
the lower, albeit elevated, risk of an elective procedure (70).
Along with the surgeon, there are a number of other special-
ists in the multidisciplinary team charged with caring for
patients with portal hypertension. Hepatologists perform an
essential “quarterback” role by diagnosing and managing the
underlying liver pathology and directing patients to other pro-
viders. Endoscopists diagnose gastroesophageal varices and
manage bleeding in the emergent setting. Interventional radi-
ologists have assumed an increasingly prominent role through
the performance of TIPS, as well as portal venography and pres-
sure measurements to guide medical therapy. Lastly, critical care
physicians come into play during acute episodes of variceal
bleeding and other events to help stabilize patients until more
definitive treatment can be delivered. The general surgeon
should never operate on a patient with portal hypertension
without involving some or all of this team, and the importance
of communication between all members of team in the man-
agement of these complex patients cannot be overemphasized.
references
1. Valla DC, Condat B, Lebrec D. Spectrum of portal vein thrombosis in the
West. J Gastroenterol Hepatol 2002; 17 (Suppl 3): S224–7.
2. Matsumoto S, Mori H, Yamada Y, et al. Intrahepatic porto-hepatic venous
shunts in Rendu-Osler-Weber disease: imaging demonstration. Eur
Radiol 2004; 14: 592–6.
3. Gabriel S, Maroney TP, Ringe BH. Hepatic artery-portal vein fistula for-
mation after percutaneous liver biopsy in a living liver donor. Transplant
Proc 2007; 39(5): 1707–9.
4. Souza MR, Toledo CF, Borges DR. Thrombocytemia as a predictor of por-
tal hypertension in schistosomiasis. Dig Dis Sci 2000; 45(10): 1964–70.
5. Rodrigues de Araujo Souza M, Fischer de Toledo C, Borges DR. Throm-
bocytemia as a predictor of portal hypertension in schistosomiasis. Dig
Dis Sci 2000; 45 (10): 1964–70.
286
6. Garcia-Pagan JC, Heydtmann M, Raffa S, et al. TIPS for Budd-Chiari syn-
drome; long-term results and prognostic factors in 124 patients.
Gastroenterology 2008; 135(3):808–15.
7. Sharma S, Texeira A, Texeira P, et al. Pharmacologic thrombolysis in Budd
Chiari syndrome: a single centre experience and review of the literature. J
Hepatol 2004; 40(1): 172–80.
8. Garcia-Pagan JC, Bosch J, Rodes J. The role of vasoactive mediators in
portal hypertension. Semin Gastrointest Dis 1995; 6(3): 140–7.
9. Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff ’s diseases of the liver.
10th edn. Philadelphia: Lippincott Williams and Wilkins; 2007.
10. Garcia-Cardena G, Martasek P, Masters BS, et al. Dissecting the interac-
tion between nitric oxide synthase (NOS) and caveolin. Functional sig-
nificance of the nos caveolin binding domain in vivo. J Biol Chem 1997;
272(41): 25437–40.
11. Fernandez M, Vizzutti F, Garcia-Pagan JC, et al. Anti-VEGF receptor-
2 monoclonal antibody prevents portal-systemic collateral vessel formation
in portal hypertensive mice. Gastroenterology 2004; 126 (3): 886–94.
12. Fernandez M, Mejias M, Angermayr B, et al. Inhibition of VEGF recep-
tor-2 decreases the development of hyperdynamic splanchnic circulation
and portal-systemic collateral vessels in portal hypertensive rats. J Hepa-
tol 2005; 43(1): 98–103.
13. Fernandez M, Mejias M, Garcia-Pras E, et al. Reversal of portal hyperten-
sion and hyperdynamic splanchnic circulation by combined vascular
ednothelial growth factor and platelet-derived growth factor blockade in
rats. Hepatology 2007; 46(4): 1208–17.
14. Park DK, Um SO, Lee JW, et al. Clinical significance of variceal hemor-
rhage in recent years in patients with liver cirrhosis and esophageal vari-
ces. J Gastroenterol Hepatol 2004; 19(9): 1042–51.
15. Zaman A, Becker T, Lapidus J, et al. Risk factors for the presence of varices
in cirrhotic patients without a history of variceal hemorrhage. Arch Int
Med 2001; 161(21): 2564–70.
16. Merli M, Nicolini G, Angeloni S, et al. Incidence and natural history of
small esophageal varices in cirrhotic patients. J Hepatol 2003; 38(3): 361–3.
17. Salerno F, Borroni G, Moser P, et al. Survival and prognostic factors of
cirrhotic patients with ascites: a study of 134 outpatients. Am J
Gastroenterol 1993; 88(4): 514–9.
18. Belghiti J, Durand F. Abdominal wall hernias in the setting of cirrhosis.
Semin Liver Dis 1997; 17(3): 219–26.
19. Li ZF, Zhang S, Huang Y, et al. Morphologic changes of blood spleen bar-
rier in portal hypertensive spleen. Chin Med J 2008; 121(6): 561–5.
20. N’Kontchou G, Seror O, Bourcier V, et al. Partial splenic embolization in
patients with cirrhosis: efficacy, tolerance, and long-term outcome in
32 patients. Eur J Gastroenterol Hepatol 2005; 17(2): 179–84.
21. Rodriguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome- a liver-
induced lung vascular disorder. N Engl J Med 2008; 358(22): 2378–87.
22. Swanson KL, Wiesner RH, Krowka MJ. Natural history of hepatopulmonary
syndrome: impact of liver transplantation. Hepatology 2005; 41(5): 1122–9.
23. Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cir-
rhosis: incidence and risk factors. Gastroenterology 2004; 127: S35–50.
24. De Masi S, Tosti ME, Mele A. Screening for hepatocellular carcinoma. Dig
Liver Dis 2005; 37: 260–8.
25. Northern Italian Endoscopy Club for the Study and Treatment of Esopha-
geal Varices. N Engl J Med 1988; 319(15): 983–9.
26. Merkel C, Zoli M, Siringo S, et al. Prognostic indicators of risk for first
variceal bleeding in cirrhosis: a multicenter study in 711 patients to vali-
date and improve the North Italian Endoscopic Club (NIEC) index. Am J
Gastroenterol 2000; 95(10): 2915–20.
27. Stewart CA, Sanyal AJ. Grading portal gastropathy: validation of a gas-
tropathy scoring system. Am J Gastroenterol 2003; 98(8): 1758–65.
28. Lee CH, Lee JH, Choi YS, et al. Natural history of gastric varices and risk
factors for bleeding. Korean J Hepatol 2008; 14(3): 331–41.
29. Albillos A, Banares R, Gonzales M, et al. Value of the hepatic venous pres-
sure gradient to monitor drug therapy for portal hipertensión: a meta-
analysis. Am J Gastroenterol 2007; 102(5): 1116–26.
30. D’Amico G, Garcia-Pagan JC, Luca A, et al. Hepatic vein pressure gradient
reduction and prevention of variceal bleeding in cirrosis: a systematic
review. Gastroenterology 2006; 131(5): 1611–24.
31. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hyper-
tension: an evidence-based approach. Semin Liver Dis. 1999; 19(4): 475–505.
 PORTAL HYPERTENSION
32. Garcia-Pagan JC, Bosch J. Endoscopic band ligation in the treatment of
portal hypertension. Nat Clin Pract Gastroenterol Hepatol 2005; 2(11):
526–35.
33. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a pro-
spective randomized trial of propranolol versus placebo in the prevention
of a first variceal hemorrhage. Gastroenterology 1990; 99(5): 1401–7.
34. Feu F, Garcia-Pagan JC, Bosch J, et al. Relation between portal pressure
response to pharmacotherapy and risk of recurrent varicela haemorrhage
in patients with cirrhosis. Lancet 1995; 346(8982): 1056–9.
35. Escorsell A, Bordas JM, Castaneda B, et al. Predictive value of the variceal
pressure response to continued pharmacological therapy in patients with
cirrhosis and portal hypertension. Hepatology 2000; 31(5): 1061–7.
36. Merkel C, Bolognesi M, Sacerdote D, et al. The hemodynamic response to
medical treatment of portal hypertension as a predictor of clinical effec-
tives in the primary prophylaxis of varicela bleeding in cirrhosis. Hepatol-
ogy 2000; 32(5): 930–4.
37. Morales GF, Pereira Lima JC, Hornos AP, et al. Octreotide for esophageal
variceal bleeding treated with endoscopic sclerotherapy: a randomized,
placebo-controlled trial. Hepatogastroenterology. 2007; 54(73):195–200.
38. Soares-Weiser K, Brezis M, Tur-Kaspa R, et al. Antibiotic prophylaxis for
cirrhotic patients with gastrointestinal bleeding. Cochrane Database Syst
Rev 2002; (2): CD002907.
39. Ioannou G, Doust J, Rockey DC. Terlipressin for acute esophageal varicela
hemorrhage. Cochrane Database Syst Rev 2003; (1): CD002147.
40. Feu F, Ruiz del Arbol L, Banares R, et al. Double-blind randomized con-
trolled trial comparing terlipressin and somatostatin for acute variceal
hemorrhage. Variceal Bleeding Study Group. Gastroenterology 1996;
111(5): 1291–9.
41. Walker S, Kreichgauer HP, Bode JC. Terlipressin (glypressin) versus soma-
tostatin in the treatment of bleeding esophageal varices—final report of a
placebo—controlled, double-blind study. Z Gastroenterol 1996; 34(10):
692–8.
42. Krige JE, Kotze UK, Bornman PC, et al. Variceal recurrence, rebleeding,
and survival after endoscopic injection sclerotherapy in 287 alcoholic cir-
rhotic patients with bleeding esophageal varices. Ann Surg 2006;
244(5):764–70.
43. Lo GH, Lai KH, Cheng JS, et al. Emergency Banding ligation versus sclero-
therapy for the control of active bleeding from esophageal varices. Hepa-
tology 1997; 25(5): 1101–4.
44. Carbonell N, Pauwels A, Serfaty L, et al. Improved survival alter varicela
bleeding in patients with cirrhosis over the past two decades. Hepatology
2004; 40(3): 652–9.
45. Yang MT, Chen HS, Lee HC, et al. Risk factors and survival of early bleed-
ing after esophageal variceal ligation. Hepatogastroenterology 2007;
54(78):1705–9.
46. Kravetz D. Prevention of recurrent esophageal variceal hemorrhage:
review and current recommendations. J Clin Gastro 2007; 41 (Suppl 3):
S318–22.
47. de la Pena J, Brullet E, Sanchez-Hernandez E, et al. Variceal ligation plus
nadolol compared with ligation for prophylaxis of variceal rebleeding: a
multicenter trial. Hepatology 2005; 41(3): 572–8.
48. Bosch J, Garcia-Pagan JC. Prevention of variceal bleeding. Lancet 2003;
361(9361): 952–4.
49. Turnes J, Garcia-Pagan JC, Abraldes JG, et al. Pharmacological reduction
in portal pressure and long-term risk of first variceal bleeding in patients
with cirrhosis. Amer J Gastroenterol 2006; 101(3): 506–12.
50. Abraldes JG, Villanueva C, Banares R, et al. Hepatic venous pressure gra-
dient and prognosis in patients with acute variceal bleeding treated with
pharmacologic and endoscopic therapy. J Hepatol. 2008; 48(2): 229–36.
51. Zheng M, Chen Y, Bai J, et al. Transjugular intrahepatic portosystemic
shunt versus endoscopic therapy in the secondary prophylaxis of variceal
rebleeding in cirrhotic patients: meta-analysis update. J Clin Gastroen-
terol 2008; 42(5): 507–16.
52. Tripathi D, Helmy A, Macbeth K, et al. Ten-years’ follow-up of 472 patients
following transjugular intrahepatic portosystemic stent-shunt insertion
at a single centre. Eur J Gastroenterol Hepatol 2004; 16(1): 9–18.
53. Bureau C, Garcia-Pagan JC, Otal P, et al. Improved clinical outcome using
polytetrafluoroethylene-coated stents for TIPS: results of a randomized
study. Gastroenterology 2004; 126(2): 469–75.
54. Bureau C, Garcia-Pagan JC, Layrargues GP, et al. Patency of stents covered
with polytetrafluoroethylene in patients treated by transjugular intrahe-
patic portosystemic shunts: long-term results of a randomized multicen-
tre study. Liver Int 2007; 27(6): 742–7.
55. Stipa S, Balducci G, Ziparo V. Total shunting and elective management of
variceal bleeding. World J Surg 1994; 18(2): 200–4.
56. Collins JC, Ong J, Rypins EB, et al. Partial portocaval shunt for variceal
hemorrhage; longitudinal analysis of effectiveness. Arch Surg 1998; 133:
590–3.
57. Rosemurgy AS, Serafini FM, Zweibel BR, et al. Transjugular intrahepatic
portosystemic shunt vs. small-diameter prosthetic H-graft portocaval
shunt: extended follow-up of an expanded randomized prospective trial.
J Gastrointest Surg 2000; 4: 589–97.
58. Henderson JM, Boyer TD, Kutner MH, et al. Distal splenorenal shunt ver-
sus transjugular intrahepatic portosystemic shunt for variceal bleeding: a
randomized trial. Gastroenterology 2006; 130(6):1643–51.
59. Sugiura M, Futagawa S. A new technique for treating esophageal varices. J
Thorac Cardiovasc Surg 1973; 66(5): 677–85.
60. Selzner M, Tuttle-Newhall JE, Dahm F, et al. Current indication of a mod-
ified sugiura procedure in the management of variceal bleeding. J Am
Coll Surg 2001; 193(2): 166–73.
61. Orozco H, Mercado MA, Takahashi T, et al. Elective treatment of bleeding
varices with the Sugiura operation over 10 years. Am J Surg 1992; 163(6):
585–9.
62. 2007.Annual Report of the U.S. Organ Procurement and Transplantation
Network and the Scientific Registry of Transplant Recipients: Transplant
Data 1997-2006. Health Resources and Services Administration, Healthcare
Systems Bureau, Division of Transplantation, Rockville, MD. Available from:
URL: http://www.ustransplant.org/annual_reports/current/914a_cv_li.htm
63. Nobre SR, Cabral JE, Gomes JJ, et al. In-hospital mortality in spontaneous
bacterial peritonitis: a new predictive model. Eur J Gastroenterol Hepatol.
2008; 20(12): 1176–81.
64. Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment and pro-
phylaxis of spontaneous bacterial peritonitis: a consensus document. J
Hepatol 2000; 32(1): 142–53.
65. Sandhu BS, Sanyal AJ. Management of ascites in cirrhosis. Clin Liver Dis
2005; 9(4): 715–32.
66. Salerno F, Camma C, Enea M, et al. Transjugular intrahepatic portosys-
temic shunt for refractory ascites: a meta-analysis of individual patient
data. Gastroenterology 2007; 133 (3): 825–34.
67. Krowka MJ. Hepatopulmonary syndrome versus portopulmonary hyper-
tension: distinctions and dilemmas. Hepatology 1997; 25(5): 1282–4.
68. Hoeper MM, Krowka MJ, and Strassburg CP. Portopulmonary hyperten-
sion and hepatopulmonary syndrome. Lancet 2004; 363: 1461–8.
69. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and
perioperative cardiopulmonary-related mortality in patients with porto-
pulmonary hypertension undergoing liver transplantation. Liver Transpl
2000; 6: 443–50.
70. Mansour A, Watson W, Shayani V, et al. Abdominal operations in patients
with cirrhosis: still a major surgical challenge. Surgery 1997; 122(4): 730–5.
71. del Olmo JA, Flor-Lorente B, Flor-Civera B, et al. Risk factors for nonhe-
patic surgery in patients with cirrosis. World J Surg 2003; 27(6): 647–52.
72. Puggioni A, Wong L. A metaanalysis of laparoscopic cholecystectomy in
patients with cirrhosis. J Am Coll Surg 2003; 197(6): 921–6.
73. Meunier K, Mucci S, Quentin V, et al. Colorectal surgery in cirrhotic
patients: assessment of operative morbidity and mortality. Dis Colon
Rectum 2008; 51(8): 1225–31.
74. Northrup PG, Wanamaker RC, Lee VD, et al. Model for end-stage liver
disease (MELD) predicts nontransplant surgical mortality in patients
with cirrhosis. Ann Surg. 2005; 242(2): 244–51.
75. Teh SH, Nagorney DM, Stevens SR, et al. Risk factors for mortality after
surgery in patients with cirrhosis. Gastroenterology 2007; 132(4):1261–9.
76. Slakey DP, Benz CC, Joshi S, et al. Umbilical hernia repair in cirrhotic
patients: utility of temporary peritoneal dialysis catheter. Am Surg 2005;
71(1): 58–61.
77. Henderson JM. Multidisciplinary approach to the management of portal
hypertension. In: Yeo CJ, Dempsey DT, Klein AS, Pemberton JH, Peters
JH, eds. Shackelford’s Surgery of the Alimentary Tract, 6th edn. Philadel-
phia: Saunders, 2007: 1751–70.
287
32 Liver transplantation for acute and chronic liver failure
Vincent Kah Hume Wong and J. Peter A. Lodge
introduction
Since the first successful liver transplant in 1963, liver trans-
plantation (LT) has become an established form of therapy for
patients with acute and chronic liver failure. With reported 5-
and 10-year survival rates for patients with liver transplant of
70% and 60%, respectively (1), indications for LT have
expanded resulting in an increasing demand in this era of
donor shortage. To augment the donor pool, expanded donor
criteria and novel LT techniques are utilized increasingly. Arti-
ficial liver systems and hepatocyte cell transplantation, while
still much in development, are exciting potential therapies to
reduce the organ shortage burden. This chapter will look at the
latest development in LT for acute and chronic liver failure and
their indications.
selection of the recipient
According to the European Liver Transplant Registry (1), the
major indications for LT in adults are cirrhosis (58%), cancers
(13%), cholestatic disease (11%), acute liver failure (9%), met-
abolic disease (6%), and others (3%). The leading cause for
chronic liver disease in the West is alcohol-induced liver dis-
ease (2) while acetaminophen overdose (AOD) is the com-
monest cause of acute liver failure (ALF) in the West,
accounting for approximately 40% of cases in the United
Kingdom (3,4) and United States (5,6).
The widening discrepancy between the number of patients
who would benefit from LT and the availability of deceased
donor livers in the United Kingdom have led to overburdening
of the system: approximately 14% of all patients on the waiting
list die before a graft becomes available (7). Therefore, clear,
evidence-based patient selection criteria are necessary to allow
those on the list to expect a LT within a reasonable timeframe.
This is based primarily on risk of death without transplanta-
tion and secondarily on the ability of transplant to improve
quality of life (7).
Patients with End-Stage Liver Disease
The current 1-year post-liver transplant mortality risk is 9% in
the United Kingdom and as a minimum listing criteria,
patients with end-stage liver disease (ESLD) must have pre-
dicted 1-year mortality greater than 9% (7). In the past, the
Child–Turcotte–Pugh score (8,9) was used to assess the prog-
nosis of patients with ESLD (Table 32.1). Increasingly, the
model of end-stage liver disease (MELD) (10) scoring system,
based on patient’s serum bilirubin, creatinine, and INR, are
adopted by regulatory bodies, UNOS and Eurotransplant to
stratify mortality risk in ESLD patients (11). In the United
Kingdom, a modified MELD scoring system with the addition
of serum sodium (12,13), the UKELD score (United Kingdom
Model for end-stage liver disease), is used (7,14). For ESLD
patients to be listed in the liver transplant waiting list, a
288
UKELD score of > 49 needs to be achieved which predicts a
1-year mortality risk of greater than 9% (7). Exceptions to this
rule are patients with HCC (discussed in Chapters 20 and 21),
and variant syndromes consisting of diuretic-resistant ascites,
intractable pruritus, hepatopulmonary syndrome, chronic
hepatic encephalopathy, familial amyloidosis, primary hyper-
lipidemias, and polycystic liver disease (7).
Patients with Acute Liver Failure
Etiology (5,15), grade of encephalopathy (16,17), serum
pH (18), and serum lactate (19–21) are among the important
prognostic indicators for acute liver failure (ALF) and in the
United Kingdom, these factors are incorporated into the selec-
tion criteria for super-urgent LT (Table 32.2) (7). Timing of LT
for ALF patients is vital as clinical deterioration can occur rap-
idly such that LT may be too risky. Therefore, patients listed on
the super-urgent liver transplant waiting list are prioritized to
be offered a deceased donor liver from any region within the
United Kingdom, increasing the chances of receiving a
deceased donor liver. Similarly, patients with ALF or primary
nonfunction graft requiring retransplantation in the United
States are exempted from MELD allocation and are listed with
highest priority for available organs (22).
Patients with Viral Hepatitis
Hepatitis B virus (HBV)-associated liver cirrhosis was a rela-
tive contraindication for LT in the past but the introduction of
potent antiviral agents and hepatitis B surface antigen anti-
body has resulted in a markedly reduced rate of recurrence
post-LT (recurrence rate 5–8% in 5 years) (23,24) with con-
comitant improved patient and graft survival outcome com-
parable to that of non-viral hepatitis LT (25).
In contrast, outcomes for hepatitis C virus (HCV)-related
LT remain poorer in comparison with LT for other non-viral
causes (26). Unlike HBV, there is no medication as yet for HCV
able to provide excellent control of the virus and eventual
recurrence of HCV in graft is inevitable. Risk factors for HCV
recurrence include donor age >40 years (27), high viral load
pre- and early post-LT, cytomegalovirus (CMV) and human
immunodeficiency virus (HIV) co-infection (28), HCV geno-
type 1b (29), and over-immunosuppression or abrupt changes
to the immunosuppression (30).
Patients with HIV
The improved prognosis of HIV (31) in the recent years with
the advent of highly active anti-retroviral therapy (HAART),
combined with effective prophylaxis of HBV re-infection, and
a deeper understanding of HCV recurrence in LT, have made
LT possible for HIV patients. HIV itself does not directly dam-
age the liver parenchyma but rather the co-infection with HBV
and HCV, HAART-related hepatotoxicity, and malignancies
 LIVER TRANSPLANTATION FOR ACUTE AND CHRONIC LIVER FAILURE

Table 32.1a Child–Turcotte–Pugh Scoring System

Measure 1 point 2 points 3 points units
Bilirubin (total) <34 (<2) 34–50 (2–3) >50 (>3) µmol/l (mg/dl)
Serum albumin >35 28–35 <28 g/l
INR <1.7 1.71–2.20 >2.20 No unit
Ascites None Suppressed with medication Refractory No unit
Hepatic encephalopathy None Grade I–II (or suppressed with medication) Grade III–IV (or refractory) No unit

account for the majority of the LT indications in HIV patients.

In addition to the selection criteria mentioned previously,
Table 32.1b Stratification of Mortality Risk According to
criteria specific to HIV in the United Kingdom (32) include
Child–Turcotte–Pugh Score
Points Class 1-yr survival (%) 2-yr survival (%)
1. CD4 counts >200 cells/µl or >100 cells/µl in the
presence of portal hypertension
5–6 A 100 85 2. Absence of viremia
7–9 B 81 57
3. Absence of AIDS defining illness after immune
10–15 C 45 35
reconstitution
4. Anti-retroviral therapeutic options available if HIV
disease reactivates.

Table 32.2 Current UK Blood and Transplant Criteria for
Listing as a Super-Urgent Transplant
Category 1: Etiology: AOD: pH <7.25 more than 24 hrs after
overdose and after fluid resuscitation
Category 2: Etiology: AOD: Co-existing PT >100 sec or INR
>6.5, and serum creatinine >300 µmol/l or anuria, and grade
3–4 encephalopathy
Category 3: Etiology: AOD: Serum lactate more than 24 h after
overdose >3.5 mmol/l on admission or >3.0 mmol/l after fluid
resuscitation
Category 4: Etiology: AOD: Two of the three criteria from
category 2 with clinical evidence of deterioration (eg, increased
ICP, FiO2 >50%, increasing inotrope requirements) in the
absence of clinical sepsis
Category 5: Etiology: Seronegative hepatitis, hepatitis A, or
hepatitis B or an idiosyncratic drug reaction. PT >100 sec or
INR >6.5, and any grade of encephalopathy
Category 6: Etiology: Seronegative hepatitis, hepatitis A, or
hepatitis B, or an idiosyncratic drug reaction. Any grade of
encephalopathy and any three from the following: unfavorable
etiology (idiosyncratic drug reaction, seronegative hepatitis),
age >40 yrs, jaundice to encephalopathy time >7 days, serum
bilirubin >300 µmol/l, PT >50 sec or INR >3.5
Category 7: Etiology: Acute presentation of Wilson’s disease, or
Budd–Chiari syndrome. A combination of coagulopathy and
any grade of encephalopathy
Category 8: Hepatic artery thrombosis on days 0–21 after liver
transplantation
Category 9: Early graft dysfunction on days 0–7 after liver
transplantation with at least two of the following: AST >10,000
IU/l, INR >3.0, serum lactate >3 mmol/l, absence of bile
production
Category 10: Any patient who has been a live liver donor who
develops severe liver failure within 4 wks of the donor operation
AOD – Acetaminophen overdose, PT – Prothrombin time, INR – Interna-
tional Normalized Ratio, ICP – Intracranial Pressure, FiO2 – inspired
oxygen concentration
selection of donor
The “ideal” deceased donor profile is as follows: age <40 years,
trauma as the cause of death, donation after brain death,
hemodynamic stability at the time of procurement, no steato-
sis or any other underlying chronic liver lesions, and no trans-
missible disease (33). This implies a very low risk of initial
poor graft function or primary graft failure resulting in death
or retransplantation. However, the profile of deceased donors
is changing and the past decade has seen an increasing propor-
tion of donors >50 years of age with cerebrovascular disease as
cause of death (34,35).
Expanded Criteria Donor
The impact of changing deceased donor characteristics and
widening gap between the donor pool and the waiting list
means that deceased donors with features deviating from the
donor profile are increasingly utilized (36,37). The term
“extended or expanded criteria donor” (ECD) has been coined
for such donors (Table 32.3), which suggests a higher risk of
graft failure and decreased survival. Rather than a clear “good or
bad” liver graft, ECD represents a spectrum of cumulative donor
risks which should be taken into consideration (33,38,39).
Steatosis and Abnormal Liver Function
A recent international consensus meeting on ECD grafts (40)
recommended against using liver allografts with severe steato-
sis (>60%) and from elderly donors in HCV-infected recipients.
Abnormal liver function tests are not contraindications but
careful assessment of other donor factors is essential, especially
if there is a marked rise in gamma glutamyl transpeptidase level
(>200 UI/L).
Elderly Donors
Patients with liver transplant from elderly donors have shown
comparable survival, provided that there are no additional risk
factors (41,42). While there is no clear age limit in utilizing an

289
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Table 32.3 Definition for Expanded Criteria Liver
Donors (ECD)a
Elevated risk for transmission of a disease (viral, eg, Hepatitis C
or B) or bacterial infection (especially recovery after sepsis with
bacteriemia or donor malignancy, etc.)
Acute hemodynamic deterioration with the risk of organ loss
Donor age >65 yrs
Donor BMI >30 kg/m2
Bilirubin (total) >3 mg/dl or 51 µmol/l
ASAT (GOT) or ALAT (GPT) above three times the upper
reference threshold
Serum sodium >165 mmol/l
Hospitalization in ICU >7 days
Hepatic steatosis >40%
a
There is no internationally agreed definition of ECD as yet. Above is
the German Medical Association definition of ECD donors for liver
donation (154).
elderly donor liver, there are two caveats: (i) liver grafts of
advanced age have reduced regenerative capacity and synthetic
function, and are more susceptible to cold ischemic injury and
(ii) elderly liver grafts should not be used for HCV-positive
patients because of the high risk of severe HCV recurrence (43)
and reduced graft and patient survival (44).
Donors with Infection
The use of donors with bacteremia or bacterial meningitis
seems safe as the risk transmission is low (∼4%) (40,45), espe-
cially when appropriate prophylactic antibiotic therapy is
instituted (46). However, donors with systemic sepsis, multi-
organ failure, tuberculosis, or infected with multi-resistant
organisms should be avoided (46,47).
Donors with Hepatitis B Core Antibody Positive
The use of hepatitis B core antibody (anti-HBc) positive donor
livers and post-operative management remain controversial.
Recipients who receive anti-HBc-positive livers are at a greater
risk of developing de novo HBV with reported incidences of
72% (48) to 78% (49), compared to candidates who had anti-
HBc-negative livers (0.5%) (49). This is due to detectable levels
of HBV DNA in serum and/or liver tissues of anti-HBc-positive
donors, despite no other serological markers of HBV being
present (50,51). Interestingly, studies have shown that recipi-
ents who are anti-HBc and/or anti-HBs-positive are protected
with a much lower risk of de novo HBV from an anti-HBc-
positive liver (48,52).
Management strategies to prevent de novo HBV in recipi-
ents of anti-HBc-positive livers involve using lamivudine and/
or hepatitis B immunoglobulin (HBIG) depending on the
serological status of the donor and recipient. Recently, adefo-
vir dipivoxil was proposed as an alternative to HBIG (23).
There is no consensus as yet on the prophylactic strategies
with some units preferring HBIG monotherapy (53) and oth-
ers using lamivudine only (54). Our unit’s protocol comprises
of long-term lamivudine for recipients of anti-HBc-positive
livers. For patients receiving hepatitis B surface antigen-positive
livers, long-term lamivudine and adefovir regimens are used.
290
Donors with Hepatitis C Infection
Livers from donors infected with HCV represent 2% to 6% of
the donor pool. As the risk of HCV transmission is high, HCV-
infected liver grafts should be limited to HCV-positive recipi-
ents only. Ideally, a biopsy of the HCV-positive graft should be
obtained prior to transplantation to assess fibrosis (47). Using
HCV-positive grafts with minimal inflammation and fibrosis
does not negatively impact outcome. Several studies (55–58)
have shown comparable 5-year graft and patient survival
between HCV-positive and HCV-negative liver grafts in HCV-
infected patients.
Donors with Malignancy
As the age of donors increases, the risk of cadaveric donors
with previous malignancy increases. Currently, the incidence
of donors having either an active or treated malignancy is
3% (59) and the risk of transmitted cancer is between
0.02% (60) and 0.2% (61). The most common cancer in an
organ donor is skin malignancy followed by brain tumor (59).
The risk of donor transmitted malignancy increases with
tumor grade (Table 32.4) and any donors with a history of
metastatic cancer should be excluded.
Split-Liver
Split-liver transplantation (SLT) in adults is associated with
increased graft failure and recipient morbidity (33,62,63).
Current UNOS criteria for potential splittable donors are
donor age <40 years, on not more than a single vasopressor,
rise in transaminases not more than three times of normal
range, and BMI ≤28 (64). A recent study (65) interrogated the
UNOS/OPTN data base and suggested two further risk criteria
for considering donors for SLT: donor weight ≤40 kg and his-
tory of cardiac arrest after declaration of death.
In our unit, criteria for splitting a deceased donor liver are
(i) donor age <50 years, (ii) body weight >40 kg, (iii) ICU stay
<5 days, (iv) minimal inotropic support, (v) good liver func-
tion, (vi) minimal hepatic steatosis, and (vii) suitable anatomy.
Donation after Cardiac Death
In donation after cardiac death (DCD), also called non-
heart-beating donation, grafts can be procured either in a
controlled setting, after a planned withdrawal of life support,
or in an uncontrolled situation with the onset of sudden car-
diac arrest. This can be classified into five categories, accord-
ing to the Maastricht criteria (66) ( Table 32.5). DCD grafts
are associated with a significantly increased risk of graft fail-
ure (67,68) and biliary complications (69–72), although
recent large studies (73,74) have shown that with judicious
selection of DCD donors and recipients, comparable results
to donation after brain death (DBD) liver allografts can
be achieved.
In the United Kingdom, guidelines on the use of solid organ
transplants from DCD donors were drawn up by the British
Transplantation Society (Table 32.6) (75). Our unit practices
controlled DCD with planned withdrawal treatment of patient
in the ICU, with regular reassessment of success rates. Thus,
our current criteria are donor age less than 50 years, asystole
 LIVER TRANSPLANTATION FOR ACUTE AND CHRONIC LIVER FAILURE

Table 32.4 Risk of Transmission of Malignancy from Donor to Recipient and Recommendations for Use of Organs
Tumor Type Risk of Transmission (%) Level of Risk Recommendations
Skin
SCC 0 Low Use with caution
Melanoma 81 Extreme Reject
Central nervous
System malignancy
Grade I/II 0 Low Use with caution
Grade III/IV 40 High Reject
Lung 39 High Reject
Colon 19 Intermediate Dependent on tumor stage and interval from
diagnosis.
Breast 29 Intermediate Dependent on tumor stage and interval from
diagnosis.
Renal cell carcinoma 61 Intermediate Use with caution as transmission has been often
limited to the kidney graft
Choriocarcinoma 93 Extreme Reject

cell-mediated rejection. Early reports (77,78) showed much

Table 32.5 First International Workshop on Donation after
Cardiac Death, Masstricht, 1994
Categories of Donation After Cardiac Death (categories 1 and 2
for uncontrolled DCD, 3 and 4 for controlled DCD)
Dead on arrival
Unsuccessful resuscitation
Awaiting cardiac arrest-ventilator switch off
Cardiac arrest while brain-dead
Unexpected cardiac arrest while in ITU/ or critical care unita
a
Category 5 is an addition to the original four categories of the Maastricht
criteria.(155)
Table 32.6 British Transplantation Society Selection Criteria
for Potential DCD Donor for Liver Allografts (75)
Age < 70 yrs
Warm ischemia timea ≤ 20 min
No history of renal impairment
No uncontrolled hypertension or complicated insulin dependent
diabetes
No uncontrolled systemic sepsis or malignancy using the same
criteria as for potential DBD donors
a
This time is defined as starting when there is hypotension below a systolic
BP of 55 mmHg and is measured up to the point of the cold perfusion of
the organ.
within 45 minutes after treatment withdrawal, and traveling
time less than 2 hours. A 10 minutes “stand off ” period is insti-
tuted from time of asystole to confirm cardiac death. Failure of
rapid asystole results procedure abandonment and a resultant
increased unit workload without impacting the transplant rate.
ABO-Incompatible Liver
LT across the ABO barrier remains rare in the West and is
used only in the setting of super-urgent need or as a bridg-
ing transplantation (76) because of the risk of antibody and
reduced graft survival for ABO-incompatible (ABO-I) LT
with 1-, 2-, and 5-year graft survival of 66%, 30%, and 20%
but recent reports (79–81) have demonstrated that compa-
rable short- and long-term patient and graft survival with
blood-matched LT is achievable. Various treatment strategies
to reduce risk of rejections have been advocated including
plasmapheresis, immunoadsorption, splenectomy, quadru-
ple immunosuppression, rituximab, and hepatic artery or
portal vein infusion of prostaglandin E1 (80,82).
retrieval of deceased donor liver graft
Standard Retrieval
Prior to retrieval, the surgical team will need to ensure that
brainstem death is confirmed, check the consent from next of
kin and confirm the identity of the potential donor. A midline
laparotomy is performed and a thorough inspection of the
abdominal organs is carried out to rule out any malignancy.
The liver is assessed visually for suitability. The aorta is isolated
at the bifurcation, in preparation for systemic perfusion. If
there is no retrieval of the pancreas, inferior mesenteric vein
(IMV) is isolated for portal vein perfusion. Hepatic arterial
anatomy is assessed. Cannulas for perfusion are inserted into
the aorta and IMV and secured with ligation of aortic bifurca-
tion. Heparin is given intravenously, followed by aortic clamp-
ing applied either at the subdiaphragmatic level or in the
thoracic cavity, in coordination with the donor coordinator,
other retrieval teams and anesthetist. The IVC is vented to
allow drainage of venous blood and rapid cooling of liver is
achieved by perfusion of cold UW preservation fluid and ice
slush in the abdominal cavity. Typically, 4 to 6 l of preservation
fluid is used. Once there is adequate perfusion of liver, the liver
is then mobilized, with careful dissection of the vascular and
anatomy and bile duct. Once retrieved, the liver is assessed at
the backbench and further perfusion of the portal vein, hepatic
artery, and common bile duct is performed. The liver with the
preservation fluid is then double bagged and kept at 4°C in an
ice box for transport to the implanting center.

291
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Donation After Cardiac Death Retrieval
As mentioned earlier, there is a “stand off ” period of 10 min-
utes from asystole prior to retrieval. Once cardiac death is con-
firmed, a midline laparotomy is performed and rapid cooling
of abdominal organs is achieved via aortic perfusion of cold
preservation solution with heparin or streptokinase and ice
slush in the abdominal cavity. The IVC is vented and the aorta
is clamped at the subdiaphragmatic level or in the thoracic
cavity. The rest of the retrieval procedure is performed as per
standard retrieval.
splitting of deceased donor liver graft
Splitting of a deceased donor liver graft can be performed at
the donor institution (in situ) or at the liver transplant center
(ex situ). While some argue that in situ splitting offers supe-
rior results with reduction of the cold ischemia time, better
identification of vascular and biliary structures, and reduced
bleeding from the cut surface (83), recent studies (65,84) sug-
gest that there is no significant difference in terms of graft
survival between in situ and ex situ surgical techniques in
experienced centers.
Our preference is ex situ splitting because in situ splitting will
require extensive logistical coordination at the donor institu-
tion and between various different organ retrieval teams, highly
specialized skills, and a prolonged donor operating time.
Surgical Technique of Splitting Deceased Donor Liver to an
Extended Right Lobe and a Left Lateral Segment Grafts
The portal triad and hepatic venous anatomy are assessed
prior to the decision to split. We do not routinely performed
on-table cholangiography, although some centers advocate
this. For splitting the liver into an extended right lobe (right
trisectional graft—segments I and IV–VII) and left lateral seg-
ment (left lateral section graft—segment II and III), parenchy-
mal transection at approximately 1 cm to the right of the
falciform ligament is carried out usually using bipolar dia-
thermy at a high setting. All ductal and vascular branches dur-
ing hepatic transaction are ligated or sutured. The left lateral
segment contains the left hepatic vein, left or segmental hepatic
ducts, left portal vein, and the hepatic artery, while the inferior
vena cava, common bile duct, portal vein, and right hepatic
artery are left with the extended right lobe. Full right–full left
splitting is also carried out but is less commonly reported.
orthotopic liver transplantation
The surgical technique for orthotopic LT (OLT) has evolved
since its first conception in the 1960s (85). Refinement in sur-
gical techniques with focus on intraoperative hemodynamic
stability, vascular and biliary anastomosis, and hemostasis has
led to novel surgical variations including veno-venous bypass
(VVB) (86) during the anhepatic phase, IVC preservation
using the “piggyback” technique (87), and temporary portoca-
val shunt (88,89).
Up until fairly recently, VVB was used routinely during OLT
in our institution with low VVB-related mortality and mor-
bidity (90). However, the lack of evidence-based benefit of
VVB over IVC preservation (91,92) and its potential complica-
tions (93) have resulted in a change of policy to selective VVB.
292
The senior author has used VVB only once in the last 100 liver
transplants and has only once used a portocaval shunt.
Operative Technique of Orthotopic Liver Transplantation
Hepatectomy of Recipient’s Native Liver
OLT can be performed using a variety of incisions, most com-
monly the “Mercedes” incision in the literature, but the senior
author prefers an inverted L, gentle rooftop or midline incision
in order to offer a better cosmetic result. A mechanical retraction
system is used to allow adequate exposure to the liver. The com-
mon bile duct (CBD) and hepatic artery are ligated and divided,
preserving length to increase implantation options. The portal
vein is then isolated. Hepatectomy begins with mobilization of
the liver from the abdominal wall and IVC with ligation of retro-
hepatic and caudate lobe veins. The portal vein is clamped and
divided and then the hepatic veins are stapled or suture-ligated
and divided, allowing completion of the hepatectomy.
Implantation of Deceased Donor Liver
In the authors’ center, IVC anastomosis is by triangular cavo-
cavostomy or self-triangulating cavocavostomy in most cases
(90). Both surgical techniques have the advantage of having no
posterior suture line and by triangulating the cavocavostomy,
the outflow tract is widened, reducing the risk of venous out-
flow obstruction (90). The self-triangulating cavocavostomy is
worthy of description. A side-biting clamp is placed on the
IVC, below the level of the hepatic veins, to allow a 6 to 8 cm
cavotomy, without occluding the IVC. The donor IVC is
bisected from the top posteriorly for 4 to 6 cm, trimming the
excess IVC from the split to create a 5 mm cuff of IVC around
the caudate lobe. Two 3-0 polypropylene sutures are used for
caval anastomosis, one from the top end and the other from
the bottom end of the cavotomy of recipient IVC. The graft is
flushed through the portal vein with 500 ml of 4.5% albumin
(as UW is high in potassium and adenosine content), and the
lower end of the donor IVC closed using a vascular stapler.
End-to-end portal vein anastomosis is performed 5-0 poly-
propylene and the liver is reperfused. Removal of the IVC
clamp creates the triangulation as the cuff of donor IVC will
open the anastomosis transversely.
Hepatic artery reconstruction is performed onto the recipi-
ent’s hepatic artery using 7-0 or 8-0 polypropylene sutures.
CBD anastomosis is performed either end-to-end with recipi-
ent’s CBD or hepaticojejunostomy if there is a significant
donor–recipient CBD size discrepancy or if recipient’s liver
disease involves biliary strictures (e.g., primary sclerosing
cholangitis—PSC). Once satisfactory hemostasis is achieved,
drains are placed in the subhepatic regions and abdominal clo-
sure is performed under minimal tension. Modern liver trans-
plant surgery takes on average 3 to 4 hours, although complex
cases may take considerably longer.
Post-operative Management and Immunosuppression
Patients are normally nursed in the intensive care unit initially,
although most will be extubated and returned to the general
ward within 24 hours. Unit protocols vary but we use an intra-
venous infusions of heparin (40 units/kg/24 hours) and
N-acetylcysteine (10 g over 24 h) for the first 4 to 7 days.
 LIVER TRANSPLANTATION FOR ACUTE AND CHRONIC LIVER FAILURE
Prophylactic broad spectrum antibiotics are given in the first
48 hours post-surgery. Antiviral therapy (oral valganciclovir) is
initiated if there is a mismatch between recipient and donor’s
cytomegalovirus (CMV) serological status (recipient CMV-
negative—donor CMV-positive) (94). Antifungal therapy is
prescribed as outlined in Table 32.7. In general, in our
unit, immunosuppression consists of a calcineurin inhibitor
(tacrolimus or cyclosporine), azathioprine or mycophenolate
mofetil and steroid but this varies, depending on the etiology of
liver failure and clinical condition of patient. Patients with pre-
operative renal impairment, high blood transfusion require-
ments, or post-operative oliguria are given basiliximab, in
addition with delayed introduction of the calcineurin inhibitor
and tailoring the doses according to patient’s renal function.
Immunosuppression regimen for OLT in HCV-infected
recipients remains unclear with no standardized treat-
ment (95). Studies have shown conflicting results regarding
different immunosuppressions (96–98) and use of steroid
(99–101) and the risk of HCV recurrence and liver fibrosis. A
recent meta-analysis (102) of randomized trials on steroid
avoidance in OLT demonstrated a lower risk of HCV recur-
rence with steroid avoidance (RR 0.90, p = 0.03). Others (103)
have found that slow steroid tapering, rather than rapid with-
drawal, and avoidance of steroid boluses were associated with
less severe recurrent disease. Currently, we favor gradual
reduction of steroids over 3 months post-operatively.
As HAART medication for HIV can affect recipients’ immu-
nosuppression levels, tacrolimus and cyclosporine blood con-
centration should be carefully monitored. For HCV/HIV
co-infected recipients, a similar immunosuppression strategy
as for HCV monoinfected recipients should be adopted with
slow withdrawal of steroids and avoiding steroid boluses.
Outcomes in Orthotopic Liver Transplantation
The improvement in surgical techniques and anesthesia, a deeper
understanding of disease pathology and immunotherapy, better
Table 32.7 Post-operative Prophylactic Antifungal Therapy
Type of Patient
Routine elective patients
High-risk patients defined as below:
● Acute liver failure
● Peri-operative blood transfusion ≥ 8 units
● Renal failure requiring renal replacement therapy
● Re-transplantation
High-risk patients requiring amphotericin defined as below:
● Prolonged ITU stay >5 days
● Re-admission to ITU
● Re-laparotomy while in ICU
donor and recipient selection, and the introduction of new
immunosuppression, antibiotics and antiviral drugs have led to
favorable short- and long-term survival rates: a 15-year survival
rate of 64% has been reported recently (104). Analysis of a large
cohort of OLT patients demonstrated that the long-term survival
outcome is dependent on multiple factors including donor and
recipient characteristics, etiology of liver disease, and surgical
team experience (104). Despite the shift of donor profile to older
donors and increasing use of ECD grafts, both super-urgent and
elective patient survivals have improved in the most recent years
(104,105). Among the elective OLT group, primary biliary cir-
rhosis (PBC), primary sclerosing cholangitis (PSC), and HBV
have superior 5-year survival rates at 82%, 78%, and 76%,
respectively. Results for OLT for ALF remain inferior at about
66% at 5 years (105).
While patient survival for HCV recipients is comparable
with HBV at 1 year, 5-year survival remains poorer at
69% (105). Chronic HCV infection occurs in 75% to 90% of
HCV recipient post-OLT (106) and approximately 20% to
30% of recurrent HCV patients will develop cirrhosis within
5 years (30,107). Pegylated interferon and ribavarin have been
shown to improve long-term outcomes for recurrent HCV
(108) but antiviral therapy is poorly tolerated (109) and the
sustained virology response is low at between 33% and
42% (30). Retransplantation for recurrent HCV-cirrhosis is
contentious, although similar 1- and 3-year survival rates after
retransplantation between HCV retransplantation and non-
HCV retransplantation groups have been reported (110).
Overall 1- and 3-year patient survival rates post-OLT for
HIV-recipients are reported to be between 83% to 91% and
58% to 64%, respectively (31,111). HCV/HIV co-infections
have a significantly worse prognosis compared with HBV/HIV
or HIV alone, with frequent development of aggressive HCV
recurrence post-OLT (28,112).
Recurrence of PSC is one of the leading causes of graft fail-
ure in the long term (113) with risk of recurrence at 1-, 5-, and
Antifungal Therapy
5 days of 200 mg fluconazole per day (reduced dose in renal impaired
recipients, according to serum creatinine)
14–28 days fluconazole (reduced dose in renal impaired recipients,
according to serum creatinine)
If normal renal function: 1 mg per kg amphotericin maximum 50 mg
standard preparation (Change to liposomal amphotericin if renal
function deteriorates).
If established renal failure on renal dialysis: 1 mg per kg amphotericin
to maximum 50 mg or liposomal amphotericin at the team’s
discretion.
If impaired renal function but not requiring dialysis: 1 mg per kg
liposomal amphotericin – rounded off to nearest ampoule
All patients receiving amphotericin prophylaxis should have regular
fungal cultures including weekly aspergillus antigen.
293
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
10-year estimated at 2%, 12%, and 20%, respectively (114).
Following re-emergence of disease, PSC patients may require a
second liver with a retransplantation rate reported at
12% (115). In comparison, the cumulative recurrent rate for
PBC is 22%, 37%, and 43% at 5, 10, and 15 years (116) but the
retransplantation rate for recurrent PBC is significantly lower
at 8.5% (115). This may be due to the fact that recurrent PBC
in the graft does not have a significant adverse influence on
graft function and patient survival (116,117).
auxiliary liver transplantation
First proposed in the 1960s (118), auxiliary liver transplanta-
tion (ALT) was developed because it is recognized that a
significant group of patients with ALF who fulfill the trans-
plant criteria can have a complete recovery of their native liver
with no long-term sequelae (119–121). In particular is the
subset of ALF patients secondary to acetaminophen overdose
(AOD) (122). ALT consists of implantation of partial or whole
liver allograft, either orthotopically or heterotopically while
leaving all or part of the native liver. The attractiveness of ALT
is the possibility of eventual immunosuppression withdrawal
once the native liver has regenerated sufficiently.
In the United Kingdom (3) and the United States (15,123),
AOD is the leading cause of ALF, accounting for approximately
40% of all ALF cases. In our unit, patients with AOD ALF
make up 4.4% of liver transplant activity (124). In the 1980s
and 1990s our results of patients with AOD who had ortho-
topic liver transplantation (OLT) were disappointing, with a
chronic rejection rate of 36.3%, and the 1- and 5-year survival
rate of 52.9% and 47.1%, respectively (124). Patients with
AOD ALF represent a highly vulnerable and potentially non-
compliant group of patients. It is thought that our high chronic
rejection rate was attributed to poor patient compliance. Psy-
chiatric assessment prior to LT is not always possible as patients
are often encephalopathic and rapidly develop coma by the
time they are transferred to our unit or ICU.
Auxiliary Whole Orthotopic Liver Transplantation (AWOLT)
While most ALT currently performed are auxiliary partial
orthotopic liver transplantation (APOLT), our unit utilizes a
novel procedure for AOD patients fulfilling transplant criteria
(125). It consists of a subtotal hepatectomy with auxiliary
whole orthotopic liver transplantation (AWOLT) as a tempo-
rary hepatic support (125). The rationale and principles for
this technique are as follows:
1. Reduction of the “toxic liver syndrome” (126) and
thereby aiding hemodynamic and metabolic stabili-
ty, by subtotal hepatectomy to remove approximately
75% of liver volume (right trisectionectomy—
resection of hepatic segments 4–8).
2. Transplantation of whole donor LT for a maximal
liver volume to aid recovery
3. Orthotopic positioning of the graft:
a. IVC reconstruction by a piggy-back technique
b. Anastomosis of the donor portal vein to the
recipient right portal vein
c. Hepatic artery anastomosis to the recipient
right hepatic artery or to an arterial conduit
294
constructed from donor iliac artery anastomosed
to the recipient common/ external iliac artery
d. Donor biliary diversion via a Roux-en-Y hepati-
cojejunostomy to avoid potential damage to the
native biliary tree
Recipient Selection Criteria for AWOLT
The following criteria were applied for patient selection for
AWOLT:
1. King’s College Hospital Criteria (18) for emergency
LT for acetaminophen overdose.
2. No previous evidence of chronic liver disease and no
macroscopic evidence of cirrhosis at laporatomy.
3. Age ≤ 50 years.
4. No prolonged circulatory arrest pre-operatively.
5. Cerebral perfusion pressure (mean arterial blood
pressure—intracranial pressure) ≥40 mmHg, except
for momentary surges in intracranial pressure (ICP).
Surgical Technique of AWOLT
Subtotal Hepatectomy by Right Trisectionectomy
A midline laporatomy incision (with a right transverse exten-
sion if needed) and a mechanical retraction system (Omni-
Tract Surgical, Division of Minnesota Scientific Inc.,
Minneapolis, MN) are used to allow adequate access to the
liver and to the aorto-iliac system. The right portal structures
are delineated extrahepatically, avoiding liver mobilization at
this stage as this can cause a rise in ICP. The right hepatic
artery is divided, allowing access to the right portal vein which
is then stapled using a vascular stapler (TA30, Autosuture,
United States Surgical, Tyco Healthcare Group LP, Norwalk, CT,
USA.) and divided, leaving an adequate stump for subsequent
anastomosis. The right liver is then mobilized off the IVC by
dividing the multiple short hepatic veins with ligaclips (Autosu-
ture, United States Surgical, Tyco Healthcare Group LP, Nor-
walk, CT, USA) and the right hepatic vein using a TA30 stapler.
No attempt is made to control the middle hepatic vein before
parenchymal dissection or to isolate the portal structures to seg-
ment 4 extrahepatically, as this may cause hemorrhage.
The IVC flow is preserved during the entire procedure, negat-
ing the need for VVB. In contrast to the low central venous
pressure (0–5 mmHg) used for hepatic resection (127,128), we
have had to accept a central venous pressure of 10 to 25 mmHg
in these cases. Parenchymal transaction is carried out using a
Cavi-Pulse Ultrasonic Surgical Aspirator (CUSA, Model 200T,
Valleylab, Boulder, CO, USA) in a plane 5 to 10 mm to the
right of the falciform ligament. Pringle’s maneuver is applied
during the hepatic resection because of the high central venous
pressure and coagulopathy in these cases. The portal pedicles
to segment 4 are delineated, ligated, and divided intraparen-
chymally, as is the middle hepatic vein. The right hepatic bile
duct is ligated along with segmental portal and hepatic venous
structures on the cut surface of the liver.
Hemostasis of the cut edge of the liver is achieved with
suture ligation and Argon beam coagulation (Erbe, ICC 350
INT UK, Elektromedizin GmbH, Tübingen, Germany) and by
packing with oxidized cellulose absorbable hemostatic pads
 LIVER TRANSPLANTATION FOR ACUTE AND CHRONIC LIVER FAILURE
(Surgical Nu-Knit, Johnson & Johnson, Arlington, TX, USA)
during the implantation phase.
Orthotopic Implantation of the Donor Liver
A side clamp is applied to the recipient IVC including the sta-
pled right hepatic vein. The right hepatic vein stump is excised
with a further extension by a cavotomy to accommodate the
upper end of the donor IVC. The caval anastomosis is with 3-0
polypropylene. The graft is flushed through the portal vein
with 500 ml of 4.5% albumin, and the lower end of the donor
IVC closed using a TA30 vascular stapler. The donor portal
vein is anastomosed end-to-end with the recipient right portal
vein using 5-0 polypropylene and the liver is reperfused.
Hepatic artery reconstruction is performed onto the recipi-
ent’s right hepatic artery using 7-0 or 8-0 polypropylene
sutures. Alternatively, a donor aorto-iliac conduit can be used
for arterialization of the graft with end-to-side anastomosis to
the right common or external iliac artery.
Donor Biliary Diversion and Considerations
in Abdominal Closure
The recipient left hepatic duct, common hepatic duct and
common bile duct are left undisturbed to reduce the potential
risk of long-term biliary structuring. A 50-cm Roux-en-Y
hepaticojejunostomy is created with anastomosis of the donor
common bile duct to the Roux using 10 interrupted 5-0
polydioxine sutures. Abdominal closure should be performed
under minimal tension to avoid a rapid rise in ICP, difficulty
with mechanical ventilation and compartment syndrome.
This may necessitate undermining the abdominal wall and the
use of a polypropylene mesh.
Post-operative Management, Immunosuppression
Withdrawal, and Follow-up
Continuous hemofiltration established pre-operatively should
be continued intra-operatively to create intravascular space
for transfusion of blood products. Post-operative hemodialy-
sis is guided by the patient’s clinical condition and biochemical
results. To reduce the risk of cerebral edema, the patient is
nursed in the reverse Trendelenberg position with about
45-degree head up in the operating room and for about 48 hours
post-operatively.
Full immunosuppression (as above) is initiated for 3 months.
Withdrawal of immunosuppression is staggered, beginning
with discontinuation of corticosteroids within 12 weeks from
transplantation for all patients. A hepatic iminodiacetic acid
(HIDA) and computerized tomography (CT) scans are used to
assess recovery of native liver at 3 months post-operative. If
radiological appearances are satisfactory, azathioprine/myco-
phenolate mofetil are withdrawn. The calcineurin inhibitors
are reduced by one-third the dose every month with the aim to
discontinue all Immunosuppression by 6 to 12 months.
Outcome of Auxiliary Liver Transplantation
In general, the results of ALT for ALF are mixed (see Table 32.8),
reflecting the heterogeneity of causation, type of ALT proce-
dure and experiences in different centers. The key issue for
ALF is for recipients to be immunosuppression-free which is
dependent on the ability of native liver to recover. AOD- and
viral hepatitis-related ALF have a higher likelihood of native
liver regeneration post-ALT and immunosuppression-free
compared to seronegative or autoimmune ALF (122,124,129).
A recent study (122) analyzing the histopathology of native
liver regeneration in ALF patients post-ALT showed two dis-
tinct patterns of liver insults: “diffuse” or “map-like” appear-
ance. Diffuse liver pattern injury, seen mainly in AOD ALF, was
associated with rapid native liver regeneration whereas the
outcome for “map-like” liver injury, observed in AIH- and
seronegative hepatitis-related ALF, was unpredictable (122).
Heterotopic ALT (HALT) consists of graft transplantation in
a non-anatomical position, often on the infrahepatic vena cava
while the native liver is left in situ. Results of HALT have been
discouraging with a higher incidence of vascular complica-
tions (130), primary non-function (130), and delayed native
liver regeneration (131). This has led to the abandoning of
HALT currently (131).
In contrast, orthotopic ALT, both APOLT and AWOLT, have
shown comparable results with OLT for ALF with recent studies
(122,124,129,132,133) reporting 1-year survival rates ranging
from 57% to 80% (Table 32.8). The rate of immunosuppression
cessation ranges from 25% (133) to 100% (124,132).
A recent Japanese study (134), however, reported dismal
outcomes with APOLT in ALF patients with no survivors. This
may be due to patient selection (five unknown, one HBV;
median jaundice–encephalopathy interval 42 days) and the
use of portal vein diversion which can impair native liver
regeneration (134).
Portal vein diversion in ALT for ALF remains a controversial
issue. It was first proposed because of the concern of func-
tional competition between the graft and the native liver for
shared portal blood flow. We do not think that portal vein
diversion is indicated for ALT in ALF patients. We agree
with Shaw’s (135) observations that the dynamics of portal
flow between both livers benefit the recipient; with portal flow
directed to the donor graft in the early stage because of low
volume and high portal pressure in the injured native liver and
reversal of portal flow on immunosuppressant withdrawal and
native liver recovery.
Two caveats remain in using APOLT for ALF. First, the graft
volume should be carefully assessed to avoid graft insufficiency
(small-for-size syndrome). Second, APOLT continues to have
a higher incidence of morbidity compared to OLT, which may
relate to graft insufficiency and the presence of a larger volume
of remaining necrotic native liver (130,133). The AWOLT pro-
cedure overcomes the concern of small-for-size (136), provid-
ing a maximal functional hepatocyte mass to meet the
metabolic demands and recovery of AOD ALF patients; a sub-
total hepatectomy allows a maximal removal of necrotic liver
contributing to “Toxic Liver Syndrome” and at the same time,
leaving behind enough native liver to regenerate.
future perspectives on liver transplantation
Liver Support Devices
Limited organ availability and potential spontaneous recovery
in ALF patients have resulted in innovative attempts to develop
extracorporeal liver support systems as a bridge to LT or to
295
296
Table 32.8 Recent Published Studies of ALT for ALF
Native Liver Donor Liver Vascular Biliary Primary ALT Off
Studies Patients Indications Operation Transplant Complication Complication Nonfunction Retransplant Mortality 1-yr Survival IS (%)
Leeds (124) 13 AOD 13 R Trix 13 Whole 13 2 0 2 3 4 69 100
2008
London (122)a 49 Non-ABC 24 NR Whole 5 2 NR 1 4 11 80 53
2008 AOD 15 R Tri 16
HBV 4 RL 7
Drug 3 LL 4
AIH 2 LLS 8
Mushroom 1 (only 40
recorded op)
Kyoto (134)ab 6 HBV 1 NR LLS 2 1 1 0 2 6 0 0
2005 Unknown 5 LL 3
RL 1
Strasborg (120)a 15 HAV 3 NR LL 6 1 0 1 2 5 67 60
2002 HBV 3 RL 9
Drugs 4
Others 5
Clichy (129) 6 HBV 6 L Hep 2 LL 2 0 0 0 0 1 66 80
2002 R Hep 4 RL 4
Villejuif (133)a 12 HAV 1 LLSx 1 LLS 1 3 5 1 3 4 66 25
2001 HBV 2 L Hep 4 LL 4
Drug 1 R Hep 7 RL 7
Unknown 7
Other 1
EURALT (130)a 47 (includes Viral 18 LLSx 17 Whole 5 11 NR 6 7 18 62 38
1999 12 HALT) Nonviral 29 L Hep 11 Whole – APOLT 6 APOLT 3 APOLT 10 APOLT 71
(AOD 5) R Trix 2 Caudate 2 HALT 5 HALT 3 HALT 8 HALT 33
R trix + LL 20
caudate 1 LLS 8
R Hep 4 R Tri 6
R Tri +
Caudate 1
RL 5
Omaha (156)a 7 Varicella 1 L Hep 5 LL 2 0 4 1 1 3 57 100
1997 Non-ABC 4 L Trix 2 LLS 2
SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

HAV 2 Whole 2
a
Contains both adult and children recipients; bLiving donors; Abbreviations: LLSx indicates left lateral sectionectomy; R Hep, Right hepatectomy; L Hep, Left hepatectomy; R Trix, Right trisectionectomy; L Trix, Left
trisectionectomy; LLS, Left lateral section; LL, Left lobe; RL, Right lobe; R Tri, Right Trisectional graft; AOD, Acetominophen overdose; AIH, Autoimmune hepatitis; HAV, Hepatitis A virus; HBV, Hepatitis B virus;
EBV, Epstein-Barr virus; HALT, Heterotropic auxiliary liver transplantation; APOLT, Auxiliary partial orthotopic liver transplantation; Whole, Auxiliary whole orthotopic liver graft transplantation; NR, Not recorded.
Source: From Ref. 157.
 LIVER TRANSPLANTATION FOR ACUTE AND CHRONIC LIVER FAILURE
provide support until the native liver recovers. Extracorporeal
liver support devices can be divided into two categories
(i) dialysis-based therapies and (ii) bioartificial liver (BAL)
devices. Dialysis-based therapies include the molecular absor-
bent recirculation system (MARS), single pass albumin dialy-
sis (SPAD), and a fractionated plasma separation and
adsorption system (Prometheus). While MARS, SPAD, and
Prometheus have been shown to improve biochemical mark-
ers, no reduction in mortality has been demonstrated (5,137)
and further robust randomized controlled studies are needed.
BAL devices utilize cultured hepatocytes (porcine or
human), with a semi-permeable membrane to separate the
hepatocytes from the patient’s circulation (5). It works on the
principle of uptake and processing of toxins and nutrient by
the hepatocytes while processed metabolites and synthesized
proteins by the hepatocytes are passed back into the patient’s
circulation (138). A prospective, randomized, multi-center,
controlled trial (139) with BAL devices for ALF and primary
non-function patients demonstrated that overall 30-day sur-
vival was not significantly different between the BAL group
and the control arm. When survival was analyzed just for the
ALF subset, the ALF subgroup treated with BAL had signifi-
cantly higher 30-day survival. However, despite studies
(140–142) demonstrating benefit in using BAL systems as a
bridge to LT, none has demonstrated successful bridging to
recovery as yet.
Hepatocyte Transplantation
Hepatocyte transplantation (HT) involves infusion of cryo-
preserved or freshly isolated human hepatocytes to repopulate
a diseased liver. HT in animal models has been promising and
human clinical application was started about 10 years
ago (143). HT has been performed in recipients with meta-
bolic liver disorders, ALF, acute-on-chronic liver diseases, and
decompensated cirrhosis (143). The most promising results
are seen in metabolic liver disease recipients with a beneficial
effect of HT maintained up to 2 years (144,145). Active
research is still ongoing to improve engraftment and efficacy
of HT, development of alternative sources for hepatocytes, opti-
mal immunosuppression regimens, and innovation of efficient
means of monitoring presence and function of HT (5,143).
Immune Tolerance
The liver is unique among transplanted organs in that it is an
immune privileged organ. LT recipients require less immuno-
suppression than other organ recipients and LT confers a degree
of immune protection on other organ grafts during simul-
taneous transplantation. It is known that in some LT animal
models, spontaneous tolerance to liver allografts can occur
(146,147). Documented reports (148,149) on patients main-
taining a healthy graft while immunosuppression-free has
supported this observation and studies (150–152) have shown
that approximately 20% of LT patients may be successfully
withdrawn from immunosuppression. The prospect of identi-
fying potential recipients in whom all immunosuppression can
be discontinued along with their concomitant side effects is
exciting. This prospect is aided by a recent discovery of a set of
biomarkers which can identify tolerant LT recipients (153).
references
1. European Liver Transplant Registry. (Accessed 19th December, 2008, at
http://www.eltr.org.)
2. Berlakovich G. Wasting your organ with your lifestyle and receiving a
new one? Ann Transplant 2005; 10: 38–43.
3. Bernal W. Changing patterns of causation and the use of transplanta-
tion in the United Kingdom. Semin Liver Dis 2003; 23: 227–37.
4. O’Grady JG. Acute liver failure. Postgrad Med J 2005; 81: 148–54.
5. Lee WM, Squires RH, Jr., Nyberg SL, Doo E, Hoofnagle JH. Acute liver
failure: summary of a workshop. Hepatology 2008; 47: 1401–15.
6. Norris W, Paredes AH, Lewis JH. Drug-induced liver injury in 2007.
Curr Opin Gastroenterol 2008; 24: 287–97.
7. Neuberger J, Gimson A, Davies M, et al. Selection of patients for liver
transplantation and allocation of donated livers in the UK. Gut 2008;
57: 252–7.
8. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, ed.
The Liver and Portal Hypertension. Philadelphia: Saunders; 1964: 50–64.
9. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Tran-
section of the oesophagus for bleeding oesophageal varices. Br J Surg
1973; 60: 646–9.
10. Santori G, Andorno E, Antonucci A, et al. Potential predictive value of
the MELD score for short-term mortality after liver transplantation.
Transplant Proc 2004; 36: 533–4.
11. Broering DC, Walter J, Braun F, Rogiers X. Current status of hepatic
transplantation. Anatomical basis for liver transplantation. Curr Probl
Surg 2008; 45: 587–661.
12. Ruf AE, Kremers WK, Chavez LL, et al. Addition of serum sodium into
the MELD score predicts waiting list mortality better than MELD alone.
Liver Transpl 2005; 11: 336–43.
13. Biggins SW, Kim WR, Terrault NA, et al. Evidence-based incorporation
of serum sodium concentration into MELD. Gastroenterology 2006;
130: 1652–60.
14. Huo TI, Lee SD, Lin HC. Selecting an optimal prognostic system for
liver cirrhosis: the model for end-stage liver disease and beyond. Liver
Int 2008; 28: 606–13.
15. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective
study of acute liver failure at 17 tertiary care centers in the United States.
Ann Intern Med 2002; 137: 947–54.
16. Polson J. Assessment of prognosis in acute liver failure. Semin Liver Dis
2008; 28: 218–25.
17. Dhiman RK, Jain S, Maheshwari U, et al. Early indicators of prognosis in
fulminant hepatic failure: an assessment of the Model for End-Stage
Liver Disease (MELD) and King’s College Hospital criteria. Liver
Transpl 2007; 13: 814–21.
18. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of
prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439–45.
19. Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early
predictor of outcome in paracetamol-induced acute liver failure: a
cohort study. Lancet 2002; 359: 558–63.
20. Cholongitas E, O’Beirne J, Betrossian A, et al. Prognostic impact of lac-
tate in acute liver failure. Liver Transpl 2008; 14: 121–2; author reply 3.
21. Hadem J, Stiefel P, Bahr MJ, et al. Prognostic implications of lactate,
bilirubin, and etiology in German patients with acute liver failure. Clin
Gastroenterol Hepatol 2008; 6: 339–45.
22. Ahmed A, Keeffe EB. Current indications and contraindications for
liver transplantation. Clin Liver Dis 2007; 11: 227–47.
23. Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A ran-
domized study of adefovir dipivoxil in place of HBIG in combination
with lamivudine as post-liver transplantation hepatitis B prophylaxis.
Hepatology 2008; 48: 1460–6.
24. Degertekin B, Lok AS. What is the optimal regimen for preventing
hepatitis B recurrence after liver transplantation? Nat Clin Pract Gastro-
enterol Hepatol 2009; 6: 68–9
25. Gaglio P, Singh S, Degertekin B, et al. Impact of the hepatitis B virus
genotype on pre- and post-liver transplantation outcomes. Liver
Transpl 2008; 14: 1420–7.
26. Hong Z, Smart G, Dawood M, et al. Hepatitis C infection and survivals
of liver transplant patients in Canada, 1997–2003. Transplant Proc
2008; 40: 1466–70.
297
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
27. Roche B, Sebagh M, Canfora ML, et al. Hepatitis C virus therapy in liver
transplant recipients: Response predictors, effect on fibrosis progres-
sion, and importance of the initial stage of fibrosis. Liver Transpl 2008;
14: 1766–77.
28. Duclos-Vallee JC, Feray C, Sebagh M, et al. Survival and recurrence of
hepatitis C after liver transplantation in patients coinfected with human
immunodeficiency virus and hepatitis C virus. Hepatology 2008; 47:
407–17.
29. Pradat P, Tillmann HL, Sauleda S, et al. Long-term follow-up of the
hepatitis C HENCORE cohort: response to therapy and occurrence of
liver-related complications. J Viral Hepat 2007; 14: 556–63.
30. Mukherjee S, Sorrell MF. Controversies in liver transplantation for hep-
atitis C. Gastroenterology 2008; 134: 1777–88.
31. Roland ME, Barin B, Carlson L, et al. HIV-infected liver and kidney
transplant recipients: 1- and 3-year outcomes. Am J Transplant 2008; 8:
355–65.
32. O’Grady J, Taylor C, Brook G. Guidelines for liver transplantation in
patients with HIV infection (2005). HIV Med 2005; 6(Suppl 2): 149–53.
33. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associ-
ated with liver graft failure: the concept of a donor risk index. Am J
Transplant 2006; 6: 783–90.
34. Merion RM, Goodrich NP, Feng S. How can we define expanded criteria
for liver donors? J Hepatol 2006; 45: 484–8.
35. Bruna Esteban M, Lopez Andujar R, et al. [Donors yesterday and today:
have the characteristics of liver donors changed over the last 15 years?].
Cir Esp 2008; 83: 194–8.
36. Barshes NR, Horwitz IB, Franzini L, Vierling JM, Goss JA. Waitlist mor-
tality decreases with increased use of extended criteria donor liver grafts
at adult liver transplant centers. Am J Transplant 2007; 7: 1265–70.
37. Tector AJ, Mangus RS, Chestovich P, et al. Use of extended criteria livers
decreases wait time for liver transplantation without adversely impact-
ing posttransplant survival. Ann Surg 2006; 244: 439–50.
38. Afonso RC, Hidalgo R, Paes AT, et al. Impact of cumulative risk factors
for expanded criteria donors on early survival after liver transplanta-
tion. Transplant Proc 2008; 40: 800–1.
39. Fischer-Frohlich CL, Lauchart W. Expanded criteria liver donors (ECD):
effect of cumulative risks. Ann Transplant 2006; 11: 38–42.
40. Durand F, Renz JF, Alkofer B, et al. Report of the Paris consensus meet-
ing on expanded criteria donors in liver transplantation. Liver Transpl
2008; 14: 1694–707.
41. Alghamdi HM, Crawford MD, Gallagher JP, McCaughan GW, Strasser
SI, Verran DJ. Cadaveric liver transplant from older donors. Saudi Med
J 2008; 29: 533–8.
42. Cescon M, Grazi GL, Cucchetti A, et al. Improving the outcome of liver
transplantation with very old donors with updated selection and man-
agement criteria. Liver Transpl 2008; 14: 672–9.
43. Petridis I, Gruttadauria S, Nadalin S, et al. Liver transplantation using
donors older than 80 years: a single-center experience. Transplant Proc
2008; 40: 1976–8.
44. Perez-Daga JA, Ramirez-Plaza C, Suarez MA, et al. Impact of donor age
on the results of liver transplantation in hepatitis C virus-positive recip-
ients. Transplant Proc 2008; 40: 2959–61.
45. Cerutti E, Stratta C, Romagnoli R, et al. Bacterial- and fungal-positive
cultures in organ donors: clinical impact in liver transplantation. Liver
Transpl 2006; 12: 1253–9.
46. Gonzalez-Segura C, Pascual M, Garcia Huete L, et al. Donors with posi-
tive blood culture: could they transmit infections to the recipients?
Transplant Proc 2005; 37: 3664–6.
47. Mueller NJ, Fishman JA. How should we evaluate organ donors with
active or prior infections? J Hepatol 2006; 45: 507–13.
48. Dodson SF, Issa S, Araya V, et al. Infectivity of hepatic allografts with
antibodies to hepatitis B virus. Transplantation 1997; 64: 1582–4.
49. Dickson RC, Everhart JE, Lake JR, et al. Transmission of hepatitis B by
transplantation of livers from donors positive for antibody to hepatitis B
core antigen. The National Institute of Diabetes and Digestive and Kid-
ney Diseases Liver Transplantation Database. Gastroenterology 1997;
113: 1668–74.
50. Van Thiel DH, De Maria N, Colantoni A, Friedlander L. Can hepatitis B
core antibody positive livers be used safely for transplantation: hepatitis
298
B virus detection in the liver of individuals who are hepatitis B core
antibody positive. Transplantation 1999; 68: 519–22.
51. Chazouilleres O, Mamish D, Kim M, et al. “Occult” hepatitis B virus as
source of infection in liver transplant recipients. Lancet 1994; 343:
142–6.
52. De Feo TM, Poli F, Mozzi F, Moretti MP, Scalamogna M. Risk of trans-
mission of hepatitis B virus from anti–HBC positive cadaveric organ
donors: a collaborative study. Transplant Proc 2005; 37: 1238–9.
53. Takemura N, Sugawara Y, Tamura S, Makuuchi M. Liver transplantation
using hepatitis B core antibody-positive grafts: review and university of
Tokyo experience. Dig Dis Sci 2007; 52: 2472–7.
54. Celebi Kobak A, Karasu Z, Kilic M, et al. Living donor liver transplanta-
tion from hepatitis B core antibody positive donors. Transplant Proc
2007; 39: 1488–90.
55. Testa G, Goldstein RM, Netto G, et al. Long-term outcome of patients
transplanted with livers from hepatitis C-positive donors. Transplanta-
tion 1998; 65: 925–9.
56. Vargas HE, Laskus T, Wang LF, et al. Outcome of liver transplantation in
hepatitis C virus-infected patients who received hepatitis C virus-
infected grafts. Gastroenterology 1999; 117: 149–53.
57. Velidedeoglu E, Desai NM, Campos L, et al. The outcome of liver grafts
procured from hepatitis C-positive donors. Transplantation 2002; 73:
582–7.
58. Ricchiuti A, Brunati A, Mirabella S, et al. Use of hepatitis C virus-posi-
tive grafts in liver transplantation: a single-centre experience. Trans-
plant Proc 2005; 37: 2569–70.
59. Buell JF, Alloway RR, Steve Woodle E. How can donors with a previous
malignancy be evaluated? J Hepatol 2006; 45: 503–7.
60. Myron Kauffman H, McBride MA, Cherikh WS, Spain PC, Marks WH,
Roza AM. Transplant tumor registry: donor related malignancies.
Transplantation 2002; 74: 358–62.
61. Birkeland SA, Storm HH. Risk for tumor and other disease transmission
by transplantation: a population-based study of unrecognized malig-
nancies and other diseases in organ donors. Transplantation 2002; 74:
1409–13.
62. Bonney GK, Aldouri A, Attia M, et al. Outcomes in right liver lobe
transplantation: a matched pair analysis. Transpl Int 2008; 21: 1045–51.
63. Burroughs AK, Sabin CA, Rolles K, et al. 3-month and 12-month mor-
tality after first liver transplant in adults in Europe: predictive models
for outcome. Lancet 2006; 367: 225–32.
64. UNOS Policy 3.6.11 Organ distribution: Allocation of livers for seg-
mental transplantation. 2007. (Accessed 23rd December, 2008, at http:
//www.unos.org/PoliciesandBylaws2/policies/pdfs/policy_8.pdf.)
65. Lee KW, Cameron AM, Maley WR, Segev DL, Montgomery RA. Factors
affecting graft survival after adult/child split-liver transplantation: anal-
ysis of the UNOS/OPTN data base. Am J Transplant 2008; 8: 1186–96.
66. Kootstra G, Daemen JH, Oomen AP. Categories of non-heart-beating
donors. Transplant Proc 1995; 27: 2893–4.
67. Merion RM, Pelletier SJ, Goodrich N, Englesbe MJ, Delmonico FL.
Donation after cardiac death as a strategy to increase deceased donor
liver availability. Ann Surg 2006; 244: 555–62.
68. Bernat JL, D’Alessandro AM, Port FK, et al. Report of a National Confer-
ence on Donation after cardiac death. Am J Transplant 2006; 6: 281–91.
69. Maheshwari A, Maley W, Li Z, Thuluvath PJ. Biliary complications and
outcomes of liver transplantation from donors after cardiac death. Liver
Transpl 2007; 13: 1645–53.
70. Dezza MC, Berrevoet F, Sainz-Barriga M, et al. The choice of recipient
does not have a bearing on early outcome in liver transplant patients
receiving grafts from non-heart-beating donors: a reappraisal? Trans-
plant Proc 2007; 39: 2675–7.
71. Foley DP, Fernandez LA, Leverson G, et al. Donation after cardiac death:
the University of Wisconsin experience with liver transplantation. Ann
Surg 2005; 242: 724–31.
72. D’Alessandro AM, Fernandez LA, Chin LT, et al. Donation after cardiac
death: the University of Wisconsin experience. Ann Transplant 2004; 9:
68–71.
73. Lee KW, Simpkins CE, Montgomery RA, Locke JE, Segev DL, Maley
WR. Factors affecting graft survival after liver transplantation from
donation after cardiac death donors. Transplantation 2006; 82: 1683–8.
 LIVER TRANSPLANTATION FOR ACUTE AND CHRONIC LIVER FAILURE
74. Mateo R, Cho Y, Singh G, et al. Risk factors for graft survival after liver
transplantation from donation after cardiac death donors: an analysis of
OPTN/UNOS data. Am J Transplant 2006; 6: 791–6.
75. Guidelines relating to solid organ transplant from non-heart beating
donors. British Transplantation Society, 2004. (Accessed 9th December,
2008, at www.bts.org.uk/Forms/Guidelines_Nov_2004.pdf )
76. Reddy MS, Wilson C, Torpey N, Manas DM. ABO incompatible liver
transplantation: a case of immediate need. Transpl Int 2007; 20:
904–5.
77. Gugenheim J, Samuel D, Reynes M, Bismuth H. Liver transplantation
across ABO blood group barriers. Lancet 1990; 336: 519–23.
78. Farges O, Kalil AN, Samuel D, et al. The use of ABO-incompatible grafts
in liver transplantation: a life-saving procedure in highly selected
patients. Transplantation 1995; 59: 1124–33.
79. Toso C, Al-Qahtani M, Alsaif FA, et al. ABO-incompatible liver trans-
plantation for critically ill adult patients. Transpl Int 2007; 20: 675–81.
80. Egawa H, Ohdan H, Haga H, et al. Current status of liver transplanta-
tion across ABO blood-type barrier. J Hepatobiliary Pancreat Surg 2008;
15: 131–8.
81. Egawa H, Teramukai S, Haga H, et al. Present status of ABO-incompat-
ible living donor liver transplantation in Japan.[see comment]. Hepa-
tology 2008; 47: 143–52.
82. Troisi R, Noens L, Montalti R, et al. ABO-mismatch adult living donor
liver transplantation using antigen-specific immunoadsorption and
quadruple immunosuppression without splenectomy. Liver Transpl
2006; 12: 1412–7.
83. Malago M, Hertl M, Testa G, Rogiers X, Broelsch CE. Split-liver trans-
plantation: future use of scarce donor organs. World J Surg 2002; 26:
275–82.
84. Noujaim HM, Gunson B, Mayer DA, et al. Worth continuing doing ex
situ liver graft splitting? A single-center analysis. Am J Transplant 2003;
3: 318–23.
85. Starzl TE, Marchioro TL, Vonkaulla KN, et al. Homotransplantation of
the liver in humans. Surg Gynecol Obstet 1963; 117: 659–76.
86. Griffith BP, Shaw BW Jr., Hardesty RL, et al. Veno-venous bypass with-
out systemic anticoagulation for transplantation of the human liver.
Surg Gynecol Obstet 1985; 160: 270–2.
87. Tzakis A, Todo S, Starzl TE. Orthotopic liver transplantation with pres-
ervation of the inferior vena cava. Ann Surg 1989; 210: 649–52.
88. Tzakis AG, Reyes J, Nour B, et al. Temporary end to side portacaval
shunt in orthotopic hepatic transplantation in humans. Surg Gynecol
Obstet 1993; 176: 180–2.
89. Belghiti J, Noun R, Sauvanet A. Temporary portocaval anastomosis with
preservation of caval flow during orthotopic liver transplantation. Am J
Surg 1995; 169: 277–9.
90. Dasgupta D, Sharpe J, Prasad KR, et al. Triangular and self-triangulating
cavocavostomy for orthotopic liver transplantation without posterior
suture lines: a modified surgical technique. Transpl Int 2006; 19: 117–21.
91. Hilmi IA, Planinsic RM. Con: venovenous bypass should not be used in
orthotopic liver transplantation. J Cardiothorac Vasc Anesth 2006; 20: 744–7.
92. Reddy K, Mallett S, Peachey T. Venovenous bypass in orthotopic liver
transplantation: time for a rethink? Liver Transpl 2005; 11: 741–9.
93. Budd JM, Isaac JL, Bennett J, Freeman JW. Morbidity and mortality asso-
ciated with large-bore percutaneous venovenous bypass cannulation for
312 orthotopic liver transplantations. Liver Transpl 2001; 7: 359–62.
94. Guidelines for the prevention and management of cytomegalovirus dis-
ease after solid organ transplantation. British Transplantation Society,
2004. (Accessed 16th December, 2008, at http: //www.bts.org.uk/
Forms/4164_BTS%20Standards%20AW.pdf.)
95. Gedaly R, Clifford TM, McHugh PP, et al. Prevalent immunosuppressive
strategies in liver transplantation for hepatitis C: results of a multi-
center international survey. Transpl Int 2008; 21: 867–72.
96. Oton E, Barcena R, Castillo M, et al. Hepatitis C virus recurrence after
liver transplantation: influence of immunosuppressive regimens on
viral load and liver histology. Transplant Proc 2006; 38: 2499–501.
97. O’Grady JG, Hardy P, Burroughs AK, Elbourne D. Randomized con-
trolled trial of tacrolimus versus microemulsified cyclosporin (TMC) in
liver transplantation: poststudy surveillance to 3 years. Am J Transplant
2007; 7: 137–41.
98. Berenguer M, Royuela A, Zamora J. Immunosuppression with calci-
neurin inhibitors with respect to the outcome of HCV recurrence after
liver transplantation: results of a meta-analysis. Liver Transpl 2007; 13:
21–9.
99. Kato T, Gaynor JJ, Yoshida H, et al. Randomized trial of steroid-free
induction versus corticosteroid maintenance among orthotopic liver
transplant recipients with hepatitis C virus: impact on hepatic fibrosis
progression at one year. Transplantation 2007; 84: 829–35.
100. Klintmalm GB, Washburn WK, Rudich SM, et al. Corticosteroid-free
immunosuppression with daclizumab in HCV(+) liver transplant
recipients: 1-year interim results of the HCV-3 study. Liver Transpl
2007; 13: 1521–31.
101. Llado L, Fabregat J, Castellote J, et al. Impact of immunosuppression
without steroids on rejection and hepatitis C virus evolution after liver
transplantation: Results of a prospective randomized study. Liver
Transpl 2008; 14: 1752–60.
102. Segev DL, Sozio SM, Shin EJ, et al. Steroid avoidance in liver transplan-
tation: meta-analysis and meta-regression of randomized trials. Liver
Transpl 2008; 14: 512–25.
103. Vivarelli M, Burra P, La Barba G, et al. Influence of steroids on HCV
recurrence after liver transplantation: A prospective study. J Hepatol
2007; 47: 793–8.
104. Busuttil RW, Farmer DG, Yersiz H, et al. Analysis of long-term outcomes
of 3200 liver transplantations over two decades: a single-center experi-
ence. Ann Surg 2005; 241: 905–16; discussion 16–8.
105. van der Meulen JH, Lewsey JD, Dawwas MF, Copley LP. Adult ortho-
topic liver transplantation in the United Kingdom and Ireland between
1994 and 2005. Transplantation 2007; 84: 572–9.
106. Roche B, Samuel D. Aspects of hepatitis C virus infection relating to
liver transplantation. Eur J Gastroenterol Hepatol 2006; 18: 313–20.
107. Roche B, Samuel D. Risk factors for hepatitis C recurrence after liver
transplantation. J Viral Hepat 2007; 14(Suppl 1): 89–96.
108. Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral
therapy in patients with recurrent hepatitis C following liver transplan-
tation. Am J Transplant 2008; 8: 679–87.
109. Mukherjee S, Lyden E. Impact of pegylated interferon alpha-2B and
ribavirin on hepatic fibrosis in liver transplant patients with recurrent
hepatitis C: an open-label series. Liver Int 2006; 26: 529–35.
110. McCashland T, Watt K, Lyden E, et al. Retransplantation for hepatitis C:
results of a U.S. multicenter retransplant study. Liver Transpl 2007; 13:
1246–53.
111. Vennarecci G, Ettorre GM, Antonini M, et al. Liver transplantation in
HIV-positive patients. Transplant Proc 2007; 39: 1936–8.
112. de Vera ME, Dvorchik I, Tom K, et al. Survival of liver transplant
patients coinfected with HIV and HCV is adversely impacted by recur-
rent hepatitis C. Am J Transplant 2006; 6: 2983–93.
113. Alexander J, Lord JD, Yeh MM, et al. Risk factors for recurrence of pri-
mary sclerosing cholangitis after liver transplantation. Liver Transpl
2008; 14: 245–51.
114. Campsen J, Zimmerman MA, Trotter JF, et al. Clinically recurrent pri-
mary sclerosing cholangitis following liver transplantation: a time
course. Liver Transpl 2008; 14: 181–5.
115. Maheshwari A, Yoo HY, Thuluvath PJ. Long-term outcome of liver
transplantation in patients with PSC: a comparative analysis with PBC.
Am J Gastroenterol 2004; 99: 538–42.
116. Charatcharoenwitthaya P, Pimentel S, Talwalkar JA, et al. Long-term
survival and impact of ursodeoxycholic acid treatment for recurrent
primary biliary cirrhosis after liver transplantation. Liver Transpl 2007;
13: 1236–45.
117. Jacob DA, Neumann UP, Bahra M, et al. Long-term follow-up after
recurrence of primary biliary cirrhosis after liver transplantation in
100 patients. Clin Transplant 2006; 20: 211–20.
118. Absolon KB, Hagihara PF, Griffen WO Jr., Lillehei RC. Experimental
and clinical heterotopic liver homotransplantation. Rev Int Hepatol
1965; 15: 1481–90.
119. Chenard-Neu MP, Boudjema K, Bernuau J, et al. Auxiliary liver trans-
plantation: regeneration of the native liver and outcome in 30 patients
with fulminant hepatic failure--a multicenter European study. Hepatol-
ogy 1996; 23: 1119–27.
299
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
120. Jaeck D, Boudjema K, Audet M, et al. Auxiliary partial orthotopic liver
transplantation (APOLT) in the treatment of acute liver failure. J Gas-
troenterol 2002; 37(Suppl 13): 88–91.
121. Pereira SP, McCarthy M, Ellis AJ, et al. Auxiliary partial orthotopic liver
transplantation for acute liver failure. J Hepatol 1997; 26: 1010–7.
122. Quaglia A, Portmann BC, Knisely AS, et al. Auxiliary transplantation for
acute liver failure: histopathological study of native liver regeneration.
Liver Transpl 2008; 14: 1437–48.
123. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute
liver failure: results of a United States multicenter, prospective study.
Hepatology 2005; 42: 1364–72.
124. Lodge JP, Dasgupta D, Prasad KR, et al. Emergency subtotal hepatec-
tomy: a new concept for acetaminophen-induced acute liver failure:
temporary hepatic support by auxiliary orthotopic liver transplantation
enables long-term success. Ann Surg 2008; 247: 238–49.
125. Lodge JP, Prasad KR, Toogood GJ, et al. Auxiliary orthotopic liver trans-
plantation: new technique and results in toxic liver injury. Transplant
Proc 2001; 33: 1403–4.
126. Ringe B, Lubbe N, Kuse E, Frei U, Pichlmayr R. Total hepatectomy and
liver transplantation as two-stage procedure. Ann Surg 1993; 218: 3–9.
127. Halazun KJ, Al-Mukhtar A, Aldouri A, et al. Right hepatic trisectionec-
tomy for hepatobiliary diseases: results and an appraisal of its current
role. Ann Surg 2007; 246: 1065–74.
128. Nishio H, Hidalgo E, Hamady ZZ, et al. Left hepatic trisectionectomy
for hepatobiliary malignancy: results and an appraisal of its current
role. Ann Surg 2005; 242: 267–75.
129. Durand F, Belghiti J, Handra-Luca A, et al. Auxiliary liver transplanta-
tion for fulminant hepatitis B: results from a series of six patients with
special emphasis on regeneration and recurrence of hepatitis B. Liver
Transpl 2002; 8: 701–7.
130. van Hoek B, de Boer J, Boudjema K, Williams R, Corsmit O, Terpstra
OT. Auxiliary versus orthotopic liver transplantation for acute liver fail-
ure. EURALT Study Group. European Auxiliary Liver Transplant Regis-
try. J Hepatol 1999; 30: 699–705.
131. Jaeck D, Pessaux P, Wolf P. Which types of graft to use in patients with
acute liver failure? (A) Auxiliary liver transplant (B) Living donor liver
transplantation (C) The whole liver. (A) I prefer auxiliary liver trans-
plant. Journal of Hepatology 2007; 46: 570–3.
132. Sudan DL, Langnas AN, Shaw BW, Jr. Long-term follow-up of auxiliary
liver transplantation for fulminant hepatic failure. Transplant Proc
1997; 29: 485–6.
133. Azoulay D, Samuel D, Ichai P, et al. Auxiliary partial orthotopic versus
standard orthotopic whole liver transplantation for acute liver failure: a
reappraisal from a single center by a case-control study. Ann Surg 2001;
234: 723–31.
134. Kasahara M, Takada Y, Egawa H, et al. Auxiliary partial orthotopic living
donor liver transplantation: Kyoto University experience. Am J Trans-
plant 2005; 5: 558–65.
135. Shaw BW, Jr. Auxiliary liver transplantation for acute liver failure. Liver
Transpl Surg 1995; 1: 194–200.
136. Heaton N. Small-for-size liver syndrome after auxiliary and split liver
transplantation: donor selection. Liver Transpl 2003; 9: S26–8.
137. Karvellas CJ, Gibney N, Kutsogiannis D, Wendon J, Bain VG. Bench-to-
bedside review: current evidence for extracorporeal albumin dialysis
systems in liver failure. Crit Care 2007; 11: 215.
138. Singhal A, Neuberger J. Acute liver failure: bridging to transplant or
recovery--are we there yet? J Hepatol 2007; 46: 557–64.
300
139. Demetriou AA, Brown RS Jr., Busuttil RW, et al. Prospective, random-
ized, multicenter, controlled trial of a bioartificial liver in treating acute
liver failure. Ann Surg 2004; 239: 660–7; discussion 7–70.
140. Ellis AJ, Hughes RD, Wendon JA, et al. Pilot-controlled trial of the extra-
corporeal liver assist device in acute liver failure. Hepatology 1996; 24:
1446–51.
141. van de Kerkhove MP, Di Florio E, Scuderi V, et al. Phase I clinical
trial with the AMC-bioartificial liver. Int J Artif Organs 2002; 25:
950–9.
142. Patzer JF, 2nd, Mazariegos GV, Lopez R. Preclinical evaluation of the
Excorp Medical, Inc, Bioartificial Liver Support System. J Am Coll Surg
2002; 195: 299–310.
143. Smets F, Najimi M, Sokal EM. Cell transplantation in the treatment of
liver diseases. Pediatr Transplant 2008; 12: 6–13.
144. Grossman M, Rader DJ, Muller DW, et al. A pilot study of ex vivo gene
therapy for homozygous familial hypercholesterolaemia. Nat Med 1995;
1: 1148–54.
145. Dhawan A, Mitry RR, Hughes RD. Hepatocyte transplantation for
liver-based metabolic disorders. J Inherit Metab Dis 2006; 29:
431–5.
146. Calne RY, Sells RA, Pena JR, et al. Induction of immunological tolerance
by porcine liver allografts. Nature 1969; 223: 472–6.
147. Murase N, Starzl TE, Tanabe M, et al. Variable chimerism, graft-versus-
host disease, and tolerance after different kinds of cell and whole organ
transplantation from Lewis to brown Norway rats. Transplantation
1995; 60: 158–71.
148. Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism
after whole-organ transplantation: the basis of graft acceptance.
Hepatology 1993; 17: 1127–52.
149. Alexander SI, Smith N, Hu M, et al. Chimerism and tolerance in a
recipient of a deceased-donor liver transplant. N Engl J Med 2008; 358:
369–74.
150. Koshiba T, Li Y, Takemura M, et al. Clinical, immunological, and patho-
logical aspects of operational tolerance after pediatric living-donor liver
transplantation. Transpl Immunol 2007; 17: 94–7.
151. Devlin J, Doherty D, Thomson L, et al. Defining the outcome of immu-
nosuppression withdrawal after liver transplantation. Hepatology 1998;
27: 926–33.
152. Mazariegos GV, Reyes J, Marino IR, et al. Weaning of immunosup-
pression in liver transplant recipients. Transplantation 1997; 63:
243–9.
153. Martinez-Llordella M, Lozano JJ, Puig-Pey I, et al. Using transcriptional
profiling to develop a diagnostic test of operational tolerance in liver
transplant recipients. J Clin Invest 2008; 118: 2845–57.
154. Bundesaerztekammer (German Medical Association) ed.: Richtlinien
zur Organtransplantation nach §16 TPG. Aenderung; Deutsches
Aerzteblatt 2004; 101: A246–A7.
155. Sanchez-Fructuoso AI, Prats D, Torrente J, et al. Renal transplantation
from non-heart beating donors: a promising alternative to enlarge the
donor pool. J Am Soc Nephrol 2000; 11: 350–8.
156. Sudan DL, Shaw BW Jr., Fox IJ, Langnas AN. Long-term follow-up of
auxiliary orthotopic liver transplantation for the treatment of fulmi-
nant hepatic failure. Surgery 1997; 122: 771–7; discussion 7–8.
157. Lodge JP, Dasgupta D, Prasad KR, et al. Emergency subtotal hepatec-
tomy: a new concept for acetaminophen-induced acute liver failure:
temporary hepatic support by auxiliary orthotopic liver transplantation
enables long-term success. Ann Surg 2008; 247: 238–49.
33 Benign cystic disease of the liver
Stephen W. Fenwick and Dowmitra Dasgupta
introduction
Benign cystic lesions of the liver were historically an uncom-
mon clinical entity, presenting only when symptoms or com-
plications occurred. However, with the wider availability of
sophisticated radiological techniques, these lesions are being
recognized more commonly. In spite of this they sometimes
represent a diagnostic challenge. Common cystic lesions range
from the single, simple, small liver cyst to the florid appear-
ance of polycystic liver disease. More uncommon lesions are
mesenchymal hamartomas (in pediatric patients), biliary
hamartomas, and ciliated foregut hepatic cysts. Once a firm
diagnosis is made, management is usually expectant unless
symptoms worsen.
simple cysts
Simple biliary hepatic cysts are congenital lesions which are
thought to result from progressive dilatation of biliary micro-
hamartomas, otherwise known as von Meyenberg’s complexes.
They are lined by flattened biliary epithelium which rests on a
thin underlying rim of fibrous stroma, without a distinct sepa-
ration from adjacent hepatic parenchyma. They may be soli-
tary or multiple, and do not normally communicate with the
biliary tree (1). The cysts contain serous fluid which is con-
tinuously excreted by the lining epithelial cells.
clinical presentation
Most simple hepatic cysts are asymptomatic and are detected
as an incidental finding during imaging of the abdomen for
other indications. Ultrasound scanning demonstrates a
rounded, anechoic intra-hepatic mass with good-through
transmission and an imperceptible wall (2). On unenhanced
computed tomography (CT) imaging a simple cyst appears as
a homogenous lesion of low attenuation, with no enhance-
ment of the wall or content following the administration of
contrast (3) (Fig. 33.1). With magnetic resonance (MR) scan-
ning, simple cysts show low attenuation on T1-weighted
images (Fig. 33.2A) and homogeneous, very high signal inten-
sity on T2-weighted images (Fig. 33.2B).
The differential diagnosis includes multiple cysts arising as a
result of polycystic liver disease, juvenile hydatid cysts, para-
sitic liver cysts, and biliary cystadenomas or cystadenocarcino-
mas. The differentiation between these lesions can largely be
made on imaging characteristics. Hepatic metastases can occa-
sionally appear cystic, particularly neuroendocrine tumors
and sarcomas.
natural history
An early series, based on findings at laparotomy, estimated a
low prevalence of simple hepatic cysts of 0.17%, although
many small cysts were probably missed (4). More recent data
based on imaging studies suggests the prevalence is between
1.6% and 18% (5–9). Females are affected more than males (6).
The frequency of diagnosis increases with age with the peak
incidence occurring between the ages of 50 and 60 years (10,11).
Typically, patients with simple hepatic cysts have no symp-
toms. However, larger cysts may exert a mass effect and cause
upper abdominal discomfort and early satiety. Symptoms are
more common with right sided cysts (10). Complications are
rare but include intra-cystic hemorrhage (12), biliary obstruc-
tion due to compression of the biliary tree (13,14), vascular
compression (15), cyst rupture (16), and cyst torsion. Bacterial
infection can occur within a cyst, particularly when there is
communication with the biliary tree (17).
treatment
The vast majority of simple hepatic cysts are incidental and,
once the diagnosis is established, require no treatment. Even
for those patients with abdominal symptoms the possibility of
another underlying cause must always be considered and
investigated.
aspiration
Ultrasound-guided percutaneous cyst aspiration has little role in
the treatment of symptomatic simple cysts as the recurrence rate
is high (78–100%) (18–20), sometimes as rapid as 2 weeks (18).
However, cyst aspiration can be used as a trial of therapy. If symp-
toms persist after needle aspiration then the cyst is unlikely to be
the cause, and other pathology must be sought. Conversely, if
symptoms abate after cyst aspiration, and return with recurrence
of the cyst, then a definitive treatment of the cyst is indicated.
aspiration sclerotherapy
Aspiration sclerotherapy is a well-tested therapeutic technique
for the treatment of simple hepatic cysts. The procedure
involves the aspiration of cyst fluid followed by the instillation
of a sclerosant. A number of sclerosing agents have been used
including tetracycline (21,22), minocycline (23,24), pan-
topaque (25), and alcohol (11,26–29).
The procedure is performed under ultrasound or CT guid-
ance. A pigtail catheter is inserted into the cyst, and the cyst
fluid aspirated. The fluid is usually clear and should be sent for
cytology to exclude malignancy, culture to exclude infection,
and microscopy to look for hydatid scolices. In addition the
fluid should be assessed for the tumor marker CA19–9 which,
if elevated, suggests an underlying diagnosis of cystadenoma
or cystadenocarcinoma (30). Any bile staining of the fluid
would suggest a communication with the biliary tree and
would mandate abandoning the procedure and further assess-
ment with cholangiography. The consequence of inadvertent
injection of sclerosant into the biliary tree is devastating, and
following cyst drainage a contrast cystogram should always be
performed (28).
301
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
The most commonly used sclerosant is alcohol. Reported
techniques vary widely. Alcohol strengths of 95% (11,26),
96% (28), and 99% (27) have all been reported with favorable
results. Prior to instillation of the alcohol into the cyst, it is
imperative to remove as much of the cyst fluid as possible to
prevent dilution of the alcohol. An alcohol volume of approxi-
mately 25% of the cyst aspirate is instilled (26) for up to
2 hours (11,31), during which time the patient’s position is
altered frequently to maximize contact between the cyst wall
and the alcohol. The alcohol fixes the epithelial cells lining the
cyst cavity. Most authors advocate a single procedure with
withdrawal of the catheter on completion. However, if the cyst
is large (>400 ml) then multiple procedures can be attempted.
The catheter should be left in place and the procedure repeated
according to daily cyst drainage.
Complications from the procedure are mild pain, transient
hyperpyrexia, nausea and vomiting. To reduce these symp-
toms, patients can be premedicated with an opiate analgesic
and an anti-emetic, and a local anesthetic, such as lignocaine
can be instilled into the cyst prior to the injection of the
Figure 33.1 Multidetector computed tomography (MDCT) image with iodin-
ated intravenous contrast media. A large simple cyst is seen in segments 6 and
7. A small cyst is noted on the periphery of segment 2.
(A)
Figure 33.2 (A) T1-weighted MRI image through the upper abdomen showing multiple cysts throughout the liver. Fluid is dark on T1-weighting (B) T2-weighted
coronal view of the abdomen of the same patient as in Figure 33.2A. The cysts are clearly seen as bright throughout the liver. This section is taken through the
vascular pedicle of the liver.
302
alcohol. Severe pain can be a sign of alcohol leaking into the
peritoneal cavity. If this occurs the procedure should be aban-
doned and repeated at a later date. Significant but uncommon
complications relate to the needle puncture. These include
pleural effusion and hemothorax (32). There are also reports
of a transient elevation of blood alcohol level, and for this rea-
son patients should be advised not to drive or operate machin-
ery following the procedure.
Aspiration sclerotherapy does have several advantages over
other more invasive approaches. It is a relatively simple tech-
nique which does not require general anesthesia and can be
performed on an out-patient basis. However, it does require
experienced radiologists with expertise in the interpretation of
hepatobiliary imaging and with competence in interventional
hepatobiliary procedures. For these reasons the procedure
should only be performed where such expertise is available.
The published results of aspiration sclerotherapy appear
encouraging. Recurrence rates are reported at between 0 and
30% (11,26–28,31–37), although there is significant disparity
between series. The number of patients is often small; the indi-
cations are variable with polycystic patients often enrolled
alongside patients with simple cysts. The techniques reported
vary in terms of sclerosant concentration, volume adminis-
tered, duration of sclerosis, and whether single or multiple
procedures were performed. The length of patient follow-up is
variable and reported outcome measures include symptomatic
relief or a reduction in cyst volume or the complete ablation of
the cyst. Recently, one group has reported similar results when
comparing prolonged negative-pressure catheter drainage
with single session alcohol sclerotherapy (38). Clearly further
studies with greater patient numbers and standardized out-
come measures, including quality of life assessment, are
required to fully assess this technique.
surgical treatment
There are three surgical techniques that have been employed
in the management of simple benign liver cysts. These are
fenestration (deroofing of the cyst), local excision of the cyst
(cystectomy), and anatomic or non-anatomic liver resection.
(B)
 BENIGN CYSTIC DISEASE OF THE LIVER
Fenestration has emerged as the most popular technique
with fewer complications than the more radical procedures.
The concept of cyst fenestration was first described by Lin
et al. in 1968 (39). The principle is to form a permanent com-
munication between the cyst cavity and the peritoneum so
that any fluid subsequently produced by the cyst lining can be
re-absorbed by the peritoneum. The technique involves aspi-
ration of the cyst content, which can be inspected and sent for
cytology, microbiological culture, and tumor marker analysis,
followed by a wide excision of the extra-hepatic portion of the
cyst wall. The cavity can be inspected and biopsies taken from
any area of concern. The excised cyst wall should be subjected
to histopathological assessment. Hemostasis can be achieved
by oversewing the edge of the cyst wall.
laparoscopic surgery
In recent years, the technique of laparoscopic cyst fenestration
has developed and should now be the first-line surgical
approach for patients with symptomatic simple cysts. Laparo-
scopic cyst fenestration has all the advantages of minimally
invasive surgery including reduced postoperative pain, shorter
hospital stay, and quicker recovery. The laparoscopic proce-
dure was initially recommended for cysts in segments II, III,
IVb, and V. However, with increasing experience, location
should not be considered a contraindication to laparoscopic
surgery (40). A standard 4 port laparoscopic technique is used
with the patient in a supine position, although for right-sided
posteriorly placed cysts a left lateral position can give superior
access. An angled laparoscope (30 or 45 degrees) gives superior
views of the cyst cavity. The cyst can be punctured by insertion
of a trocar through the exposed wall. The contents are sent for
analysis. A wide excision of the cyst wall is then made, taking
great care not to venture into the hepatic parenchyma. Various
techniques have been employed to achieve hemostasis of the
remnant cyst wall including diathermy, over sewing of the
remnant cyst wall edge and using a laparoscopic linear cutting
vascular stapler to excise the cyst wall. The authors’ preference
is to use harmonic shears.
The resected cyst wall is removed in an endoscopic retrieval
bag, and the remnant cyst wall is inspected. Although unusual,
if a bile leak is identified it must be controlled either with a
suture or with a laparoscopic clip. Some authors advocate
obliteration of the residual cyst wall with electrocautery. If this
is attempted it should be done without breaching the cyst wall
as major vascular structures, distorted by the cyst, can lie just
underneath. The argon beam coagulator is probably best
suited to the task (41) as the burn is very superficial. There is
the potential risk of gas embolus and careful control of intra-
peritoneal pressure must be maintained.
To prevent recurrence of the cyst, particularly when the
exposed cyst cavity will come to lie against the abdominal wall,
an omentoplasty should be performed. A pedicle of omentum
is mobilized from the transverse colon and advanced into the
cyst cavity. It can be secured either with sutures or with lapa-
roscopic clips. A cholecystectomy is not routinely performed
unless there is evidence of cholecystolithiasis, or where the cyst
drainage leaves the gallbladder excessively mobile and at risk
of subsequent torsion.
The results of laparoscopic cyst fenestration are encouraging
though most reported studies have few patients with short
follow-up periods. Three recent studies have reported out-
comes in patients treated with laparoscopic cyst fenestration
with a mean follow-up greater than 4 years (40,42,43). There is
no reported mortality, with asymptomatic recurrence seen in
up to 50% (40) but symptomatic recurrence noted in only
4.5% (43).
open surgery
With the development of the laparoscopic technique, the pro-
cedure of open cyst fenestration for benign simple cysts should
be reserved for those patients with recurrent disease or with
extensive abdominal adhesions that preclude the laparoscopic
technique. More radical procedures, including cystectomy and
liver resection, carry a greater morbidity and mortality than
cyst fenestration (44). Cystectomy can be particularly danger-
ous as the adjacent parenchyma is compressed and major vas-
cular structures are often within the walls of the cyst. The main
indication for resection is when there is suspicion that the cyst
may be neoplastic in nature.
polycystic liver disease
Adult Polycystic Liver Disease (PCLD) is a hereditary condi-
tion characterized by the development of multiple macro-
scopic and microscopic cysts throughout the liver. They are
histopathologically similar to simple biliary cysts. There are
two main forms of the disease and both show an autosomal
dominant pattern of inheritance.
The most common form of PCLD develops in association
with autosomal-dominant polycystic kidney disease (ADPKD)
(Figs. 33.3 and 33.4). This is one of the most common inher-
ited diseases with a prevalence of 1 in 400 to 1 in 1000 and
accounts for 8% to 10% of all cases of end stage renal failure
(45). Factors associated with more extensive hepatic involve-
ment are increasing age, female gender, severity of renal dis-
ease, and severity of renal dysfunction (46). The prevalence of
liver cysts in ADPKD rises from 20% in the third to 70% in the
seventh decade of life (47). The severity of disease in females
correlates with the number of pregnancies and the use of exog-
enous female hormones (46), and may be due to the stimula-
tory effects of estrogen (48). The much rarer hereditary form
of PCLD, known as Autosomal Dominant Polycystic Liver
Disease (ADPLD), occurs with liver-only involvement (49).
clinical presentation
The majority of patients with PCLD are asymptomatic and, as
with simple cysts, the diagnosis is made during routine inves-
tigation (50). Laboratory tests of liver function including bili-
rubin, alkaline phosphatase, alanine aminotransferase, and
prothrombin time are usually normal. Symptoms tend to
occur in patients with longstanding disease and are related to
liver enlargement and compression of adjacent organs. Patients
may complain of an increase in abdominal girth, upper
abdominal pain, early satiety, nausea, respiratory compromise,
and limitation in physical ability.
More significant complications include hemorrhage into a
cyst, infection within a cyst and compression of vascular and
303
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 33.3 Portal venous phase MDCT image showing multiple large cysts
throughout the liver. Cysts are also noted within the kidneys.
Figure 33.4 T2-weighted MRI image of the upper abdomen showing the
appearance of multiple fluid filled simple cysts both in the liver and in the left
kidney of a patient with PCLD. Fluid is bright on T2-weighting.
biliary structures. Infection within a cyst is a rare but serious
complication and the patient will usually present with
abdominal pain and raised inflammatory markers. Awareness
of the diagnosis along with prompt treatment with antibiotics
and a drainage procedure are necessary to reduce morbidity
and mortality (51,52). Jaundice can occur in PCLD due to
direct compression of the extrahepatic biliary tree by cysts (53).
Most patients with PCLD have well-preserved parenchyma
and hepatic failure is rarely reported.
Gigot et al. produced a useful classification of adult PCLD
according to the number and size of liver cysts and the amount
of remaining liver parenchyma (54) (Table 33.1). This classifi-
cation of PCLD is of use in determining treatment algorithms
for patients.
treatment
Therapeutic intervention should only be considered for
those patients with significant symptoms or complications
304
Table 33.1 Gigot Classification of Adult Polycystic
Liver Disease
Classification Features
Type I Limited number (<10) of large cysts with
large areas of non-cystic parenchyma.
Type II Diffuse involvement of liver with multiple
medium sized cysts with remaining large
areas of non-cystic parenchyma.
Type III Massive diffuse involvement of all areas of
liver by small and medium-sized cysts with
only a few areas of normal parenchyma
between cysts.
due to PCLD. The aim of treatment should be to reduce the
size of the cystic component of the liver, whilst preserving
parenchymal liver function, leading to long-term relief of
symptoms.
aspiration sclerotherapy
The techniques of serial cyst aspiration (55) and serial aspira-
tion sclerotherapy (56) have been used with success in the
treatment of PCLD. However, there is a higher rate of recur-
rence in PCLD than seen in the treatment of simple hepatic
cysts, one explanation being that the more rigid hepatic paren-
chyma prevents complete collapse of the cysts (27). As a result,
this technique is probably best suited to patients with Gigot
type I disease in whom more aggressive surgical options would
be contraindicated. One exception would be in treating the
life-threatening complication of cyst infection where a combi-
nation of antibiotic therapy and cyst drainage is required to
reduce mortality (52).
surgical treatment
Surgical options for the treatment of PCLD include cyst fenes-
tration, liver resection, a combination of cyst fenestration and
liver resection, and liver transplantation.
The procedure of cyst fenestration, either by an open or by
a laparoscopic approach, involves the progressive deroofing
of liver cysts, starting superficially and working through to
cysts placed deeper within the liver parenchyma. This
approach is best suited to patients with Gigot type I disease.
The resulting decrease in liver volume can lead to a signifi-
cant improvement in symptoms for the majority of patients
(57,58).
For patients with more severe parenchymal involvement,
classified as Gigot types II and III, fenestration alone is rarely
successful. A combination of hepatic resection with fenestra-
tion may, however, offer alleviation of symptoms through a
reduction in liver volume and mass (59–61). The procedure
typically involves a non-anatomical resection of either the
right or left hemi-liver with fenestration of accessible cysts on
the remnant side. The preservation of hepatic parenchyma is
crucial when planning the resection. The procedure can be
technically challenging as the hepatic anatomy is distorted by
the cysts. The absence of landmarks predisposes to injury of
the remnant liver inflow or outflow. The major vasculo-biliary
structures are often compressed between adjacent cyst walls,
 BENIGN CYSTIC DISEASE OF THE LIVER
and during resection major bleeding can be encountered.
Whilst hepatic pedicle inflow control is usually possible, venous
outflow control can be difficult to secure. For these reasons
the procedure should only be undertaken by experienced
hepatobiliary surgeons.
One recent study of resection-fenestration in 21 PCLD
patients reported symptom resolution in 100% of cases
(62). However, procedure-related morbidity was high
(76.2%), with the main complications being ascites (71%),
pleural effusion (43%), and bile leak (10%). Transfusion
requirements were high (mean 4.5 units per patient) and
hospital stay was long (mean 15.5 days). This high morbid-
ity rate has been reported in earlier series (59–61). There-
fore, although this procedure can offer long-term relief of
symptoms for patients with advanced PCLD, the benefits
must be weighted against the significant morbidity related
to the surgery.
While the majority of patients with PCLD have well-
preserved liver function, cadaveric (63–66) and live
donor (67–70) orthotopic liver transplantation have been
successfully used in the treatment of symptomatic patients. It
can be argued that such an approach is overly aggressive.
However, for patients with numerous truly diffuse small cysts
there may be no other effective treatment. In those patients
who are dialysis dependent the procedure can also be com-
bined with a kidney transplant using a graft from the same
donor. The first successful series of liver transplantation for
PCLD was reported by Starzl and colleagues for patients with
what they described as the syndrome of “lethal exhaustion”
(71). These patients are cachectic and have severe functional
limitation due to the weight of their enlarging livers. They
fatigue easily, have intractable pain, and are usually opiate
dependent.
The outcome of liver transplantation for PCLD has been
reported from a number of centres. The largest is a series of
36 patients transplanted over a period of 13 years (63). Twenty
one received a liver-only graft, with 15 receiving combined liver
and kidney grafts. The 1- and 5- year patient survival was 86%.
Five deaths occurred in the series, all within 2 months. Four
deaths were attributed to sepsis and one to a myocardial infarc-
tion. Perhaps most importantly, measures of post transplant qual-
ity of life were assessed using a combination of questionnaires. Of
the 74% of patients who responded, 91% reported feeling “much
better” or “better,” with only 9% feeling “worse” than before.
Fatigue, physical fitness, loss of appetite, and vomiting improved
significantly after transplantation, and 78% of patients said they
would opt for transplantation again. In summary, liver transplan-
tation offers a complete and definitive treatment for a minority of
patients with end stage PCLD. The benefits of transplantation,
however, must be balanced by the risks of the procedure and the
need for life-long immunosuppression.
novel treatments
Medical treatments have in the past had little role in the treat-
ment of PCLD. There are reports of a reduction in cyst vol-
ume using the somatostatin analog octreotide. The effect is
thought to be due to a direct reduction of fluid secretion by
cholangiocytes (72). In one recent clinical trial, the treatment
of patients with PCLD with the immunosuppressive agent
sirolimus was associated with decreased polycystic liver vol-
ume. The mechanism for this effect is not clear, but may be
through preventing aberrant activation of mTOR in the cyst
epithelial cells (73).
Recently, percutaneous transcatheter hepatic artery emboli-
zation has been reported in the treatment of polycystic liver
disease (74,75). Polyvinyl alcohol particles and micro-coils are
used to selectively embolize the segmental hepatic arteries of
the most affected segments of the liver. Initial results are
encouraging, with a reduction in both total liver and cyst vol-
umes, and an improvement in symptoms. Further studies will
be required to investigate long term effectiveness, but the pro-
cedure may have a role in treating patients unsuitable for more
invasive therapy.
rare benign cystic lesions of the liver
Mesenchymal hamartomas are the second commonest benign
liver lesion in children. They account for 5% of pediatric liver
tumors (76). Presentation is usually with progressive abdomi-
nal distension. Radiologically a large, multicystic liver mass is
seen, more commonly in the right lobe than the left. Histo-
logically they are composed of bile ducts, immature mesen-
chymal cells and hepatocytes (77). Surgical resection is usually
necessary.
Ciliated foregut cysts are rare and usually solitary. Microscopi-
cally they have an inner ciliated pseudostratified columnar epi-
thelium, a smooth muscle layer and a fibrous capsule (78). They
are commonly located in segment IV (77) and can rarely undergo
malignant transformation (squamous metaplasia) (79). Surgical
treatment is required if the diagnosis is uncertain or if there is
compression of the vasculobiliary tree.
Bile duct hamartomas are small, usually less than 1 cm in
size. They are composed of dilated bile ducts with a dense col-
lagenous stroma. They do not communicate with the biliary
system (80). Since this lesion can appear to have solid ele-
ments, it can be difficult to differentiate from a metastasis or a
cyst adenocarcinoma (81). T2-weighted MRI images are very
useful in the diagnosis since biliary hamartomas are hyperin-
tense (82). Diagnostic uncertainty can occasionally lead to a
percutaneous or surgical biopsy.
summary
Benign cystic lesions of the liver are being increasingly recog-
nized due to improvements in and wider availability of radio-
logical techniques. They only require treatment if they produce
symptoms or if there is a diagnostic uncertainty. Treatment is
usually in the form of percutaneous aspiration, aspiration
sclerotherapy or surgery. Surgical treatment ranges from fenes-
tration of the cyst wall, cystectomy, or liver resection. These can
be performed as open or laparoscopic procedures according to
the surgeon’s expertise. PCLD may rarely require liver trans-
plantation. As yet there are no randomized or case control
studies comparing different treatment options. Therefore,
treatment decisions have to be based on level 3 evidence (the
case report or small case series) and the experience of the
treating physician.
305
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
key points
The vast majority of benign cystic lesions of the liver do
not require treatment. Rarer forms of these lesions may have
an element of diagnostic uncertainty. Indications for
treatment are
● Increase in size in surveillance scans
● Pain affecting quality of life
● Symptoms due to compression of the stomach,
duodenum, biliary tree, portal venous system or
inferior vena cava
● Intracystic hemorrhage
● Spontaneous/traumatic rupture
● Evidence of infection in the cyst
● Diagnostic uncertainty
acknowledgments
The authors would like to acknowledge and thank Dr
David White, Consultant Radiologist, University Hospital
Aintree, Liverpool, for contributing the images reproduced in
this chapter.
references
1. Dhumeaux D. Congenital cystic diseases of the intra and extrahepatic bile
ducts. Gastroenterol Clin Biol 2005; 29: 878–82.
2. Mergo PJ, Ros PR. Benign lesions of the liver. Radiol Clin N Am 1998;
36: 319–31.
3. Mortelé KJ, Ros PR Cystic focal liver lesions in the adult: differential CT
and MR imaging features. Radiographics 2001; 21: 895–910.
4. Sanfelippo PM, Beahrs OH, Weiland LH. Cystic disease of the liver. Ann
Surg 1974; 179: 922–5.
5. Chang CS, Lin KC, Hwang SL, et al. Nonparasitic hepatic cysts detected in
ultrasonographic examination: analysis of 95 cases. Taiwan Yi Xue Hui Za
Zhi 1989; 88: 394–9.
6. Gaines PA, Sampson MA. The prevalence and characterization of simple
hepatic cysts by ultrasound examination. Br J Radiol 1989; 62: 335–7.
7. Caremani M, Vincenti A, Benci A, et al. Ecographic epidemiology of non-
parasitic hepatic cysts. J Clin Ultrasound 1993; 21(2):115–8.
8. Carrim ZI, Murchison JT. The prevalence of simple renal and hepatic
cysts detected by spiral computed tomography. Clin Radiol 2003;
58: 626–9.
9. Larssen TB, Rørvik J, Hoff SR, et al. The occurrence of asymptomatic and
symptomatic simple hepatic cysts. A prospective, hospital-based study.
Clin Radiol 2005; 60: 1026–9.
10. Sanchez H, Gagner M, Rossi RL, et al. Surgical management of nonpara-
sitic cystic liver disease. Am J Surg 1991; 161: 113–8.
11. Erdogan D, van Delden OM, Rauws EA, et al. Results of percutaneous
sclerotherapy and surgical treatment in patients with symptomatic simple
liver cysts and polycystic liver disease. World J Gastroenterol 2007;
13: 3095–100.
12. Takahashi G, Yoshida H, Mamada Y, et al. Intracystic hemorrhage of a
large simple hepatic cyst. J Nippon Med Sch 2008; 75: 302–5.
13. Ishikawa H, Uchida S, Yokokura Y, et al. Nonparasitic solitary huge liver
cysts causing intracystic hemorrhage or obstructive jaundice. J Hepatobi-
liary Pancreat Surg 2002; 9: 764–8.
14. Kanai T, Kenmochi T, Takabayashi T, et al. Obstructive jaundice caused by
a huge liver cyst riding on the hilum: report of a case. Surg Today 1999;
29: 791–4.
15. England RA, Wells IP, Gutteridge CM. Benign external compression of the
inferior vena cava associated with thrombus formation. Br J Radiol 2005;
78: 553–7.
16. Poggi G, Gatti C, Delmonte A, et al. Spontaneous rupture of non-parasitic
hepatic cyst. Int J Clin Pract 2006; 60: 99–103.
306
17. Klingler PJ, Gadenstätter M, Schmid T, et al. Treatment of hepatic cysts in
the era of laparoscopic surgery. Br J Surg 1997; 84: 438–44.
18. Saini S, Mueller PR, Ferrucci JT Jr, et al. Percutaneous aspiration of
hepatic cysts does not provide definitive therapy. Am J Roentgenol 1983;
141: 559–60.
19. Koperna T, Vogl S, Satzinger U, et al. Nonparasitic cysts of the liver: results
and options of surgical treatment. World J Surg 1997; 21: 850–4.
20. Regev A, Reddy KR, Berho M, et al. Large cystic lesions of the liver in adults:
a 15-year experience in a tertiary center. J Am Coll Surg 2001; 193: 36–45.
21. Lopes HM, Portela FA, e Silva Pontes JM, et al. Treatment of benign
hepatic cysts by instillation of tetracycline hydrochloride. Hepatogastro-
enterology 1998; 45: 496–9.
22. McFarlane ME, Venugopal R, McDonald A, Ewing, et al. Management of
hepatic cysts by percutaneous drainage and instillation of tetracycline
hydrochloride. Indian Med J 2001; 50: 230–3.
23. Cellier C, Cuenod CA, Deslandes P, et al. Symptomatic hepatic cysts:
treatment with single-shot injection of minocycline hydrochloride. Radi-
ology 1998; 206: 205–9.
24. Yoshida H, Onda M, Tajiri T, et al. Long-term results of multiple minocy-
cline hydrochloride injections for the treatment of symptomatic solitary
hepatic cyst. J Gastroenterol Hepatol 2003; 18: 595–8.
25. Goldstein HM, Carlyle DR, Nelson RS. Treatment of symptomatic hepatic
cyst by percutaneous instillation of Pantopaque. Am J Roentgenol 1976;
127: 850–3.
26. Bean WJ, Rodan BA. Hepatic cysts: treatment with alcohol. Am J Roent-
genol 1985; 144: 237–41.
27. Kairaluoma MI, Leinonen A, Ståhlberg M, et al. Percutaneous aspiration
and alcohol sclerotherapy for symptomatic hepatic cysts. An alternative to
surgical intervention. Ann Surg 1989; 210: 208–15.
28. Larssen TB, Jensen DK, Viste A, et al. Single-session alcohol sclerotherapy
in symptomatic benign hepatic cysts. Long-term results. Acta Radiol
1999; 40: 636–8.
29. Blonski WC, Campbell MS, Faust T, et al. Successful aspiration and etha-
nol sclerosis of a large, symptomatic, simple liver cyst: case presentation
and review of the literature. World J Gastroenterol 2006; 12: 2949–54.
30. Horsmans Y, Laka A, Gigot JF, et al. Serum and cystic fluid CA 19-9 deter-
minations as a diagnostic help in liver cysts of uncertain nature. Liver
1996; 16: 255–7.
31. Yang CF, Liang HL, Pan HB, et al. Single-session prolonged alcohol-retention
sclerotherapy for large hepatic cysts. Am J Roentgenol 2006; 187: 940–3.
32. vanSonnenberg E, Wroblicka JT, D’Agostino HB, et al. Symptomatic
hepatic cysts: percutaneous drainage and sclerosis. Radiology 1994;
190: 387–92.
33. Andersson R, Jeppsson B, Lunderquist A, et al. Alcohol sclerotherapy of
non-parasitic cysts of the liver. Br J Surg 1989; 76254–5.
34. McCullough KM. Alcohol sclerotherapy of simple parenchymal liver
cysts. Austr Radiol 1993; 37: 177–81.
35. Simonetti G, Profili S, Sergiacomi GL, et al. Percutaneous treatment of
hepatic cysts by aspiration and sclerotherapy. Cardiovasc Intervent Radiol
1993; 16: 81–4.
36. Montorsi M, Torzilli G, Fumagalli U, et al. Percutaneous alcohol sclero-
therapy of simple hepatic cysts. Results from a multicentre survey in Italy.
HPB Surg 1994; 8: 89–94.
37. Tikkakoski T, Mäkelä JT, Leinonen S, et al. Treatment of symptomatic
congenital hepatic cysts with single-session percutaneous drainage and
ethanol sclerosis: technique and outcome. J Vasc Interv Radiol 1996;
7: 235–9.
38. Zerem E, Imamović G, Omerović S. Percutaneous treatment of symp-
tomatic non-parasitic benign liver cysts: single-session alcohol sclerother-
apy versus prolonged catheter drainage with negative pressure. Eur Radiol
2008; 18: 400–6.
39. Lin TY, Chen CC, Wang SM. Treatment of non-parasitic cystic disease of
the liver: a new approach to therapy with polycystic liver. Ann Surg 1968;
168: 921–7.
40. Fabiani P, Iannelli A, Chevallier P, et al. Long-term outcome after laparo-
scopic fenestration of symptomatic simple cysts of the liver. Br J Surg
2005; 92596–7.
41. Tan YM, Chung A, Mack P, et al. Role of fenestration and resection for
symptomatic solitary liver cysts. ANZ J Surg 2005; 75: 577–80.
 BENIGN CYSTIC DISEASE OF THE LIVER
42. Palanivelu C, Jani K, Malladi V. Laparoscopic management of benign
nonparasitic hepatic cysts: a prospective nonrandomized study. South
Med J 2006; 99: 1063–7.
43. Bai XL, Liang TB, Yu J, et al. Long-term results of laparoscopic fenestra-
tion for patients with congenital liver cysts. Hepatobiliary Pancreat Dis
Int 2007; 6: 600–3.
44. Gigot JF, Hubert C, Banice R, et al. Laparoscopic management of benign
liver diseases: where are we? HPB 2004; 6: 197–212.
45. Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med
1993; 329: 332–42.
46. Gabow PA, Johnson AM, Kaehny WD, et al. Risk factors for the develop-
ment of hepatic cysts in autosomal dominant polycystic kidney disease.
Hepatology 1990; 11: 1033–7.
47. Chauveau D, Fakhouri F, Grunfeld JP. Liver involvement in autosomal-
dominant polycystic kidney disease: therapeutic dilemma. J Am Soc
Nephrol 2000; 11: 1767–75.
48. Sherstha R, McKinley C, Russ P, et al. Postmenopausal estrogen therapy
selectively stimulates hepatic enlargement in women with autosomal
dominant polycystic kidney disease. Hepatology 1997; 26: 1282–6.
49. Pirson Y, Lannoy N, Peters D, et al. Isolated polycystic liver disease as a
distinct genetic disease, unlinked to polycystic kidney disease 1 and poly-
cystic kidney disease 2. Hepatology 1996; 23: 249–52.
50. Russell RT, Pinson CW. Surgical management of polycystic liver disease.
World J Gastroenterol 2007; 13: 5052–9.
51. Abascal J, Moya M, Martin F. Infection of hepatic cysts in polycystic dis-
ease. World J Surg 1984; 8: 424–5.
52. Telenti, A, Torres, VE, Gross, JB, et al. Hepatic cyst infection in autoso-
mal dominant polycystic kidney disease. Mayo Clin Proc 1990; 65:
933–42.
53. Dmitrewski J, Olliff S, Buckels JA. Obstructive jaundice associated with
polycystic liver disease. HPB Surg 1996; 10: 117–20.
54. Gigot JF, Jadoul P, Que F, et al. Adult polycystic liver disease: is fenestra-
tion the most adequate operation for long-term management? Ann Surg
1997; 225: 286–94.
55. Arrivé L, Tubiana JM. Serial needle aspiration in polycystic liver disease.
Am J Roentgenol 2003; 181: 1717.
56. Ferris JV. Serial ethanol ablation of multiple hepatic cysts as an alternative
to liver transplantation. AJR 2003; 180: 472–4.
57. Konstadoulakis MM, Gomatos IP, Albanopoulos K, et al. Laparoscopic
fenestration for the treatment of patients with severe adult polycystic liver
disease. Am J Surg 2005; 189: 71–5.
58. Robinson TN, Stiegmann GV, Everson GT. Laparoscopic palliation of
polycystic liver disease. Surg Endosc 2005; 19: 130–2.
59. Vauthey JN, Maddern GJ, Blumgart LH. Adult polycystic disease of the
liver. Br J Surg 1991; 78: 524–7.
60. Que F, Nagorney DM, Gross JB Jr, et al. Liver resection and cyst fenestra-
tion in the treatment of severe polycystic liver disease. Gastroenterology
1995; 108: 487–94.
61. Yang GS, Li QG, Lu JH, et al. Combined hepatic resection with fenestra-
tion for highly symptomatic polycystic liver disease: a report on seven
patients. World J Gastroenterol 2004; 10: 2598–601.
62. Li TJ, Zhang HB, Lu JH, et al. Treatment of polycystic liver disease with
resection-fenestration and a new classification. World J Gastroenterol
2008; 14: 5066–72.
63. Kirchner GI, Rifai K, Cantz T, et al. Outcome and quality of life in patients
with polycystic liver disease after liver or combined liver-kidney trans-
plantation. Liver Transpl 2006; 12: 1268–77.
64. Ueno T, Barri YM, Netto GJ, et al. Liver and kidney transplantation for
polycystic liver and kidney-renal function and outcome. Transplantation
2006; 82: 501–7.
65. Rossi M, Spoletini G, Bussotti A, et al. Combined liver-kidney transplan-
tation in polycystic disease: case reports. Transplant Proc 2008; 40: 2075–6.
66. Schnelldorfer T, Torres VE, Zakaria S, et al. Polycystic liver disease: a criti-
cal appraisal of hepatic resection, cyst fenestration, and liver transplanta-
tion. Ann Surg 2009; 250: 112–8.
67. Takegoshi K, Tanaka K, Nomura H, et al. Successful living donor liver
transplantation for polycystic liver in a patient with autosomal-dominant
polycystic kidney disease. J Clin Gastroenterol 2001; 33: 229–31.
68. Koyama I, Fuchinoue S, Urashima Y, et al. Living related liver transplanta-
tion for polycystic liver disease. Transpl Int 2002; 15: 578–80.
69. Ueda M, Egawa H, Oike F, et al. Living-donor liver transplantation for
polycystic liver disease. Transplantation 2004; 77: 480–1.
70. Mekeel KL, Moss AA, Reddy KS, et al. Living donor liver transplantation
in polycystic liver disease. Liver Transpl 2008; 14: 680–3.
71. Starzl TE, Reyes J, Tzakis A, et al. Liver transplantation for polycystic liver
disease. Arch Surg 1990; 125: 575–7.
72. van Keimpema L, de Man RA, Drenth JP. Somatostatin analogues reduce
liver volume in polycystic liver disease. Gut 2008; 57: 1338–9.
73. Qian Q, Du H, King BF, et al. Sirolimus reduces polycystic liver volume in
ADPKD patients. J Am Soc Nephrol 2008; 19: 631–8.
74. Takei R, Ubara Y, Hoshino J, et al. Percutaneous transcatheter hepatic
artery embolization for liver cysts in autosomal dominant polycystic kid-
ney disease. Am J Kidney Dis 2007; 49: 744–52.
75. Park HC, Kim CW, Ro H, et al. Transcatheter arterial embolization ther-
apy for a massive polycystic liver in autosomal dominant polycystic kid-
ney disease patients. J Korean Med Sci 2009; 24: 57–61.
76. D’ Angelica M, Fong Y. The Liver. In: Townsend CM, Beauchamp RD,
Evers BM, Mattox KL, eds. Sabiston Textbook of Surgery, 17th edn. Phila-
delphia: Elsevier, 2004: 1513–75.
77. Del Poggio P, Buonocore M. Cystic tumours of the liver: a practical
approach. World J Gastroenterol 2008; 14: 3616–20.
78. Bogner B, Hegedus G. Ciliated hepatic foregut cyst. Pathol Oncol Res
2002; 8: 278–9.
79. Shaw JM, Krige JE, Beningfield SJ, et al. Ciliated hepatic foregut cyst: a
rare cystic liver lesion. J Gastrointest Surg 2008; 12: 1304–6.
80. Precetti S, Gandon Y, Vilgrain V. Imaging of cystic liver diseases. J Radiol
2007; 88: 1061–72.
81. Karahan OI, Kahriman G, Soyuer I, et al. Hepatic von Meyenburg com-
plex simulating biliary cystadenocarcinoma. Clin Imaging 2007; 31: 50–3.
82. Maher MM, Dervan P, Keogh B, et al. Bile duct hamartomas (von Meyen-
burg complexes): value of MR imaging in diagnosis. Abdom Imaging
1999; 24: 171–3.
307
34 Management of hydatid disease of the liver
Adriano Tocchi
biological and pathological basis
of modern surgery
The echinococcus, or hydatid cyst, represents the larval stage
of Echinococcus granulosus, a 2 to 6 mm long tapeworm. The
adult tapeworm consists of a head (scolex) and three following
segments (proglottides). The scolex has four suckers and a
prominent rostellum armed with a double row of 30 to
36 hooks. Sexual, mature organs and countless eggs are con-
tained in the more distal of the three proglottides. Each egg
consists of a shell containing six hook armed embyo hexacant
(six hooks). In the adult stage, the tapeworm lives in the gut of
the dog, the definitive host. The intermediate animal hosts,
where the parasite lives and develops at the larval stage, are
sheep, cattle, pigs, and man (considered an “accidental” inter-
mediate host). There are also “sylvatic cycles” of echinococcus
which occur in Canada, Alaska, Australia, and other countries
with different definitive and intermediate hosts according to
the local prevalence of animal species.
Human infection is direct or indirect from the dog through
the parasite eggs. Once ingested, they hatch and liberate the
hexacant embryo. This attaches to and crosses the intestinal
mucosa and via the portal system migrates to the liver where
the parasite develops into the larval stage which is the hydatid
cyst. However, the parasite may cross the portal network and
reach the lung, where it may lodge or continue beyond and
into the vascular network, toward the various organs by way of
systemic arterial vessels.
structure of the cyst
The echinococcus cyst is composed of the wall and contents. The
parasite-derived endocyst, namely the wall of the true vesicular
metacestode, may consist of either one or two layers. The outer
one, laminated or chitinous layer, is a totally acellular membrane,
composed of concentric hyaline laminae, permeable to water
and electrolytes, which protects the cyst from host enzymes, bile,
and bacteria. The inner layer consists of a thin (10–25 mm) ger-
minal or parenchymal layer, which represents the living element
of the parasite, composed of an outer basal syncytial layer and an
inner nucleated cell layer. Invaginations of the germinal layer
form brood capsules each containing 5 to 10 protoscolex. Cyst’s
growth leads to the formation in the surrounding parenchyma,
in the case of man the liver, of a connective lamina ectocyst or
pericyst, able to ensure nutritional exchanges for a long time
(Fig. 34.1). Cysts provided of the sole laminated layer are sterile
cysts also called univesicular or clear cysts (exempt from vesicu-
lation!) whereas cysts provided with both laminated and germi-
nal layers are fertile or multivesicular cysts. When brood capsules
open, protoscoleces are released into the cystic fluid giving raise
to daughter cysts: endogenic vesiculation.
The origin and cause of daughter cyst formation are not well
understood, apart from a non-specific stress of the germinal
308
layer for impaired vital exchanges with the host and decreased
endocyst pressure (1). Among the various causes suggested,
pericyst thickening and the penetration of bile between the peri-
cyst and cyst wall and inside it are of concern for the surgeon.
The pericyst, initially composed of very thin connective
lamina, subsequently tends to become thicker (up to 1 cm or
more), sclerose, and calcify. The process of cyst expansion
causes compression of hepatic parenchymal structures, in turn
engulfed into the pericyst. Large vessels are compressed and
displaced while remaining, however, patent for a long time.
Similarly, bile ducts remain patent and may open into the peri-
cyst, between it, and the parasite wall. This phenomenon
occurs frequently, unlike the rare frank rupture of the cyst with
effusion of the cyst contents into a large duct and the main bile
duct. This is of the utmost importance for surgery, since on the
one hand its appearance causes major changes in the cyst and
pericyst development, and on the other it favors the develop-
ment of postoperative complications such as biliary fistulas.
Bile filtration in the virtual interstitium between the pericyst
and the chitinous membrane can form a perivesicular biloma
with loss of direct contact of the cyst with the pericyst, a
decrease in the mother cyst pressure and membrane rupture.
At the same time, the appearance of bile is preliminary to
cyst infection.
Whatever the cause, endogenous vesiculation should be
considered as an initial attempt at survival by the primary par-
asite. Subsequently the neoformed hydatid material packed
into the cystic cavity tends to show signs of stress and to degen-
erate extensively with varying consistencies akin to: fruit jelly,
putty, plaster, dry clay, or pus (Fig. 34.2). At the same time, the
fibrous pericyst becomes thicker and calcium deposits appear
as increasingly extended and confluent granules and laminae,
forming in some cases a continuous thick shell. These degen-
erative aspects have been considered as corresponding to the
parasite’s death, which is not. Viable hydatids are most often
found within this degenerate material (2).
Protoscoleces and brood vesicles generated by the germinal
layer can penetrate the chitinous membrane through fissures
and then tend to advance into the pericyst (3). Alternatively,
there may be germinal islets trapped between the lamellae of
the syncytial layer. Once the germinal elements penetrate the
pericyst, they may grow inside and then project toward the
liver parenchyma as diverticular protrusions surrounded by
their own thin pericyst: exogenous vesiculation (Fig. 34.3). In
their cavity, they contain growing cysts, favored by easy
exchanges through the thin neoformed pericyst and behave as
the mother cyst. As there is no connection with the inner
surface of primary pericyst they cannot be detected or even
suspected with the most careful examination after emptying
(Fig. 34.4). The exogenous cyst, while growing, can pull away
from the mother cyst and this results in the commonly
 MANAGEMENT OF HYDATID DISEASE OF THE LIVER

observed pattern of two or more adjacent cysts, or “satellite
cysts” (4), separated by a parenchymal septum usually rich in
vascular and ductal structures already displaced by the mother
cyst. In other frequently observed instances, the exogenous
cyst remains in contact with the primary cyst separated by a
L series the recurrence rates of clear and multivesicular cysts are
P
C
G real incidence of recurrence in multivesicular cysts. However,
BC
P
DC
Figure 34.1 Structure of the liver hydatid cyst. Abbreviations: L, liver; P,
pericyst; C, chitinous layer; G, germinal layer; BC, brood capsules or vesicles;
P, protoscoleces; DC, daughter cysts (similar to mother cyst).
thin residual septum (“sand-glass-like cyst”), or with the col-
lapse of separating septum, the two cavities communicate
through a more or less wide operculum (“sacculations”).
As for the presence and frequency of ectogenic vesiculation, the
phenomenon is either ignored or largely underestimated (5–9),
because of the preference for conservative operations which
do not allow their identification, and because in all reported
calculated together, thus leading to an under-reporting of the
ectogenic vesiculation is recognized in about 30% of radical
operations for multivesicular cysts (10,11). Once this phe-
nomenon was identified and quantitatively assessed, its impor-
tance was recognized beyond just biological and pathological
interest. Consequently, in a large number of patients in whom
procedures performed including no removal of the pericyst,
this could not be considered effective: actually, only the cyst
was resected. Viable, vital parasite foci remained, bound to
lead to disease progression. This was incorrectly considered a
recurrence attributed to implantation from accidental dissem-
ination of the operating field or reinfection. The latter inter-
pretations, already unconvincing, have lost credibility, based
on the observation that the findings of ectogenic vesiculation,
compared with the incidence of recurrence in series of conser-
vative surgery, interestingly enough, were similar, at about
30%. This was furthermore confirmed by the fact that the
so-called recurrences were practically absent in series of radical
surgery (12–14).

(A) (B)

(C) (D)
Figure 34.2 Cyst features (total pericystectomy specimens). (A) Multivesicular cyst; (B) yellow-colored cystic membrane for biliary infiltration; (C) calcific cyst of
jelly-like necrotic contents and intense biliary infiltration; (D) calcific coarctate cyst of chalk-colored contents and dry clay consistency.

309
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A) (B)

(C) (D)
Figure 34.3 Exogenous vesiculation: microscopic appearance. (A) Brood capsules and protoscoleces contained in a protrusion of germinal layer within the cuticle;
(B and C) intrapericyst exogenous vesiculation hydatid membranes within the pericyst of primary cyst; (D) extrapericyst exogenous vesiculation encircled by a
new pericyst and protruding in the liver parenchyma adjacent to the mother cyst.

(A) (B)

(C) (D)
Figure 34.4 Intra- and extrapericyst exogenous vesiculation. Macroscopic appearance in four total pericystectomy specimens. (A and B) Within the pericyst of
open cysts viable daughter cysts are observed, separated from the mother cyst cavity; (C and D) clusters of pedunculated pseudodiverticula, non-communicating
with the mother cyst cavity, covered with a thin pericyst and containing daughter cysts.

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 MANAGEMENT OF HYDATID DISEASE OF THE LIVER
diagnosis
Hydatid cyst of the liver may be asymptomatic for years, some-
times for decades. Diagnosis may be accidental, based on an inci-
dental clinical exam that detects swelling when the cyst is located
in a palpable abdominal area or, in the case of hepatomegaly,
subsequently assessed with other examinations. Liver hydatidosis
may be an incidental finding in a plain radiograph of the hepatic
region when the cyst is calcified, during a chest radiograph for a
raised hemidiaphragm or during US examination performed for
other reasons such as gallstones. In children, large hepatic
swellings from hydatid cysts are accompanied by evident defor-
mities of the chest involving the last ribs and arches. Apart from
a sensation of pressure, a cyst of the liver may cause deep-seated
pain at the chest base because of diaphragmatic pleural or peri-
toneal reactive process. Dyspepsia, possibly from reflexes origi-
nating in the periductal nervous network, is not unusual.
Cholestasis from major bile duct compression may be responsi-
ble for fever, also of high grade. Liver function tests remain
normal for a long time.
Diagnosis is established using several investigations.
Conventional radiology may show a raised hemidiaphragm. In
calcific cysts, high-density roundish shadows are readily
visualized (Fig. 34.5).
Diagnostic Imaging
Ultrasonography (US)
Ultrasound is the preferred first-line imaging method for
hydatid liver cysts. It is non-invasive, low-cost and reproduc-
ible, thus suitable for postoperative follow-up or during
medical therapy. US supplies precise information on the size,
number, location, and vascular and biliary relationships of
the cyst as well as on its structure. Cysts are staged according
to the content patterns. Based on several studies and classifi-
cations (15–18), liver hydatid cysts can be divided into six
types:
● CL type (univesicular cyst), a well circumscribed,
round liquid, anechogenic image with a clearly
defined wall.
(A)
Figure 34.5 Plain radiographs. (A) Partial “en brioche” image of diaphragm profile; (B) calcific image pathognomonic of hydatid cyst.
● CE 1 type, a concentric hyperechogenic halo around
the cyst containing free-floating hyperechogenic foci
corresponding to “hydatid sand”
● CE 2 type includes multivesicular cysts that have the
most characteristic appearance with daughter cysts
identified by “honeycomb,” “rosette,” ”spoke wheel,”
or “cluster” images (Fig. 34.6)
● CE 3 type is characterized by a partial or total detach-
ment of the chitinous layer showing the “dual wall,”
“water-lily,” and “water snake” signs.
● CE 4 type includes cysts containing cystic and solid
components without visible daughter cysts.
● CE 5 includes cysts with a matrix or amorphous mass
with a solid or semisolid appearance. Calcification in
the rim of the host adventitial tissue is common.
Staging is important to allow more objective comparison of
different management strategies. US is also useful in postop-
erative follow-up.
Computed Tomography (CT)
CT is the procedure of choice when considering radical sur-
gery. Besides precise information on the cyst features, similar
to those acquired by US (Fig. 34.7), CT is fundamental in iden-
tifying vascular relationships, number, site, and type of the
cysts: dual, sand-glass like, with vesiculations (Fig. 34.8). CT is
invaluable for the diagnosis of recurring patterns. Spiral CT is
presently the gold standard investigation (19).
Magnetic Resonance Imaging (MRI)
A low-signal intensity rim on T2-weighted magnetic reso-
nance imaging is a characteristic sign of hydatid liver disease
that represents the outer collagen-rich laminated membrane
of the cyst. When present, daughter cysts are seen as cystic
structures attached to the germinal layer that are hypointense
relative to intracystic fluid on T1-weighted images and hyper-
intense on T2-weighted images (20). MRI cholangiography
can provide good visualization of the intrahepatic and extra-
hepatic biliary tree and its relationship with the hydatid cysts
and cystobiliary communication (21,22) (Fig. 34.9).
(B)
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A) (B)
Figure 34.6 US image. (A) Total detachment of parasite membrane from pericyst; (B) multivesicular hydatid cyst: “rosette” sign.

(A) (B)
Figure 34.7 CT image. (A) Univesicular cyst; (B) “water-snake” sign of membrane detachment.

(A) (B)
Figure 34.8 CT image. (A) Multivesicular cyst: “honeycomb” or “rosette” sign; (B) calcific cyst of segment VII in contact with the caval vein and causing intrahe-
patic duct dilation stasis.

312
 MANAGEMENT OF HYDATID DISEASE OF THE LIVER
(A)
Figure 34.9 (A) MRI coronal T1-weighted sequence after DTPA gadolinium injection with visualization of a cyst, about 2 cm in diameter, of segment IV at the
level of portal vein bifurcation (in the same patient a bulky hydatid cyst of segments VII, VIII, and V is present); (B) same technique in another patient. Inferior
caval vein compression with marked stenosis caused by a bulky cyst of right hemiliver.
Angiography
Hepatic artery angiography, inferior caval vein, and hepatic
vein venography have been progressively abandoned following
the introduction of US and CT-angiography. They may be still
of some use in the case of huge cysts to define their relation-
ships with the main parenchymal vessels.
Percutaneous cholangiography is contraindicated in liver
hydatidosis because of the risk of perforation of the cystic wall
and dissemination of hydatid contents. Endoscopic retrograde
cholangiopancreatography (ERCP) can be considered the most
suitable procedure for the characterization of the common bile
duct and the biliary relationships and communication of the
cyst. It allows pre- or postoperative papillotomy and bile duct
clearing (23–25). Perioperative cholangiography through the
remnant of the cystic duct may be of great use to detect the site
of cystobiliary fistulas.
Radioisotope Imaging
Scintigraphic imaging of the liver has been practically aban-
doned as a preoperative exam. Its use is presently restricted to
monitor postoperative liver function.
Serology
The hydatid cyst secretes and exposes numerous immuno-
modulatory molecules to the host’s immune system. These
molecules modulate both the innate and the adaptive arms of
the immune response and appear to target cellular and
humoral response. Several techniques for biologic diagnosis
and follow-up of human cystic hydatidos are used and there
are significant differences in specificity and sensitivity among
various tests (26). The diagnostic value of hydatidosis with
immunoelectrophoresis ranges between 91% and 94%. Immu-
noelectrophoresis can be used for post-treatment follow-
up (27). Sensitivities for enzyme-linked immunosorbent assay
(ELISA) vary from 64% to 100% depending on the antigens
(B)
used (28,29). This test is not suitable for post-treatment
follow-up because of its longstanding positivity after success-
ful treatment (30). Western blotting proved to be highly useful
in the diagnosis and postsurgical monitoring of hydatidosis
patients. Purification of antigens strongly affects the diagnos-
tic value of the test which, however, when using purified frac-
tions enriched in antigens 5 and B and glycoprotein, yield
sensitivity and specificity close to 100% (31,32).
complications
During its development, hydatid cysts of the liver may undergo
a number of complications, some of them clinically dramatic.
Infection
Infection of the cystic cavity and its contents is an ill defined
and frequently asymptomatic complication (33). It is most
likely caused by the penetration of bile into the cavity. Together
with the contents, the mother membrane can be destroyed and
consequently the altered escavated pericystic wall loses its
function of delimiting the infectious process which reaches the
hepatic parenchyma. Clinical course and related treatment are,
in this case, those of a hepatic abscess (34,35).
Rupture
Frank rupture (major communication) into the bile ducts
should be distinguished from simple biliary communication
(minor communication). Minor communications are usually
asymptomatic, revealed intraoperatively by a yellowish stain-
ing of the cystic content and the finding of biliary leakage in
the residual cavity. The true incidence of minor communica-
tion is ill defined; and the reported rates range between 28.6%
and 70% (36,37). The risk of biliary cyst communication has
been reported to be higher in patients with multiple cysts, in
patients to multilocular and degenerated cysts, and in patients
with cysts near the biliary bifurcation (38). Cyst diameter
313
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
greater than 10 cm has been considered as an independent
clinical predictor for the presence of intrabiliary rupture (39).
Major biliary communications are defined by a fistula greater
than 5 mm diameter or by a cystic communication into the
main bile duct (40). The pattern of symptoms usually includes
colicky pain accompanied and preceded by jaundice and
cholangitic fever (41). Ultrasound and CT are considered
first-line diagnostic tools to detect frank cystic rupture into
the biliary tree (42). ERCP has proved to be an invaluable tool
for the diagnosis and treatment of frank rupture into the bili-
ary tract (43). Intraperitoneal rupture of hydatid cyst is a seri-
ous but uncommon complication of liver hydatidosis (44).
Rupture may occur spontaneously, but in most cases, the
determining cause is blunt trauma. A further cause of perito-
neal effusion of hydatid contents is iatrogenic from percuta-
neous puncture for diagnosis or emptying, or it may occur
during surgery. Although this complication may be clinically
silent (45), abdominal pain, vomiting, and anaphylactic reac-
tions of varying degree to severe shock, characterized by
intense dyspnea, tachycardia, marked hypotension, and urti-
caria (46–48). The reaction is due to the abrupt release of
allergens reabsorbed from the peritoneal serosa and conveyed
to the circulation in a sensitized subject. The cyst rupture may
be followed by bile peritonitis with either a well defined or
insidious clinical pattern. The release of brood cystic fluid
into the peritoneal cavity leads to multiple cysts throughout
the peritoneal cavity (49). Consequences include occupancy,
compression, and displacement phenomena of organs and
structures with extremely severe and complex clinical pat-
terns and corresponding general impairment. Benzoimid-
azole therapy has represented a marked improvement in the
treatment of rupture of a cyst into the peritoneal cavity (50).
In cases of manifest, diffuse and inoperable peritoneal hyda-
tidosis, ultrasonography-guided emptying of huge, packed
cysts is useful to relieve the most severe clinical patterns of
compression and dysfunction.
Bile-stained cysts located in segments VII and VIII may
induce inflammatory adhesions. Necrosis of the latter results
in cyst communication with the pulmonary parenchyma at
(A)
Figure 34.10 Residual surfaces after removal of deep or vasculobiliary cysts: dissected and preserved vascular and biliary elements are indispensable for the survival
and function of parenchymal structures adjacent to the cyst. (A) The caval vein (c) and right hepatic vein with branchings are well visualized; (B) vasculobiliary
network of hilar origin distribution.
314
the lung base. Pulmonary inflammation, together with the
necrotizing action of bile, cause erosion into a peripheral
bronchus with consequent passage of hydatid material and
bile into the bronchial tree. Rupture of the cyst into the bron-
chial tree may be dramatic with abundant expectoration of
bile and hydatid material. Daily bile effusion is persistent and
increasing, resulting in an extremely severe clinical pattern
characterized by cough, abundant expectoration of up to
1000 ml of bile and hydatid contents, fever, and very poor gen-
eral condition. Bronchopulmonary involvement tends to
involve several segments (fatal necrotizing bronchitis) leading
to serious injury to the bronchial tree (51,52). Hydatid bron-
cho-biliary fistula is a very severe complication which imposes
early, demanding surgery requiring the simultaneous radical
treatment of all pathological aspects of broncho-biliary
fistula (53).
cyst’s topography ₍location₎
According to location and size, cysts can be divided into
parenchymal or superficial and vasculobiliary or deep. In
turn the distinction may be based on the predominant vascu-
lar relationship. Obviously, the validity of the topographic
definition according to hemilivers, sectors, segments, or sub-
segments adopted by the most reliable classifications is con-
firmed (54,55). However, since hydatid cysts are spherical
and often huge, and since they can be removed sparing the
healthy tissue, they do not fit properly into the anatomical
distribution usually adopted for cancer surgery. While no
intrahepatic expanding neoplasm is free from vasculobiliary
contacts, especially the hepatic veins, superficial cysts have
vascular relationships limited to minor peripheral structures.
Vasculobiliary or deep cysts represent about 75% of cysts
that come to surgery and are those with relationships to
first-, second-, and third-order branches of hilar elements,
the hepatic veins, and the inferior caval vein in both its supra-
retro and subhepatic segments (Fig. 34.10) (10). First- and
second-order portal branches may be involved when deep
cysts are located close to the hilum. They are bulky, thus their
dissection is difficult both in the case of hemihepatectomy or
(B)
 MANAGEMENT OF HYDATID DISEASE OF THE LIVER
the more frequent total pericystectomy. Usually, the cysts of
segments VII and VIII, on the right, and segment II on the
left, have relationships with the major hepatic veins. In these
cases dissection of the cyst from the cava and involved hepatic
vein is mandatory. The latter might be ligated and sectioned
or more frequently dissected and preserved with adjacent
lateral sutures. As for bile ducts, their adhesion to the peri-
cyst is very dense and dissection is difficult. If there is a
communication, this requires very careful dissection for
effective repair.
With reference to the hepatic segments of the Couinaud clas-
sification, it is suitable to distinguish vasculobiliary or deep cysts
according to the topographical denominations immediately
indicative of their predominant relationship with hilar
vascular and/or hepatic venous or caval vein structures:
● Hepatic venous cysts
● Right or caval intermediate cysts (segments VII,
VIII, VI, V)
● Hilar cysts
● Central cysts (interportohepatic) (VIII, IV and V) (55).
In turn, hepatic venous cysts are divided into right (VII and
VIII), median (IV), left (II); hilar cysts are divided into
right (V), anterior median (IV), and posterior (I), left (II and/
or III) (Fig. 34.11).
Clearly, there may be some overlap between locations. For
example, right hepatic cysts may extend to the midright lobe
and left hepatic cysts may be located across the hilum. Obvi-
ously, these possibilities do not affect the principles on which
the classification is based.
treatment
The desired goals of treatment of liver hydatidosis include
complete elimination of the parasite, prevention of recurrent
disease, achieved with minimum mortality. In spite of other
proposed techniques, surgery remains the first-line treatment.
There is, however, considerable disagreement about the surgi-
cal technique to be adopted. The major issue of debate is
whether complete removal of the pericyst is necessary for the
proper care of the disease. The focused concepts about the
8
1 4
7 emptying of the cyst the gauze pads should be placed around
2
9
5 larly large non-collapsible tube. As soon as the cyst pressure is
3 relieved and the protruding pericyst tends to collapse, two of
6 its folds are grasped and raised with Allis or ovum forceps. The
Figure 34.11 Topography of vasculobiliary hydatid cysts. 1, 4, 8: Right, median,
left hepatic cysts; 3, 5, 6, 9: right, anterior median, posterior median, left hilar
cysts; 2: intermediate cyst; 7: interportohepatic cyst.
parasite’s biology and interrelationship between the cyst and
liver represent the scientific basis for a rational approach to
surgery for hydatid liver disease. The choice of the procedure
should not be at the surgeon’s discretion but determined by
the cyst’s characteristics.
For the two different types of sterile and fertile cysts, indica-
tions for surgery are as follows:
● Univesicular (sterile), clear cysts, lacking of the peri-
cyst, can be safely treated by conservative surgery.
● Multivesicular (fertile) cysts at different develop-
mental stage should be treated by radical surgery
because of the risk of exogenous vesiculation and
because of high rates of postoperative complications.
With the concept of radicality, surgery of liver hydatidosis
becomes demanding and therefore selective surgical experi-
ence is required as the only means of ensuring a good chance
of recovery.
approaches
Access must be generous for two main reasons: first, because of
the frequent presence of adhesions of the protruding cyst to
adjacent structures and organs, in particular the diaphragm.
Second, because of the need for extended liver mobilization to
control the vessels and exploit the liver flexibility to reduce the
cavities or residual surfaces after pericyst removal. The bilat-
eral subcostal approach, possibly extended depending on the
location and size of the cyst(s), to the right as far as the midax-
illary line, to the left as far as the lateral end of the rectus mus-
cle, and medially upward as far as the xiphoid process of the
sternum (mercedes incision) is the classic approach for liver
surgery and hence for the surgical treatment of liver hydatido-
sis. Median laparotomy may be adequate for cysts located in
the left lobe, when the right liver is known to be unaffected.
The thoraco-abdominal approach is a no longer used, except
in case of hydatid cysts involving the right lung base.
Intraoperative General Concerns
Protection of the operating field is mandatory before the
planned operation on the cyst or before the cyst is emptied. A
cautious approach is to apply protection before liver dissec-
tion, and when the cyst is protruding from the liver surface
and adhering to the adjacent structures and organs. Isolation
of the peritoneal and/or pleural cavity to limit the access to the
operative field is achieved with dry gauze, preferred by the
authors, or soaked in a parasiticidal or hypertonic saline solu-
tion, not unanimously considered harmless. During prior
the site of puncture by the trocar. When emptying the cyst, a
large caliber trocar is connected with an aspirator by a simi-
amount emptied depends on the contents: it will be practically
complete in univesicular cysts, more or less partial in multi-
locular cysts where the hydatid material is abundant and
dense. If the pericyst wall is opened with electric cautery, direct
emptying is completed through a large tube with a frontal
315
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

opening, connected to a powerful aspirator. If possible, two
alternate, separate systems are more suitable because of the
unavoidable tube blockage. Now and then paraffin oil aspira-
tion is useful to facilitate the flow of material in the tube. Aspi-
ration is eased by mobilizing with a long ovum forceps the
material attached to the endocyst walls or removing big daugh-
ter cysts. Clearing of possible communicating sacculations is
also mandatory. In the case of adjacent cysts, separated by a
relatively thin septum, emptying is performed with the trocar
introduced into the cavity through the septum to minimize
the risk of dissemination. Several parasiticidal substances have
been proposed for sterilization by injection of the cyst before
emptying: 2% to 10% formalin solution, 33% hypertonic
saline, 0.5% silver nitrate, 10 vol hydrogen dioxide, 1% iodide
alcohol solution, and 0.1% cetrimide (56–59). This method
should be proscribed for two reasons. First, it appears decep-
tive to pretend that the entire contents of a multivesicular cyst
could be reached by the substance in a few minutes, undergo-
ing the supposed parasiticidal effect (60). In any case, it would
be ineffective against vital parasitic elements trapped into the
pericyst or developed externally as exogenous vesiculations.
Second, practically all solutions markedly damage bile ducts,
the cause of severe sclerosing cholangitis, even if in the absence
of an open communication (61–66). Consequently, apart from
the actual efficacy, the injection of parasiticidal substances,
leaving them in the cavity for some time, should be aban-
doned (59). Some, such as iodine solution, can be applied after
emptying of the cyst. Benzoimidazole drugs have been used
preoperatively for cyst sterilization; however, surgery must be
delayed and this is not attractive to patients and surgeons
because of the indefinite outcome of these drugs (67,68).
relationships with the hepatic ducts and biliary communica-
tion should be carefully evaluated. In fact, it becomes evident
only after emptying and removal of membrane. The extent of
pericyst resection is based on how much of it is protruding or
how close it is to the hilar and adjacent major vasculobiliary
structures. A pericyst margin adequate for subsequent sutur-
ing should be considered. Resection is performed with electric
cautery and the help of Allis forceps on the residual margin;
particular attention should be paid to adjacent structures at
risk (Fig. 34.12). The analogy of the method with the “dome
saillant” resection proposed by Lagrot in the 1950s (69) and
still used (70) is only apparent because here it is limited to
clear cysts with a thin and soft pericyst after wide-field expo-
sure, complete liver mobilization, control of hilar and caval
structures. All these measures enable the resection of ample
pericyst surfaces up to two-thirds of it, while suturing of resid-
ual margins exploits the flexibility of the liver once free of
its ligaments.
The control of bile leaks is very important. Bile transudation
may occur on the resection margins from small orifices, which
must be sutured to prevent bile collection within the cavity. As
for the search for major communications, the induction of
biliary hypertension by compression of the distal hepatic ped-
icle over the duodenum, squeezing the gallbladder at the same
time, may be useful. Then even minimal communication is
evidenced by a drop or flow of bile. The use of dyes must be
considered pointless because the site of the leak is always rec-
ognizable after having cleansed the residual cavity with a pad.
However, these are not the typical patterns of univesicular
cysts. Once the residual cystic wall has been controlled, closure

Conservative Procedures
Operations not involving the removal of pericyst adhering to
the hepatic parenchyma are considered conservative or non-
radical. They were devised many years ago and continued
because there were no alternatives, with unsatisfactory results,
high morbidity, biliary complications in particular, and a high
incidence of recurrence (2). At present conservative opera-
tions should be limited to the treatment of clear univesicular
cysts possibly extended to CE1 cysts. Radical procedures are
unnecessary in the former cases because of the absence of the
pericyst in clear cysts, while in CE1 cysts the pericyst is so thin
and elastic making it possible to exhaustively inspect the
underlying parenchyma through it.
Exogenous vesiculation or biliary fissurations cannot be
missed; the latter evidenced by the color of cystic fluid. How-
ever, the large size and high pressure of these cysts may excep-
tionally be responsible for biliary wall impairment which
results, after the cyst removal, in postoperative bile leakage. In
these rare cases, bile will be seen from the drainage tube for no
longer than 15 to 20 days, which is not following conservative
operations on cysts with thick or calcific pericyst that hinders
the reduction of the residual cavity and the closure of the cys-
tobiliary communication.
After emptying and clearing the cyst cavity, its size and pen-
etration in the depth of liver, especially toward the hilum, the Figure 34.12 Resection of protruding pericyst during conservative surgery.
hepatic veins, and the retrohepatic caval vein, are assessed. The The left-hand fingers protect the inferior caval vein.

316
 MANAGEMENT OF HYDATID DISEASE OF THE LIVER
is performed by suturing the resection edges. Approximation
can be longitudinal, transverse, or oblique, but traction should
be prevented and circulation in the adjacent parenchyma
should not be jeopardized. A double, continuous inverting
suture is made with atraumatic 3/0 prolene. In many cases the
procedure corresponds to the canalization of the cavity on a
rubber tube, advanced outside the cavity in the most suitable
position through a counter incision at the level of the hypo-
chondrium or flank. The progress of postoperative cyst col-
lapse until complete obliteration of the cavity can be
documented by imaging. Drainage is preferred because in
spite of the absence of obvious biliary communications, some
days after surgery a bile leakage might occur which, if drained,
heals with no further consequences. In theory, a cavity, reduced
as described above, or even left in its original size, could be
closed without drainage and heals with no complications.
However, the actual possibility of bile collection with the risk
of infection and abscess formation, argues in favor of the
placement of drains. The use of omentum (71–73) to fill the
cavity or cover the residual surface should be avoided. As for
the omentum, an excellent barrier against infections, is not
equally effective against bile and may even become necrotic.
When packed into the cavity, it hinders the interpretation of
US or CT images in long-term follow-up then possibly
concealing the occurrence of recurrences (74,75).
(A)
(C)
Figure 34.13 Right hepatectomy extended to segment IV and caudate lobe. (A) Bulky cyst mass; (B) the residual surface is sutured; (C) surgical specimen; (D) the
gallbladder is packed with hydatid material.
Radical Procedures
Radical procedures include major hepatic resection and total
pericistectomy. Hepatic resection since ever has not been con-
sidered the principal technique to resort to when treating liver
hydatidosis. The notable development of liver resective sur-
gery in more recent years has not changed this trend so that
the rate of hepatic resections rarely exceeds 10% (76,77). Tech-
nically these resections are similar to those performed for
other indications, except for the possible extension of the cyst
beyond the anatomical limits of the hemiliver or sector to be
removed and the biliary relationship on which the indication
was based (Fig. 34.13). The first occurrence may involve diffi-
cult pericyst dissection from vasculobiliary structures supply-
ing territories to be preserved. Furthermore, resections are
adopted in case entire sectors, lobes, or hemilivers are destroyed
by the cyst(s) and interruption of main bile ducts would make
their repair questionable because of a very high risk of serious
cholerrhagia. With the exception of these particular cases the
general policy should be to avoid liver resection in order to
spare as much health hepatic parenchyma as possible.
Wedge resections and liver transplantation should be men-
tioned in passing. Actually while the former might find an
occasional indication in case of minute marginal anterior
cysts, the use of liver transplantation should be considered to
the utmost anedoctical (78).
(B)
(D)
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Total pericystectomy (or cystopericystectomy) is presently
considered to be the ideal radical operation suitable for the
requirements of radicality for the hydatid disease, with maxi-
mal preservation of hepatic tissue and complete early recovery.
Its feasibility is similar to that of liver resections. The same
basic training is required, enhanced by a specific experience.
The operation was conceived and proposed by Napalkoff (79)
in 1927 and again described in 1936 by Melnikoff (80). How-
ever, in subsequent experiences, results were unsatisfactory
and even disastrous due to hemorrhage; thus, following unan-
imous disapproval, it was practically abandoned. Costantini
applied it again in 1950s (81) and Yovanovitch in 1959 (82),
with indications for peripheral cysts, distant to porta hepatis.
Bourgeon, the most convinced supporter, advocated it in fol-
lowing years, even if, in many cases, he favored partial pericys-
tectomy (83,84).
Since the early 1970s it was understood that the persistence
of pericyst, with its close biliary relationships, more or less
wide fissurations and true ruptures, represented the main
cause of frequent postoperative complications: abundant, pro-
longed bile leakage, infections, longstanding residual cavities,
biliary fistulas (85,86). The correlation of persistent hydatid
material with the frequent recurrences with which surgery of
hydatidosis seemed to be inevitably burdened was noted only
later on (33,87). For all these reasons and because of the devel-
opment of hepatic surgery the operation has gained wide-
spread acceptance (88–90).
Pericystectomy can be performed either as a closed or as an
open procedure. In the first case, en bloc removal of the peri-
cyst and its contents is a safe operation with respect to the risk
of contamination. The closed procedure is mainly indicated in
case of superficial cysts and unilobar deep cysts. Open pericys-
tectomy should be performed every time there is a risk of
breaking the cyst wall, in case of cysts of the hepatic dome,
strictly adherent to the hepatic veins and vena cava, and in case
of deep intraparenchymal cysts with interporto-cava location.
However, protective measures are necessary also before dissec-
tion of a closed cyst. The latter procedure is more elegant,
rapid, and simpler, but in the case of bulky, deep cysts or those
which have ruptured into the common bile duct, the proce-
dure may be risky, thus operations on the open cyst are prefer-
able and necessary. This enables the dissection of the pericyst
from vasculobiliary structures, even in the most difficult
conditions.
When the cyst protrudes at any site of the liver surface, dis-
section is developed along the transition line, sometimes
delineated by a groove, between the pericyst and the paren-
chyma. Concomitant, chronic, non-parasitic liver disease, or
consequent to hepatic vein stasis caused by the cyst, a true
Budd–Chiari syndrome, creates major difficulties. The
smaller vascular branches entering the pericyst must be elec-
trocoagulated or ligated and dissected. Step by step hemosta-
sis is a determinant caution of the procedure, or else
consequent bleeding would hinder the operatory field and
cause an unnecessary and considerable blood loss. Dissection
of large vessels from the pericyst should be centriperipheral
and along the course of vascular and biliary structures,
following the direction of its emerging or confluent branches
318
(Fig. 34.14). In short, when entailing the hepatic veins the
direction of the dissection should be from the apical liver
convexity toward the free margin. Dissection of the hilar
elements should be developed from the hilum toward the
periphery. Therefore, in vessel dissection, the surface corre-
sponding to the obtuse angle the branches describe when
emerging or merging should be preferred. The large vessel is
more readily dissected and longitudinal lacerations are
prevented when scissors are trapped into the acute angle
between it and its branch. The tight adhesion of large vessels
to the pericyst might encourage the finger fracture procedure
which would result, in these cases, incorrect and hazardous.
The use of the ultrasound dissector, which favors the visual-
ization of the vascular network, and hemostasis seems advan-
tageous, while dissection of large vessels from pericyst is still
feasible (91,92).
Dissection is circumferential yet conditioned by the cyst
location. The dissected parenchyma tends to flatten its spherical
hollow surface, leaving a largely naked area previously adher-
ent to the pericyst. The dissection of very deep and/or bulky
cysts is hazardous because most of the operatory field is not
under visual control. For this reason, and to prevent excessive
manipulation of the cyst, its emptying is suitable and then
open cyst pericystectomy can be safely performed. The same
procedure should be adopted in cases of cysts with peduncu-
lated protrusions from exogenous vesiculations. They have a
very thin pericyst, which may breach specially at the pedicle
level. As a general rule, whenever the risk of cyst rupture,
prompt emptying of the cyst should be performed and the
operation carried on as an open procedure. By folding the
pericyst at the level of the dissection plane the procedure is
facilitated, especially if the dissected pericyst is sectioned in
strips, subjecting each to tension independently (Fig. 34.15). If
the pericyst is not very calcific, a further very useful “trick” is
Figure 34.14 Total pericystectomy. Dissection of pericyst from vasculobiliary
structures should be along the presumed centriperipheral direction (following
the direction of emerging and merging branches).
 MANAGEMENT OF HYDATID DISEASE OF THE LIVER
to carefully incise it with a scalpel on its internal surface to
reach the adhering parenchyma. With a cross- or star-shaped
incision, and by lifting backward each strip with Allis or
Kocher forceps and dissecting from different sides, apparently
unfavorable situations are resolved and dissection can be com-
pleted (Fig. 34.16). Access to mid-sized cysts through one of
the hepatic fissures is another very effective and in some cases
Figure 34.15 Total open pericystectomy. Stripping of pericyst and traction on
each strip by folding facilitates deep dissection of vasculobiliary structures
also in case of calcific pericyst.
Figure 34.16 Total open pericystectomy. Cautious full depth incision of peri-
cyst with a lancet on the cavity bottom allows access to vessel dissection from
several directions, even in the case of very thick cysts.
resolving technique. Once major vasculobiliary structures are
reached with dissection, the corresponding fissure is identi-
fied, opened, and extended to the cyst wall. The cyst turns, this
way, seems to become more superficial and then accessible
from several sides (Fig. 34.17). Retraction of intersectorial sur-
faces resolves the problem of the difficult access to the deep
hemisphere of the cyst. Therefore, operations on the closed
cyst are facilitated with relevant vascular relationships as the
interportal liver becomes accessible (Fig. 34.18).
Despite all precautions, vascular lacerations may occur during
pericystectomy, especially the hepatic veins. The dissection may
be interrupted, in this case, and temporary hemostasis obtained
by compressing the parenchyma against the pericyst while pro-
gressing with the operation on a different side. Also direct digital
compression on the bleeding vessel will allow the surgeon to
Figure 34.17 Total pericystectomy. In deep, non-emerging cysts, opening of
the corresponding fissure is very useful. The cyst becomes accessible from
several sides, somewhat similar to more superficial cysts.
Figure 34.18 Total pericystectomy of deep cysts with multiple vasculobiliary
relationships such as interportohepatic cysts is facilitated by opening the
median fissure. Venous stasis from compression and compensatory collaterals
may be present.
319
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

continue the dissection and achieve a better exposure of the All patients with large biliary cyst communication should
breach. Once adequately identified and exposed, the laceration undergo operative cholangiography and exploration of the
is sutured, yet paying attention to maintain vessel patency. main duct is mandatory in cases of presence of common bile
Pringle’s maneuver is not suitable for pericystectomy duct filling defects on cholangiography. T-tube drainage is
because of the long time usually required for pericyst dissec- usually added in case of the presence of hydatid debris in the
tion. However, during the critical phase of the procedure, common bile duct. Access to the common bile duct is through a
intermittent clamping followed by brief period of reperfusion choledochotomy and less commonly transduodenal (Fig. 34.19).
may come in very handy. Clamping of hepatic veins is rarely In fact, surgical trans-duodenal papillosphincterotomy has
necessary. In particular cases preventive isolation and encircl- been, more or less completely, replaced by endoscopic papil-
ing of the subhepatic and suprahepatic vena cava above the losphincterotomy.
confluence of hepatic veins may turn out to be a wise precau-
tion. Dissection of the right hepatic vein and of the right edge Laparoscopy
of the vena cava is a cornerstone of the procedure, especially Limited area of manipulation, difficulty in controlling spillage
for cysts of segment VII and VIII. It should be kept in mind during puncture, difficulty in aspirating the thick, degenerated
that a hepatic vein laceration proximal to the confluence is to cyst contents, putting pressure by the pneumoperitoneum on
be feared more for air embolism than for bleeding. the hydatid cyst and consequent increased risk of hydatid fluid
Bleeding, possibly occurring during total pericystectomy, contamination have been reported as the main disadvantages
represented the principal cause of surgical aversion to this of the laparoscopic approach (93). However several authors
operation. According to the site of the cyst, 2 to 4 units of have performed conservative procedures, mainly cistotomy
blood should be available for transfusion. Intraoperative and drainage, on superficial cysts located in the left lobe and in
recovery, obviously limited to the sterile phases of the opera- the anterior aspect of the right lobe (94,95). Laparoscopic
tion, offers great advantage. pericystectomy performed on selected cases has been reported
In the course of pericystectomy the surgeon might decide to as a safe and effective procedure (96).
leave behind one or several areas of the pericyst in case their
excision is felt to be too hazardous because of their adherence PAIR
to vascular structures. The use of this fairly common solution Since 1985, Puncture Aspiration Injection Reaspiration (PAIR)
will progressively lessen as the experience of each surgeon has been proposed as an alternative to surgery (97). After
increases. Such a decision is anyway advisable in some crucial percutaneous puncture under ultrasonographic guidance,
areas such as the confluence of hepatic veins into the caval vein
and at hilar structures, in particular contralateral ones, and in
case of cysts extending beyond the involved hemiliver. This is
also the not rare case of the retrohepatic caval vein protruding
in large cystic cavities of the right lobe.
During pericystectomy, a limited part of the neighboring
hepatic parenchyma may turn ischemic because of impair-
ment of blood supply. In this case, the extension of the involved
region should be carefully evaluated for a worthwhile and, if
no recovery occurs, resected together with pericyst removal.
Vascular impairment of a wider extension of hepatic paren-
chyma is, of course, an entirely different problem, but as a rule
this should not be the case.
The residual liver surfaces, after pericystectomy, are charac-
terized by a pattern of protruding hepatic veins or Glissonian’s
vessels. The closure of the residual cavity, even if easier after
the excision of deep cysts, does neither entail main difficulties
after the removal of superficial cysts nor imply any vascular
impairment. As a matter the procedure does not correspond as
much to the closure of a residual cavity as rather to the simple
approximation of the residual, smooth liver surfaces. If
approximation is complete and there is no reason to doubt for
bile loss, drainage in the residual space may be omitted. If the
pericyst has been completely removed and bile leakage
excluded, then an omental flap can be used on residual sur-
faces to prevent adhesion of displaced intestinal loops.
In the course of operations on hydatid cysts complementary
Figure 34.19 Exploration and cleansing of biliary tract. Through papil-
surgery may be required for “parahydatid” biliary pathology losphincterostomy the spoon for stones or a probe can be carefully advanced
such as cholelithiasis; en bloc cholecystectomy is routinary to identify the biliary breach and specify the type of communication, whether
performed in case of cysts of segments IV and V. lateral or terminal, with the cyst cavity.

320
 MANAGEMENT OF HYDATID DISEASE OF THE LIVER
aspiration of as much as possible of the cyst content is per-
formed; the residual cavity is then filled with a protoscolicide,
usually ethanol, reaspired 10 minutes later. Detailed practical
guidelines have been defined after a careful evaluation of the
technique by the WHO-IWGE (98). As in the PAIR technique,
the daughter cysts and the germinal membrane would remain
inside the cavity; this technique is advocated for uncomplicated
univesicular cysts, but not for multivesicular, so-called mother
and daughter cysts. In accordingly selected series, complete dis-
appearance of the cyst has been reported in 48% of cases (99).
PAIR is contraindicated if there is a communication between
the cyst and the biliary tree because of the risk of sclerosing
cholangitis. Vacuum aspiration and dissection of the endocyst
non-drainable material through a stiff sheath, introduced into
the cavity at the site of puncture after removal of the needle, is
an alternative method to PAIR called PEVAC (100).Radiofre-
quency ablation, mainly focused on solid hydatid cysts, has
been proposed as a further alternative to PAIR (101). Only pre-
liminary results on the efficacy of this technique are so far avail-
able as only very few patients have been treated with this
technique.
Medical Therapy
Benzimidazole carbamates (mebendazole and albendazole)
are antihelminthic drugs that affect the parasite viability,
mainly, by impairing its glucose uptake. Mebendazole was
introduced first (102), but albendazole became the drug of
choice because of its better absorption and better clinical
results (103). These results are achieved after long treat-
ment (104). Adverse events of this treatment have been
reported in about 10% of patients treated (105). General
complaints are headache, nausea, anorexia, vomiting, abdom-
inal pain, and itching. A transient increase in liver enzymes
may be observed in the first weeks of treatment. For clinical
practice, albendazole should be administered in a dose of
10 mg/kg twice daily during a meal in four 1-month cycles
with a 15-day rest, or 10 to 12 mg/kg/day continuously for
3 months. It should not be associated with drugs that reduce
gastric acidity (106). Factors affecting the efficacy of benz-
imidazoles have not been well defined, but it is known that
penetration of drug across the cyst walls depends on the
nature of the cyst. Young cysts without thick, fibro calcified
pericyst are more sensitive to drugs (107,108).
It is difficult to understand how the drug could overcome
the barrier of a dense fibrotic or calcific pericyst, up to 0.5 cm
thick, and kill the hydatid material packed into the cavity.
Moreover, it is hardly believable that exogenous vesiculations
within the pericyst might be reached by the drug. Recurrence
following albendazole therapy occurs in at least 20% to 30% of
responsive cases (108,109), to which a further 20% of patients,
considered negative in whom no change was visualized, should
be added. Preoperative albendazole treatment has been sug-
gested in order to lower cyst viability. However, contrasting
outcomings have been reported possibly because viability tests
on the surgical specimen cannot be considered conclusive as
confirmed by the development of parasites from culture of
cystic fluid shown to be negative on direct microscopy (110).
Although no conclusive data on the efficacy of perioperative
profilaxis are available, it is generally advised at least 2 days
before surgery. Similarly, postoperative treatment is recom-
mended for 6 months in case of intraoperative hydatid
spillage (98).
key points
● Complications of hepatic hydatidosis include:
Metastatic hydatid
Secondary bacterial infection
Intrabiliary rupture
Intraperitoneal rupture
Bronchobiliary fistula
● Diagnosis of hepatic hydatidosis:
Incidental finding (in patient from endemic
region)
Abdominal mass
Calcified hepatic cyst on the plain abdominal
photograph (AXR)
Ultrasound/CT/MRI
Hydatid serology/Casoni skin test.
● Preoperative management:
Systemic albendazole/mebendazole
ERCP (exclude cystobiliary fistula)
Protection of operative field before surgical
emptying of cyst contents
Sterilization of cyst cavity
references
1. Akinoglu A, Arparslan, Kaza K. Hydatid disease of the liver: prevention
of postoperative biliary fistula. Arch Hidatid 1991; 30: 649–55.
2. Chigot JP, Langlois P, Teboul F, et al. Le traitement des kystes hydatiques
du foie. Ann Chir 1986; 40: 177–82.
3. Euzeby J. L’echinococcose larvaire. Rev Med Vet 1955 ; 106 : 456-468.
4. Kalovidouris A, Voros D, Gouliamos A, Vlachos L. Papavasiliou C. Extra-
capsular (satellite) hydatid cysts. Gastrointest Radiol 1992; 17: 353–6.
5. Bourgeon R, Catalano H, Guntz M. La pE9rikystectomie dans le traite-
ment des kystes hydatiques du foie. J Chir 1961; 81: 153–74.
6. Belli L, Del Favero E, Marni A, Romani F. Resection versus pericystec-
tomy in the treatment of hydatidosis of the liver. Am J Surg 1983;
145: 239–42.
7. Moreno Gonzales E, Jovez Navalon JM, Landa Garcia JI, et al. Surgical
management of liver hydatidosis. 10-year experience with 269 patients.
It J Surg Sci 1985; 15: 267–73.
8. Debesse B, Dujon A. La pE9rikystectomie au plus prE8s dans le traite-
ment du kyste hydatique du foie. Ann Chir 1987; 41: 646–51.
9. Moreno Gonzales E, Rico Selas P, Bercedo Martinez J, et al. Results of
surgical treatment of hepatic hydatidosis: current therapeutic modifica-
tions. World J Surg 1991; 15: 254–63.
10. Tagliacozzo S, Daniele GM, Pisano G. Pericistectomia totale per echino-
cocco epatico. Arch Atti Soc It Chir 1979; 1: 657–712.
11. Tagliacozzo S, Daniele GM, Pisano G. Total pericystectomy for hydatid
disease of the liver. 6B0 World Congr Coll Int Chir Dig, Lisbona 1980,
abst SP5–03.
12. Magistrelli P, Masetti R, Coppola R, et al. Surgical treatment of hydatid
disease of the liver. A 20 year experience. Arch Surg 1991; 126: 518–23.
13. Moreno Gonzales E, Rico Selas P, Martinez B, et al. Results of surgical
treatment of hepatic hydatidosi: current therapeutic modifications.
World J Surg 1991; 15: 254–63.
14. Aydin U, Yazici P, Onen Z, et al. The optimal treatment of hydatid cyst
of the liver: radical surgery with a significant reduced risk of recurrence.
Turk J Gastroenterol 2008; 19: 33–9.
321
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
15. Beggs I The radiological appearance of hydatid disease of tha liver. Clin
Radiol 34: 555–63.
16. Gharbi HA, Hassine W, Brauner MW, Dupuch K. Ultrasound examina-
tion of the hydatic liver. Radiology 1981; 139: 459–63.
17. Hassine W, Dupuch K, Gharbi HA. Aspects E9chographiques de
l’hydatidose. J Radiol 1979; 60: 660–6.
18. Lewall DB, McCorkell SJ. Hepatic echinococcal cysts: sonographic
appearance and classification. Radiology 1985; 155: disease of the liver.
Clin Radiol 198; 34: 555–63.
19. Bobek-Billewicz B, Szurowska E, Zapasnik A, et al. Localization of focal
liver lesions to specific heapatic segments. Comparison of multiphase
spiral CT and MR imaging. Folia Morphol (Wars) 2002; 61: 291–7.
20. Pedrosa I, Saiz A, Arrazola J, Ferreiros J, Pedrosa CS. Hydatid disease:
radiologic and pathologic fatures and complications. Radiograph-
ics2000; 20: 795–817.
21. Basaran C, Karcaaltincaba M, Akata D, et al. Fat containing lesions of
the liver: cross sectional imaging findings with emphasis on MRI. AJR
2005, 184: 1103–10
22. Little AF, Lee WK, Mathison K MR cholangiography in the evaluation
of suspected intrabiliary rupture of hepatic hydatid cys. Abdom Imag-
ing 2002; 27: 333–5.
23. Simsek H, Ozaslan E, Sayek I, et al. Diagnostic and therapeutic ERCP in
hepatic hydatid disease. Gastrointest Endosco 2003; 58: 384–9.
24. Galati G, Sterpetti AV, Caputo M, et al. Endoscopic retrograde cholangi-
ography for intrabiliary rupture of hydatid cyst. Am J Surg 2006;
191: 206–10.
25. Cicek B, Parlak E, Disibeyaz S, et al. Endoscopic therapy of hepatic
hydatid cyst disease in preoperative and postoperative settings. Dig Dis
Sci 2007; 52: 931–5.
26. Sbihi Y, Rmiqui A, Rodriguez-Cabezas MN, et al. Comparative sensitiv-
ity of six serological tests and diagnostic value of ELISA using pirified
antigen in hydatidosis. J Clin Lab Anal 2001; 15: 14–8.
27. Varela-Diaz VM, Coltorti EA, de Zavaleta O, et al. Immunodiagnosis of
human hydatid disease: applications and contributions to a control pro-
gram in Argentina. Am J Trop Med Hyg 1983; 32: 1079–87.
28. Coltorti EA. Standardization and evaluation of an enzyme immunoas-
say as a screening test for the seroepidemiology of human hydatidosis.
Am J Trop Med Hyg 1986; 35: 1000–5.
29. Sadjjadi SM, Abidi H, Sarkari B, Izadpanah A, Kazemian S. Evaluation
of enzyme linked immunosorbent assay, utilizing native antigen B for
serodiagnosis of human hydatidosis. Iran J Immunol 2007; 4: 167–72.
30. Zhang W, Li J, McManus DP. Concepts in immunology and diagnosis of
hydatid disease. Clin Microbiol Rev 2003; 16: 18–36.
31. Sbihi Y, Jansse D, Osuna A. Serologic recognition of hydatid cyst anti-
gens using different purification methods. Diagn Microbiol Infect Dis
1996; 24: 205–11.
32. Logar J, Soba B, Kotar T. Serological evidence for human cystic echino-
coccosis in Slovenia. BMC Infect Dis.2008; 9: 63–72.
33. Tagliacozzo S, Daniele GM, Pisano G. Total pericistectomy for hyda-
tid of the liver. 6 (th) World Congress Coll Int Chir Dig. Lisbona, abst
SP5–03.
34. Monterola C, Barroso M, Vial M, et al. Liver abscess of hydatid origin: clini-
cal features and results of aggressive treatment. ANZ J Surg 2003; 73: 220–4.
35. Gaibatov SP, Gaibatova DS. Clinical finding and treatment of festered
hepatic echinococcosis. Khirurgiia (Mosk) 2006; 6: 16–8.
36. Ozmen V, Igci A, Kebudi A, et al. Surgical treatment of hepatic hydatid
disease. Can J Surg 1992, 35: 423–7.
37. Assadourian R, Bricot R, Djilalli G. Les kystes hydatiques du foie 1984.
Rev Ass Fr Chir 1984; 33: 15–39.
38. Kayaalp C, Bostanci B, Yol S, Akoglu M. Distribution of hydatid cysts
into the liver with reference to cystobiliary communications and cavity-
related complications. Am J Surg 2003; 185: 175–9.
39. Atli M, Kama NA, Yuksek YN, et al. Intrabiliary rupture of a hepatic
hydatid cyst: associated clinical factors and proper management. Arch
Surg 2001; 136: 1249–55.
40. Bourgeon R. L’ouverture des kyststes hydatiques aux voies biliares intr-
hepatiques. Lyon Chir 1985; 81: 161–4.
41. Lygidakis NJ. Diagnosis and treatment of intrabiliary rupture of hydatid
cyst of the liver. Arch Surg 1983; 118: 1186–89.
322
42. Valle-Sanz YD, Lorente-Ramos RM. Sonograaphic and computer tomo-
graphic demonstration of hydatid cysts communication with the biliary
tree. J Clin Ultrasound 2004; 32: 144–8.
43. Bilsel Y, Bulut T, Yamaner S, et al. ERCP in the diagnosis and manage-
ment of complications after surgery for hepatic echinococcosis 2003;
57: 210–3.
44. Sozuer EM, Ok E, Arslan M. The perforation problem in hydatid dis-
ease. Am J Trop Med Hyg 2002; 66: 575–7.
45. Abdel Hameed AA, Abu Aisha H. Uneventful intraperitoneal rupture of
a hepatic cyst: a case report Trop Geogr Med 1987, 39: 80–2.
46. Barros JL. Hydatid disease of the liver. Am J Surg 1978; 135: 597–600.
47. Marcos Sanchez F, Turabian Fernandez JL, Caballero Gomez F, et al.
Reacciones alergicas-shock anafilactico como manifestacion de enfer-
midad hidatica hepatica. Rev Clin Esp 1984; 173: 49–52.
48. Giulekas D, Papacosta D, Papacostantinou C, Barbarousis D, Angel J.
Recurrent anaphylactic shock as a manifestation of echinococcosis.
Scand J Thorac Cardiovasc Surg 1986; 20: 175–7.
49. Lewall DB, McCorkell SJ. Rupture of echinococcal cysts: diagnosis, clas-
sification and clinical implications. AJR 1986; 146: 391–94.
50. Morris DL, Chinnery JB, Hardcaster JD. Can albendazole reduce the
risk of implication of spilled protoscolices? An animal study. Trans R
Soc Trop Med Hyg 1986; 80: 481–4.
51. Gerazounis M, Athanassiadi K, Metaxas E, Athanassiou M, Kalantzi N.
Bronchobiliary fistulae due to echinococcosis. Eur J Cardiothorac Surg
2002; 22: 306–8.
52. Gomez R, Moreno E, Loinaz C, et al. Diaphragmatic or transdiaphrag-
matic thoracic involvement in hepatic disease: surgical trends and clas-
sification. World J Surg 1995; 19: 714–9.
53. Tocchi A, Mazzoni G, Miccini M, et al. Treatment of hydatid broncho-
biliary fistulas: 30 years of experience. Liver Int 2007; 27: 209–14.
54. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Paris:
Masson; 1957; 9 : 335–74.
55. Goldsmith NA, Woodburne RT. Surgical anatomy pertaining to liver
resection. Surg Gynecol Obstet 1957; 105: 310–18.
56. Cirenei A, Bertoldi I. Evolution of surgery for liver hydatidosis from
1950 to to-day: analysis of personal experience. World J Surg 2001;
25: 87–92.
57. Agaoglu N, Turkilaz S, Arslan MK. Surgical treatment of hydatid cysts of
the liver. British J Surg 2003; 90: 1536–41.
58. Meymarian E, Luttermoser GW, Frayha GJ, Schwabe DVM, Prescott B.
Host parasite relationship in echinococcosis. Laboratory evaluations of
chemical scolicides as adjuncts hydatid surgery. Ann Surg 1963;
158: 211–5.
59. Saidi F. A new approach to the surgical treatment of hydatid cyst. Ann R
Coll Surg Engl 1977; 59: 115–28.
60. Frayha GJ, Bikhazi KJ, Kachachi TA. Treatment of hydatid cysts (Echi-
nococcus granulosus) by Cetrimide (AE). Trans R Soc Trop Med Hyg
1981; 75: 447–50.
61. Morris DL. Surgical management of hepatic hydatid cyst. In:
Morris DL, Richards KS, eds. Hydatid Disease. Current medical and
surgical management. Philadelphia: Butterworth-Heinemann 1992:
57–75.
62. Little JM. Hydatid disease of the liver. In: Hadfield J, Hobsley M,
Tressure T, eds. Current Surgical Practice, Vol 5. London: Edward
Arnold, 1990: 146–61.
63. Khodadadi DJ, Kurgan A, Schmidt B. Sclerosing cholangitis follow-
ing the treatment of echinococcosis of the liver. Int Surg 1981; 66:
361–2.
64. Cohen-Solal JL, Eroukmhanoff P, Desoutter P, et al. Cholangite scle-
rosante survE9nue aprE8s traitement chirurgical d’un kyste hydatique
du foie. Sem HF4pitaux Paris 1983; 59: 1623–4.
65. Teres J, Gomez-Moli J, Bruguera M, et al. Sclerosing cholangitis after
surgical treatment of hepatic echinococcal cysts. Report of three cases.
Am J Surg 1984; 148: 694–7.
66. Belghiti J, Benhamou JP, Houry S, Grenier P, Huguier M, Fekete F. Caus-
tic sclerosing cholangitis. A complication of the surgical treatment of
hydatid disease of the liver. Arch Surg 1986; 121: 1162–5.
67. Stubbs RS. Management of hydatid disease: scolicidal agent instillation
versus perioperative chemotherapy. HPB Surgery 1990; 2(Suppl): 155.
 MANAGEMENT OF HYDATID DISEASE OF THE LIVER
68. Erzurumlu K, Ozdemir M, Mihmanli M, Cevikbas U. The effect of
intraoperative mebendazole-albendazole applications on the hepatobi-
liary system. Eur Surg Res 1995; 27: 340–5.
69. Falagas M, Bliozotis I. Albendazole for the treatment of human echino-
coccosis: a review of comparative clinical trials. Am J Med Sci 2007;
334: 171–9.
70. Monterola M, Monsilla JA, Fonseca, F. Preoperative albendazole and
scolices viability in patients with hepatic echinococcosis. World J Surg
2005; 29: 750–3.
71. Lagrot F, Coriat P. Justification et valeur de la resection du dome saillant
dans les kystes hydatiques du foie. Lyon Chir 1959 ; 55: 826–37.
72. Moumen M, Elalauni ME, Mehane M, Jami D, Mokhtari M, El Fares. La
rE9section du dF4me saillant du kyste hydatique du foie. A propos de
360 cas. J Chir 1990; 127: 83–6.
73. Goinard P, Note D, Girardot M. IIe: sur le traitement de KHF (kyste
hydatique du foie). L’E9piploonplastie intracavitaire. Presse ME9d
1950; 58: 1203–5.
74. Xu M-Q. Diagnosis and management of the liver: hydatidosis compli-
cated with biliary fistula. HPB Surgery 1990; 2 (Suppl): 153.
75. Safioleas M, Misiakos E, Manti C, Katsikas D, Skalkeas G. Diagnostic
evaluation and surgical management of hydatid disease of the liver.
World J Surg 1994; 18: 859–65.
76. Chaimoff C, Lubin E, Dintsman M. The postoperative appearance of
the liver on scanning following omentopexy of the hydatid cyst. Int Surg
1980; 65: 331–3.
77. Beggs I, Walmsley K, Cowie AGA. The radiological appearances of the
liver after surgical removal of hydatid cyst. Clin Radiol 1983; 34: 555–63.
78. Moreno-Gonzales E, Loinaz Segurola C, Garcia Urena A, et al. Liver
transplantation for Echinococcus Granulosus hydatid disease. Trans-
plantation 1994 ; 58 : 797–800.
79. Napalkoff N. A propos de la decortication des Kystes hydatiques. Rev
Chir 1927; 65: 524–8.
80. Melnikoff AW. Sur la chirurgie des kystes hydatiques. J Chir 1936; 47:
197–219.
81. Costantini H, Bourgeon R, Pantin JP, Rives J. Des indications de
l’ablation du sac pE9ri parasitaire dans le traitement des kystes hyda-
tiques du foie. La kystectomie de routine des kystes suppures du foie. J
Chir 1950; 66: 177–89.
82. Yovanovitch BY. Place de la kystectomie dans le traitement des kystes
hydatique du foie. Ann Chir 1959; 13: 31–6.
83. Bourgeon R. Les bases physiopathologiques necessaires à la conduite
therapeutique du kyste hydatique du foie, en particulier par perikystec-
tomie. In: Cirenei A, Hess W, eds. Chirurgie du foie, des voies biliares et
du pancreas. Padova: Piccin, 1977: 21–35.
84. Bourgeon R, Guntz M, Catalano H, Alexandre JH, Mouiel J. Incidence
de la topographie sur le traitement des kystes hydatiques du foie. J Chir
1964; 88: 375–88.
85. Tagliacozzo S. Total pericystectomy and complementary papillostomy
in the treatment of hepatic hydatid cyst. Proc XX Biennal World Congr
Int Coll Surg, Atene, 1976: 630–1.
86. Tagliacozzo S. Typical and atypical (total pericystectomies) resections in
the surgical treatment of hydatid disease of the liver. Surg It 1977;
7: 133–42.
87. Tagliacozzo S. Exogenous vesiculation and radical treatment of hepatic
hydatid cyst. 30(th)Congr Soc Int Chir, Hamburg, 1983: 51.
88. Magistrelli P, Masetti R, Coppola R, et al. Surgical treatment of hydatid
disease of the liver. A 20-year experience. Arch Surg 1991; 126: 518–23.
89. Moreno Gonzales E, Rico Selas P, Martinez B, et al. Results of surgical
treatment of hepatic hydatidosis: current therapeutic modifications.
World J Surg 1991; 15: 254–63.
90. Aydin U, Yazici P, Onen Z, et al. The optimal treatment of hydatid cyst
of the liver: radical surgery with a significant reduced risk of recurrence.
Turk J Gastroenterol 2008; 19: 33–9.
91. Little JM. Hydatid disease of the liver. In: Hadfield J, Hobley M, Tressure
T, eds. Current Surgical Practice, Vol. 5. London: Edward Arnold 1990:
146–61.
92. Vicente E, Devesa JM, Nuno J, Fernandez JM, Angel V. Progress in the
surgical treatment of hepatic hydatid cysts. 34th World Congr ISS/SIC,
Stockholm, 1991, A139: 255.
93. Kayalp C. Hydatid cyst of the liver. In Blumgart LH, ed. Surgery of the
Liver, Biliary Tract, and Pancreas, Vol. 2. Philadelphia: Saunders 2006:
963–4.
94. Baskaran V, Patnaik PK. Feasibility and safety of laparoscopic manage-
ment of hydatid disease of the liver. JSLS 2004; 8: 359–63.
95. DervenisC, Delis S, Avgerinos C, Madariaga J Milicevic M. Changing
concepts in the management of liver hydatid disease. J Gastrointest Surg
2005; 9: 869–77.
96. Busic Z, Lemac D, Stipancic I, et al. Surgical treatment of liver echino-
coccosis: the role of laparoscopy. Acta Chir Belg 2006; 106: 688–91.
97. Mueller PR, Dawson SL, Ferrucci JT, Nardi GL. Hepatic echinococcal
cyst: successful percutaneous drainage. Radiology 1985; 155: 627–8.
98. WHO – Informal Working Group on Echinococcosis. Guidelines for
treatment of cystic and alveolar echinococcosis in humans. Bull WHO
1996; 74: 231–42.
99. Giorgio A, de Stefano G, Esposito V, et al. Long-term results of percuta-
neous treatment of hydatid liver cysts: a single center 17 years experi-
ence. Infection 2008; 36: 256–61.
100. Saremi F, McNamara TO. Hydatid cysts of the liver: long term results of
percutaneous treatment using a cutting instrument. AJR Am J Roent
1995; 165: 1163–7.
101. Brunetti E, Filice C. Radiofrequency treatment ablation of echinococcal
liver cyst. Lancet 2001; 358: 1464.
102. Belghiti A, Scaaps JP, Capron M, et al. Treatment of hepatic hydatid dis-
ease with mebendazole: preliminary results in four cases. Br Med J 1977;
2: 1047–51.
103. Lacey E. Mode of action of benzoimidazole. Parasitol Today 1990;
6: 112–5.
104. Morris DL, Dykes PW, Dickson B, et al. Albendazole in hydatid disease.
Br Med J 1983; 286: 103–4.
105. Schipper HG, Koopmans RP, Nagy J, et al. Effect of dose increase or
cimetidine co-administration on albendazole bioavailability. Am J Trop
Med Hyg 2002; 63: 270–3.
106. Teggi A, Lastilla MG, De Rosa F. Therapy of human hydatid disease with
benzoimidazole carbamates. Arch Hidatid 1991; 30: 773–95.
107. Teggi A, Lastilla MG, De Rosa F. Therapy of human hydatid disease with
mebendazole and albendazole. Antimicrob Agents Chemother 1993; 37:
1679–84.
108. Todorov T, Vutova K, Mechkov G, et al. Evaluation of response to chemo-
therapy of human cystic echinococcosis. Br J Radiol 1990; 63: 523–31.
109. Morris DL. Albendazole treatment of hydatid disease, follow up at five
years. Trop Doc 1989; 19: 179–80.
110. Filice C, Trosselli M, Brunetti E, et al. P.A.I.R. (Puncture, Aspiration,
Introduction, Reaspiration) with alcohol under US guidance of hydatid
liver cysts. Arch Hydatid 1991; 30: 811–7.
323
35 Surgical management of primary sclerosing cholangitis
Jason A. Breaux and Steven A. Ahrendt
overview
Primary sclerosing cholangitis (PSC) is a chronic, progressive
disease characterized by inflammation and fibrotic strictures
of the biliary tree. Strictures are usually multi-focal, with 75%
of patients demonstrating both intra- and extrahepatic duct
involvement. Only 10% of patients have isolated extrahepatic
duct involvement (1–3). The incidence of dominant strictures
accounting for the majority of symptoms is approximately 45%
and most (up to 80%) of these occur at or near the hilum (4).
PSC is not only associated with inflammatory bowel disease
(IBD) in 70% of cases, most commonly ulcerative colitis, but
also occurs in the setting of autoimmune diseases such as
ankylosing spondylitis, celiac sprue, autoimmune pancreatitis,
thyroiditis, and others. The overall risk of developing PSC in
patients with ulcerative colitis approaches 10%, for patients
with Crohn’s disease the risk is lower, approximately 2%. As
with inflammatory bowel disease there is an approximate
2:1 male to female predominance and most patients present in
young adulthood or middle age (5,6).
diagnosis
Patients with PSC usually present with signs of cholestasis
including right upper quadrant abdominal pain, jaundice,
pruritis, and/or abnormal serum liver studies. Some IBD
patients are diagnosed during routine screening for liver dis-
ease revealing elevated liver function tests particularly an ele-
vated serum alkaline phosphatase (2,6). In the absence of
alternative etiologies of cholestatic liver disease, the diagnosis
is usually confirmed with high-quality imaging of the biliary
tree utilizing endoscopic retrograde cholangiography (ERC),
or more recently, magnetic resonance cholangiography
(MRC). Both methods effectively demonstrate the characteris-
tic “beads-on-a string” strictures (Fig. 35.1) of PSC making
diagnosis possible in over 95% of cases using image criteria
alone (3). ERC offers the ability to perform concurrent inter-
vention, with the disadvantage of the low (3–8%) but well-
defined incidence of complications related to this invasive
procedure. MRC is diagnostic only, but has the advantage of
minimal risk. MRC is also superior for visualization of ductal
anatomy proximal to dominant strictures, and the two modal-
ities may be used in complimentary fashion. Percutaneous
transhepatic cholangiography (PTC) and intervention can
also be utilized where the expertise exists, but PTC is notori-
ously difficult in patients with the altered ductal anatomy
inherent to PSC.
Regardless of imaging modality, detailed knowledge of a
patient’s ductal anatomy is essential prior to any surgical inter-
vention. Liver biopsy should be obtained at the time of diag-
nosis to assess the hepatic parenchyma for the presence and
degree of fibrosis, which can alter treatment plans. Colonoscopy
should also be performed to identify patients with subclinical
324
IBD and because PSC patients may harbor a higher risk of
colorectal cancer (7).
natural history
The natural history of primary sclerosing cholangitis is vari-
able but generally involves progression from cholestasis to
biliary cirrhosis and ultimately hepatic failure leading to liver
transplant or death. Many more patients are being diagnosed
in the asymptomatic stage as screening for IBD patients with
serum liver studies has become routine. PSC generally follows
an insidious course and some patients remain asymptomatic
for many years. However, others progress rapidly or present
initially with high-grade obstruction, cirrhosis, or cholangio-
carcinoma. The median time from diagnosis to death or need
for liver transplantation is 12 to 18 years. Liver failure and
cholangiocarcinoma are the leading causes of death, in order
of frequency (6). The Mayo Clinic developed a mathematical
model to stratify patients’ risk, which has recently been
updated. It utilizes data on patient age, total bilirubin level,
aspartate aminotransferase level, presence of variceal bleeding,
and serum albumin level to predict survival and assign a Mayo
Risk Score (8). This can be used to prioritize treatment plans
for individual patients. Unfortunately, surgical treatment for
inflammatory bowel disease such as proctocolectomy for ulcer-
ative colitis does not alter the natural course of PSC and patients
may even present years after successful treatment for IBD.
cholangiocarcinoma
Cholangiocarcinoma (CCA) develops in 10% to 30% of
patients with PSC, and the incidence of CCA increases with
the length of follow-up (5–10 years). The incidence of 10% at
5 years correlates with an increased risk of 160-fold over the
general population. It is an ominous finding as the majority of
patients have unresectable disease at the time of diagnosis and
an overall median survival of only 5 to 11 months. A high
index of suspicion is warranted, as just over half of patients
with CCA related to PSC are diagnosed concurrently or within
1 year of their initial presentation (9,10).
The diagnosis of cholangiocarcinoma in PSC can be chal-
lenging. Imaging techniques such as CT, MR, and positron
emission tomography have proven largely unreliable in distin-
guishing benign from malignant biliary strictures. The major-
ity (approximately 80%) of CCAs in PSC occur at the liver
hilum, corresponding with the most frequent location for
dominant strictures in this disease. Brushings and/or biopsies
for cytology taken at the time of ERC have only up to 43%
sensitivity in detecting malignancy (11). Recently, advanced
cytologic techniques that identify chromosomal abnormalities
including digital image analysis (DIA) and fluorescence in situ
hybridization (FISH) have shown promise, but further study is
warranted before widespread application is possible (12).
 SURGICAL MANAGEMENT OF PRIMARY SCLEROSING CHOLANGITIS
(A)
Figure 35.1 Cholangiograms (A and B) demonstrating the characteristic “beads on a string” strictures of PSC.
Tumor markers are moderately helpful in distinguishing
benign from malignant strictures in PSC. Serum CEA and
CA19-9 levels may both be elevated in CCA. Of the two tests,
CA19-9 is the most useful and is relatively sensitive and spe-
cific in the diagnosis of CCA (78% and 98%, respectively)
when elevated greater than 129 U/ml in the setting of PSC,
based on a recent Mayo Clinic study. However, the majority of
patients diagnosed by an elevated serum CA 19-9 level have
unresectable disease and the utility of CA19-9 as a screening
tool to identify early-stage disease in PSC patients is lacking.
The best approach to diagnosis in patients with suspicious
history or imaging findings seems to include the combination
of a high index of suspicion, high-quality imaging, endoscopic
brushings/biopsy, and CA19-9 levels. However, the diagnosis
often remains in question and surgical excision with histo-
pathologic examination is the only option in many cases to
definitively rule out malignancy. Margin-negative surgical
resection, when possible, also offers the only chance for long-
term survival as traditional chemotherapeutic agents and radi-
ation have poor efficacy in cholangiocarcinoma (10–13).
Recent trials indicating improved survival with newer agents
such as gemcitabine given neoadjuvantly followed by resection
or transplantation have shown promise, but these approaches
await validation and can only be recommended in the protocol
setting (14,15).
medical treatment
The inflammation and strictures of primary sclerosing chol-
angitis are thought to be immune-mediated and various
immunosuppressive medications have been used in an attempt
to slow the progression of PSC. However, numerous prospec-
tive randomized trials have failed to identify an agent that
slows progression or improves outcome in patients with
PSC (6). The most extensively studied drug, ursodeoxycholic
acid, has been shown anecdotally to improve bile acid trans-
port and have immuno-modulatory effects. However, despite
initial encouraging studies showing improvement in serum
liver studies and histologic findings on liver biopsy in PSC
patients, no definitive improvement in survival or outcome
has been observed in two large randomized trials (16,17). The
National Institute of Health has sponsored a multicenter trial
(B)
of high-dose ursodeoxycholic acid in PSC in an attempt to
resolve this issue (18).
endoscopic management
Endoscopic treatment involving balloon dilation to relieve
symptomatic obstruction has become first-line treatment for
benign dominant biliary strictures in primary sclerosing chol-
angitis. Stents were routinely employed in the past but have
fallen out of favor due to studies identifying an increased risk
of bacterial cholangitis with their use (19,20). Dominant stric-
tures are defined as common bile duct or common hepatic
duct stricture with a cross-sectional diameter of <1.5 mm and/
or a hepatic duct stricture with a diameter <1.0 mm within
2 cm of the hepatic duct bifurcation (21). Dilation of domi-
nant strictures relieves symptoms, improves serum liver stud-
ies, and can produce durable improvement in imaging
findings. Most patients require multiple interventions for ade-
quate biliary drainage (20).
The effect of endoscopic treatment on disease progression
and survival is controversial. Two studies by Stiehl et al. and
Baluyut et al. demonstrated improved overall survival and
transplant-free survival with repeated endoscopic dilation,
compared to that which would be predicted using the Mayo
mathematical model. The incidence of cholangiocarcinoma
developing during the follow-up period in the two series was
3% and 8%, respectively (Table 35.1) (21,22).
surgical management
Surgical resection for primary sclerosing cholangitis was the
only therapeutic option for patients with dominant strictures
before the development of advanced endoscopic techniques
and liver transplantation (23–25). The fact that most of the
dominant strictures in PSC occur at or near the hepatic bifur-
cation makes resection and biliary-enteric drainage feasible
and effective therapy (26). However, morbidity and mortality
are high in patients with advanced disease and cirrhosis. Liver
transplant is the treatment of choice for these patients and PSC
has become a leading indication for transplantation. However,
although advancements in endoscopy and transplantation have
made resection of dominant strictures in PSC less common,
there is still a role for this approach in select patients.
325
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 35.1 Overall Survival Results and Incidence of Cholangiocarcinoma in Recent Studies on Endoscopic and Surgical
Treatment of Dominant Strictures in Noncirrhotic Patients with Primary Sclerosing Cholangitis
1 year 3 year 5 year 10 year CCA
Endoscopic therapy
Baluyut et al. n = 63 97% 87% 83% – 8%
Stiehl et al. n = 106 –87% 86% 77% – 3%
Ahrendt et al. n = 35 74% 59% – 8%
Surgical therapy
Ahrendt et al. n = 40 95% 92% 85% – 0
Pawlik et al. n = 67 95% 89% 83% 60% 0
Abbreviation: CCA, cholangiocarcinoma incidence.

Table 35.2 Transplant-free Survival in Recent Studies bile duct at the pancreatic head, and reconstruction with
on Endoscopic and Surgical Treatment of Dominant Roux-en-Y bilateral hepaticojejunostomies. Bile cultures
Strictures in Noncirrhotic Patients with Primary Sclerosing should be obtained intraoperatively to guide therapy if post-
Cholangitis operative cholangitis persists. Bilateral percutaneous transhe-
1 year 3 year 5 year patic biliary stents are usually placed preoperatively to aid in
portal dissection, and these are exchanged intraoperatively for
Endoscopic therapy
Stiehl et al. – 93% 89% silastic stents which are placed across the anastamosis and
Ahrendt et al. 85% 59% 46% remain in long term to provide drainage and access to the bili-
Surgical therapy ary tree (23–28,30–33). There is some debate on the duration
Ahrendt et al. 95% 92% 82% of post-operative drainage, but most experts advocate removal
of the stents at approximately 1 year if the biliary-enteric anasta-
mosis is widely patent. Major hepatic resection may also be
Table 35.3 Survival of Patients with Primary Sclerosing included, using standard techniques, to achieve margins in the
Cholangitis Without Cholangiocarcinoma Treated by case of cholangiocarcinoma or extensive hilar fibrosis (11,30).
Surgical Resection (Extrahepatic Bile Duct Resection) Postoperative mortality following extrahepatic biliary resec-
Versus Transplantation tion for PSC is low (2–4%) as reported by centers with a high
volume of hepatobiliary surgical experience. Morbidity is
3 year 5 year 10 year approximately 35%, with the majority of postoperative com-
Surgical resection plications being mild and related to cholangitis. The effect of
Overall 85% 76% 52% surgical resection on long-term outcome remains controver-
Noncirrhotics 95% 83% 60% sial. Early series suggested an overall and transplant-free sur-
Cirrhotics 60% 36% 12% vival benefit in favor of resection, when compared with similar
Transplantation 87% 67% 57%
series on endoscopic management (Tables 35.1 and 35.2). The
Source: Adapted from Ref. (31). most extensive investigation into this subject to date has come
from data collected and published from The Johns Hopkins
Hospital. This was recently expanded and updated by Pawlik
The indications for surgical resection in noncirrhotic PSC et al. to include data from multiple centers with an extended
patients include symptomatic dominant strictures not ame- follow-up of 10 years (31). They observed overall survival in
nable or recalcitrant to endoscopic dilation, failure to rule out noncirrhotic PSC patients undergoing resection of 95%, 83%,
malignancy in suspicious lesions, the finding of dysplasia or and 60% at 1 year, 5year and 10 year follow-up, respectively.
atypia on endoscopic brushings/biopsies and when resectable They also reported favorable results resection, especially in
cholangiocarcinoma is identified (27–29). Biliary strictures noncirrhotic patients, when compared with liver transplanta-
that persist or recur despite dilation raise suspicion for malig- tion (Table 35.3). Only 4 of 66 patients (6%) in the resection
nancy and resection should be considered. High-quality pre- group went on to require transplant in this series. They also
operative imaging to define biliary and hepatic vascular reported a relatively low rate of readmission following resec-
anatomy is essential for operative planning. Broad-spectrum tion for PSC, with over half of patients requiring no readmis-
antibiotics covering biliary-enteric organisms should be admin- sions for PSC-related problems at 3-year follow-up. The most
istered preoperatively and continued postoperatively for 24 to common indication for readmission was for stent change and/
48 hours or until postoperative fever and cholangitis resolve. or treatment of cholangitis. Most significantly, no patients
Surgical treatment involves resection of the extrahepatic developed cholangiocarcinoma during the median follow-up
biliary tree including the biliary bifurcation at the hilum, cho- time of 10.5 years (Table 35.1). This is likely due to the removal
lecystectomy, division and oversewing of the distal common of the most common source of malignancy with this approach,

326
 SURGICAL MANAGEMENT OF PRIMARY SCLEROSING CHOLANGITIS
a concept supported by transplant data reporting that over
70% of incidental CCAs found in explanted livers of patients
with PSC occur at the hepatic bifurcation (34). Finally, as
expected, cirrhotic patients undergoing resection fair much
worse when compared to liver transplant (Table 35.3), and this
should be the preferred treatment in cases of cirrhosis.
Orthotopic liver transplant is the surgical treatment of
choice for PSC patients with cirrhosis and without evidence of
cholangiocarcinoma preoperatively. Standard techniques are
employed and previous biliary surgery does not seem to influ-
ence overall survival, based on recent large series. Overall sur-
vival and graft survival in PSC patients are similar to results
for other indications for transplant (35–37). The risk for
recurrent PSC in the transplanted liver is approximately 15%
and may lead to retransplant (38).
summary
Primary sclerosing cholangitis is a chronic, stricturing disease
of the bile ducts leading to progressive cholestatic liver disease
and a dramatic increase in risk for cholangiocarcinoma. Dom-
inant strictures are common and usually involve the hepatic
bifurcation. Medical therapy is ineffective in preventing pro-
gression of disease or improving outcomes. Optimal manage-
ment of symptomatic noncirrhotic patients with dominant
strictures has been somewhat controversial. Endoscopic ther-
apy palliates symptoms and is relatively low risk and outcomes
seem to be improved over mathematical predictions. However,
the risk of cholangiocarcinoma remains in endoscopically
treated patients and close follow-up is necessary. Surgical
resection of the extrahepatic biliary tree also improves survival
over predicted, and the primary site for the development of
cholangiocarcinoma is removed.
Therefore, a treatment strategy for symptomatic, noncirrhotic
patients with PSC should involve a multi-disciplinary approach.
High-quality imaging and a high index of suspicion for cholan-
giocarcinoma with appropriate screening measures are essential
after diagnosis. Initially, endoscopic dilation of seemingly benign
dominant strictures should be undertaken. Recurrent or suspi-
cious lesions should be strongly considered for resection due to
the risk of CCA. The surgical approach should involve resection
of the extrahepatic biliary tree including the hepatic bifurcation
with hepaticojejunostomy. PSC patients that progress to cirrho-
sis are best treated with orthotopic liver transplant.
references
1. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995;
332: 924–33.
2. Zyromski NJ, Pitt HA. Primary sclerosing cholangitis. In: Cameron JL, ed.
Current Surgical Therapy, 9th edn, Philadelphia: Mosby/Elsevier, 2008:
438–42.
3. LaRusso NF, Shneider BL. Primary sclerosing cholangitis: summary of a
workshop. Hepatology 2006; 44: 746–64.
4. Bjornsson E, Lindquist-Ottosson J, Asztely M, et al. Dominant stricture in
patients with primary sclerosing cholangitis. Am J Gastroenterol 2004; 99:
502–8.
5. Talwalkar JA, Lindor KD. Primary sclerosing cholangitis. Inflamm Bowel
Dis 2005; 11: 62–72.
6. Silveria MG, Lindor KD. Clinical Features and management of primary
sclerosing cholangitis. World J Gastroenterol 2008; 14(21): 3338–49.
7. Broome U, Berg quist A. Primary slerosing cholangitis, inflammatory
bowel disease and colon cancer. Semin Liver Dis 2006; 26: 31–41.
8. Kim WR, Therneau TM, Wiesner RH, et al. A revised natural history
model for primary sclerosing cholangitis. Mayo Clin Proc 2000; 75:
688–94.
9. Rosen CB, Nagorney DM, Wiesner RH, et al. Cholangiocarcinoma com-
plicating primary sclerosing cholangitis. Ann Surg 1991; 213: 21–5.
10. Kaya M, de Groen PC, Angulo P, et al. Treatment of cholangiocarcinoma
complicating primary sclerosing cholangitis: the Mayo Clinic experience.
Am J Gastroenterol 2001; 96: 1164–9.
11. Ahrendt SA, Pitt HA, Nakeeb A, et al. Diagnosis and management of chol-
angiocarcinoma in primary sclerosing cholangitis. J Gastrointest Surg
1999; 3: 357–67.
12. Charatcharoenwitthaya P, Lindor KD. Primary sclerosing cholangitis:
diagnosis and management. Current Gastroenterol Rep 2006; 8:
75–82.
13. Levy C, Lymp J, Anulo P, et al. The value of serum CA 19-9 in predicting
cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig
Dis Sci 2005; 50: 1734–40.
14. Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoad-
juvant chemoradiation is more effective than resection for hilar cholan-
giocarcinoma. Ann Surg 2005; 242: 451–61.
15. Heimbach JK, Gores GJ, Nagorney DM, et al. Liver transplantation for
perihilar cholangiocarcinoma after aggressive neoadjuvant therapy: a
new paradigm for liver and biliary malignancies? Surgery 2006; 140:
331–4.
16. Mitchell SA, Bansi DS, Hunt N, et al. A preliminary trial of high-dose
ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology
2001; 121: 900–7.
17. Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic
acid in primary sclerosing cholangitis: a 5-year multicenter, randomized,
controlled study. Gastroenterology 2005; 129: 1464–72.
18. Hoofnagle JH. Primary sclerosing cholangitis. Hepatology 2005; 41: 955.
19. Kaya M, Petersen BT, Angulo P, et al. Balloon dilation compared to stent-
ing of dominant strictures in primary sclerosing cholangitis. Am J Gastro-
enterol 2001; 96: 1059–66.
20. Linder S, Soderlund C. Endoscopic therapy in primary sclerosing cholan-
gitis: outcome of treatment and risk of cancer. Hepatogastroenterology
2001; 48: 387–92.
21. Stiehl A, Rudolph G, Sauer P, et al. Efficacy of ursodeoxycholic acid
treatment and endoscopic dilation of major duct stenoses in primary
sclerosing cholangitis. An 8-year prospective study. J Hepatol 1997; 26:
560–6.
22. Baluyut AR, Sherman S, Lehman GA, et al. Impact of endoscopic therapy
on the survival of patients with primary sclerosing cholangitis. Gastroin-
test Endosc 2001; 53: 308–12.
23. Cameron JL, Pitt HA, Zinner MJ, et al. Resection of hepatic duct bifurca-
tion and transhepatic stenting for sclerosing cholangitis. Ann Surg 1988;
207: 614–22.
24. Pitt HA, Thompson HH, Tompkins RK, et al. Primary sclerosing chol-
angitis: results of an aggressive surgical approach. Ann Surg 1982; 196:
259–68.
25. Cameron JL, Gayler BW, Herlong HF, et al. Sclerosing cholangitis: bili-
ary reconstruction with Silastic transhepatic stents. Surgery 1983; 94:
324–30.
26. Cameron JL, Gayler BW. Sclerosing cholangitis: anatomical distribution
of obstructive lesions. Ann Surg 1984; 200: 54–60.
27. Martin FM, Rossi RL, Nugent FW, et al. Surgical aspects of sclerosing
cholangitis. Ann Surg 1990; 212: 551–8.
28. Ahrendt SA, Pitt HA, Kalloo AN, et al. Primary sclerosing cholangitis:
resect, dilate, or transplant? Ann Surg 1998; 227: 412–23.
29. Ahrendt SA, Domajnko B. Indications for non-transplant surgery in pri-
mary sclerosing cholangitis. HPB 2005; 7: 292–7.
30. Ahrendt SA. Surgical approaches to strictures in primary sclerosing chol-
angitis. J Gastrointest Surg 2008; 12: 423–5.
31. Pawlik TM, Olbrecht VA, Pitt HA, et al. Primary sclerosing cholangitis:
role of extrahepatic biliary resection. J Am Coll Surg 2008; 206:
822–30.
327
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
32. Yamamoto T, Hirohashi K, Kubo S, et al. Surgery for segmental primary
sclerosing cholangitis. Hepatogastroenterology 2004; 51: 668–71.
33. Hirai I, Ishiyama S, Fuse A, et al. Primary sclerosing cholangitis success-
fully treated by resection of the confluence of the hepatic duct. J Hepato-
biliary Pancreat Surg 2001; 8: 169–73.
34. Abu-Elmagd KM, Selby R, Iwatsuki S, et al. Cholangiocarcinoma and scle-
rosing cholangitis: clinical characteristics and effect on survival after liver
transplantation. Transplant Proc 1993; 25: 1124–25.
35. Goss JA, Shackleton CR, Farmer DG, et al. Orthotopic liver transplanta-
tion for primary sclerosing cholangitis. A 12-year single center experience.
Ann Surg 1997; 225: 472–81.
328
36. Farges O, Malassagne B, Sebagh M, et al. Primary sclerosing cholangitis:
liver transplantation or biliary surgery. Surgery 1995; 117: 146–55.
37. Abu-Elmagd KM, Malinchoc M, Dickson ER, et al. Efficacy of hepatic
transplantation in patients with primary sclerosing cholangitis. Surg
Gynecol Obstet 1993; 177: 335–44.
38. Oldakowsk-Jedynak U, Nowak M, Mucha K, et al. Recurrence of primary
sclerosing cholangitis in patients after liver transplantation. Transplant
Proc 2006; 38: 240–3.
36 Management of advanced gallbladder cancer
Hiromichi Ito and William R. Jarnagin
Gallbladder cancer is uncommon disease, although it is not
rare. Indeed, gallbladder cancer is the fifth most common gas-
trointestinal cancer and the most common biliary tract cancer
in the United States. The incidence is 1.2 per 100,000 persons
per year (1). It has historically been considered as an incurable
malignancy with a dismal prognosis due to its propensity for
early invasion to liver and dissemination to lymph nodes and
peritoneal surfaces. Therefore, clinical attitudes toward gall-
bladder cancer were pervaded with pessimism and nihilism.
Population data in United States from 1988 through 2003 sug-
gested >95% of surgically resectable gallbladder cancer has
been treated with only simple cholecystectomy (2). Although
recent advances in surgical technique and perioperative man-
agement have allowed an increased role for radical surgery in
appropriately selected cases, the outcomes of majority of
patients with advanced gallbladder cancer remains poor.
Patients with gallbladder cancer usually present in one of
three ways: (1) advanced unresectable cancer; (2) detection of
suspicious lesion preoperatively and resectable after staging
work-up; (3) incidental finding of cancer during or after cho-
lecystectomy for benign disease. In this chapter, we describe a
contemporary approach to advanced gallbladder cancer in the
former two scenarios. We define “advanced” cancer as tumor
penetrating through gallbladder wall (T3 or greater), metasta-
sizing to regional lymph node (N1) or distant organ (M1). In
the AJCC staging system, this is staged as II or higher on 6th
edition (3) and as III, IVa, or IVb on 5th edition system (4).
Refer previous chapter for more detailed discussion for staging
systems of gallbladder cancer.
clinical presentation and work-up
The symptoms associated with gallbladder cancer are in gen-
eral vague and non-specific; most patients with gallbladder
cancer present when the disease is at an advanced stage, and
majority of patients are diagnosed when the disease is beyond
the borders of resection (5–9). The most common symptoms
at presentation are abdominal pain or biliary colic (5,8,9).
Patients with advanced disease may also present with jaundice
from tumor invasion of the biliary tree or with systemic signs
such as malaise and weight loss. Jaundice is well recognized as
predictor of worse outcomes. In the series from Memorial
Sloan-Kettering from 1995 through 2005, one-third of patients
presented with jaundice and only 7% had resectable disease (6).
The diagnosis is often suspected on an ultrasound done to
evaluate right upper quadrant abdominal pain. Echogenic or
discontinuous gallbladder mucosa, submucosal echolucency,
or a mass should lead one to suspect gallbladder cancer. The
presence of gallstones trapped within the tumor during its
growth is a useful sign of possible gallbladder cancer (10,11).
Although the detection of early lesions is challenging, ultra-
sound has a sensitivity of 85% and accuracy of 80% to diagnose
advanced gallbladder cancer (10,12). Doppler ultrasound is
helpful not only to identify the presence of hepatic arterial or
portal venous invasion, but also to improve specificity of US
by differentiating malignant tumor from benign lesions by
measuring blood flow into the suspected lesions (13).
Endoscopic retrograde cholangiopancreatography (ERCP)
or percutaneous transhepatic cholangiography (PTC) is useful
to identify the spread of gallbladder cancer into biliary tree. A
mid bile duct stricture is a classic sign of gallbladder cancer
involving bile duct (Fig. 36.1). For patients with jaundice,
cholangiography is useful for localizing the obstruction and
also facilitating stent placement and establishing a diagnosis of
cancer via brush cytology (14).
If gallbladder cancer is suspected, abdominal cross-sectional
imaging (CT or MRI) is mandatory to evaluate for nodal or
metastatic disease as well as to further define the local extent of
disease (Fig. 36.2). Lymph nodes involved by cancer are usu-
ally >1 cm diameter and ring-shaped heterogeneous enhance-
ment with IV contrast. Ohtani and his colleagues reported the
positive predictive value of conventional CT scan for detecting
involvement in various lymph node stations as 75% to 100%
despite lower sensitivity as 17% to 78% (15). The same authors
reported the sensitivity of CT scan to detect of tumor invasion
into liver, bile duct, or other adjacent organs such as pancreas
and transverse colon as 50% to 65% and the positive predictive
value as 77% to 100% (16). The use of spiral CT provides a
better diagnostic accuracy in both nodal spread as well as in-
depth invasion than conventional CT scan (17,18). In a report
by Yoshimitsu and his colleagues, the sensitivity of detecting
tumor invasion into liver or other adjacent organ was 80% to
100%. MRI is less frequently used for staging of gallbladder
cancer, but sometimes the use of MR cholangiography
(MRCP) or angiography (MRA) provides more information
than US or CT. Schwartz and colleagues demonstrated in ret-
rospective analysis of 34 patients with gallbladder cancer that
combination of conventional MRI and MRCP achieved a sen-
sitivity of 100% for liver invasion and 92% for lymph node
involvement (19).
Positron emission tomography (PET) using fluorine-18-
labeled fluoro-deoxyglucose (FDG) is an emerging imaging
modality that may prove to be of clinical value in the preop-
erative work-up of patients with gallbladder cancer. Multiple
studies have shown that PET scans reliably detect primary
and metastatic gallbladder cancer (20,21) as well as residual
tumor after cholecystectomy (22). Corvera and his colleagues
demonstrated that PET added information and altered man-
agement in 23% of selected patients with gallbladder who
were preoperatively staged using US/CT/MRI (23). Since
PET is not routinely available and the data for real contribu-
tion to preoperative staging are relatively limited, the role of
PET in the multimodality work-up of patients with suspected
329
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
gallbladder cancer is still being defined and its use should be
individualized.
surgical management
Although, many studies have suggested improved survival in
patients with early gallbladder cancer with radical surgery
including en bloc resection of gallbladder fossa and regional
lymphadenectomy, its role for those with advanced gallbladder
cancer remains controversial. First, patients with more
advanced disease often require more extensive resections than
early stage tumors, and operative morbidity and mortality
rates are higher (24). Second, the long-term outcomes after
resection, in general, tend to be poorer; long-term survival
after radical surgery has been reported only for patients with
limited local and lymph node spread. Therefore, the indication
of radical surgery should be limited to well-selected patients
based on thorough preoperative and intra-operative staging
and the extent of surgery should be determined based on the
area of tumor involvement.
Surgical resection is warranted only for those who with
locoregional disease without distant spread. Because of the
limited sensitivity of current imaging modalities to detect
metastatic lesions of gallbladder cancer, staging laparoscopy
prior to proceeding to laparotomy is very useful to assess the
abdomen for evidence of discontinuous liver disease or perito-
neal metastasis and to avoid unnecessary laparotomy. Weber
et al. reported that 48% of patients with potentially resectable
gallbladder cancer on preoperative imaging work-up were
spared laparotomy by discovering unresectable disease by lap-
aroscopy (25). Laparoscopic cholecystectomy should be
avoided when a preoperative cancer is suspected because of
the risk of violation of the plane between tumor and liver and
the risk of port site seeding.
Figure 36.1 ERCP of an advanced gallbladder cancer showing mid-bile duct
obstruction.
330
The goal of resection should always be complete extirpation
with microscopic negative margins. Tumors beyond T2 are not
cured by simple cholecystectomy and as with most of early
gallbladder cancer, hepatic resection is always required. The
extent of liver resection required depends upon whether
involvement of major hepatic vessels, varies from segmental
resection of segments IVb and V, at minimum to formal right
hemihepatectomy or even right trisectionectomy. The right
portal pedicle is at particular risk for advanced tumor located
at the neck of gallbladder, and when such involvement is sus-
pected, right hepatectomy is required. Bile duct resection and
reconstruction is also required if tumor involved in bile duct.
However, bile duct resection is associated with increased peri-
operative morbidity (26) and it should be performed only if
it is necessary to clear tumor; bile duct resection does not
necessarily increase the lymph node yield.
Because of its propensity to spread to regional lymph nodes
at early stage, resection of the liver involved and regional
lymph node should be included for definitive treatment. In
fact, frequency of metastasis to regional lymph nodes (hilar,
celiac, peripancreatic, periduodenal) is fairly high for advanced
tumors; pT3/4 60% to 81% versus pT1/2 0 to 62 (27–30). The
most common lymph nodes involved are pericholedochal
(42%) and retropancreatic (37%). Other nodal stations
including celiac, SMA, para-aortic are involved in 20% to 25%
of patients (31). However, optimal extent of lymphadenec-
tomy is ill defined. It is the authors’ practice to include extirpa-
tion of lymph nodes within the hepatoduodenal ligament but
not retropancreatic or celiac nodes as patients with involve-
ment in these nodal basin are unlikely to benefit from resec-
tion. Nodal metastasis beyond the hepatoduodenal ligament
on exploration is associated extremely poor outcomes (24)
and we generally do not proceed with operation if gross metas-
tasis is discovered on exploration.
In the other hand, direct involvement of colon, pancreas, or
duodenum is not an absolute contraindication of surgery.
Several authors have reported that en bloc resection of adjacent
organs (26,32–34), such as duodenum or pancreas, can be
Figure 36.2 Axial, contrast-enhanced computed tomogram of an advanced
gallbladder cancer showing invasion into the liver parenchyma (arrowhead)
and involvement of the stomach and first portion of the duodenum (arrow).
 MANAGEMENT OF ADVANCED GALLBLADDER CANCER
associated with prolonged survival. In a recent study from our
institution, resection of adjacent organ was performed in
21 patients for presumable malignant involvement; the resected
adjacent organ was histologically involved only in half of the
cases and only 16 of 21 cases were node negative, emphasizing
that the finding of adherent organs does not necessarily imply
advanced disease. Most importantly, adjacent organ resection
was not associated with changes in long-term survival of
patients (26).
outcomes
Although advances in surgical technique and improvement in
perioperative care allow us to perform radical resection for
patients with gallbladder cancer safely, the outcomes for those
with advanced cancer remain disappointing. The 5-year sur-
vival rates for patients having radical surgery ranged from 0%
to 51%, most of them fall in 20% to 30% (Table 36.1). Nodal
status and histological margin have been reported as predic-
tive factors of survival after radical resection for this group of
patients throughout the literature. For example, Behari and his
colleague reported that positive node was associated with
incomplete resection and none of the patients with N1 disease
survived beyond 5 years (30). Endo and his colleague reported
in their analysis of 55 patients who underwent complete resec-
tion, a 77% 5-year survival for patients without nodal involve-
ment, 33% for those with single lymph node involvement, and
0% for those with two or more lymph nodes involvement (35).
These findings suggest that radical resection should not be
performed for patients with gross lymph nodes involvement
or extensive tumor infiltration to adjacent structure on peri-
operative evaluation, both of which make complete resection
with histological negative margin unlikely.
adjuvant therapy
Because of its propensity to spread to regional lymph nodes at
early stage and high rate of locoregional recurrence, adjuvant
chemotherapy and/or chemoradiation therapy seems a ratio-
nal therapeutic option for gallbladder cancer. Traditionally
5-FU based chemotherapeutic regimen has been used with or
without combination of chemoradiation. However, there are
few data to support its efficacy. The rarity of gallbladder cancer
and further limitation of patients who can undergo complete
resection make the randomized trial difficult to conduct. To
date, there is only one randomized trial examining the efficacy
of adjuvant chemotherapy for gallbladder cancer. This study
Table 36.1 Outcomes of Radical Surgery for Advanced Gallbladder Cancer
Authors Year N Stage
Fong et al. (5) 2000 58
Kondo et al. (47) 2002 38
Behari et al. (30) 2003 24
Shih et al. (40) 2007 39
Kayahara et al. (48) 2008 631
D’Angelica et al. (26) 2009 72
a
AJCC 5th edn.
b
UICC 5th edn.
c
AJCC 6th edn.
reported significant improvement in 5-year overall survival
rate (26% vs. 14.4%) with postoperative mitomycin C and
5-FU following surgery compared with surgery alone as well as
improvement in 5-year disease-free survival rate (20.3% vs.
11.6%) (36). However, definitive conclusion from this trial is
limited by the small numbers of patients and the inclusion of
patients undergoing incomplete (i.e., R1) resections. Indeed,
subgroup analysis of patients who underwent a complete
resection showed no survival benefit with adjuvant treatment.
Most other data for the use of adjuvant or neo-adjuvant ther-
apy in patients with gallbladder cancer is derived from phase II
trials, in which treated patients were compared with historical
controls (37,38). Kreral and his colleagues reported a 64%
5-year survival rate of patients who received 5-FU and external
beam radiation following surgical resection compared to 33%
of those their historical control (38). In contrast, Houry and
his colleagues reported no survival benefit from adjuvant
chemoradiation therapy on patients who underwent curative
resection (39). Unfortunately, no study has provided conclu-
sive evidence for benefit of adjuvant chemo or chemoradiation
treatment for gallbladder cancer.
palliative care
Most patients with gallbladder cancer present with advanced,
incurable disease and many are not candidates for surgical
resection. The median survival of patients with advanced
gallbladder cancer who are deemed inoperable ranges between
2 and 4 months (6,9,40) and palliation of symptoms should
be the primary goal. Symptoms and conditions associated
with incurable gallbladder cancer include jaundice, cholangi-
tis, pain, and gastrointestinal obstruction. For obstructive
jaundice or gastrointestinal obstruction, palliative interven-
tion may be required. The common procedure for biliary
obstruction due to gallbladder cancer is a segment III
bypass (41). In their series of 41 consecutive segment III
bypass for patients with advanced gallbladder cancer, Kapoor
and his colleagues reported 87% success rate with 12% mor-
tality and 51% morbidity rate (42). Because of poor survival,
biliary stent is a preferred option for most of the patients. It
can be placed via either percutaneous transhepatic route or
endoscopic approach with minimal morbidity. Intestinal
bypass should be performed only in patients who have symp-
tomatic obstruction.
Systemic chemotherapy and radiation therapy have, in gen-
eral, little impact on unresectable gallbladder cancer. Multiple
5-yr survival rate Note
a
III/IVa 28/25%
III/IVab 33/17%
III/IVaa 28/0%
IIc 34%
III/IVaa 39–51/22–24% Multi-institutional study
IIc 22%
331
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
regimens have been tested including combinations of 5-FU,
leucovorin, mitomycin C, doxorubicin, and methotrexate.
However, the effects have been mostly disappointing with
poor response rates of 10% to 20% (43). Recent phase II trials
using combination of gemcitabine and oxaliplatin showed an
improved response rate ranging from 40% to 50% (44–46),
and large scale randomized trial is warranted.
references
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin
2008; 58(2): 71–96.
2. Coburn NG, Cleary SP, Tan JC, et al. Surgery for gallbladder cancer: a
population-based analysis. J Am Coll Surg 2008; 207(3): 371–82.
3. Greene F, Page D, Fleming I, et al. AJCC Cancer Staging Manual, 6th edn.
New York: Springer-Verlag, 2002.
4. Fleming I, Cooper J, Henson D, et al. AJCC Cancer Staging Manual, 5th
edn. Philadelphia: Lippincott-Raven, 1998.
5. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of
patients presenting initially for definitive operation with those presenting
after prior noncurative intervention. Ann Surg 2000; 232(4): 557–69.
6. Hawkins WG, DeMatteo RP, Jarnagin WR, et al. Jaundice predicts
advanced disease and early mortality in patients with gallbladder cancer.
Ann Surg Oncol 2004; 11(3): 310–5.
7. Chan SY, Poon RT, Lo CM, et al. Management of carcinoma of the gall-
bladder: a single-institution experience in 16 years. J Surg Oncol 2008;
97(2): 156–64.
8. Dixon E, Vollmer CM, Jr., Sahajpal A, et al. An aggressive surgical approach
leads to improved survival in patients with gallbladder cancer: a 12-year
study at a North American Center. Ann Surg 2005; 241(3): 385–94.
9. Ito H, Matros E, Brooks DC, et al. Treatment outcomes associated with
surgery for gallbladder cancer: a 20-year experience. J Gastrointest Surg
2004; 8(2): 183–90.
10. Gandolfi L, Torresan F, Solmi L, et al. The role of ultrasound in biliary and
pancreatic diseases. Eur J Ultrasound 2003; 16(3): 141–59.
11. Levy AD, Murakata LA, Rohrmann CA Jr. Gallbladder carcinoma: radio-
logic-pathologic correlation. Radiographics 2001; 21(2): 295–314; ques-
tionnaire, 549–55.
12. Onoyama H, Yamamoto M, Takada M, et al. Diagnostic imaging of early
gallbladder cancer: retrospective study of 53 cases. World J Surg 1999;
23(7): 708–12.
13. Komatsuda T, Ishida H, Konno K, et al. Gallbladder carcinoma: color
Doppler sonography. Abdom Imaging 2000; 25(2): 194–7.
14. Gourgiotis S, Kocher HM, Solaini L, et al. Gallbladder cancer. Am J Surg
2008; 196(2): 252–64.
15. Ohtani T, Shirai Y, Tsukada K, et al. Carcinoma of the gallbladder: CT
evaluation of lymphatic spread. Radiology 1993; 189(3): 875–80.
16. Ohtani T, Shirai Y, Tsukada K, et al. Spread of gallbladder carcinoma: CT
evaluation with pathologic correlation. Abdom Imaging 1996; 21(3): 195–201.
17. Kumaran V, Gulati S, Paul B, et al. The role of dual-phase helical CT in
assessing resectability of carcinoma of the gallbladder. Eur Radiol 2002;
12(8): 1993–9.
18. Yoshimitsu K, Honda H, Shinozaki K, et al. Helical CT of the local spread
of carcinoma of the gallbladder: evaluation according to the TNM system
in patients who underwent surgical resection. AJR Am J Roentgenol 2002;
179(2): 423–8.
19. Schwartz LH, Black J, Fong Y, et al. Gallbladder carcinoma: findings at MR
imaging with MR cholangiopancreatography. J Comput Assist Tomogr
2002; 26(3): 405–10.
20. Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated positron
emission tomography and computed tomography on staging and man-
agement of gallbladder cancer and cholangiocarcinoma. J Hepatol 2006;
45(1): 43–50.
21. Rodriguez-Fernandez A, Gomez-Rio M, Llamas-Elvira JM, et al. Positron-
emission tomography with fluorine-18-fluoro-2-deoxy-D-glucose for
gallbladder cancer diagnosis. Am J Surg 2004; 188(2): 171–5.
22. Anderson CD, Rice MH, Pinson CW, et al. Fluorodeoxyglucose PET imag-
ing in the evaluation of gallbladder carcinoma and cholangiocarcinoma.
J Gastrointest Surg 2004; 8(1): 90–7.
332
23. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose posi-
tron emission tomography influences management decisions in patients
with biliary cancer. J Am Coll Surg 2008; 206(1): 57–65.
24. Kondo S, Nimura Y, Hayakawa N, et al. Regional and para-aortic lymph-
adenectomy in radical surgery for advanced gallbladder carcinoma.
Br J Surg 2000; 87(4): 418–22.
25. Weber SM, DeMatteo RP, Fong Y, et al. Staging laparoscopy in patients
with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg
2002; 235(3): 392–9.
26. D’Angelica M, Dalal KM, Dematteo RP, et al. Analysis of the Extent of
Resection for Adenocarcinoma of the Gallbladder. Ann Surg Oncol 2008.
27. Matsumoto Y, Fujii H, Aoyama H, et al. Surgical treatment of primary
carcinoma of the gallbladder based on the histologic analysis of 48 surgi-
cal specimens. Am J Surg 1992; 163(2): 239–45.
28. Pawlik TM, Gleisner AL, Vigano L, et al. Incidence of finding residual dis-
ease for incidental gallbladder carcinoma: implications for re-resection.
J Gastrointest Surg 2007; 11(11): 1478–86; discussion 1486–7.
29. You DD, Lee HG, Paik KY, et al. What is an adequate extent of resection
for T1 gallbladder cancers? Ann Surg 2008; 247(5): 835–8.
30. Behari A, Sikora SS, Wagholikar GD, et al. Longterm survival after extended
resections in patients with gallbladder cancer. J Am Coll Surg 2003; 196(1): 82–8.
31. Shimada H, Endo I, Togo S, et al. The role of lymph node dissection in the
treatment of gallbladder carcinoma. Cancer 1997; 79(5): 892–9.
32. Doty JR, Cameron JL, Yeo CJ, et al. Cholecystectomy, liver resection, and
pylorus-preserving pancreaticoduodenectomy for gallbladder cancer:
report of five cases. J Gastrointest Surg 2002; 6(5): 776–80.
33. Miyazaki M, Itoh H, Ambiru S, et al. Radical surgery for advanced gall-
bladder carcinoma. Br J Surg 1996; 83(4): 478–81.
34. Shirai Y, Ohtani T, Tsukada K, et al. Combined pancreaticoduodenectomy
and hepatectomy for patients with locally advanced gallbladder carci-
noma: long term results. Cancer 1997; 80(10): 1904–9.
35. Endo I, Shimada H, Tanabe M, et al. Prognostic significance of the num-
ber of positive lymph nodes in gallbladder cancer. J Gastrointest Surg
2006; 10(7): 999–1007.
36. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemo-
therapy useful for gallbladder carcinoma? A phase III multicenter pro-
spective randomized controlled trial in patients with resected
pancreaticobiliary carcinoma. Cancer 2002; 95(8): 1685–95.
37. Czito BG, Hurwitz HI, Clough RW, et al. Adjuvant external-beam radiother-
apy with concurrent chemotherapy after resection of primary gallbladder car-
cinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 2005; 62(4): 1030–4.
38. Kresl JJ, Schild SE, Henning GT, et al. Adjuvant external beam radiation
therapy with concurrent chemotherapy in the management of gallbladder
carcinoma. Int J Radiat Oncol Biol Phys 2002; 52(1): 167–75.
39. Houry S, Schlienger M, Huguier M, et al. Gallbladder carcinoma: role of
radiation therapy. Br J Surg 1989; 76(5): 448–50.
40. Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of
laparoscopy and radical resection. Ann Surg 2007; 245(6): 893–901.
41. Jarnagin WR, Burke E, Powers C, et al. Intrahepatic biliary enteric bypass
provides effective palliation in selected patients with malignant obstruc-
tion at the hepatic duct confluence. Am J Surg 1998; 175(6): 453–60.
42. Kapoor VK, Pradeep R, Haribhakti SP, et al. Intrahepatic segment III chol-
angiojejunostomy in advanced carcinoma of the gallbladder. Br J Surg
1996; 83(12): 1709–11.
43. Hejna M, Pruckmayer M, Raderer M. The role of chemotherapy and radi-
ation in the management of biliary cancer: a review of the literature. Eur
J Cancer 1998; 34(7): 977–86.
44. Harder J, Riecken B, Kummer O, et al. Outpatient chemotherapy with
gemcitabine and oxaliplatin in patients with biliary tract cancer.
Br J Cancer 2006; 95(7): 848–52.
45. Andre T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with
oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a
GERCOR study. Ann Oncol 2004; 15(9): 1339–43.
46. Verderame F, Russo A, Di Leo R, et al. Gemcitabine and oxaliplatin com-
bination chemotherapy in advanced biliary tract cancers. Ann Oncol
2006; 17(Suppl 7): vii68–72.
47. Kondo S, Nimura Y, Hayakawa N, et al. Extensive surgery for carcinoma of
the gallbladder. Br J Surg 2002; 89(2): 179–84.
48. Kayahara M, Nagakawa T, Nakagawara H, et al. Prognostic factors for gall-
bladder cancer in Japan. Ann Surg 2008; 248(5): 807–14.
37 Extrahepatic cholangiocarcinoma
Yuji Nimura
surgical anatomy of the bile duct
Although the middle and distal bile ducts follow the simple
anatomy of the duct (see chapter 1), the proximal bile duct
anatomy is frequently complicated, especially at the hepatic
hilus for which many variations have been described (1–3).
In cases of hilar cholangiocarcinoma, the hepatic confluence
is separated into multiple units and possible proximal exten-
sion of the cancer must be determined in each isolated sec-
tional or segmental bile duct. Therefore a fundamental
knowledge of surgical anatomy of the intrahepatic sectional,
segmental, and subsegmental bile ducts is essential for hepato-
biliary gastroenterologists, radiologist, and surgeons to diag-
nose the preoperative stage of the disease and to design the
planned surgical procedure for each individual patient with
complex hilar cholangiocarcinoma. The applied surgical anat-
omy of the intrahepatic bile duct and the hepatic hilus has
been clinically modified (Fig. 37.1) (4–7). Surgical experiences
with aggressive hepatobiliary resection for biliary malignan-
cies have led to more precise investigation of surgical anatomy
of the hepatic hilus, revealed important variations of the intra-
hepatic bile ducts, and developed comprehensive studies on
the biliary tree and vascular systems at the hepatic hilus which
are mandatory when designing more complicated surgical pro-
cedures for locally advanced cholangiocarcinoma (Figs. 37.2
and 37.3) (8–11). As described in the above studies, the preop-
erative investigation of normal and/or abnormal anatomy,
usual or unusual variations of the segmental bile ducts and the
type of the hepatic confluence are necessary not only to design
difficult hepatobiliary resections and reconstructions but also
to prevent postoperative biliary complications (12).
preoperative managements
Staging of Cholangiocarcinoma
Recent developments in diagnostic modalities have changed
the preoperative staging system, with invasive techniques
being replaced by non-invasive diagnostic procedures. Extra-
corporeal ultrasonography (US) is first used to detect biliary
dilation proximally to a possible biliary lesion, and magnetic
resonance cholangiopancreatography (MRCP) is performed
to demonstrate gross anatomy of the biliary tree and the varia-
tion of the intrahepatic bile ducts. Surgical anatomy and the
extent of the cancer along the involved intrahepatic segmental
ducts also have to be clarified in patients with hilar cholangio-
carcinoma (Fig. 37.4A). Multi-detector row CT (MDCT) is
helpful not only to assess the depth of invasion and longitudi-
nal extension of cholangiocarcinoma but also to find lymph
node and distant organ metastases. Furthermore multiplanar
reformation (MPR) images provide more useful information
about complex structures at the hepatic hilus and display
the entire length of the involved bile duct, and show ductal
thickening and intraductal masses (Fig. 37.4B). Also volume
rendered (VR) images clarify the anatomical variations of the
hepatic artery and portal vein, and possible vascular invasion
can be diagnosed by combined axial, MPR, and VR images
(13,14) (Fig. 37.5).
According to the above information, the resection site of the
liver can be determined. Also a site of biliary drainage, the
right or left hepatic duct and/or the right anterior or right pos-
terior sectional duct, can be recommended. Further possible
portal vein embolization prior to major hepatectomy can
be advised.
MDCT should be taken prior to biliary drainage (BD) to
prevent artifacts of the drainage catheter which can influence
the precise diagnosis of cancer extension along the involved
bile ducts. Peroral cholangioscopy (POC) with or without intra-
ductal ultrasonography (IDUS) should be performed before
placing an endoscopic nasobiliary drainage (ENBD) catheter
which produces artifacts: inflammation with or without granu-
lomatous hyperplasia. Those changes hinder endoscopic diag-
nosis of mucosal spread of cholangiocarcinoma (15,16).
Biliary Drainage (BD)
Most patients with distal cholangiocarcinoma can safely
undergo pancreatoduodenectomy (PD) without preoperative
BD; however, there have been several controversies about BD
prior to hepatectomy for jaundiced patients with proximal
cholangiocarcinoma (17). The incidence of contaminated bile
increases after biliary stenting, which is higher after endo-
scopic BD than percutaneous BD (18). Some retrospective
studies did not show any difference in postoperative mortality
after major hepatectomy for patients with or without preop-
erative BD, but reported higher morbidity in jaundiced
patients (19,20). Another retrospective study showed signifi-
cantly higher rate of infectious complications after major hep-
atectomy for proximal bile duct cancer in patients following
preoperative BD than those without BD (21). Although no
randomized controlled trial (RCT) have been performed to
clarify the value of preoperative BD for jaundiced patients
undergoing major hepatectomy, most major centers prefer to
use preoperative BD followed by portal vein embolization
(PE) prior to major hepatectomy for such patients with hilar
cholangiocarcinoma (22–28).
Preoperative BD has another diagnostic advantage to take
selective tube cholangiography through both endoscopic BD
and percutaneous transhepatic biliary drainage (PTBD),
which clarifies the complicated anatomy of the intrahepatic
segmental ducts and provides precise information about
longitudinal cancer extension along the involved extrahepatic
bile duct and/or the intrahepatic segmental ducts in the
future remnant liver. The resection and reconstruction line
of the intrahepatic bile ducts can then be defined prior
to surgery (Fig. 37.6). In cases of superficially spreading
333
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Supine position Right lateral position

8c 8a
8a 4b
4b 8c
8b 4c 8b
4c
2 3a
3a 2
7b
7a 3b
3b 7a 7b
6c
5c
5c 6c
4a 5a
4a
5a
6b 5b

5b
6a 6b
6a

Figure 37.1 Cholangiographic anatomy of the intrahepatic subsegmental bile duct. Numerals refer to Couinaud’s segments. 3a, Superior branch; 3b, inferior
branch; 4a, inferior branch; 4b, superior branch; 4c, dorsal branch; 5a, ventral branch; 5b, dorsal branch; 5c, lateral branch; 6a, ventral branch; 6b, dorsal branch;
6c, lateral branch; 7a, ventral branch, 7b, dorsal branch; 8a, ventral branch; 8b, lateral branch; 8c, dorsal branch.

curative hepatobiliary resection (29–36). These invasive diag-

nostic procedures are carried out during the preoperative
period of biliary drainage.

1r 1r
1ls Portal Vein Embolization
At the final stage of preoperative BD, liver function tests
including indocyanine green (ICG) test are performed. Also
2
the functional capacity of each section of the liver is carefully
estimated by both the CT volumetric study and the ICG test
A (37,38). PE is performed safely before extended hepatectomy
U to prevent postoperative liver failure for patients with mar-
P 3
ginal functional capacity of the future remnant liver and to
4
increase the resectability rates for patients with advanced hilar
cholangiocarcinoma (39,40). At a minimum of 2 weeks later,
P
liver resection volume and functional capacity of the future
remaining liver are estimated again by CT volumetry and ICG
1li
test to decide the timing of the definitive surgery (Fig.37.7).
Clinical studies on PE offered revolutionary progress in hepa-
1c
tobiliary surgery and have actually increased resectability and
the safety of major liver resection for locally advanced hilar
cholangiocarcinoma (41,42).

Synbiotics Treatments with Bile Replacement

Figure 37.2 Surgical anatomy of the hepatic hilus, including the biliary and
portal branches of the caudate lobe. U, Umbilical portion of the left portal
vein; P, right posterior branch; A, right anterior branch; 1ls, superior branch of
the left caudate lobe; 1li, inferior branch of the left caudate lobe; 1r, branch of
the right caudate lobe; 1c, branch of the caudate process; 2, left lateral poste-
rior branch; 3, left lateral anterior branch; 4, left medial branch.
cholangiocarcinoma, per-oral cholangioscopy (POC) or per-
cutaneous transhepatic cholangioscopy (PTCS), followed by
mapping biopsy is useful to detect minor mucosal changes and
define the proximal mucosal extension of the cancer into the
intrahepatic segmental ducts, and so design an appropriate
Obstructive jaundice is associated with an increased inci-
dence of bacterial translocation and infectious complications
after hepatectomy for biliary cancer patients still remain a
major problem, although surgical techniques and periopera-
tive care have been improved. External BD alone cannot
re-establish the defense system against bacterial translocation
and absence of intestinal bile plays an important role in the
development of infectious complications related to biliary
obstruction. On the contrary, internal BD prevents the loss of
bile from the gastrointestinal tract, preserves the enterohe-
patic biliary circulation, and normalizes the enhanced intesti-
nal permeability in obstructive jaundice. Therefore bile
replacement should be carried out during external BD to

334
 EXTRAHEPATIC CHOLANGIOCARCINOMA

Round ligament Round ligament Round ligament

S4 S3 S4 S3 S4 S3
B3a
P4 P3 P4 P3 P4 P3
B4 B3 B4 B3 B4 B3b
B2 B2 B2
P2 P2 P2
LHD LHD LHD

LPV LPV LPV

(A) (B) (C)
Figure 37.3 Schema of the infraportal variation of the anterior branch of the left lateral section (B3). (A) Normal anatomy, (B) infraportal B3 joining B4,
(C) supraportal B3d (superior branch) and infraportal B3b (inferior branch).

(A) (B) (C)

Figure 37.4 (A) MRCP shows biliary stricture at the hepatic hilus. A possible diagnosis is hilar cholangiocarcinoma separating the hepatic confluence. (B) Coronal
images of multiplanar reformation (MPR) show a soft tissue tumor at the hepatic confluence separating the right and left hepatic duct (arrow). (C) The soft tissue
tumor separates the confluence of the right anterior and posterior sectional ducts (arrow).

(A) (B)
Figure 37.5 Volume rendered (VR) images of the hepatic artery (A) and portal vein (B). 3D images can be obtained. (A). Irregular encasement is demonstrated on
the right hepatic artery (arrow). (B) The left portal vein is obstructed and the right portal vein is involved (arrow). P, right posterior sectional branch; 7d, paracaval
branch of the segment 7.

335
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

repair the physical damage to the intestinal mucosa and to
restore the intestinal barrier function in patients with obstruc-
tive jaundice (43).
In addition to bile replacement during external BD, periopera-
tive synbiotic treatment is an useful measure to prevent bacterial
translocation triggered by intestinal microbial imbalance and
host immunodeficiency. Several RCTs reported that consecutive
preoperative and postoperative synbiotic treatment could reduce
postoperative infectious complications after high-risk hepatobi-
liary resection for patients with biliary tract carcinoma (44,45).
These RCTs revealed that administration of synbiotics could
enhance immune responses, attenuate systemic postoperative
inflammatory responses, and improve intestinal microbial envi-
ronment by increasing beneficial bacteria and decreasing harm-
ful bacteria during recovery from major hepatobiliary surgery.
Preoperative oral intake of synbiotics followed by postoperative
administration through an enteral feeding tube is safe, simple,
and convenient treatment of choice which also reduces medical
costs in shortening the period of postoperative antibiotics treat-
ment and hospital stay.
operative procedures
Pancreatoduodenectomy for Mid-third and
Distal Cholangiocarcinoma
PD and pylorus-preserving pancreatoduodenectomy (PPPD)
have been used as the standard operation not only for pancre-
atic cancer but also for distal cholangiocarcinoma. Although
the details of this surgical procedure are presented in the chap-
ter of pancreatic cancer, an important part of the procedure as
related to cholangiocarcinoma is presented to avoid an overlap
of description.
PD versus PPPD
PPPD is preferably used in biliary tract cancer surgery to pre-
serve the important organs as much as possible. Also, as the
risk of peripyloric lymph node metastasis is low in extrahepatic

L
A B2
B4b

B1
B3

B4a1 B4a2

(A) (B)
Figure 37.6 (A) PTBD tube cholangiography in a supine position. A tip of the PTBD catheter (arrow) is introduced from the right anterior sectional duct into the
left hepatic duct across the hepatic confluence occupied by the tumor to drain bile from the future remnant hepatic lobe. Another PTBD catheter (arrow head) is
placed in the right posterior sectional duct. A: right anterior sectional duct, P: right posterior sectional duct, L: left hepatic duct. (B) PTBD tube cholangiography
in a right anterior and cranioanterior oblique position. Selective cholangiography of the left hepatic duct clearly demonstrates each segmental duct and the
expected resection line can be defined at the confluence of the left medial segmental duct proximally to the confluence of the caudate lobe branch. B1: caudate lobe
branch, B2: lateral posterior branch, B3: lateral anterior branch, B4a: medial inferior branch, B4b: medial superior branch.

Before After
Figure 37.7 Volumetric changes of the liver sections before and after right trisectional portal vein embolization. Hypertrophy of the left lateral section is observed
after portal vein embolization.

336
 EXTRAHEPATIC CHOLANGIOCARCINOMA
cholangiocarcinoma, PPPD is advisable as appropriate surgery
for distal cholangiocarcinoma.
Extent of Lymph Node Dissection
Lymph node metastasis, perineural invasion, surgical resection
margins, and pancreatic invasion are prognostic factors after
curative resection for middle and distal cholangiocarci-
noma (46–51). Therefore regional lymph node dissection is nec-
essary, including the nodes in the hepatoduodenal ligament and
along the common hepatic and superior mesenteric arteries.
Proximal Extension of Resection
In cases of distal cholangiocarcinoma with proximal extension
close to the hepatic confluence, the proximal bile duct is care-
fully dissected while detaching the portal bifurcation and the
left hepatic duct is transected on the left extremity of the hilar
plate along the right wall of the umbilical portion of the left
portal vein (UP). At the resected margin of the left hepatic
duct, the openings of the resected segmental ducts (B2, B3,
and B4) are identified according to their anatomical variation.
On the right extremity of the hilar plate, the right hepatic
artery is carefully skeletonized in Rouviere’s sulcus and the
right posterior sectoral duct is carefully divided with a nega-
tive margin. Next, the right anterior sectoral duct is divided.
The caudate lobe branches are sometimes identified and
divided according to their anatomical variation (Fig. 37.8).
Hepaticojejunostomy
After resecting the proximal bile duct, each individual sec-
tional or segmental bile duct should be anatomically identi-
fied and sutured side by side to complete the hepaticoplasty
and to minimize the number of hepaticojejunostomies with a
Roux-en-Y jejunal limb. A running suture of 5-0 PDS is pref-
erably used for both posterior and anterior wall anastomosis.
A 1
P
1 A
A
P RH
A
Figure 37.8 Hilar bile duct resection. The right and left sectional or segmental ducts and caudate lobe branches are identified and divided with free margins.
Numerals refer to Couinaud’s segments. A, anterior sectional duct; P, posterior sectional duct; RHA, right hepatic artery; MHA, middle hepatic artery; LHA, left
hepatic artery.
Hepatobiliary Resection for Hilar Cholangiocarcinoma
Most of hilar cholangiocarcinoma involving the hepatic
confluence are indicated for liver and extrahepatic bile duct
resection with caudate lobe resection, because the caudate
lobe branches join the right and left hepatic ducts and/or
their confluence and mostly be involved by carcinoma at
the hepatic confluence (4–6). In this section, important
parts of the surgical procedures for cholangiocarcinoma are
described.
Left Hepatectomy, Caudate Lobectomy, and Extrahepatic Bile
Duct Resection
Left-sided hepatectomy is indicated for hilar cholangiocarci-
noma predominantly involving the left hepatic duct (51).
After regional node and connective tissue dissection, the dis-
tal bile duct is resected in the pancreas with a histologically
free margin. After dividing the vascular structures for the left
liver and the caudate lobe, the left lateral section of the liver is
mobilized toward the right anteriorly and the caudate lobe is
also mobilized to the right anteriorly, while ligating and divid-
ing all the short hepatic veins. Then the caudate lobe is com-
pletely detached from the inferior vena cava (IVC). Next, the
liver is transected along the demarcation line and this dissec-
tion progressed toward the hepatic hilus to identify the right
hepatic duct and the right anterior sectional duct crossing
behind the middle hepatic vein (MHV).
The dorsal aspect of liver dissection is aligned along the
right lateral edge of the IVC and the caudate process is detached
from the segment 7 to remove the entire caudate lobe. Then
the isolated right anterior sectional duct or segmental ducts
are divided with free margins. Next, the right posterior sec-
tional duct is exposed cranially to the right portal vein and
divided with a negative margin; and the left liver, caudate lobe,
and extrahepatic duct are removed en bloc.
4
3
2
LH
M HA
337
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Right Hepatectomy, Caudate Lobectomy, and Extrahepatic Bile
Duct Resection
Right hepatectomy is indicated for hilar cholangiocarcinoma
which predominantly involves the right hepatic duct. Regional
node and connective tissue dissection is performed, and the
right hepatic artery, the right portal vein, and the caudate lobe
branches are divided. During this procedure, the proximal and
distal ends of the Arantius canal are ligated and divided below
the UP and close to the confluence of the left hepatic vein
(LHV) or the IVC.
As in most cases of this operation, right PE has been per-
formed pre-operatively to increase the safety of major hepa-
tectomy, careful attention should be paid to observe the lumen
of the resected margin of the right portal vein and not to over-
look possible remaining portal thrombus at the portal bifurca-
tion which can precipitate postoperative portal thrombosis in
the future remnant left liver.
Next, the right liver is mobilized ventrally to the left and
short hepatic veins are ligated and divided step by step. Finally,
the right hepatic vein (RHV) is clamped, divided, and closed at
the confluence of the IVC. Then the caudate lobe and the right
liver are completely detached from the IVC.
Liver dissection is started along the demarcation and pro-
gressed horizontally on the visceral aspect of the segment 4 about
1 cm above the hilar plate to keep a surgical resection margin and
reaches to the left hepatic duct on the right of the UP.
Then the left hepatic duct is divided with a free margin per-
pendicularly parallel to the UP, and the right liver, caudate
lobe, and extrahepatic duct are removed en bloc. Openings of
the segmental branches are identified on the resected margin
of the left hepatic duct.
Left Trisectionectomy
Left trisectionectomy is indicated for hilar cholangiocarci-
noma which predominantly involves the left hepatic duct and
the right anterior sectional duct. Left trisectional PE and right
posterior sectional BD should be carried out prior to
definitive surgery.
After skeletonization and dissection of the hepatoduodenal
ligament and division of the distal bile duct in the pancreas,
the left hepatic artery and the right anterior branch are ligated
and divided.
Next, the portal bifurcation is dissected and the caudate lobe
branches are ligated and divided. The left portal vein and the
right anterior branch are divided and closed after careful
observation of the lumen of the divided portal vein to exclude
portal thrombi.
Next, the left liver is mobilized right anteriorly and the cau-
date lobe is also mobilized while all short hepatic veins are
ligated and divided to detach the caudate lobe from the IVC.
This procedure is progressed cranially and the common trunk
of the LHV and MHV is divided and closed.
Liver transection is carried out along the demarcation on the
right portal fissure while exposing the RHV on the raw surface of
the liver and progressed toward Rouviere’s sulcus to expose and
encircle the right posterior sectional duct which should carefully
be detached from the right posterior branches of the both hepatic
artery and portal vein running behind the bile duct.
338
Dorsal liver dissection is started between segment 7 and the
caudate process and advanced cranially along the right edge of
the IVC and reaches to the caudal aspect of the distal end of
the RHV to remove the entire caudate lobe en bloc. Finally the
right posterior sectional duct is divided with a free margin,
and the liver and the extrahepatic bile duct are removed en
bloc. At the resected margin of the right posterior sectional
duct, single or double openings, which is a sectional or seg-
mental ducts, are identified (Fig. 37.9).
Right Trisectionectomy
Right trisectionectomy is indicated for hilar cholangiocarci-
noma which predominantly involves the right hepatic duct
and the left medial sectional duct and has been considered as
the most high-risk liver resection which sometimes is associ-
ated with serious liver failure. Therefore careful preoperative
management is necessary and functional reserve of the liver
should be carefully estimated before surgery to prevent post-
operative hepatic failure. BD of the left lateral sectional duct
with right trisectional PE should be performed prior to defini-
tive surgery. CT volumetric study with ICG test before and
after right trisectional PE is helpful to estimate the functional
capacity of the future remnant left lateral section of the
liver (7,8,40–42) (Fig. 37.7).
After skeletonization and dissection of the hepatoduodenal
ligament and resection of the distal bile duct in the pancreas,
the right and middle hepatic arteries are ligated and divided.
Then a demarcation appears on the umbilical fissure if the
right trisectional PE has already been carried out.
Next, the portal vein is dissected distally up to the bifurca-
tion and the caudate lobe branches are ligated and divided.
Also the proximal portion of the Arantius canal is ligated and
divided to free the left portal vein from the surrounding hilar
plate. Next, the right portal vein is divided at the bifurcation
while the lumen is carefully inspected to exclude portal
thrombi at the bifurcation, and the vein is closed transversely.
Next, the right liver is mobilized to the left anteriorly and all
short hepatic veins are ligated and divided to detach the
Figure 37.9 The right posterior segmental and subsegmental ducts are identified
at the resected margin of the right posterior sectional duct. P6, posterior infe-
rior portal branch; P7, posterior superior portal branch; B6a, ventral biliary
branch; B6bc, dorsal and lateral biliary branch; B7, posterior superior biliary
branch; RHV, right hepatic vein..
 EXTRAHEPATIC CHOLANGIOCARCINOMA
caudate lobe from the IVC. At the cranial part of this proce-
dure, the distal end of the RHV is divided and closed at the
confluence of the IVC.
Next, liver transection is started from the right edge of the
attachment of the round ligament and progressed dorsally
along the right edge of the UP and the portal branches for the
left medial section (S4) are ligated and divided. During this
procedure, the lumen of the divided portal branches must be
carefully observed not to overlook portal thrombi at the bifur-
cation if the right trisectional PE has already been carried out.
When medial branches of the left portal vein are divided, the
demarcation is observed more clearly along the right edge of
the falciform ligament. Then liver transection is advanced cra-
nially along the demarcation and reaches the distal end of the
MHV at the confluence of the LHV or the IVC. And the MHV
is divided and closed at the confluence. Finally the left lateral
sectional duct is exposed and isolated cranially close to the UP
and divided with a free resection margin, and the right trisec-
tion of the liver, caudate lobe and the extrahepatic bile duct are
removed en bloc.
Anatomic Right Trisectionectomy
Anatomic right trisectionectomy is a more extensive hepatec-
tomy than traditional right trisectionectomy and this more
aggressive procedure is indicated for more advanced hilar
cholangiocarcinoma which involves not only the right hepatic
duct and the left medial sectional duct but also the confluence
of the left medial and lateral sectional ducts (52).
The actual surgical procedure is slightly different from that
of traditional right trisectionectomy in dividing all the portal
branches for the left medial section (S4), including the main
superior and inferior branches and the dorsal branches which
ramify from the dorsal aspect of the UP. By progressing this
procedure, the UP is gradually turned counterclockwise to
expose the left lateral sectional duct more proximally on the
Figure 37.10 All left medial branches of the portal vein are divided to turn the umbilical portion of the vein and to expose the left lateral sectional duct more
proximally and left laterally to the vein. B2: lateral posterior branch, B3: lateral anterior branch, B4, P4: medial branch, P4c: dorsal branch, RPV: right portal vein.
left of the UP (Fig. 37.10). Then a clear demarcation appears
on the umbilical fissure behind or left laterally to the falciform
ligament. Then liver transection along the umbilical fissure
reaches left laterally to the UP or just behind the UP, and the
left lateral sectional duct or segmental ducts can be divided
more proximally with free margins (Fig. 37.11).
Intrahepatic Cholangiojejunostomy
After hepatobiliary resection and removal of the tumor, the
resected margins of the intrahepatic ducts must be identified
anatomically and sutured side by side to complete the hepati-
coplasty and to minimize the number of anastomotic orifices
for intrahepatic cholangiojejunostomy with a Roux-en-Y jeju-
nal limb lifted via the retrocolic–retrogastric route (12,53).
Previously, single layer cholangiojejunostomy was performed
using interrupted sutures of 5-0 or 6-0 PDS and all anasto-
mosed bile ducts drained externally with 6 Fr. polyvinyl chlo-
ride tubes. However, a continuous suture of 5-0 or 6-0 PDS has
recently been used for each anterior and posterior wall anasto-
mosis of all cholangiojejunostomies and external biliary drain-
age tube(s) has not been used routinely. Thus, difficult and
time-consuming hepatobiliary resectional and reconstruc-
tional surgery became simplified.
Combined Liver and Portal Vein Resection
for Advanced Cholangiocarcinoma
Combined liver and portal vein resection is indicated for
locally advanced cholangiocarcinoma, and several types of
liver resection and combined portal vein resection and recon-
struction have been reported as an aggressive surgical approach
which provides both negative surgical margins and contrib-
utes to prolonged survival for resected patients compared to
non-resected patients (54–58).
The portal vein is usually resected at the final step of hepato-
biliary resection and is reconstructed after removal of the
339
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 37.11 The left lateral sectional or segmental ducts ( ) are resected
left dorsally to the umbilical portion of the left portal vein. In this case, right
hepatopancreatoduodenectomy with portal vein resection and reconstruction
(arrow) are performed. P, pancreas; RL, round ligament.
tumor. However, in case of right-sided hepatectomy, the portal
bifurcation can be resected and reconstructed prior to liver
dissection using an end-to-end anastomosis between the left
portal vein and the main trunk to establish the non-touch
resection of hilar cholangiocarcinoma (59).
Several techniques have been reported for portal vein recon-
struction. In addition to the end-to-end anastomosis which is
commonly used, a graft interposition using an external iliac
vein (54,60), a hepatic vein segment (61), a saphenous
vein (54), or a left renal venous patch (62) are used for difficult
portal vein reconstruction after segmental or wedge resection
of the portal bifurcation.
Hepatopancreatoduodenectomy for
Advanced Cholangiocarcinoma
Hepatopancreatoduodenectomy (HPD) has been used as the
most extensive surgery for advanced carcinoma of the biliary
tract (63). Recent development of diagnostic modalities has
increased the opportunity to demonstrate the extent of chol-
angiocarcinoma precisely by MDCT, selective cholangiogra-
phy, and cholangioscopy, and increasing numbers of patients
with cholangiocarcinoma have been considered for HPD. Dis-
tal or middle bile duct cancer with superficial spread to the
intrahepatic bile duct or intrahepatic cholangiocarcinoma
with superficial spread to the distal bile duct are indications
for HPD (33,64,65). As HPD is composed of PD or PPPD for
distal bile duct cancer and hepatectomy for proximal cholan-
giocarcinoma, PD or PPPD is carried out at the first step of
this operation, and the hepatoduodenal ligament is dissected
upward to skeletonize the hepatic arteries and portal bifurca-
tion. As the next step, hemihepatectomy or hepatic sectionec-
tomy is performed according to the preoperative diagnosis of
340
the extent of cholangiocarcinoma as described in the previous
section (Fig. 37.11).
discussion
Recent improvement in preoperative staging system and man-
agements of difficult biliary cancer patients, as well as techni-
cal developments in hepatobiliary surgery have increased the
rate of potentially curative resection and decreased postopera-
tive morbidity and mortality (13,14,36–40,42–44). Although
preoperative BD has recently not been used prior to PD, the
value of preoperative BD before cholestatic liver resection has
not been clarified by RCTs (28).
As the HPD is the ultimate surgery for the visceral organs,
unexpectedly high morbidity and mortality have been
encountered (63); however, recent progress in surgical tech-
niques and perioperative management for biliary cancer
patients with difficult preoperative complications improved
the outcome of this surgery and an increasing number of
operations and 5-year survivors have been reported not only
from aggressive surgeons in Japan but also from the United
States (64–68). It is expected that an increasing number of
patients with locally advanced cholangiocarcinoma will be
considered for difficult surgeries employing HPD with or
without vascular resection, which should be justified by
improved outcome (69–72).
Recent retrospective analysis of the impact of future liver rem-
nant (FLR) volume and preoperative BD on postoperative hepatic
insufficiency and mortality rates revealed that preoperative BD
did not appear to improve perioperative outcome in patients
with FLR ≥30% and PVE is likely to offer little benefit (73).
According to the continued and utmost efforts of aggressive
hepatobiliary surgeons, favorable results of PD and hepatec-
tomy have been reported and prognostic factors after curative
resection of extrahepatic cholangiocarcinoma have been
revealed (22–27,42,46–51).
Although preoperative BD followed by PE has been used
prior to major hepatectomy for biliary cancer patients with
obstructive jaundice in many centers all over the world, it may
be difficult to clarify the value of this strategy by RCTs.
references
1. Healey JE Jr, Schroy PC. Anatomy of the biliary ducts within the human
liver, analysis of the prevailing pattern of branchings and the major varia-
tions of the biliary ducts. AMA Arch Surg 1953; 66: 599–616.
2. Couinaud C. Surgical anatomy of the liver revisited. Paris: Couinaud C,
1989: 61–74.
3. Mizumoto R, Suzuki H. Surgical anatomy of the hepatic hilum with spe-
cial reference to the caudate lobe. World J Surg 1988; 12: 2–10.
4. Nimura Y, Hayakawa N, Kamiya J, Kondo S, Shionoya S. Hepatic segmen-
tectomy with caudate lobe resection for bile duct carcinoma of the hepatic
hilus. World J Surg 1990; 14: 535–44.(Category III) (Grade C).
5. Kamiya J, Nimura Y, Hayakawa N, et al. Preoperative cholangiography of
the caudate lobe: Surgical anatomy and staging for biliary carcinoma.
J Hepatobiliary Pancreat Surg 1994; 1: 385–9.
6. Nimura Y, Hayakawa N, Kamiya J, et al. Hilar cholangiocarcinoma –
surgical anatomy and curative resection. J Hepatobiliary Pancreat Surg
1995; 2: 239–48. (Category III) (Grade C).
7. Nimura Y. Surgical anatomy of the biliary ducts. In: Rossi P, ed. Biliary
Tract Radiology. Berlin, Heidelberg, Springer-Verlag, 1997: 21–30.
8. Nimura Y. Living donor liver transplantation: importance of anatomical
variations of biliary tree and vascular systems. Transpl Proc 2003; 35: 955.
 EXTRAHEPATIC CHOLANGIOCARCINOMA
9. Ozden I, Kamiya J, Nagino M, et al. Clinicoanatomical study on the infra-
portal bile ducts of segment 3. World J Surg 2002; 26: 1441–5.
10. Ohkubo M, Nagino M, Kamiya J, et al. Surgical anatomy of the bile ducts
at the hepatic hilum as applied to living donor liver transplantation. Ann
Surg 2004; 239: 82–6.
11. Sugiura T, Nagino M, Kamiya J, et al. Infraportal bile duct of the caudate
lobe: a troublesome anatomic variation in right-sided hepatectomy for
perihilar cholangiocarcinoma. Ann Surg 2007; 246: 794–8.
12. Nagino M, Nishio H, Ebata T, et al. Intrahepatic cholangiojejunostomy
following hepatobiliary resection. Br J Surg 2007; 94: 70–7. (Category III)
(Grade C).
13. Choi JY, Lee JM, Lee JY, et al. Assessment of hilar and extrahepatic bile
duct cancer using multidetector CT: value of adding multiplanar refor-
mations to standard axial images. Eur Radiol 2007; 17: 3130–8. (Category
III) (Grade C).
14. Senda Y, Nishio H, Oda K, et al. Value of multidetector row CT in the
assessment of longitudinal extension of cholangiocarcinoma-correlation
between MDCT and microscopic findings. World J Surg 2009; 33: 1459–
67. (Category III) (Grade C).
15. Fukuda Y, Tsuyuguchi T, Sakai Y, Tsuchiya S, Saisyo H. Diagnostic utility
of peroral cholangioscopy for various bile-duct lesions. Gastrointest
Endosc 2005; 62: 374–82. (Category IV) (Grade D).
16. Itoi T, Sofuni A, Itokawa F, et al. Peroral cholangioscopic diagnosis of bil-
iary-tract diseases by using narrow-band imaging (with videos). Gastro-
intest Endosc 2007; 66: 730–6. (Category IV) (Grade D).
17. Nishio H, Hidalgo E, Hamady ZZ, et al. Left hepatic trisectionectomy for
hepatobiliary malignancy: results and an appraisal of its current role. Ann
Surg 2005; 242: 267–75. (Category III) (Grade C).
18. Hochwald SN, Burke EC, Jarnagin WR, Fong Y, Blumgart LH. Association
of preoperative biliary stenting with increased postoperative infectious
complications in proximal cholangiocarcinoma. Arch Surg 1999; 134:
261–6. (Category III) (Grade C).
19. Figueras J, Llado L, Valls C, et al. Changing strategies in diagnosis and
management of hilar cholangiocarcinoma. Liver Transpl 2000; 6: 786–94.
(Category III) (Grade C).
20. Cherqui D, Benoist S, Malassagne B, et al. Major liver resection for carci-
noma in jaundiced patients without preoperative biliary drainage. Arch
Surg 2000; 135: 302–8. (Category III) (Grade C).
21. Ferrero A, Lo Tesoriere R, Viganò L, et al. Preoperative biliary drainage
increases infectious complications after hepatectomy for proximal bile
duct tumor obstruction. World J Surg 2009; 33: 318–25. (Category III)
(Grade C).
22. Nimura Y, Kamiya J, Kondo S, et al. Aggressive preoperative management
and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J
Hepatobiliary Pancreat Surg 2000; 7: 155–62. (Category III) (Grade C).
23. Lee SG, Lee YJ, Park KM, Hwang S, Min PC. One hundred and eleven liver
resections for hilar bile duct cancer. J Hepatobiliary Pancreat Surg 2000; 7:
135–41. (Category III) (Grade C).
24. Seyama Y, Kubota K, Sano K, et al. Long-term outcome of extended hemi-
hepatectomy for hilar bile duct cancer with no mortality and high sur-
vival rate. Ann Surg 2003; 238: 73–83. (Category III) (Grade C).
25. Kawasaki S, Imamura H, Kobayashi A, et al. Results of surgical resection
for patients with hilar bile duct cancer: application of extended hepatec-
tomy after biliary drainage and hemihepatic portal vein embolization.
Ann Surg 2003; 238: 84–92. (Category III) (Grade C).
26. Hemming AW, Reed AI, Fujita S, Foley DP, Howard RJ. Surgical manage-
ment of hilar cholangiocarcinoma. Ann Surg 2005; 241: 693–702. (Cate-
gory III) (Grade C).
27. Sano T, Shimada K, Sakamoto Y, et al. One hundred two consecutive hep-
atobiliary resections for perihilar cholangiocarcinoma with zero mortal-
ity. Ann Surg 2006; 244: 240–7. (Category III) (Grade C).
28. Nimura Y. Preoperative biliary drainage before resection for cholangio-
carcinoma (Pro). HPB 2008; 10: 130–3. (Category III) (Grade C).
29. Nimura Y, Shionoya S, Hayakawa N, et al. Value of percutaneous transhe-
patic cholangioscopy (PTCS). Surg Endosc 1988; 2: 213–9. (Category III)
(Grade C).
30. Nimura Y, Kamiya J, Hayakawa N, Shionoya S. Cholangioscopic differen-
tiation of biliary strictures and polyps. Endoscopy 1989; 21(Suppl 1):
351–6. (Category IV) (Grade D).
31. Nimura Y. Staging of biliary carcinoma: cholangiography and cholangios-
copy. Endoscopy 1993; 25: 76–80. (Category IV) (Grade D).
32. Seo DW, Lee SK, Yoo KS, et al. Cholangioscopic findings in bile duct
tumors. Gastrointest Endosc 2000; 52: 630–4. (Category IV) (Grade D).
33. Kato M, Nimura Y, Kamiya J, et al. Carcinoma of the common bile duct
with superficial spread to the intrahepatic segmental bile ducts: a case
report. Am Surg 1997; 63: 943–7.
34. Itoi T, Shinohara Y, Takeda K, et al. Detection of telomerase activity in
biopsy specimens for diagnosis of biliary tract cancers. Gastrointest
Endosc 2000; 52: 380–6. (Category III) (Grade C).
35. Murata T, Nagasaka T, Kamiya J, et al. P53 labeling index in cholangio-
scopic biopsies is useful for determining spread of bile duct carcinomas.
Gastrointest Endosc 2002; 56: 688–95. (Category III) (Grade C).
36. Nimura Y. Staging cholangiocarcinoma by cholangioscopy. HPB 2008; 10:
113–5. (Category IV) (Grade D).
37. Uesaka K, Nimura Y, Nagino M. Changes in hepatic lobar function after
right portal vein embolization: an appraisal by biliary indocyanine green
excretion. Ann Surg 1996; 1: 77–83. (Category III) (Grade C).
38. Nagino M, Nimura Y, Kamiya J, et al. Changes in hepatic lobe volume in
biliary tract cancer patients after right portal vein embolization. Hepatol-
ogy 1995; 21: 434–9. (Category III) (Grade C).
39. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization
to increase safety of major hepatectomy for hilar bile duct carcinoma: a
preliminary report. Surgery 1990; 107: 521–7.
40. Nagino M, Nimura Y, Kamiya J, Kondo S, Kanai M. Selective percutaneous
transhepatic embolization of the portal vein in preparation for extensive
liver resection: the ipsilateral approach. Radiology 1996; 200: 559–63.
(Category III) (Grade C).
41. Nagino M, Kamiya J, Kanai M, et al. Right trisegment portal vein emboli-
zation for biliary tract carcinoma: technique and clinical utility. Surgery
2000; 127: 155–60. (Category III) (Grade C).
42. Nagino M, Kamiya J, Nishio H, et al. Two hundred forty consecutive por-
tal vein embolizations before extended hepatectomy for biliary cancer:
surgical outcome and long-term follow-up. Ann Surg 2006; 243: 364–72.
(Category III) (Grade C).
43. Kamiya S, Nagino M, Kanazawa H, et al. The value of bile replacement dur-
ing external biliary drainage: an analysis of intestinal permeability, integrity,
and microflora. Ann Surg 2004; 239: 510–7. (Category Ib) (Grade A).
44. Kanazawa H, Nagino M, Kamiya S, et al. Synbiotics reduce postoperative
infectious complications: a randomized controlled trial in biliary cancer
patients undergoing hepatectomy. Langenbecks Arch Surg 2005; 390:
104–13. (Category Ib) (Grade A).
45. Sugawara G, Nagino M, Nishio H, et al. Perioperative synbiotic treatment
to prevent postoperative infectious complications in biliary cancer sur-
gery: a randomized controlled trial. Ann Surg 2006; 244: 706–14. (Cate-
gory Ib) (Grade A).
46. Bhuiya MR, Nimura Y, Kamiya J, et al. Clinicopathologic studies on peri-
neural invasion of bile duct carcinoma. Ann Surg 1992; 215: 344–9. (Cat-
egory III) (Grade C).
47. Kayahara M, Nagakawa T, Ohta T, et al. Role of nodal involvement and the
periductal soft-tissue margin in middle and distal bile duct cancer. Ann
Surg 1999; 229: 76–83. (Category III) (Grade C).
48. Wakai T, Shirai Y, Moroda T, Yokoyama N, Hatakeyama K. Impact of duc-
tal resection margin status on long-term survival in patients undergoing
resection for extrahepatic cholangiocarcinoma. Cancer 2005; 103:
1210–6. (Category III) (Grade C).
49. Jang JY, Kim SW, Park DJ, et al. Actual long-term outcome of extrahepatic
bile duct cancer after surgical resection. Ann Surg 2005; 241: 77–84.
(Category III) (Grade C).
50. Cheng Q, Luo X, Zhang B, et al. Distal bile duct carcinoma: prognostic
factors after curative surgery. A series of 112 cases. Ann Surg Oncol 2007;
14: 1212–9. (Category III) (Grade C).
51. Murakami Y, Uemura K, Hayashidani Y, et al. Pancreatoduodenectomy
for distal cholangiocarcinoma: prognostic impact of lymph node metas-
tasis. World J Surg 2007; 31: 337–42. (Category III) (Grade C).
52. Nagino M, Kamiya J, Arai T, et al. “Anatomic” right hepatic trisectio-
nectomy (extended right hepatectomy) with caudate lobectomy for
hilar cholangiocarcinoma. Ann Surg 2006; 243: 28–32. (Category III)
(Grade C).
341
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
53. Nagino M, Kamiya J, Kanai M, et al. Hepaticojejunostomy using a Roux-
en-Y jejunal limb via the retrocolic-retrogastric route. Langenbecks Arch
Surg 2002; 387: 188–9. (Category III) (Grade C).
54. Nimura Y, Hayakawa N, Kamiya J, et al. Combined portal vein and liver
resection for carcinoma of the biliary tract. Br J Surg 1991; 78: 727–31.
(Category III) (Grade C).
55. Neuhaus P, Jonas S, Bechstein WO, et al. Extended resections for hilar
cholangiocarcinoma. Ann Surg 1999; 230: 808–19. (Category III)
(Grade C).
56. Muñoz L, Roayaie S, Maman D,et al Hilar cholangiocarcinoma involving
the portal vein bifurcation: long-term results after resection. J Hepatobili-
ary Pancreat Surg 2002; 9: 237–41. (Category III) (Grade C).
57. Ebata T, Nagino M, Kamiya J, et al. Hepatectomy with portal vein resec-
tion for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann
Surg 2003; 238: 720–7. (Category III) (Grade C).
58. Hemming AW, Kim RD, Mekeel KL, et al. Portal vein resection for
hilar cholangiocarcinoma. Am Surg 2006; 72: 599–605. (Category III)
(Grade C).
59. Kondo S, Katoh H, Hirano S, et al. Portal vein resection and reconstruc-
tion prior to hepatic dissection during right hepatectomy and caudate
lobectomy for hepatobiliary cancer. Br J Surg 2003; 90: 694–7. (Category
III) (Grade C).
60. Sakaguchi S, Nakamura S. Surgery of the portal vein in resection of cancer
of the hepatic hilus. Surgery 1986; 99: 344–9. (Category III) (Grade C).
61. Lorf T, Hanack U, Ringe B. Portal vein replacement by hepatic vein trans-
position. Am J Surg 1997; 174: 353–4. (Category III) (Grade C).
62. Miyazaki M, Kato A, Ito H, et al. Combined vascular resection in operative
resection for hilar cholangiocarcinoma: does it work or not? Surgery
2007; 141: 581–8. (Category III) (Grade C).
63. Nimura Y, Hayakawa N, Kamiya J, et al. Hepatopancreatoduodenectomy
for advanced carcinoma of the biliary tract. Hepatogastroenterology
1991; 38: 170–5. (Category III) (Grade C).
342
64. Nakamura S, Suzuki S, Serizawa A, et al. Hepatopancreatoduodenectomy
for superficially spreading bile duct carcinoma: a report of two 5 year sur-
vivals. Hepatogastroenterology 1996; 43: 138–42.
65. Kurosaki I, Hatakeyama K, Tsukada K, Date K, Tomiyama T. Major hepa-
tectomy combined with pylorus-preserving pancreatoduodenectomy for
middle bile duct cancer with multiple lymph node metastases: a case
report of 5-year survival. Hepatogastroenterology 1999; 46: 1623–6.
66. Kaneoka Y, Yamaguchi A, Isogai M, Suzuki M. Longer than 3-year survival
following hepato-ligamento-pancreatoduodenectomy for hilar cholan-
giocarcinoma with vascular involvement: report of a case. Surg Today
2003; 33: 772–6. (Category III) (Grade C).
67. Ebata T, Nagino M, Nishio H, Arai T, Nimura Y. Right hepatopancreato-
duodenectomy: improvements over 23 years to attain acceptability.
J Hepatobiliary Pancreat Surg 2007; 14: 131–5. (Category III) (Grade C).
68. D’Angelica M, Martin RC 2nd, Jarnagin WR, et al. Major hepatectomy
with simultaneous pancreatectomy for advanced hepatobiliary cancer.
J Am Coll Surg 2004; 198: 570–6. (Category III) (Grade C).
69. Nimura Y. Radical surgery: vascular and pancreatic resection for cholan-
giocarcinoma. HPB 2008; 10: 183–5. (Category III) (Grade C).
70. Yoshimi F, Asato Y, Amemiya R, Shioyama Y, Itabashi M. Comparison
between pancreatoduodenectomy and hepatopancreatoduodenectomy
for bile duct cancer. Hepatogastroenterology 2001; 48: 994–8. (Category
III) (Grade C).
71. Miwa S, Kobayashi A, Akahane Y, et al. Is major hepatectomy with pancre-
atoduodenectomy justified for advanced biliary malignancy? J Hepatobi-
liary Pancreat Surg 2007; 14: 136–41. (Category III) (Grade C).
72. Kaneoka Y, Yamaguchi A, Isogai M. Hepatopancreatoduodenectomy: its
suitability for bile duct cancer versus gallbladder cancer. J Hepatobiliary
Pancreat Surg 2007; 14: 142–8. (Category III) (Grade C).
73. Kennedy TJ, Yopp A, Qin Y, et al. Role of preoperative biliary drainage of
liver remnant prior to extended liver resection for hilar cholangiocarci-
noma. HPB 2009; 11: 445–51. (Category III) (Grade C).
38 Endoscopic management of malignant biliary obstruction
Nick Stern and Richard Sturgess
background
There are many aspects of diagnosis, staging, and therapy in
biliary malignancies that are managed by the endoscopist.
As different imaging modalities of the biliary system have
advanced, there has been a move in recent years away from using
endoscopic retrograde cholangio-pancreatography (ERCP) as a
diagnostic tool.
High-quality diagnostic images of the biliary tree can now
be obtained with modern radiological techniques. Newer MRI
scanners using an MRCP protocol (1–3) can provide high-
quality cholangiography and cross-sectional imaging. Endo-
scopic ultrasound (4,5) allows sonographic views from the
lumen of the upper GI tract, particularly of the distal biliary
system and pancreas. These, along with the improved quality
of CT scanning (6–8) can provide safe diagnosis and staging of
biliary malignancies, saving potentially risky ERCP for appro-
priate therapeutic procedures.
causes of malignant biliary obstruction
Common causes of malignant biliary obstruction include
pancreatic carcinoma, primary biliary or liver tumors: cholan-
giocarcinoma or some hepatocellular carcinomas; or meta-
static disease, including lymphadenopathy. This is often at the
porta hepatis but can also occur distally (9).
The majority of patients with these malignancies will not
undergo surgical resection of the tumor due to either the
advanced nature of the disease (inoperable disease) or the
co-existing morbidities precluding surgery.
There are therefore, a large proportion of patients that will
require a non-operative intervention to manage their biliary
obstruction that is often associated with debilitating symptoms.
This is commonly offered in the form of procedures to pal-
liate jaundice. These are normally performed endoscopically
or via a percutaneous radiological approach.
While these are normally palliative procedures, in some
cases access to the biliary system provides the opportunity to
deliver potentially survival-enhancing therapies which we will
be described later in this chapter.
radiological diagnostic imaging
Following presentation with suspected biliary malignancy,
radiological investigations are necessary to make a diagnosis
and stage the disease.
Radiology is particularly important to help clarify the
appropriate management and to target and plan any therapy
that will later be necessary for the patient.
As with all patient management, assessment should begin
with the taking of a good history and examination of the patient.
Depending on the symptoms and mode of presentation, the
pathway for investigation will vary. What we will describe will
be assuming that most patients present with symptoms and
signs of cholestatic jaundice due to their biliary obstruction.
ultrasound
One of the first investigations important in the jaundiced
patient is an ultrasound of the liver and biliary tree. This will
determine whether the jaundice is obstructive or whether it is
due to a parenchymal liver disease or pre-hepatic cause (10,11).
Obstructive jaundice cannot be diagnosed without imaging of
the biliary tree. It is worth noting that abnormal LFTs in a cho-
lestatic pattern do not necessarily equate to biliary obstruction.
Trans-abdominal ultrasound will be able to confirm whether
the patient has gall bladder calculi, which can cause obstructive
jaundice if they migrate to the bile ducts. It can also detect
whether there are intra-hepatic lesions, such as liver metastases
or primary liver malignancies (12,13). The main role in this con-
text, however, is to detect whether there is biliary obstruction.
A mildly dilated common bile duct is expected in patients
with prior cholecystectomy. It is not abnormal for the com-
mon bile duct to increase in size slightly with age. Should there
be dilatation of the intra-hepatic ducts, this almost always sug-
gests pathology and biliary obstruction.
ct scanning
For detailed information about potential causes of obstructive
jaundice, a high-quality, contrast-enhanced CT scan is often
necessary. CT scanning can give important information about
the pancreas (often obscured by bowel gas on ultrasound
scanning). Heads of pancreas tumors, that often present with
obstructive jaundice, are normally visible on targeted, enhanced
CT scans of the pancreas (14,15).
The degree of biliary dilatation and the site of any caliber
change in the biliary tree can provide additive information
about the tumor. Segmental intra-hepatic dilatation of the bile
ducts can suggest cholangiocarcinoma.
Lymphadenopathy can cause malignant biliary obstruction
and when this occurs this tends to be at the porta hepatis. This
is normally well seen on CT scans with the opportunity to get
information about a possible site of primary tumor. Large
colonic masses or widespread lymphadenopathy with spleno-
megaly may suggest a possible cause of the malignancy.
The importance of CT scanning is that of diagnosing the
primary tumor, as well as providing information for staging
and operability.
CT scanning should ideally be performed prior to any endo-
scopic intervention of the biliary tree (ERCP) as the complica-
tion of pancreatitis can interfere with accurate staging of
the disease.
While CT may give a good indication of the site of biliary
obstruction and the cause, detailed views of the biliary tree are
better obtained with MR scanning.
mr scanning
Magnetic Resonance Imaging (MRI scanning) is increasingly
important in providing good imaging of the biliary tree (1–3).
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It can complement CT scanning in selected patients and has
the advantage over CT of not exposing the patient to ionizing
radiation.
Newer MRI scanners with stronger magnets provide detailed
cholangiograms without the need of intravenous contrast using
an MRCP (magnetic resonance cholangio-pancreatography)
protocol. These are obtained without needing endoscopic
instrumentation of the bile ducts and therefore eliminate the
risks of pancreatitis and other risks associated with ERCP. While
MRCP provides important diagnostic information, it is purely
used for diagnostic information and interventional methods
(ERCP or PTC) are needed to provide therapy.
MRCP is very useful in patients with biliary strictures caused
by lesions not visible on CT scanning, such as small cholangio-
carcinomas. It helps with the planning of therapy and in deci-
sion making about whether intervention may be best carried
out endoscopically or percutaneously (Fig. 38.1).
endoscopic assessment
Endoscopic Intervention
The anatomy of the biliary tree allows good access to the bili-
ary system with an endoscope. The bile ducts drain, via the
common bile duct, through the ampulla of Vater and sphincter
of Oddi into the second part of the duodenum.
This allows an accessible port of access to the biliary system
by use of an endoscope designed to sit opposite the ampulla
within the duodenum.
The use of endoscopy in the management of malignant bili-
ary obstruction can be in the diagnosis, staging, and therapy of
the disease.
EUS is a very useful way of imaging the biliary tree. It is the
most sensitive modality for detecting small bile duct calculi
and in the context of malignancy can look intimately at the
pancreas as well as direct visualization of the ampulla and
ultrasonographic views of any lesions (Fig. 38.3).
The sensitivity of EUS does diminish with more proximal
lesions in the biliary tree and the liver itself.
As well as the imaging advantages with EUS, it provides a
useful and relatively safe way to sample tissue with EUS-guided
fine needle aspiration cytology (16,17).
This can be used to target pancreatic lesions, lymph nodes,
ampullary lesions as well as non-biliary disease such as medi-
astinal lymphadenopathy.
One of the current limitations to EUS as a modality is due to
its availability. EUS (unlike CT or MRI scanners) is only avail-
able at certain specialized centers in the United Kingdom;
however, most regional hepatobiliary units are likely to have
an EUS service.
ercp
Endoscopic Retrograde Cholangio-Pancreatography (ERCP)
is an endoscopic method of accessing the biliary tree. ERCP is
performed using a side-viewing endoscope, passed normally
to the second part of the duodenum, sitting opposite the
ampulla of Vater (Fig. 38.4).

Endoscopic Ultrasound (Endosonography, EUS)

A relatively new and very useful part of diagnosis and staging
is the method of endoscopic ultrasound (EUS) (4). This
involves an endoscope designed with an ultrasound probe at
the tip (Fig. 38.2).
The imaging can be either a “radial” EUS that provides a 360
degree image around the probe at the tip of the endoscope or
a “linear” EUS that gives an ultrasound picture in the plane of
the scope.

Figure 38.1 MRCP cholangio. Figure 38.2 EUS stack.

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When in position, the biliary tree (or pancreatic duct if
appropriate) is accessed by using a hollow cannula with a
0.035″ diameter guide wire being passed through the working
channel of the endoscope into the duct of choice under fluoro-
scopic screening. When in position, a radio-opaque contrast
agent is injected through the cannula, opacifying the duct of
interest on fluoroscopy.
The cholangiogram (or pancreatogram) can then be used to
confirm the diagnosis, often a filling defect such as a common
bile duct calculus or a stricture that may be malignant or
benign (Figs. 38.5 and 38.6).
Further diagnostic information can be gained by tissue
acquisition. This normally involves passing a cytology brush
over the wire and brushing the stricture for cytological
analysis.
Depending on the pathology confirmed, therapy can be
delivered as appropriate. Sphincterotomy can be performed
using over the wire “sphincterotome” with diathermy current
allowing better access to the duct. This can allow extraction of
calculi with either balloon trawls or basket. If strictures are
present causing jaundice, the stricture can be stented to enable
good biliary drainage.

(A) (B)
Figure 38.3 (A) EUS cholangio. (B) A Eus Ca Panc (arrow indicates the pancreatic tumor).

Figure 38.4 ERCP stack. Figure 38.5 ERCP distal stricture.

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Indications for ERCP this risk is much smaller than the risk of a non-draining,
Common Indications for ERCP obstructed biliary system.
Obstructive jaundice
● Definitive biliary drainage ERCP Complications
● Pre-operative drainage Pancreatitis
Perforation
Confirmed/strongly suspected bile duct calculi
Bleeding
(EUS/MRCP would often be used prior to ERCP)
Cholangitis
Severe gallstone pancreatitis (particularly with jaundice
Drug reactions/effects
and cholangitis)
Aspiration pneumonia
Cholangitis
Bile leak post cholecystectomy
Cytological sampling of strictures direct cholangioscopy
Pancreatic duct dilatation/stenting A technique that has developed for the assessment of intra-
Sphincter of Oddi manometry biliary pathology is that of direct, per oral cholangioscopy.
Whereas traditional ERCP provides detailed information
about intra-biliary pathology, this is normally part of a contrast-
Given the potential complications of ERCP (see below), it is enhanced radiological cholangiogram performed with the assis-
now almost totally used as a method of providing therapy to tance of an endoscope rather than direct vision. Strictures may
the biliary tree and pancreatic duct. be misclassified as malignant rather than benign, particularly
In the context of malignant biliary obstruction, therapy is with the relatively poor yield of biliary brushings (25,26).
often targeted at the relief of jaundice. With malignancy, Direct cholangioscopy provides the user the opportunity to
drainage of jaundice normally involves the insertion of one of see directly into the biliary tree to the second- or third-order
the variety of stents. When planning to drain jaundice in the ducts. A clearer impression about the nature of a stricture, be
patient with malignancy, consideration needs to be given to it benign or malignant can be obtained and the cause of the
the choice of stent type, the site of stenting – whether unilat- stricture can be biopsied as well as brushed, and this can be
eral in hilar strictures, or bilateral and the method of approach- done under direct vision, thereby improving the yield of diag-
ing this. It is because of this reason that reviewing good quality nostic histology to about 80% (27,28).
imaging prior to the procedure and planning the procedure in The original cholangioscopy via ERCP scopes, were the
advance is of paramount importance. “mother and baby scopes” that required two operators to use
Additional diagnostic information can be obtained using with one controlling the duodenoscope (mother) and the second
direct cholangioscopy. This is an emerging technology and its operating the smaller cholangioscope (baby). The baby scope
current availability is limited. It is being used for those stric- passed through the working channel of the duodenoscope.
tures that can’t be classified with conventional imaging. As well as being clumsy, irrigation and visualization were
poor and newer technologies have enabled improved and
complications of ercp constant irrigation improving cholangioscopic views.
The reason to limit the use of ERCP for therapy rather than diag-
nosis, unlike most other modalities of endoscopy, is the risk profile.
Because of the anatomy of the biliary tree, and the distal por-
tion of the common bile duct passing through the head of the
pancreas, the main risk of ERCP is that of acute pancreatitis.
A lot of effort has been put into reducing the risk as much as
possible. This includes the improved training of ERCP endos-
copists, as well as the development of guidance suggesting that
a fewer number of endoscopists perform ERCP to increase the
numbers performed by each individual. The technical changes
of wire-guided cannulation are also thought to reduce pancre-
atitis risk as wire cannulation of the pancreatic duct should
result in lower rates of ERCP-induced pancreatitis than opaci-
fication with contrast (18).
Rates of pancreatitis have been quoted very variably as 1% to
30% (18–22); however, the recent large volume British Society
of Gastroenterology (BSG) audit of ERCP practice in the
United Kingdom reported pancreatitis rates of 1.5% with an
overall complication rate of 5.1% (23).
Other ERCP complications are those for standard endos-
copy, namely bleeding and perforation. Another risk following
stenting of the ampulla is the risk of cholangitis (24); however, Figure 38.6 ERCP proximal stricture.

346
 ENDOSCOPIC MANAGEMENT OF MALIGNANT BILIARY OBSTRUCTION
A new style of cholangioscope has been developed that can
allow a single endoscopist the chance to visualize the bile ducts
(Fig. 38.7).
The SpyglassTM is a method of passing a 10 F catheter into
the bile duct over a wire as normal, and a fiberoptic cable can
be passed through one of four working channels to provide
direct vision. Intra-biliary anatomy and pathology can be
clearly identified and treatment can be targeted as necessary.
Indeterminate strictures are able to be assessed as in conven-
tional endoscopy and biopsies taken under direct vision. In the
case of large stone disease, these areas can be closely evaluated
Figure 38.7 ERCP and spyglass stack.
Figure 38.8 Spyglass—single operator.
with the additive benefit of a therapeutic channel to allow
direct electro-hydrolic or laser lithotripsy when conventional
methods have failed (Figs. 38.8 and 38.9).
Endoscopic Therapy
Indications
The use of endoscopy in the management of biliary malig-
nancy can be to aid diagnosis and staging, with the use of
endoscopic ultrasound for assessment or histological sam-
pling. A cholangiogram is a useful diagnostic adjunct, however
as detailed previously can be obtained in a safer way with lower
risk techniques.
ERCP still has a major role in the therapeutic management
of biliary malignancy. These therapies can broadly can be sub-
divided into palliating symptoms, namely jaundice (29–31),
and as a method of providing disease modifying treatment to
the biliary tree.
Most cases of biliary malignancy requiring ERCP will be
those presenting with jaundice, and the need for this to be
treated either as a palliative modality or as a bridge to surgery
to reduce peri-operative morbidity.
Methods of Therapy
Stent
The use of stenting in the drainage of obstructive jaundice is
well established (31–34). The decision that has to be made by
the multi-discipliniary team managing the jaundiced patient
with malignancy is that of the optimum way of accessing the
biliary tree (endoscopic or percutaneous), the type of stent to
be used (plastic or metal, which size, and if metal, covered or
uncovered).
The other area that needs to be assessed and decided upon,
ideally prior to intervention, is the need for unilateral or bilat-
eral stenting for patients with hilar obstruction – so-called
Klatskin tumors (35).
A variety of factors need to be considered when deciding on
the appropriateness of stent and the type of stent to be used.
The first of these is often whether this is to be used as a defi-
nitive palliative treatment, or as a bridge to surgery in the
jaundiced patient (Figs. 38.10 and 38.11).
Figure 38.9 Spyglass in use—Stone disease.
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Percutaneous Drainage of Jaundice
One of the methods available for the drainage of obstructive
jaundice is via a per-cutaneous route (36).
This involves the interventional radiologist accessing the
biliary tree percutaneously via a trans-hepatic approach (37).
Percutaneous trans-hepatic cholangiography (PTC) can be
performed as a temporary measure, with an intra-biliary cath-
eter left in situ and an external drain to relieve jaundice exter-
nally. Alternatively an “internal–external” drain can be sited
that crosses the stricture, which also allows an external drain
for the relief of jaundice, leaving a catheter in the duodenum
to allow internal drainage. This can then be internalized with
a combined approach involving a radiologist performing the
percutaneous aspect and an endoscopist performing the
ERCP (38).
Permanent stents can be sited via the percutaneous approach
as both 10 F plastic (39) and metal stents (40) can be intro-
duced collapsed and expanded as would be done at ERCP.
ercp versus ptc versus surgery
When approaching the optimal way to drain a patients’ jaun-
dice, the method of approach is important and needs to be
carefully considered.
Comparing ERCP to surgical bypass, both have been shown
to be effective in the palliation of jaundice (41–43). Surgery,
while effective does carry a higher complication rate (44,45)
and a higher procedure-related mortality (46). With the
increasing early literature on the feasibility of endoscopic and
percutaneous (36) stenting, and the advanced safety profile
compared to surgery this started to be the preferred method of
treatment (47).
Figure 38.10 Metal stent—distal stricture.
348
Operating on patients with jaundice does increase morbidity
(48–51) and mortality (52). For those patients who require pal-
liation this is normally very well achieved with non-operative
stenting done as an endoscopic or radiological procedure that
has a significantly lower morbidity than surgical palliative meth-
ods (37,39,45). In jaundiced patients with potentially curative
disease, morbidity can be reduced by the use of pre-operative
stenting (48), be it endoscopic or percutaneous (53). Recent data,
however, do suggest that in those with pancreatic cancer with a
bilirubin <250 µmol/l early surgery reduces the complication
rate when compared to pre-operative plastic stenting (54).
Due to the combination of the reasons listed above, as well
as the reduced morbidity and shorter in-hospital stays, non-
operative management of malignant jaundice has the added
advantage of being a cost-effective treatment (32,55).
While there are advantages to an endoscopic approach to
biliary stenting and drainage of jaundice, these are seen maxi-
mally in distal biliary strictures where ERCP has become the
gold standard of treatment (56). This is due to the relatively
easy access to the common bile duct and ability to site a stent
that will cover the stricture and allow complete drainage from
all areas of the liver. Morbidity is reduced in these patients
when compared to the risk of bleed and bile leak that can
occur with per-cutaneous drainage (57,58).
It is worth noting that many studies and median survivals in
regarding biliary malignancies include patients without histo-
logical proof of malignancy and so care must be taken in the
interpretation of these (59).
plastic versus metal
Early studies looking at the role of endoscopically sited biliary
stents looked at narrow caliber stents generally 6 to 8 F (30).
These often provided symptomatic relief of the patients’ jaun-
dice; however, occlusion with further episodes of obstructive
jaundice was common.
This has improved with the use of therapeutic duodeno-
scopes able to site larger plastic stents, and now in patients
Figure 38.11 Metal stents—proximal stricture.
 ENDOSCOPIC MANAGEMENT OF MALIGNANT BILIARY OBSTRUCTION
with malignant obstructive jaundice, normal practice would
be to site a stent of at least 10 F caliber (60).
While these do provide longer periods of palliation for
patients than the previously used narrow stents, there is still a
significant rate of stent occlusion and plastic stents will often
need to be replaced after about 4 to 6 months.
Self-expanding metal stents (SEMS) have been developed
for a variety of strictures and these have been shown to have
longer stent patency than plastic stents (61). SEMS can be sited
percutaneously (62–64) or endoscopically (40,65). They have
been shown to be cost-effective in patients who are expected to
survive more than 4 to 6 months (66–68) as they reduce hos-
pital admissions and repeated procedures (69–72). Favorable
increases in stent patency appeared to be related to the early
expansion of the stent (73).
SEMS are generally not removable after being sited, there-
fore these are often sited for palliative patients. In those
patients having stents sited for drainage of jaundice prior to
potentially curative resection, 10 F plastic stents are often the
stent of choice. The insertion of a short SEMS needn’t be a
contraindication to a curative resection (74) if placed with
care. The development of fully covered metal stents does allow
for the removal of SEMS following their deployment.
covered versus uncovered
Covered stents have been developed where by the SEMS has a
thin plastic covering designed to reduce tumor in-growth (75–77).
These have been developed to improve stent patency further
and have been shown to have a longer median patency before
occlusion than uncovered stents (78).
When placing metal stents at the hilum, uncovered stents are
preferable as covered stents are likely to occlude the bile flow
from the un-stented lobe and tributaries.
There is a risk that covered stents that occlude the cystic duct
insertion in patients with a gall bladder in place may put the
patients at risk of cholecystitis (79), and are therefore often avoided.
Covered stents in distal biliary strictures, such as pancreatic
carcinoma, can be useful and improve stent patency and
median time to occlusion (78).
hilar strictures
Unilateral Versus Bilateral
The more difficult scenario is in strictures that affect the bifur-
cation of the common hepatic duct, the hilar strictures. These
are commonly caused by cholangiocarcinomas and if extend
beyond the hilum a decision has to be made about the best
approach to drainage (Fig. 38.12).
While the optimal drainage is achieved by bi-lobar drainage,
this can prove technically difficult, and the great danger in this
group of patients is in failing to drain an opacified area. This
has been shown in various series to increase morbidity and
mortality due to cholangitis (80,81).
Adequate palliation of jaundice is likely to be obtained with
drainage of 30% of the liver volume and this can normally be
achieved through unilobar stenting (82–85).
Due to these problems, in some centers PTC is preferred to
ERC as at PTC the obstructed area is targeted first and this can
easily be drained.
In those patients that do not achieve adequate drainage with
a unilobar stent, subsequent attempts at bilobar stenting are
very problematic due to a track being patent into the drained
lobe, and so hilar lesions are normally best managed at centers
that perform high volumes with local policies regarding the
relative role of ERCP and PTC. In this scenario, it is likely to
be advantageous to attempt draining the un-drained lobe via
the percutaneous approach that will enable direct targeting of
the obstructed system and placement of stent.
Disease Modifying Treatment
While most of the endoscopic management concentrated on
to this point has been in the palliation of jaundice due to bili-
ary malignancies, there is a role developing for disease modify-
ing therapy that can be delivered directly to the biliary tree at
endoscopy.
We concentrate on the experience with radiotherapy as well
as photodynamic therapy.
radiotherapy
Brachytherapy
Intraductal radiotherapy, brachytherapy has been used in a
small number of studies in an attempt to improve survival in
patients with nonresectable cholangiocarcinoma.
A retrospective study comparing brachytherapy to stenting
alone did show some survival benefit, that didn’t achieve sta-
tistical significance (p = 0.06) in patients with type II or III
tumors treated with brachytherapy, but this was associated
with more stent changes and longer hospital stays. The authors
felt that the benefit was limited to those with type II or III
tumors treated within 10 months of diagnosis (86).
A more recent study looking at external beam radiotherapy
in conjunction with expandable metal stents in patients with
cholangiocarcinoma, showed longer survival in those than in
stents alone (10.6 vs. 6.4 months, p < 0.05) and longer stent
patency than metal stents alone (9.8 vs. 3.7 months, p < 0.001);
Figure 38.12 Hilar stricture (cholangiocarcinoma).
349
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
however, this was with a shorter patency than previously
described for metal stents (87).
The variety of approaches described using radiotherapy can
best be regarded as of unproven benefit.
photodynamic therapy
The greater majority of patients with cholangiocarcinoma do
not undergo resection (88). The disease has a particularly poor
prognosis, especially if the disease is advanced with a median
survival time of 62 days if there is bilateral intrahepatic dis-
ease (81). Photodynamic therapy (PDT) has emerged as a
promising new modality of treatment for patients who do not
undergo resection.
PDT uses the combination of two non-toxic moieties; light
and a photosensitizing chemical, which when combined
together produce a cytotoxic effect. The photosensitizer tends
to accumulate in proliferating tissue. This tissue is then illumi-
nated with light of a wavelength appropriate to the absorption
spectrum of the photosensitizer. A photochemical reaction
generates cytotoxic reactive oxygen species resulting in apopto-
sis or necrosis of tumor cells. PDT may also cause thrombosis
in tumor blood vessels and induce a tumor-specific immune
reaction with more distant effects from the site of illumination.
Photofrin® (Axcan Pharma Inc.) has been the most widely
used photosensitizer in this application and is a complex mix
of compounds derived from hematoporphyrin. It is activated
at a wavelength of 630 nm. The depth of necrosis obtained is 4
to 6 mm.
The technique of ERC-PDT involves the prior administra-
tion of Photofrin® at a dose of 2 mg/kg, optimally 48 hours
before the procedure. A cylindrical laser diffuser fiber is
positioned across the malignant stricture through a stan-
dard cannula. Concurrent oxygen administration (4 l/min)
optimizes the PDT effect. A light dose of 180 to 200 J/cm is
delivered. Stents, preferably plastic, are inserted after the
Refer to
gastroenterology/ Jaundiced patient
hepatology
Non-obstructed
Biliary ultrasound
biliary system
Other imaging
Hepatobiliary MDT
meeting review
Operable
Resection
±perioperative
biliary drainage
Figure 38.13 Algorithm for management of malignant biliary obstruction.
350
procedure to ensure continued biliary drainage following
treatment.
The major side effect of PDT is skin photosensitization.
Patients are advised to stay indoors away from bright light for
3 to 4 days and then cautiously increase exposure to sunlight
avoiding strong sunlight for 4 to 6 weeks. The contraindica-
tions to PDT include porphyria and decompensated cirrhosis.
After a number of uncontrolled studies suggesting signifi-
cant benefit of ERC-PDT for cholangiocarcinoma (89–93), a
randomized study, looking at non-resectable cholangiocarci-
nomas randomized to stenting alone or stenting and PDT
showed an increase in median survival from 98 to 493 days
(p < 0.0001) with some of the PDT group still alive at anal-
ysis (94). This study was terminated prematurely because of
the superior results from PDT made further randomization
unethical. In addition this study excluded patients who had a
successful stenting procedure previously. Thus the results may
not be applicable to the group of patients who do have an ini-
tial successful stenting procedure. Further controlled studies
have shown significant improvements in survival from 7 to
21 months with PDT (95). An uncontrolled study showed a
median survival post-PDT of 276 days (89).
A large retrospective study, looking at patients with hilar
cholangiocarcinoma treated with either surgery, stenting
alone, or stenting with PDT showed longer survival with PDT
compared to stenting (p < 0.01) and similar survival to R1/R2
resection (96).
Generally ERC-PDT was tolerated well with mild photosen-
sitivity, the commonest problem, and cholangitis also causing
significant problems in some studies.
These studies suggested significant promise for ERC-PDT as
a therapy for cholangiocarcinoma. In addition to the criti-
cisms detailed above, however, the studies have been small
with variability in the number and type of stent used. The
number of PDT sessions have varied and in uncontrolled
Obstructed biliary
system
Cross sectional
imaging (CT/MR)
Inoperable
Life expectancy Life expectancy
<4 months ≥4 months
ERC/PTC and ERC/PTC and
plastic stent metal stent
 ENDOSCOPIC MANAGEMENT OF MALIGNANT BILIARY OBSTRUCTION
studies, it is difficult to determine what benefit is due to PDT
and that due to stenting.
The Photostent-2 trial had been designed to look at this
area, and despite the promising prior studies, this was termi-
nated early due to an increased mortality in the PDT arm
compared to the stent arm.
Interestingly, this improvement in the non-treated arm
involved a longer median survival than previously described in
historical studies and in the pilot series. This may be due to
improved biliary drainage in this group.
current u.k. practice
In the United Kingdom, cancer care is delivered in local cancer
centers. For rarer malignancies, these tend to be based within a
regional center.
Patients treated at a regional center for hepatobiliary malig-
nancy will be discussed at the appropriate multidisciplinary
team (MDT) meeting, comprising gastroenterologists/hepa-
tologists, hepatobiliary surgeons, oncologists, GI radiologists,
and interventional radiologists as well as palliative care repre-
sentatives and specialist nurses.
Following an MDT discussion, individualized treatment
regimens will be offered to each patient when seen by a mem-
ber of the team. This will include a review of the appropriate
cross-sectional imaging and the detailed planning of any inter-
vention necessary (Fig. 38.13).
conclusions
The management of biliary malignancy can be a complex
issue. There are various treatment options that are appropriate
and the choice of optimal treatment may depend on local
expertise.
We have found that in patients with proximal biliary neopla-
sia, the risks of cholangitis are higher than in other groups,
particularly when the biliary system has been previously
instrumented. Our group strongly advocates that patients with
a proximal biliary malignancy should be transferred to the
regional specialist center for a review of the imaging and an
appropriate method of biliary decompression to be arranged
and performed there. Local data suggest that this reduces the
rate of cholangitis in this cohort of patients.
We have found that the drainage of biliary disease can be
optimized with the use of SEMS as opposed to 10 F plastic
stents and that patients can still be operable following this.
Carefully sited SEMS can allow biliary drainage and a well-
decompressed system without interfering in the surgical field.
We have also started using fully covered SEMS which have
proved safe to remove up to 3 months following deployment.
references
1. Ishizaki Y, Wakayama T, Okada Y, Kobayashi T. Magnetic resonance chol-
angiography for evaluation of obstructive jaundice. Am J Gastroenterol
1993 Dec; 88(12): 2072–7.
2. Pavone P, Laghi A, Passariello R. MR cholangiopancreatography in malig-
nant biliary obstruction. Semin Ultrasound CT MRI 1999 Oct; 20(5):
317–23.
3. Vaishali MD, Agarwal AK, Upadhyaya DN, et al. Magnetic resonance chol-
angiopancreatography in obstructive jaundice. J Clin Gastroenterol 2004;
38(10): 887–90.
4. Rösch T, Lorenz R, Braig C, et al. Endoscopic ultrasound in pancreatic
tumor diagnosis. Gastrointest Endosco 1991; 37(3): 347–52.
5. Saftoiu A, Vilmann P. Role of endoscopic ultrasound in the diagnosis and
staging of pancreatic cancer. J Clin Ultrasound 2009; 37(1): 1–17.
6. Zandrino F, Benzi L, Ferretti M, et al. Multislice CT cholangiography
without biliary contrast agent: technique and initial clinical results in the
assessment of patients with biliary obstruction. Euro Radiol 2002; 12(5):
1155–61.
7. Ochotorena IJL, Kiyosue H, Hori Y, et al. The local spread of lower bile
duct cancer: evaluation by thin-section helical CT. Euro Radiol 2000;
10(7): 1106–13.
8. Zech CJ, Schoenberg SO, Reiser M, Helmberger T. Cross-sectional imag-
ing of biliary tumors: current clinical status and future developments.
Euro Radiol 2004; 14(7): 1174–87.
9. Stern N, Sturgess R. Endoscopic therapy in the management of malignant
biliary obstruction. Euro J Surg Oncol (EJSO) 2008; 34(3): 313–7.
10. K. J. W. Taylor DACVRM. Ultrasound and scintigraphy in the differential
diagnosis of obstructive jaundice. J Clin Ultrasound 1974; 2(2): 105–16.
11. Gordon S. Perlmutter BBGGS. Ultrasonic evaluation of the common bile
duct. J Clin Ultrasound 1976; 4(2): 107–11.
12. Taylor KJW, Carpenter DA, McCready VR. Grey scale echography in the
diagnosis of intrahepatic disease. J Clin Ultrasound 1973; 1(4): 284–7.
13. Colin RM. Ultrasonic diagnosis of liver metastases. Journal of Clinical
Ultrasound 1976; 4(4): 265–8.
14. Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al. Thin-section con-
trast-enhanced computed tomography accurately predicts the resectabil-
ity of malignant pancreatic neoplasms. Am J Surg1994; 167(1): 104–13.
15. Itai Y, Araki T, Tasaka A, Maruyama M. Computed tomographic appear-
ance of resectable pancreatic carcinoma. Radiology 1982 June 1, 1982;
143(3): 719–26.
16. Vilmann P, Jacobsen GK, Henriksen FW, Hancke S. Endoscopic ultraso-
nography with guided fine needle aspiration biopsy in pancreatic disease.
Gastrointest Endosc 1992; 38(2): 172–3.
17. Agarwal B, Abu-Hamda E, Molke KL, Correa AM, Ho L. Endoscopic ultra-
sound-guided fine needle aspiration and multidetector spiral CT in the
diagnosis of pancreatic cancer. Am J Gastroenterol 2004; 99(5): 844–50.
18. Artifon ELA, Sakai P, Cunha JEM, et al. Guidewire cannulation reduces
risk of post-ercp pancreatitis and facilitates bile duct cannulation. Am J
Gastroenterol 2007; 102(10): 2147–53.
19. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic
biliary sphincterotomy. N Engl J Med 1996 September 26, 1996; 335(13):
909–19.
20. Freeman ML, DiSario JA, Nelson DB, et al. Risk factors for post-ERCP
pancreatitis: a prospective, multicenter study. Gastrointest Endosco 2001;
54(4): 425–34.
21. Freeman ML. Adverse outcomes of ERCP. Gastrointest Endosco 2002;
56(6, Suppl 1): S273–82.
22. Vandervoort J, Soetikno RM, Tham TCK, et al. Risk factors for complica-
tions after performance of ERCP. Gastrointest Endosco 2002; 56(5): 652–6.
23. Williams EJ, Taylor S, Fairclough P, et al. Are we meeting the standards set
for endoscopy? Results of a large-scale prospective survey of endoscopic
retrograde cholangio-pancreatograph practice. Gut 2007 June 1, 2007;
56(6): 821–9.
24. Motte S, Deviere J, Dumonceau J-M, et al. Risk factors for septicemia follow-
ing endoscopic biliary stenting. Gastroenterology 1991; 101(5): 1374–81.
25. Angelo Paulo F, David RL, Adam S, Catherine C, David LC-L. Brush cytol-
ogy during ERCP for the diagnosis of biliary and pancreatic malignancies.
Gastrointest Endosc 1994; 40(2): 140–5.
26. Mahmoudi N, Enns R, Amar J, AlAli J, Lam E, Telford J. Biliary brush
cytology: factors associated with positive yields on biliary brush cytology.
World J Gastroenterol 2008 January 28; 14(4): 569–73.
27. Dwyer L, Polavarapu N, Hood S, Sheard J, Sturgess R. Per oral cholangios-
copy: Systematic evaluation in clinical practice. Gut 2010; 59(Suppl 1):
A88–9.
28. Aljabiri M, Lerman A, Kalaitzakis E, et al. Initial experience of Spyglass
per-oral cholangioscopy in a UK centre. Gut 2010; 59(Suppl 1): A87.
29. Burcharth F, Jensen LI, Olesen K. Endoprosthesis for internal drainage of
the biliary tract. Technique and results in 48 cases. Gastroenterology 1979;
77(1): 133–7.
351
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
30. Cotton PB. Duodenoscopic placement of biliary prostheses to relieve
malignant obstructive jaundice. Br J Surg 1982; 69(9): 501–3.
31. Soehendra N, Reynders-Frederix V. Palliative bile duct drainage - a new
endoscopic method of introducing a transpapillary drain. Endoscopy
1980; 12(01): 8–11.
32. Brandabur J, Kozarek R, Ball T, et al. Nonoperative versus operative treat-
ment of obstructive jaundice in pancreatic cancer: cost and survival anal-
ysis. Am J Gastroenterol 1988 Oct; 83(10): 1132–9.
33. Walta DC, Fausel CS, Brant B. Endoscopic biliary stents and obstructive
jaundice. Am J Surg 1987; 153(5): 444–7.
34. Earnshaw J, Hayter J, Teasdale C, Beckly D. Should endoscopic stenting be
the initial treatment of malignant biliary obstruction? Ann R Coll Surg
Engl 1992 Sep; 74(5): 338–41.
35. Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcation within
the porta hepatis. An unusual tumour with distinctive clinical and patho-
logical features. Am J Med 1965 February; 38: 241–56.
36. Koven I, Steinhardt M, Reichstein B. Percutaneous antegrade biliary
drainage: a nonoperative approach to biliary obstruction. Can J Surg
1981; 24(6): 591–3.
37. Gouma DJ, Wesdorp RIC, Oostenbroek RJ, Soeters PB, Greep JM. Percu-
taneous transhepatic drainage and insertion of an endoprosthesis for
obstructive jaundice. Am J Surg 1983; 145(6): 763–8.
38. Robertson D, Ayres R, Hacking C, et al. Experience with a combined per-
cutaneous and endoscopic approach to stent insertion in malignant
obstructive jaundice. Lancet 1987 Dec 19; 2(8573): 1449–52.
39. Pereiras RV Jr., Rheingold OJ, Hutson D, et al. Relief of malignant obstruc-
tive jaundice by percutaneous insertion of a permanent prosthesis in the
biliary tree. Ann Intern Med 1978 November 1, 1978; 89(5_Part_1): 589–93.
40. Pinol V, Castells A, Bordas JM, et al. Percutaneous self-expanding metal stents
versus endoscopic polythene endoprostheses for treating malignant biliary
obstruction: randomized clinical trial. Radiology 2002; 225(1): 27–34.
41. Lameris J, Stoker J, Dees J, et al. Non-surgical palliative treatment of
patients with malignant biliary obstruction - the place of endoscopic and
percutaneous drainage. Clin Radiol 1987 Nov; 38(6): 603–8.
42. Andersen JR, Sorensen SM, Kruse A, Rokkjaer M, Matzen P. Randomised
trial of endoscopic endoprosthesis versus operative bypass in malignant
obstructive jaundice. Gut 1989 August 1, 1989; 30(8): 1132–5.
43. Ozaki H, Hojo K, Miwa K. A safe method of intrahepatic biliary drainage
in obstructive jaundice. Am J Surg 1977; 133(3): 379–82.
44. Sonnenfeld T, Gabrielsson N, Grangvist S, Perbeck L. Nonresectable
malignant bile duct obstruction. Surgical bypass or endoprosthesis? Acta
Chir Scand 1986 Apr; 152: 297–300.
45. Burcharth F, Efsen F, Christiansen L, et al. Nonsurgical internal biliary
drainage by endoprosthesis. Surg Gynaecol Obstet 1981; 153(6): 857–60.
46. Smith A, Dowsett J, Russell R, Hatfield A, Cotton P. Randomised trial of
endoscopic stenting versus surgical bypass in malignant low bileduct
obstruction. Lancet 1994 December 17; 344: 1655–60.
47. Gholson C, Burton F. Obstructive jaundice. Nonsurgical options for ‘sur-
gical’ jaundice. Postgrad Med 1991 Dec; 90(8): 107–10.
48. Denning DA, Ellison EC, Carey LC. Preoperative percutaneous transhe-
patic biliary decompression lowers operative morbidity in patients with
obstructive jaundice. Am J Surg 1981; 141(1): 61–5.
49. Irvin TT, Vassilakis JS, Chattopadhyay DK, Greaney MG. Abdominal
wound healing in jaundiced patients. Br J Surg 1978; 65(7): 521–2.
50. Greig JD, Krukowski ZH, Matheson NA. Surgical morbidity and mortality
in one hundred and twenty-nine patients with obstructive jaundice. Br J
Surg 1988; 75(3): 216–9.
51. Grande L, Garcia-Valdecasas JC, Fuster J, Visa J, Pera C. Obstructive
jaundice and wound healing. Br J Surg 1990; 77(4): 440–2.
52. Pitt HA, Cameron JL, Postier RG, Gadacz TR. Factors affecting mortality
in biliary tract surgery. Am J Surg 1981; 141(1): 66–72.
53. Rosen J, Young SC, Berman J, Magill T. Management of malignant obstruc-
tive jaundice. Journal of Surgical Oncology 1989; 40(4): 256–60.
54. van der Gaag NA, Rauws EAJ, van Eijck CHJ, et al. Preoperative Biliary
Drainage for Cancer of the Head of the Pancreas. N Engl J Med 2010
January 14, 2010; 362(2): 129–37.
55. Martin Rn, Vitale G, Reed D, Larson G, Edwards M, McMasters K. Cost
comparison of endoscopic stenting vs surgical treatment for unresectable
cholangiocarcinoma. Surg Endosc 2002 Apr; 16(4): 667–70.
352
56. Soehendra N, Grimm H, Berger B, Nam VC. Malignant jaundice: Results
of diagnostic and therapeutic endoscopy. World J Surg 1989; 13(2): 171–7.
57. Speer AG, Cotton PB, Russell RCG, et al. Randomised trial of endoscopic
stenting versus percutaneous stent insertion in malignant obstructive
jaundice. Lancet 1987 11 July; 1: 57–62.
58. Cowling MG, Adam AN. Internal stenting in malignant biliary obstruc-
tion. World J Surg 2001 March 2001; 25(3): 355–61.
59. Webster G, Pereira S. Mesh-metal stents for hilar cholangiocarcinoma.
Gastrointest Endosco 2009; 70(4): 817–8.
60. Speer AG, Cotton PB, MacRae KD. Endoscopic management of malignant
biliary obstruction: stents of 10 French guage are preferable to stents of 8
French gauge. Gastrointest Endosco 1988 Sep–Oct; 34(5): 412–7.
61. Lammer J, Hausegger KA, Fluckiger F, et al. Common bile duct obstruc-
tion due to malignancy: treatment with plastic versus metal stents. Radi-
ology 1996; 201: 167–72.
62. Indar AA, Lobo DN, Gilliam AD, et al. Percutaneous biliary metal wall
stenting in malignant obstructive jaundice. Euro J Gastroenterol Hepatol
2003; 15(8): 915–9.
63. Men S, Hekimoglu B, Kaderoglu H, et al. Palliation of malignant obstruc-
tive jaundice. Use of self-expandable metal stents. Acta Radiol 1996 May;
37(3 Pt 1): 259–66.
64. Rossi P, Bezzi M, Rossi M, et al. Metallic stents in malignant biliary
obstruction: results of a multicentre European study of 240 patients. J
Vasc Interv Radiol 1994 Mar–Apr; 5(2): 279–85.
65. Yoshioka T, Sakaguchi H, Yoshimura H, et al. Expandable metallic biliary
endoprostheses: preliminary clinical evaluation. Radiology 1990 October 1,
1990; 177(1): 253–7.
66. Yeoh KG, Zimmerman MJ, Cunningham JT, Cotton PB. Comparative costs
of metal versus plastic biliary stent strategies for malignant obstructive
jaundice by decision analysis. Gastrointest Endosco 1999; 49(4): 466–71.
67. Soderlund C, Linder S. Covered metal versus plastic stents for malignant
common bile duct stenosis: a prospective, randomized, controlled trial.
Gastrointest Endosc 2006; 63(7): 986–95.
68. Arguedas MR, Heudebert GH, Stinnett AA, Wilcox CM. Biliary stents in
malignant obstructive jaundice due to pancreatic carcinoma: a cost-
effectiveness analysis. Am J Gastroenterol 2002; 97(4): 898–904.
69. Kaassis M, Boyer J, Dumas R, et al. Plastic or metal stents for malignant
stricture of the common bile duct? Results of a randomized prospective
study. Gastrointest Endosc 2003; 57(2): 178–82.
70. Prat F, Chapat O, Ducot B, et al. A randomized trial of endoscopic drain-
age methods for inoperable malignant strictures of the common bile duct.
Gastrointest Endosc 1998; 47(1): 1–7.
71. Wagner H, Knyrim K, Vakil N, Klose K. Plastic endoprostheses versus
metal stents in the palliative treatment of malignant hilar biliary obstruc-
tion. A prospective and randomized trial. Endoscopy 1993; 25(3): 213–8.
72. Guo Y-X, Li Y-H, Chen Y, et al. Percutaneous transhepatic metal versus plastic
biliary stent in treating malignant biliary obstruction: a multiple centre inves-
tigation. Hepatobiliary Pancreatic Dis Int 2003 November 2003; 2(4): 594–7.
73. Kim HS, Lee DK, Kim HG, et al. Features of malignant biliary obstruction
affecting the patency of metallic stents: A multicenter study. Gastrointest
Endosc 2002; 55(3): 359–65.
74. Mullen JT, Lee JH, Gomez HF, et al. Pancreaticoduodenectomy after place-
ment of endobiliary metal stents. J Gastrointest Surg 2005; 9(8): 1094–105.
75. Hiroyuki Isayama YK, Takeshi T, Haruhiko Y, et al. Polyurethane-covered
metal stent for management of distal malignant biliary disease.
Gastrointest Endosc 2002; 55(3): 366–70.
76. Kahaleh M, Tokar J, Conaway MR, et al. Efficacy and complications of
covered Wallstents in malignant distal biliary obstruction. Gastrointest
Endosc 2005; 61(4): 528–33.
77. Yousuke Nakai HI, Yutaka K, Takeshi T, et al. Efficacy and safety of the
covered Wallstent in patients with distal malignant biliary obstruction.
Gastrointest Endosc 2005; 62(5): 742–8.
78. Isayama H, Komatsu Y, Tsujino T, et al. A prospective randomised study of
“covered” versus “uncovered” diamond stents for the management of dis-
tal malignant biliary obstruction. Gut 2004 May 1, 2004; 53(5): 729–34.
79. Fumex F, Coumaros D, Napoleon B, Barthet M, Laugier R, Yzet T, et al.
Similar performance but higher cholecystitis rate with covered biliary
stents: results from a prospective multicenter evaluation. Endoscopy
2006; 38(08): 787–92.
 ENDOSCOPIC MANAGEMENT OF MALIGNANT BILIARY OBSTRUCTION
80. Hochwald S, Burke E, Jarnagin W, Fong Y, Blumgart L. Association of pre-
operative biliary stenting with increased postoperative infectious complica-
tions in proximal cholangiocarcinoma. Arch Surg 1999 Mar; 134(3): 261–6.
81. Chang W-H, Kortan P, Haber GB. Outcome in patients with bifurcation
tumors who undergo unilateral versus bilateral hepatic duct drainage.
Gastrointest Endosc 1998; 47(5): 354–62.
82. Inal M, Akgul E, Aksungur E, Seydaoglu G. Percutaneous Placement of
Biliary Metallic Stents in Patients with Malignant Hilar Obstruction: Uni-
lobar versus Bilobar Drainage. J Vascul Interven Radiol 2003 November
2003; 14: 1409–16.
83. DePalma G, Pezzullo A, Rega M, et al. Unilateral placement of metallic
stents for malignany hilar obstruction: a prospective study. Gastrointest
Endosc 2003 Jul; 58(1): 50–3.
84. De Palma GD, Galloro G, Siciliano S, Iovino P, Catanzano C. Unilateral
versus bilateral endoscopic hepatic duct drainage in patients with malig-
nant hilar biliary obstruction: Results of a prospective, randomized, and
controlled study. Gastrointest Endosc 2001; 53(6): 547–53.
85. Liu C-L, Lo C-M, Lai ECS, Fan S-T. Endoscopic Retrograde Cholan-
giopancreatography and endoscopic endoprosthesis insertion in
patients with Klatskin tumors. Arch Surg 1998 March 1, 1998; 133(3):
293–6.
86. Bowling TE, Galbraith SM, Hatfield AR, Solano J, Spittle MF. A retrospec-
tive comparison of endoscopic stenting alone with stenting and radio-
therapy in non-resectable cholangiocarcinoma. Gut 1996 December 1,
1996; 39(6): 852–5.
87. Shinchi H, Takao S, Nishida H, Aikou T. Length and quality of survival
following external beam radiotherapy combined with expandable metal-
lic stent for unresectable hilar cholangiocarcinoma. J Surg Oncol 2000;
75(2): 89–94.
88. Shaib YH, Davila JA, Henderson L, McGlynn KA, El-Serag HB. Endoscopic
and surgical therapy for intrahepatic cholangiocarcinoma in the United
States: a population based study. J Clin Gastroenterol 2007 November/
December; 41(10): 911–7.
89. Harewood GC, Baron TH, Rumalla A, Wang KK, Gores GJ, Stadheim LM,
et al. Pilot study to assess patient outcomes following endoscopic applica-
tion of photodynamic therapy for advanced cholangiocarcinoma.
J Gastroenterol Hepatol 2005; 20(3): 415–20.
90. McCaughan JS Jr., Mertens BF, Cho C, Barabash RD, Payton HW. Photo-
dynamic therapy to treat tumors of the extrahepatic biliary ducts. A case
report. Arch Surg 1991 January 1, 1991; 126(1): 111–3.
91. Ortner M-AEJ, Liebetruth J, Schreiber S, et al. Photodynamic therapy of
nonresectable cholangiocarcinoma. Gastroenterology 1998; 114(3): 536–42.
92. Rumalla A, Baron TH, Wang KK, et al. Endoscopic application of photo-
dynamic therapy for cholangiocarcinoma. Gastrointest Endosc 2001;
53(4): 500–4.
93. Berr F, Wiedmann M, Tannapfel A, et al. Photodynamic therapy for
advanced bile duct cancer: Evidence for improved palliation and extended
survival. Hepatology 2000; 31(2): 291–8.
94. Ortner MEJ, Caca K, Berr F, et al. Successful photodynamic therapy for
nonresectable cholangiocarcinoma: a randomized prospective study.
Gastroenterology 2003; 125(5): 1355–63.
95. Zoepf T, Jakobs R, Arnold JC, Apel D, Riemann JF. Palliation of nonresect-
able bile duct cancer: improved survival after photodynamic therapy. Am
J Gastroenterol 2005; 100(11): 2426–30.
96. Witzigmann H, Berr F, Ringel U, et al. Surgical and palliative management
and outcome in 184 patients with hilar cholangiocarcinoma: palliative
photodynamic therapy plus stenting is comparable to R1/R2 resection.
Ann Surg 2006 August 2006; 244(2): 230–9.
353
39 Choledochal cyst detected in adulthood
Bilal Al-Sarireh and Hassan Malik
incidence and pathophysiology
Choledochal cysts are cystic dilatation of the biliary tree, which
present as isolated or combined dilatation of both the extra-
and the intra-hepatic biliary tree. Its incidence, although as
high as 1:1000 in Asian population, is only 1:100,000 to
1:150,000 in Western population, with a female preponder-
ance of up to 4:1 (1,2). Nearly 60% of choledochal cysts are
detected before the age of 10, but they are increasingly diag-
nosed in adult population and in nearly 20% the diagnosis is
delayed until adulthood when presentation is different com-
pared to childhood (3–5).
etiology and classification
The etiology of choledochal cysts remains speculative. It is
largely believed that the majority of choledochal cysts are con-
genital lesions (6). The most widely accepted theory is the
presence of anomalous pancreaticobiliary ductal confluence
(APBDC), which is frequently associated with choledochal
cysts (7,8). It is hypothesized that this anomaly predisposes to
reflux of pancreatic secretion up to the biliary tree leading to
mucosal break down and dilatation (9). The observation that
biliary cysts are more common in the extra-hepatic biliary tree
supports this hypothesis. Also, this hypothesis has been sup-
ported by several authors who reported the presence of a com-
mon pancreaticobiliary channel in as much as 70% of
choledochal cysts (8,10,11). In such cases the biliary amylase is
usually elevated (12). However, experimental model failed to
confirm this finding (13). This theory also seems to be rejected
by the reports of antenatal choledochal cysts at an age before
the exocrine function of the pancreas has even begun (14).
Therefore, it is unlikely that a common channel is the sole
explanation for choledochal cysts as there are many of these
lesions in which it is not present.
Other authors contend that these cysts are congenital in
nature, due to either distal aganglionosis and proximal dilata-
tion or aberrancies in embryologic recanalization (15,16).
Such theories are largely speculative, but are supported by
antenatal observational studies and experimental studies on
animals (17,18). More over, viral infection has been proposed
as a possible cause for some of these lesions as has been dem-
onstrated by Petersen et al. in his experiment on mice (19).
Since cyst location determines the type of treatment, most
authors opt for the 1997 classification of Tandoni et al. (20).
Choledochal cysts were first described by Vater and Ezler in
1723 (21). However, it was not until 1959 when Alonzo-lej
et al. gave a thorough description of the disease and classified
choledochal cysts into three types (22). This classification was
then modified by Tandoni et al. (20), who described eight dif-
ferent types: type 1 extra-hepatic bile duct cystic dilatation:
(Ia) common type, (Ib) segmental dilatation, and (Ic) diffuse
dilatation; type II common bile duct (CBD) diverticulum;
354
type III choledochocele (dilatation of intra-duodenal CBD);
type IVa intra- and extra-hepatic bile duct dilatation; type IVb
multiple cysts (extra-hepatic only), and type V intra-hepatic
cysts only (Fig. 39.1). Initially, these different types thought to
represent a spectrum of the same disease. However, subse-
quently several authors believed that each type represents a
unique disease with separate etiologies, natural course, and
ideal treatment (23,24). The most common cyst is type I
(79%), followed by type IV (13%), type III (4%), type II
(2.6%), and type V (<1%) (24–26).
presentation
The clinical triad of abdominal pain, mass, and jaundice is sel-
dom seen in adults (3,25). Clinical symptoms in most cases are
intermittent and nonspecific resulting in delayed diagnosis.
Also the majority of these patients do not have consistent
abnormalities in liver function tests (LFTs) (27). Abdominal
pain and recurrent cholangitis are the most common presen-
tation (3,28–30). The abdominal pain usually mimics that of
calculus cholecystitis and many patients do have gallstones
either in the cyst and/or in the gallbladder. This might lead to
misdiagnosis of calculus cholecystitis and or choledocholithia-
sis with biliary ductal dilatation. Subsequently, a number of
these patients who genuinely have cystic dilatation of the bili-
ary tree end up treated inadequately by simple cholecystec-
tomy and or common bile duct (CBD) exploration or
occasionally treated by biliary enteric bypass (31).
In areas where incidence of choledochal cysts is relatively
high, it is prudent to consider choledochal cyst in the differen-
tial diagnosis in patients who present with biliary colic, recur-
rent cholangitis, and evidence of dilated biliary tree (32,33).
However, in areas where incidence of choledochal cysts is rare,
this might represent a real-diagnostic dilemma requiring care-
ful management of these patients at a specialist unit to ensure
correct and adequate treatment tailored to each individual.
Other presentations include those related to complications
that might develop secondary to cystic dilatation of the biliary
tree such as calculi, recurrent hepatic abscesses, recurrent pan-
creatitis, bleeding, cyst erosion into surrounding structure,
cirrhosis, portal hypertension, and cholangiocarcinoma
(6,34). Such presentations may obscure the primary problem
and may increase the complexities of treatment (32,35).
Indeed, studies in adults have shown that nearly 80% of them
present with one or more of these conditions (5,6,27).
diagnosis
Correct diagnosis of true cystic dilatation of the biliary tree in
adults depends mainly on the use of imaging studies and some
times can be quite challenging. In indeterminate cases, careful
evaluation for anomalous pancreaticobiliary ductal conflu-
ence may be useful.
 CHOLEDOCHAL CYST DETECTED IN ADULTHOOD
Trans-abdominal ultrasonography is an extremely useful
investigation which provides adequate information about the
intra- and extra-hepatic biliary tree. However, anatomic delin-
eation of the non-dilated biliary system can be quite
limited (36,37).
Computed tomography (CT) imaging provides adequate
information about the size, extent, and characteristics of cho-
ledochal cysts as well as about its relationship to adjacent
structures. More over, CT may reveal associated pathology
within the parenchyma of related organs. CT scan is also
I II III
IVa IVb V with jaundice and in the rare instance of type III cyst; it facili-
Figure 39.1 Tandoni classification of choledochal cysts: Type 1 extra-hepatic
bile duct cystic dilatation, Type II common bile duct diverticulum, Type III
choledochocele, Type IVa intra- and extra-hepatic bile duct dilatation, Type
IVb multiple cysts (extra-hepatic only), and Type V intra-hepatic cysts only.
(A)
Figure 39.2 (A) MRCP image demonstrating segmental dilatation of the intra-hepatic biliary tree in the right lobe of the liver (Type V). (B) ERCP image demon-
strating segmental dilatation of the intra-hepatic biliary tree in the right lobe of the liver (Type V).
considered to be more accurate than ultrasonography in
demonstrating the biliary tree anatomy especially when using
the most recent spiral CT cholangiography technology which
allows three-dimensional reconstructions (38,39).
CT scan and ultrasonography can be sometimes of limited
value in demonstrating the biliary origin of choledochal cyst.
However, hepatobiliary scintigraphy with technetium-99
labeled iminodiacetic acid (IDA) derivatives will often show
the cyst and in particular helpful at establishing that the cystic
structure is an intrinsic part o the biliary tree. IDA scanning is
also helpful at assessing hepatobiliary function and anasto-
motic patency postoperatively (33,36,40).
Magnetic resonance imaging (MRI) is non-invasive and
produces clear images of the biliary tree. Also, it may even
demonstrate APBDC similar to endoscopic retrograde cholan-
giopancreaticograpgy (ERCP), but without the complications
of ERCP (3,41–43). Several studies reported that MRI has an
estimated diagnostic accuracy of 82% to 100% (43,44). Hence,
MRI is widely held as the imaging modality of choice for cho-
ledochal cysts (Figs. 39.2A and 39.3A).
ERCP defines the anatomy of the biliary tree accurately and
reveals the presence of any associated intra-ductal pathology
or an APBDC (Figs. 39.2B and 39.3B) (3,41). Also, ERCP
allows dealing with coexisting ductal stones in patients present
tates a therapeutic papillotomy simultaneously (45). However,
this is invasive investigation with a significant complication
rate and although it provides excellent anatomic delineation, it
rarely produces information which alters the subsequent man-
agement of the choledochal cysts. More over cholangiography
can always be performed intra-operatively by injecting con-
trast directly into the bile duct to display the ductal anatomy (6).
Endoscopic ultrasound scan and cholangioscopy are rela-
tively more recent investigations that can be of great use in the
diagnosis of extra-hepatic biliary cystic dilatation and more
important in the diagnosis of early malignant changes within
the cyst wall where biopsies can also be taken to confirm
abnormal tissue findings (46).
(B)
355
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
complications
The most common complication associated with choledochal
cysts is stones in the gallbladder, within the cysts or in the pan-
creatic duct (6). The calculi in the cysts are of the type seen in
biliary stasis (47). In choledochal cysts the calculi can be mis-
taken for choledocholithiasis in a dilated bile duct secondary
to obstruction. The main distinguishing features are non-
dilated proximal and intra-hepatic biliary radicles in the case
of type I cysts and non-dilated intervening ducts in the case of
type IV cysts.
Biliary strictures are another recognized complication asso-
ciated with adult choledochal cysts. This is most often related
to earlier surgical intervention but also can occur secondary
to chronic inflammation or rarely related to congenital
etiology (47,48).
Cirrhosis and liver abscesses are often associated with long-
standing biliary obstruction and recurrent cholangitis (48,49).
Some patients develop portal hypertension due to compres-
sion of the portal vein by a large choledochal cyst or more
often secondary to biliary cirrhosis (50).
Pancreatitis is a well-recognized complication related to
choledochal cysts. Incidence (10–70%) has been reported in
the literature by several authors (3,51,52).
The pathophysiology of pancreatitis in these patients is not
well understood but most authors believe that it is due to acti-
vation of pancreatic enzymes associated with biliary reflux
especially in patients with APBDC (51,53).
Choledochal cysts are associated with an increased risk of
developing cholangiocarcinoma and gallbladder tumors (54–56).
The risk is about 20 times higher than that in the general pop-
ulation ranging from 2.5% to 30% (3,56–58). The risk is age
related: 0.7% in children under the age of 10, 6.8% in patients
11 to 20 years of age, and 14.3% in patients over the age of
20 years (57). Carcinoma occurs not only in the cyst wall but
also in the remainder of the hepatobiliary and pancreatic
tree (57,59). Therefore, long-term follow-up is indicated in all
(A)
Figure 39.3 (A) MRCP image demonstrating intra- and extra-hepatic bile duct dilatation (Type IVa). (B) ERCP image demonstrating intra- and extra-hepatic bile
duct dilatation (Type IVa).
356
patients with choledochal cysts even after complete excision of
the cysts. The pathogenesis of malignant change in biliary
cysts is unknown. It has been thought to be related to bile sta-
sis and/or reflux of pancreatic juice, which give chronic irrita-
tion and metaplasia (59).
treatment
Management of choledochal cysts in adults should be per-
formed at specialist unit and tailored according to each patient’s
circumstances. Cyst type and more important patient’s general
health, presenting symptoms and risk of developing complica-
tions related to the choledochal cysts are major factors that
should be considered when deciding upon which type of treat-
ment to be adapted.
Total cyst excision when possible remains the gold standard
treatment for choledochal cysts. This has been recommended
by many investigators because of lower incidence of both early
and late postoperative complications. Therefore, this approach
has gained popularity worldwide (10,27,33,60,61). In chole-
dochal cysts types I and IVb involve complete excision of the
bile duct from the confluence of the hepatic ducts proximally
up to the pancreaticobiliary junction distally. Cholecystectomy
at the same time is a necessity, as the gallbladder usually arises
from or adheres to the cyst wall and may contain stones or
occasionally even tumor. Reconstruction of the biliary-enteric
communication in these patients is usually achieved by
Roux-en-Y hepaticojejunostomy or less commonly by hepati-
coduodenectomy. For type IVa choledochal cyst, the extra-
hepatic component should be treated in the same way as for
types I and IV cysts. The management of the intra-hepatic
component depends on the severity of the disease and extent
of involvement. This could range from percutaneous drainage
through stricture dilatation and stone removal to partial hepa-
tectomy (Fig. 39.4) or liver transplantation (3).
More radical surgery is required if malignancy is confirmed
on preoperative or fresh frozen biopsies. This might involve
(B)
 CHOLEDOCHAL CYST DETECTED IN ADULTHOOD
either pancreaticoduodenectomy or some form of hepatectomy
according to the location of the tumor. Thus, the probable
extent of surgery should be discussed with these patients before-
hand and the use of fresh frozen biopsies in this situation could
not be overemphasized bearing in mind its limitations.
Removal of the entire cyst wall is considered the most effec-
tive prophylaxis against developing malignancy and other
associated biliary tract pathology (33,61,62). Therefore, the
strategy of complete excision of the choledochal cyst should be
strictly adhered to whenever it is possible to do so (3,27,32). In
Figure 39.4 Intra-operative view following surgical resection of type IVa cho-
ledochal cyst seen in Figure 3A,B. Surgery involved left hepatectomy, total
excision of the bile duct and cholecystectomy.
(A)
Figure 39.5 (A) Demarcation of right anterior sector (segments 5 and 8) following extra-hepatic division of the right anterior sectoral hepatic artery and portal
vein. (B) Intra-operative view following segmental (central) liver resection (segments 5 and 8) for localized intra-hepatic segmental dilatation of the biliary tree
seen in Figure 2A,B.
situations where the intensity of fibrosis precludes safe dissec-
tion to allow total cyst excision, it is advisable to follow the
approach described by lilly et al. (63). In this technique, the
most densely adherent portion of the cyst wall is retained on
the hepatoduodenal ligament, removing only the less adherent
portion. The mucosal lining of the retained cyst wall should be
ablated by diathermy to minimize the risk of malignant trans-
formation in that segment of the cyst.
Simple cystenterostomy, which was used to be commonly per-
formed in the past, should no longer be considered a therapeu-
tic option due to a high incidence (30–50%) of late complications
such as cholangitis, anastomotic stricture, stone formation, bili-
ary cirrhosis, and, worst of all, malignancy (5,33,56,60–62,64).
Therefore, these patients with previous inadequate chole-
dochal cyst excision should, if appropriate, undergo further
revision surgery to reduce recurrent symptoms and the risk of
developing malignancy.
Treatment for type V cysts (Caroli’s disease) is still contro-
versial. Hepatic resection is safe and effective for part of type V
cysts (Fig. 39.5A,B) (10,65). For the type V cysts with diffuse
intra-hepatic cholangiectasia and frequent recurrent cholangi-
tis resulting in hepatic cirrhosis, liver resection is rarely feasi-
ble in which cases liver transplantation may be the only
effective treatment (66).
Type II and III cysts are rare lesions. Type II cysts may be
treated by cyst excision and primary ductal reconstruction or
reconstruction using Roux-en-Y hepaticojejunostomy while
Type III cysts, also known as choledochocele, may be excised
trans-duodenal following which both biliary and pancreatic
ducts are anastomosed to duodenum (64). Small lesions (type
III cysts) may be treated by sphincteroplasty or possibly by
endoscopic sphincterotomy (67,68).
All patients with choledochal cysts including those who had
complete choledochal cyst excision and more important those
(B)
357
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
who had previous cyst drainage procedures should be kept
under surveillance. Patients who had complete choledochal
cyst excision are prone to develop biliary-enteric anastomotic
stricture which can lead to cholangitis, jaundice, and biliary
cirrhosis. Also, these patients are still at a slightly higher risk
than the general population of developing malignancy in the
rest of the biliary tree even after complete excision of the cho-
ledochal cysts (69).
summary
Diagnosis and treatment of adult choledochal cysts can be quite
challenging. Therefore, management of these patients should be
carried out at specialist units. Choledochal cysts rarely present
for the first time in adulthood. However when they do, the pre-
sentation is variable and most often due to presence of associated
disease. Also they can be totally asymptomatic.
The appropriate treatment strategy should be selected based
on the type of the cyst and more important on the individual’s
general health and presenting symptoms. Total cyst excision
and Roux-en-Y hepaticojejunostomy are the current recom-
mended surgical options world wide for type I and IV chole-
dochal cysts while for type V cyst (diffuse Caroli’s disease)
with frequent recurrent cholangitis, liver transplantation
should be considered. Patients with previous cyst drainage
procedures should undergo revisional surgery if appropriate
to reduce recurrent symptoms and the risk of developing
malignancy. Conservative treatment might be the most appro-
priate strategy in asymptomatic individuals with poor general
health and significant co-morbidities. All patients with chole-
dochal cysts including those who had complete choledochal
cyst excision should be kept under long-term surveillance.
key points
Choledochal cysts are increasingly diagnosed in adult
population
Etiology of choledochal cysts remains speculative
Adults with choledochal cysts most commonly present
with complications related to their choledochal cysts
Choledochal cysts are associated with an increased risk of
developing cholangiocarcinoma and gallbladder tumors
MRI is widely held as the imaging modality of choice for
choledochal cysts
Patients with choledochal cysts should be managed at a
specialist unit to ensure correct and adequate treatment
tailored to each individual
Total cyst excision when possible remains the gold stan-
dard treatment for choledochal cysts
references
1. Gigot JF, Nagorney D, Farnell M, Moir C, Ilstrup D. Bile duct cysts: a
changing spectrum of disease. J Hepato-Biliary-Pancreatic Surg 1996;
3(4): 405–11.
2. Lenriot JP, Gigot JF, Segol P, et al. Bile duct cysts in adults: a multi-institu-
tional retrospective study. French Associations for Surgical Research. Ann
Surg 1998; 228(2): 159–66.
3. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Chole-
dochal cyst disease. A changing pattern of presentation. Ann Surg 1994;
220(5): 644–52.
358
4. Suita S, Shono K, Kinugasa Y, Kubota M, Matsuo S. Influence of age on the
presentation and outcome of choledochal cyst. J Pediatr Surg 1999;
34(12): 1765–8.
5. Flanigan PD. Biliary cysts. Ann Surg 1975; 182(5): 635–43.
6. Yamaguchi M. Congenital choledochal cyst. Analysis of 1,433 patients in
the Japanese literature. Am J Surg 1980; 140(5): 653–7.
7. Rattner DW, Schapiro RH, Warshaw AL. Abnormalities of the pancreatic
and biliary ducts in adult patients with choledochal cysts. Arch Surg 1983;
118(9): 1068–73.
8. Wiedmeyer DA, Stewart ET, Dodds WJ, et al. Choledochal cyst: findings
on cholangiopancreatography with emphasis on ectasia of the common
channel. AJR Am J Roentgenol 1989; 153(5): 969–72.
9. Babbitt DP. Congenital choledochal cysts: new etiological concept based
on anomalous relationships of the common bile duct and pancreatic
bulb. Ann Radiol (Paris) 1969; 12(3): 231–40.
10. Liu YB, Wang JW, Devkota KR, et al. Congenital choledochal cysts in adults:
twenty-five-year experience. Chin Med J (Engl) 2007; 120(16): 1404–7.
11. Gauthier F, Brunelle F, Valayer J. Common channel for bile and pancreatic
ducts. Presentation of 12 cases and discussion. Chir Pediatr 1986; 27(3):
148–52.
12. Davenport M, Stringer MD, Howard ER. Biliary amylase and congenital
choledochal dilatation. J Pediatr Surg 1995; 30(3): 474–7.
13. Benhidjeb T, Said S, Rudolph B, Siegmund E. Anomalous pancreatico-
biliary junction--report of a new experimental model and review of the
literature. J Pediatr Surg 1996; 31(12): 1670–4.
14. Schroeder D, Smith L, Prain HC. Antenatal diagnosis of choledochal cyst
at 15 weeks’ gestation: etiologic implications and management. J Pediatr
Surg 1989; 24(9): 936–8.
15. Schweizer P. Pathogenesis of choledochal cyst. Pediatr Surg Int 1995;
10(7): 475–7.
16. Davenport M, Basu R. Under pressure: choledochal malformation
manometry. J Pediatr Surg 2005; 40(2): 331–5.
17. Wong KC, Lister J. Human fetal development of the hepato-pancreatic
duct junction--a possible explanation of congenital dilatation of the bili-
ary tract. J Pediatr Surg 1981; 16(2): 139–45.
18. Spitz L. Experimental production of cystic dilatation of the common bile
duct in neonatal lambs. J Pediatr Surg 1977; 12(1): 39–42.
19. Petersen C, Biermanns D, Kuske M, et al. New aspects in a murine model
for extrahepatic biliary atresia. J Pediatr Surg 1997; 32(8): 1190–5.
20. Todani T, Watanabe Y, Narusue M, Tabuchi K, Okajima K. Congenital bile
duct cysts: classification, operative procedures, and review of thirty-seven
cases including cancer arising from choledochal cyst. Am J Surg 1977;
134(2): 263–9.
21. Vater a, Ezler C. Dissertatio de scirrhis viserum occasione sections viri
typanite. wittenburgae 1723; Pamphlers 88: 22.
22. Alonso-Lej F, Rever WB, Jr, Pessagno DJ. Congenital choledochal cyst, with
a report of 2, and an analysis of 94, cases. Int Abstr Surg 1959; 108(1): 1–30.
23. Visser BC, Suh I, Way LW, Kang SM. Congenital choledochal cysts in
adults. Arch Surg 2004; 139(8): 855–60; discussion 860–2.
24. Wiseman K, Buczkowski AK, Chung SW, et al. Epidemiology, presenta-
tion, diagnosis, and outcomes of choledochal cysts in adults in an urban
environment. Am J Surg 2005; 189(5): 527–31; discussion 531.
25. Singham J, Schaeffer D, Yoshida E, Scudamore C. Choledochal cysts: anal-
ysis of disease pattern and optimal treatment in adult and paediatric
patients. HPB (Oxford) 2007; 9(5): 383–7.
26. Rha SY, Stovroff MC, Glick PL, Allen JE, Ricketts RR. Choledochal cysts: a
ten year experience. Am Surg 1996; 62(1): 30–4.
27. Liu CL, Fan ST, Lo CM, et al. Choledochal cysts in adults. Arch Surg 2002;
137(4): 465–8.
28. Sela-Herman S, Scharschmidt BF. Choledochal cyst, a disease for all ages.
Lancet 1996; 347(9004): 779.
29. Soreide K, Korner H, Havnen J, Soreide JA. Bile duct cysts in adults. Br J
Surg 2004; 91(12): 1538–48.
30. de Vries JS, de Vries S, Aronson DC et al. Choledochal cysts: age of presen-
tation, symptoms, and late complications related to Todani’s classifica-
tion. J Pediatr Surg 2002; 37(11): 1568–73.
31. Banerjee Jesudason SR, Ranjan Jesudason M, Paul Mukha R, et al. Man-
agement of adult choledochal cysts – a 15-year experience. HPB (Oxford)
2006; 8(4): 299–305.
 CHOLEDOCHAL CYST DETECTED IN ADULTHOOD
32. Hewitt PM, Krige JE, Bornman PC, Terblanche J. Choledochal cysts in
adults. Br J Surg 1995; 82(3): 382–5.
33. Jesudason SR, Govil S, Mathai V, Kuruvilla R, Muthusami JC. Choledochal
cysts in adults. Ann R Coll Surg Engl 1997; 79(6): 410–3.
34. Fieber SS, Nance FC. Choledochal cyst and neoplasm: a comprehensive
review of 106 cases and presentation of two original cases. Am Surg 1997;
63(11): 982–7.
35. Chaudhary A, Dhar P, Sachdev A. Reoperative surgery for choledochal
cysts. Br J Surg 1997; 84(6): 781–4.
36. Han BK, Babcock DS, Gelfand MH. Choledochal cyst with bile duct dila-
tation: sonography and 99mTc IDA cholescintigraphy. AJR Am J Roent-
genol 1981; 136(6): 1075–9.
37. Young W, Blane C, White SJ, Polley TZ. Congenital biliary dilatation: a spec-
trum of disease detailed by ultrasound. Br J Radiol 1990; 63(749): 333–6.
38. Katyal D, Lees GM. Choledochal cysts: a retrospective review of 28 patients
and a review of the literature. Can J Surg 1992; 35(6): 584–8.
39. Groebli Y, Sarraj A, Pfister L, Lopez J. Spiral-CT cholangiography with 3D
reconstruction in the diagnosis of choledochocele. Eur Radiol 2000;
10(2): 395.
40. Grossman SA, Patel BA, Blend MJ. Use of CCK cholescintigraphy to
differentiate choledochal cyst from gallbladder. Clin Nucl Med 1991;
16(4): 226–9.
41. Komi N, Takehara H, Kunitomo K, Miyoshi Y, Yagi T. Does the type of
anomalous arrangement of pancreaticobiliary ducts influence the surgery
and prognosis of choledochal cyst? J Pediatr Surg 1992; 27(6): 728–31.
42. Yamataka A, Ohshiro K, Okada Y, et al. Complications after cyst excision
with hepaticoenterostomy for choledochal cysts and their surgical man-
agement in children versus adults. J Pediatr Surg 1997; 32(7): 1097–102.
43. Kim SH, Lim JH, Yoon HK, et al. Choledochal cyst: comparison of MR
and conventional cholangiography. Clin Radiol 2000; 55(5): 378–83.
44. Dinsmore JE, Murphy JJ, Jamieson D. Pediatric surgical images: MRCP
evaluation of choledochal cysts. J Pediatr Surg 2001; 36(5): 829–30.
45. Martin RF, Biber BP, Bosco JJ, Howell DA. Symptomatic choledochoceles
in adults. Endoscopic retrograde cholangiopancreatography recognition
and management. Arch Surg 1992; 127(5): 536–8; discussion 538–9.
46. Judah JR, Draganov PV. Intraductal biliary and pancreatic endoscopy: an
expanding scope of possibility. World J Gastroenterol 2008; 14(20):
3129–36.
47. Uno K, Tsuchida Y, Kawarasaki H, Ohmiya H, Honna T. Development of
intrahepatic cholelithiasis long after primary excision of choledochal
cysts. J Am Coll Surg 1996; 183(6): 583–8.
48. Simici P, Ratiu O. Cystic dilatation of the common bile duct with cholan-
gitis, jaundice and cholestatic cirrhosis. Rev Chir Oncol Radiol O R L
Oftalmol Stomatol Chir 1980; 29(3): 201–6.
49. Nagorney DM, McIlrath DC, Adson MA. Choledochal cysts in adults:
clinical management. Surgery 1984; 96(4): 656–63.
50. Nunez-Hoyo M, Lees CD, Hermann RE. Bile duct cysts. Experience with
15 patients. Am J Surg 1982; 144(3): 295–9.
51. Okada A, Nakamura T, Higaki J, et al. Congenital dilatation of the bile
duct in 100 instances and its relationship with anomalous junction. Surg
Gynecol Obstet 1990; 171(4): 291–8.
52. Swisher SG, Cates JA, Hunt KK, et al. Pancreatitis associated with adult
choledochal cysts. Pancreas 1994; 9(5): 633–7.
53. Todani T, Urushihara N, Watanabe Y, et al. Pseudopancreatitis in chole-
dochal cyst in children: intraoperative study of amylase levels in the
serum. J Pediatr Surg 1990; 25(3): 303–6.
54. Todani T, Tabuchi K, Watanabe Y, Kobayashi T. Carcinoma arising in the
wall of congenital bile duct cysts. Cancer 1979; 44(3): 1134–41.
55. Tsuchiya R, Harada N, Ito T, Furukawa M, Yoshihiro I. Malignant tumors
in choledochal cysts. Ann Surg 1977; 186(1): 22–8.
56. Jan YY, Chen HM, Chen MF. Malignancy in choledochal cysts. Hepatogas-
troenterology 2000; 47(32): 337–40.
57. Voyles CR, Smadja C, Shands WC, Blumgart LH. Carcinoma in chole-
dochal cysts. Age-related incidence. Arch Surg 1983; 118(8): 986–8.
58. Shi LB, Peng SY, Meng XK, et al. Diagnosis and treatment of congenital
choledochal cyst: 20 years’ experience in China. World J Gastroenterol
2001; 7(5): 732–4.
59. Kimura K, Ohto M, Saisho H, et al. Association of gallbladder carcinoma
and anomalous pancreaticobiliary ductal union. Gastroenterology 1985;
89(6): 1258–65.
60. Rush E, Podesta L, Norris M, et al. Late surgical complications of chole-
dochal cystoenterostomy. Am Surg 1994; 60(8): 620–4.
61. Lee KF, Lai EC, Lai PB. Adult choledochal cyst. Asian J Surg 2005; 28(1): 29–33.
62. Tan SS, Tan NC, Ibrahim S, Tay KH. Management of adult choledochal
cyst. Singapore Med J 2007; 48(6): 524–7.
63. Lilly JR. The surgical treatment of choledochal cyst. Surg Gynecol Obstet
1979; 149(1): 36–42.
64. Powell CS, Sawyers JL, Reynolds VH. Management of adult choledochal
cysts. Ann Surg 1981; 193(5): 666–76.
65. Madariaga JR, Iwatsuki S, Starzl TE, et al. Hepatic resection for cystic
lesions of the liver. Ann Surg 1993; 218(5): 610–4.
66. Sans M, Rimola A, Navasa M, et al. Liver transplantation in patients with
Caroli’s disease and recurrent cholangitis. Transpl Int 1997; 10(3): 241–4.
67. Zheng LX, Jia HB, Wu DQ, et al. Experience of congenital choledochal
cyst in adults: treatment, surgical procedures and clinical outcome in the
Second Affiliated Hospital of Harbin Medical University. J Korean Med
Sci 2004; 19(6): 842–7.
68. Akkiz H, Colakoglu SO, Ergun Y, et al. Endoscopic retrograde cholangio-
pancreatography in the diagnosis and management of choledochal cysts.
HPB Surg 1997; 10(4): 211–8; discussion 218–9.
69. Watanabe Y, Toki A, Todani T. Bile duct cancer developed after cyst excision
for choledochal cyst. J Hepatobiliary Pancreat Surg 1999; 6(3): 207–12.
359
40 Bile duct injuries and benign biliary strictures
Steven M. Strasberg
Benign biliary strictures are largely due to trauma or inflam-
mation. Most traumatic biliary strictures result from iatro-
genic operative injuries. In addition to causing strictures
iatrogenic operative injuries may lead to other types of biliary
abnormalities such as loss of continuity of the biliary tract and
fistula. Inflammatory strictures are due to pancreatitis and less
commonly sclerosing cholangitis, septic cholangitis, and
inflammatory pseudotumors. Today it is usually possible to
treat most inflammatory strictures by endoscopic stenting.
Consequently the focus of this chapter will be on iatrogenic
biliary injury.
iatrogenic biliary injuries
Most traumatic injuries are due to operative trauma and more
than 95% of biliary injuries occur during cholecystectomy.
Biliary injury is the most severe common complication of cho-
lecystectomy. The causes of injury are increasingly better
understood and there have been improvements in strategies
for preventing injury.
incidence of biliary injuries
Laparoscopic Versus Open Cholecystectomy in Randomized
Controlled Trials
A recent systematic review of randomized trials (evidence
level 1a) of open versus laparoscopic surgery concluded that
“laparoscopic cholecystectomy did not carry more bile duct
injuries than open cholecystectomy” (1). Thirty trials random-
izing 1914 patients were reviewed. The incidence, 0.2%, was
the same for both operations. However, there were only four
“high-quality” trials. It is questionable whether an analysis
based on many small randomized trials of variable quality is
capable of determining the true incidence of biliary injury
during laparoscopic cholecystectomy or whether it is higher
than in open cholecystectomy.
Population-Based Studies
Most registry results were published before 1998 (2–7) and
may not reflect current results a decade later. They cite an inci-
dence of major bile duct injury ranging from 0.15 (3) to
0.86 (4). Adamsen et al. described results in a rigorously main-
tained registry involving over 7000 Danish patients from
1991 to 1997. The major bile duct injury rate was 0.74% and
the total injury rate including bile leaks was 2.8%. In a tightly
controlled registry in the Department of Defense Hospitals in
the United States from 1990 to 1992, the incidence was
0.57% (7). Flum et al., using an administrative database cover-
ing 1.5 million Medicare patients in the United States (popula-
tion over 65 years) from 1992 to 1999 found a major bile duct
injury rate of 0.5% (8). In a Swedish registry covering 150,000
cholecystectomies over the period from 1987 to 2001, the
major bile duct injury rate increased from 0.40% in the earliest
360
period when all cholecystectomies were performed by lapa-
rotomy to 0.47% in the latest period of the study 1996 to 2001
when most procedures were laparoscopic (9). To summarize it
is likely that the incidence of biliary injury during laparoscopic
cholecystectomy is higher than it was when cholecystectomies
were performed by laparotomy but how much higher is uncer-
tain. Clearly, ongoing good population studies defining the
incidence of this problem are needed.
classification of biliary injuries
The Bismuth classification was the standard means of classify-
ing biliary injuries in the era of open cholecystectomy (10). It
classified strictures into five types based mainly on the upper
level of injury, i.e., the lowest level at which healthy biliary
mucosa is available for anastomosis (11). Several new classifi-
cations of laparoscopic biliary injury were proposed in the
1990s, including a classification by the Amsterdam group (12),
a classification by Stewart and Way (13), and a classification
introduced by our group in 1995 (14). The former two classi-
fications divide injuries mainly on the basis of mechanism of
injury and place strictures and complete transections in differ-
ent categories. Our classification is a more detailed anatomic
classification based on the level of the injury and essentially is
an extension of the Bismuth classification applicable to inju-
ries observed in the laparoscopic era (Fig. 40.1). For instance,
Type A–D injuries are much more common in the laparo-
scopic era and need to be represented in such a classification
(Fig. 40.2). Like that classification it is intended to help the
surgeon or endoscopist choose the appropriate technique for
the repair. Strictures and transections are in the same category
and are separated within each category. Each classification has
its advantages and disadvantages. Our classification is best
suited for studies of surgical treatment of biliary injuries.
Biliary injuries are often accompanied by vascular injuries.
Vascular injuries are associated with a greater tendency for re-
stricture of bile duct repairs (15), but apparently not when
repairs are done after an interval in expert centers using the
Hepp–Couinaud approach (16). Portal vein transection and
traumatic thrombosis have also been reported. The vascular
component may be come the predominant feature of the
injury with necrosis of the intrahepatic biliary system or
hepatic infarction. Infarction of the intrahepatic biliary tree
requires transplantation, while hepatic infarction may lead to
the need for hepatic resection or transplantation (17).
pathogenesis of bile duct injuries
Patient-Related Factors
Inflammation
Acute cholecystitis: In population studies the incidence of biliary
injury is higher when laparoscopic cholecystectomy is per-
formed for acute cholecystitis than for elective indications (2,3),
 BILE DUCT INJURIES AND BENIGN BILIARY STRICTURES

Figure 40.1 A classification of laparoscopic injuries to the biliary tract. The injuries Type A to E are illustrated. Type A injuries originate from small bile ducts in
the liver bed that or from the cystic duct. Type B and C injuries almost always involve aberrant right hepatic ducts. The notations >2 cm and <2 cm in Type E1 and
Type E2 indicate the length of common hepatic duct remaining. The corresponding Bismuth classification numbers are given when possible as B1-5. Note that
Types A and D do not exist in the Bismuth classification, which is a classification of bile duct strictures rather than injuries. Note that B,C and E5 injuries would
be classified as B5. They are separated in our classification because of the increase incidence of B and C injuries in the laparoscopic era.

Figure 40.2 Type A (left) and Type D injuries (right) are much more common in the laparoscopic era and were given separate categories in our classification. The
Type A injury figure demonstrates extravasation of contrast from the liver bed of the gallbladder due to injury to a bile duct in that location. The Type D injury
figure demonstrates an injury which was incompletely repaired over a t-tube (arrow). There is extravasation of contrast from the common bile duct when T tube
is injected. A percutaneous drain (arrowhead) was inserted to drain postoperative bilomas. The injury healed without further treatment.

although this was not borne out in a Cochrane review of ran-
domized trials (18) (evidence level 1a). However, in the latter,
conclusions were drawn from a total of four bile duct injuries
among 438 patients (0.9%) (18). Acute inflammation causes
thickening of tissues, increases friability and vascularity, and
promotes adhesions. These factors obscure normal anatomical
relationships (Fig. 40.3A) and increase difficulty of exposure
and dissection. The inflammatory mass may effectively obliter-
ate the triangle of Calot and hide the cystic duct (19) (Fig. 40.3B).
Severe inflammation is more likely to be encountered when
the time between onset of symptoms and surgery for acute
cholecystitis is greater than 72 hours (20,21), when the white
blood cell count is greater than 18,000 cells/cu mm (20,22), or if
the patient’s age is over 60 years (20,23,24). The Tokyo Severity

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Grading for Acute Cholecystitis incorporates these findings in
its recommendations regarding timing and expertise for cho-
lecystectomy in this disease (25,26).
Severe chronic inflammation with dense scarring: Repeated
episodes of acute cholecystitis result in severe scarring of the
gallbladder and adjacent tissues with the result that the gall-
bladder may contract markedly. Fibrotic retraction often
binds the gallbladder to the common hepatic duct and right
hepatic artery, effectively obliterating the triangle of Calot
(Fig. 40.3C). Such inflammation makes dissection very diffi-
cult and contributes to visual deception when certain tech-
niques are used (19).
Congenital Abnormalities
Aberrant Right Hepatic Ducts
A low-lying aberrant right hepatic duct is present in about 2%
of patients. This aberrancy is the most common type associ-
ated with biliary injury. These ducts may lie in or close to the
triangle of Calot and are in danger of injury during dissec-
tion (27). The most perilous situation occurs when the cystic
duct unites with the low-lying aberrant right duct, which then
continues to a confluence with the common hepatic duct. The
appearance of the junction of the aberrant duct with the
hepatic duct is similar to that of the normal confluence of
the cystic duct with the common hepatic duct and conse-
quently there is great potential for injury (27). Aberrant right
hepatic duct injuries are more common in laparoscopic than
open cholecystectomy.
Parallel Union Cystic Duct
The parallel union cystic duct (Fig. 40.3D) occurs in about
20% of individuals. It was a well-described risk factor for bili-
ary injury in the era of open cholecystectomy and continues to
be a risk factor today.
Aberrant Position of Cystic Duct Termination
The cystic duct may insert into the biliary tree at any point
from the right hepatic duct to the termination of the common
bile duct. Insertion into the right hepatic duct is very uncom-
mon but exposes this duct to injury.
Congenital Adhesions Between the Gallbladder
and Common Hepatic Duct
Such adhesions are prominent in some individuals. They
obscure the triangle of Calot and may fix the common hepatic
duct to the side of the gallbladder. In some cases the Pouch of
Hartmann may actually lie over and to the left of the common
bile and common hepatic ducts (Fig. 40.3E).

Triangle
of Calot

(A) (B) (C)

(D) (E) (F)

Figure 40.3 Conditions which predispose to the deception that the common bile duct is the cystic duct especially when the infundibular techniques is used.
(A) Situation in which the infundibular technique is effective. There is mild inflammation. The triangle of Calot is open and the funnel shape of the junction
between the gallbladder and cystic duct (heavy line) is readily apparent. (B–F) Conditions which may give a misleading funnel shape (heavy lines) due to conceal-
ment or obliteration of the triangle of Calot. In these cases the common bile duct is dissected by a surgeon who thinks it is the cystic duct widening to become the
gallbladder. (B) Severe acute cholecystitis. (C) Severe chronic inflammation. (D) Parallel cystic duct insertion. (E) Congenital bands. (F) Large impacted stone.

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 BILE DUCT INJURIES AND BENIGN BILIARY STRICTURES

Abnormal Diameter or Length of Bile Ducts
There is considerable variation of bile duct size from person to
person. The internal diameter of the cystic duct is normally 2
to 3 mm which would make the external diameter about 3 to
5 mm (28). The normal supraduodenal common bile duct
external diameter duct ranges from 4 to 13 mm (28) but the
normal internal diameter measured by ultrasound is consid-
ered to be 3 to 8 mm with wall thickness accounting for the
difference. Rarely duct size may be less than these norms and
expose the ducts to injury especially when certain techniques
of ductal identification are used.
Intrahepatic Gallbladder
An intrahepatic gallbladder is difficult to grasp and contrib-
utes indirectly to injury by making it difficult to expose the
cystic duct (19).
Hepatic Ducts Uniting with or Lying in Proximity
to the Gallbladder
The commonest duct of this type is a duct of Luschka, a 1 to
2 mm accessory duct that runs between an intrahepatic duct
and the gallbladder. An injury to a duct of Luschka is difficult
to recognize as the duct is tiny and hepatic bile is dilute and
lightly straw-colored.
In about 10% of individuals a right hepatic duct measuring
2 to 3 mm in diameter lies immediately deep to the cystic plate.
In this location it is in danger of injury if the cystic plate is
penetrated when dissecting the gallbladder off the plate (gall-
bladder bed).
Isolated reports describe a major hepatic duct that enters
directly into the gallbladder usually the right hepatic duct. To the
author’s knowledge they have not been described in anatomical
dissections of normal specimens. Therefore such ducts are most
likely secondary to erosion of a stone into a major bile duct caus-
ing a fistula between the gallbladder and the bile duct akin to a
Mirizzi syndrome but affecting only the right hepatic duct.
Other Patient-Related Factors
Large Impacted Gallstones
These are not infrequently mentioned in operative notes of
cholecystectomies in which biliary injuries have occurred.
They tend to impair retraction and hide the cystic duct (19)
(Fig. 40.3F). As noted they may efface the cystic duct thus
shortening or obliterating it and in severe cases cause common
bile duct compression or erosion and with severe perichole-
cystic inflammation (Mirizzi’s syndrome).
Obesity, Body Habitus
Obesity, a risk factor for cholelithiasis is common in patients
having a cholecystectomy. Morbid obesity and large body size
in general contribute to difficulty in operative exposure. The
same is true of skeletal deformities. These may be contributing
factors to biliary injury.
Procedure-Related Factors
Misidentification—A Concept Problem
There are two main types of bile duct misidentification—
misidentification of the common bile duct as the cystic duct
(Fig. 40.4A–C) and misidentification of an aberrant right

(A) (B) (C)

(D) (E) (F)

Figure 40.4 Patterns of biliary injury due to misidentification. (A). The “classical” type E injury in which the common duct is divided between clips at point x. The
ductal system is later divided again to remove the gallbladder either at point y1 producing E1 or E2 injuries, or at point y2 producing E3 or E4 injuries. (B) Variant
of Type E injury which leads to bile leakage into the operative field and thereby an increased chance of recognition before the entire injury evolves. (C) Variant of
Type E injury leading to clipping but not excision of the duct. This injury also causes intraoperative bile leakage, except when cystic and common bile ducts are
both occluded, as shown in the inset. D,E, and F represent variants of injury to aberrant right hepatic duct, producing Type B or Type C injuries. The injuries shown
in D, E, and F correspond to the injuries shown in A, B, and C, but affect the aberrant right duct.

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

hepatic duct as the cystic duct (Fig. 40.4D–F). This type of
injury has been called the “classical injury” (29). The type of
injury produced may be E1 to E4 and depends upon the level
of the second transection. These injuries either result in bile
duct obstruction or bile leak depending upon whether the
biliary tree is clipped and cut and/or only cut. The second type
of misidentification leads to injury of an aberrant right hepatic
duct (B and C injuries). The section of the aberrant right
hepatic duct, between entry of cystic duct and junction with
the common hepatic is mistaken to be the cystic duct
(Fig. 40.4D–F). The misidentified section is clipped and usu-
ally cut. To remove the gallbladder the aberrant duct must be
cut again at a higher level.
The key to understanding why misidentification occurs rests
with examining the rationale for identification of the cystic
structures during cholecystectomy. There are five techniques
in general use.
common bile duct as the cystic duct and will prevent excisional
injuries of bile ducts, if the cholangiogram is correctly inter-
preted. Unfortunately, operative cholangiograms are some-
time misinterpreted. The most common misinterpretation is
the failure to recognize that when only the lower part of the
biliary tree is seen, the common bile duct rather than the cystic
duct has been incised and cannulated. IOC is not effective at
detecting aberrant right ducts, which unite with the cystic duct
before joining the common duct. The aberrant duct appears to
be the cystic duct visually and on cholangiograms, especially
since some nonaberrant right-sided ducts usually fill
(Fig. 40.6). Since it is not unusual to obtain only partial filling
of the right hepatic ducts by IOC this is taken as a normal
pattern. Another drawback is that an incisional injury of the

“Infundibular Technique” (Fig. 40.5)

In this fallible method the putative cystic duct is traced to the
gallbladder or the gallbladder down to the cystic duct, at which Cystic plate
point, after circumferential dissection of these structures the
infundibulum (funnel) is displayed. It is this flaring or widen-
ing that was believed to give reliable identification of the cystic
duct. However, a flare may also be observed when the common
bile duct is followed up to an inflammatory mass within which
the cystic duct is hidden (“hidden cystic duct syndrome”) (19).This
visual deception is most likely to occur when one or more fac-
tors described above are present—severe acute or chronic
inflammation, a large stone in the pouch of Hartmann, adhe-
sive bands, intrahepatic gallbladder, short cystic duct, etc.
Figure 40.5 The “critical view of safety”. The triangle of Calot is dissected free
of all tissue except for cystic duct and artery and the base of the liver bed is
Intraoperative Cholangiography (IOC) exposed. When this view is achieved, the two structures entering the gallblad-
IOC reduces the incidence of biliary injury (30,31). Operative der can only be the cystic duct and artery. It is not necessary to see the common
cholangiography is best at detecting misidentification of the bile duct.

(A) (B)
Figure 40.6 (A) Intraoperative cholangiogram which was interpreted as “normal” with only a wisp of dye entering right hepatic ducts. Note stone at ampulla.
(B) Postoperative ERCP in same patient done to remove stone. Note retrograde filling of aberrant right hepatic duct, made stenotic by clips. Note how the point
of union of the aberrant duct with the common hepatic duct looks like a cystic duct- common duct junction. Problem successfully treated by stenting.

364
 BILE DUCT INJURIES AND BENIGN BILIARY STRICTURES
common bile duct, made in order to perform IOC, may not be
innocuous. However, the benefits of IOC in ductal identifica-
tion far outweigh its disadvantages.
Dissection of the Cystic Duct to the Confluence
with the Common Hepatic Duct/Common Bile Duct
This was a common and usually safe technique in performance
of open cholecystectomy. There is reason to believe that its use
during laparoscopic cholecystectomy has been associated with
an increase in lateral injuries to the common hepatic duct
(Type D), which have become much more common. The
injury is more prone to occur when this technique is used in
patients with a parallel union cystic duct.
The “Critical View Technique”
Introduced in 1992 and modified in 1995 this technique rec-
ommends clearing the triangle of Calot of fat and fibrous tis-
sue and taking the gallbladder off the lowest part of its
attachment to the gallbladder bed (cystic plate). Only two
structures will be connected to the lower end of the gallbladder
once this is done. Raising the gallbladder off the lower part of
the cystic plate is an important step, equivalent in the open
technique to taking the gallbladder off the gallbladder bed. No
attempt is made to expose the common bile duct or common
hepatic duct (Fig. 40.5). This view provides conclusive, i.e.,
convincing demonstration that the two structures entering the
gallbladder are the cystic duct and artery.
“Top-Down” Cholecystectomy
In this technique the cholecystectomy is started at the fundus,
taking the gallbladder off the gallbladder bed prior to any
dissection or identification of structures in the triangle of
Common
hepatic duct
Cystic duct
Common
bile duct
(A)
Figure 40.7 Cause of bile duct injury in “top down” cholecystectomy in the face of severe inflammation with obliteration of triangle of Calot which draws the side
of the common hepatic duct to the side of the gallbladder. (A) Real anatomical situation. (B) Apparent anatomical situation is shown by heavy line. The surgeon
sees the anatomy bounded by the heavy line as the gallbladder and the cystic duct and as the gallbladder is excised top-down (arrow) the common hepatic duct is
transected. Vascular injuries are also common with this mechanism of injury.
Calot. While it may be an effective technique of identification
in most instances, our experience is that it may lead to serious
biliary and vascular injuries in the presence of severe inflam-
mation and usually after conversion to open cholecystectomy.
The problem is that the surgeon dissecting from above may
“see” the inflammatory mass containing the gallbladder and
critical vessels and bile ducts as the gallbladder alone and lac-
erate or divide one or more of these structures (Figs. 40.7
and 40.8).
Also it has been recognized since the earliest days of laparo-
scopic cholecystectomy that the direction of traction of the
gallbladder may contribute to the mistaken conclusion that the
common bile duct is the cystic duct—and that this may lead to
the misidentification injury. When the pouch of Hartmann is
pulled superiorly rather than laterally, the cystic and common
bile ducts appear to be a single continuous structure.
Technical Problems
Bile ducts may be injured in the course of dissection much in
the same way that an enterotomy occurs in the course of dis-
secting adhesions. Inflammation, aberrant anatomy, small
duct size, and large body habitus contribute to the likelihood
of this occurrence. gallbladder. As noted above about 10% of
patients have a sizable hepatic duct which lies immediately
deep to the cystic plate and is therefore prone to injury.
Failure to Obtain Secure Closure of the Cystic Duct
The cystic duct is normally occluded with metallic clips. When
the duct is thick, rigid or wide, clips may fail and their use
should usually be avoided under these circumstances. Retained
common duct stones may contribute to clip failure by raising
bile duct pressure.
(B)
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

III

IV
Sg 6,7 LHD
II
Sg 5,8

Figure 40.8 Intraoperative photo (left) and diagram (right) showing transection of multiple hepatic ducts during open cholecystectomy by the fundus down tech-
nique in a very inflamed gallbladder. The right anterior sectional duct (Sg 5,8), the right posterior sectional duct (Sg 6,7) and the left hepatic duct (LHD) were
transected in this high E4 injury.

Thermal Injuries (Fig. 40.9)

Thermal injuries are more likely to occur in the presence of
severe inflammation, because hemorrhage is more common
when dissecting in the face of acute inflammation and higher
power settings may be used to control hemorrhage. These
injuries are often not recognized at surgery and usually result
in bile duct stenosis rather than loss of continuity.

Tenting Injuries
The junction of the common bile duct and hepatic bile ducts
may be occluded when clipping the cystic duct while pulling
up forcefully on the gallbladder. This is a very uncommon
laparoscopic injury perhaps due to the magnification afforded
by laparoscopy.

Surgeon/Hospital-Related Factors
Learning Curve Effect
Inexperience with laparoscopic cholecystectomy was a well
documented cause of bile duct injuries in the 1990s. The likeli-
hood of biliary injury was much greater during the early expe-
rience of a surgeon than subsequently. It is possible that
inexperience in the procedure during acute cholecystitis is still
contributing to injury.
Figure 40.9 T-tube cholangiogram in a patient 2 months after a thermal
injury. The common hepatic duct (arrow) appears “shrink wrapped” over the
The Psychology of Human Error T-tube. At the time of reconstruction the common hepatic duct was replaced
Hugh (32) and then Way et al. (33) described traits of human by scar.
behavior that cause or contribute to biliary injury. Surgery is a
complex task in which visual disorientation will occur occa- Equipment
sionally and persistence in error due to the deadly mind set Laparoscopic equipment must be regularly maintained. Focal
error is a common human failing. The mind set error is the loss of insulation on cautery instruments can result in arcing
tendency to interpret information incorrectly after one has and thermal injuries to bile ducts or bowel.
first made a decision. The point of departure of the author
with this view is that the visual disorientation is more likely to avoidance of biliary injuries
occur with certain methods of procedure and can be greatly General
diminished with the use of routine cholangiography or the Only surgeons trained and proctored in laparoscopic cholecys-
critical view technique of identification. tectomy should perform it. Since laparoscopic cholecystectomy

366
 BILE DUCT INJURIES AND BENIGN BILIARY STRICTURES
for acute cholecystitis is more difficult and associated with a
higher incidence of biliary injury, it should not be attempted
until experience is gained. Special note should be taken of con-
ditions that make surgery during acute cholecystitis particularly
difficult and consideration given to percutaneous cholecystos-
tomy as a temporizing measure (25). When inflammation is
severe and mandates conversion the open procedure may also
be very difficult especially for the surgeon inexperienced in dif-
ficult open cholecystectomy. Cholecystostomy or partial chole-
cystectomy with occlusion of the cystic duct using a pursestring
suture placed from the interior of the gallbladder are excellent
options under these conditions.
Misidentification Injuries
Although still in widespread use the author believes that the
infundibular technique ought to be discarded as a sole means
of ductal identification. It is an error trap, i.e., it works well in
most circumstances and seems to be very reliable, but it is
actually prone to fail under particular circumstances. Similarly
dissection of the cystic duct down to the union with the major
bile ducts ought to be discouraged as a routine method of duc-
tal identification. The author favors identification of biliary
anatomy by the “critical view of safety” technique since this
method is good at identifying the cystic duct even when aber-
rant ducts are present. Studies attest to the effectiveness of this
method and it has been adopted in the guidelines for perfor-
mance of cholecystectomy in Holland (34,35) If this method is
not used then routine use cholangiography is recommended.
technical problems
Injury to a Bile Duct in the Course of Dissection
Avoidance depends on the principles of careful dissection and
experience, as well as recognition of circumstances in which
the potential hazard in continued dissection may outweigh the
benefit of completing a cholecystectomy. Also the author rec-
ommends not using the “top-down” technique in the face of
severe inflammation either in open or laparoscopic surgery.
Failure to Obtain Secure Closure of the Cystic Duct
Tips of clips should be noted to project beyond the cystic duct.
Pre-formed ligature loops should be used for closure of the
cystic duct if the cystic duct is thick, rigid or wide. Two loops
should be applied on the side of the cystic duct to be retained.
Thermal Injuries
Cautery should be used with great care in the porta hepatis.
Low cautery settings are essential, characteristically 30 W or
less. Attempts to stop hemorrhage by blind application of cau-
tery clamps, or clips are very unwise. Brisk bleeding requires
conversion. Adhesions should be divided sharply or with min-
imum application of power.
Tenting Injuries
The injury is avoided by not lifting the gallbladder forcefully
when applying clips to the cystic duct. It is recommended that
the surgeon sees that a length of cystic duct will remain below
the clip closest to the common bile duct end of the cystic duct
before applying that clip.
presentation and investigation
About 1/3 of the more serious injuries are diagnosed during
surgery. Most of the rest are identified in the first 30 days after
surgery. Postoperative presentations are influenced by the type
of injury and whether a drain has been left. The commonest
presentations are pain and sepsis with or without jaundice,
jaundice without other symptoms, and biliary fistula. Some
patients present only with distension and malaise. The latter is
usually due to bile ascites. It is a particularly insidious presen-
tation that may lead to delay in diagnosis.
Pain/Sepsis
CT scan is performed first to identify fluid collections, which
may then be aspirated to determine if they are bilious. Usually
a drain is placed in the biloma and an ERCP follows. MRI with
MRC has the potential to replace CT scan plus ERCP with a
single study.
Jaundice
Jaundice is usually indicative of the more severe Type E inju-
ries. If jaundice is the only symptom, duct occlusion alone,
e.g., by clips, is most likely. Conversely, transections are often
accompanied by pain and sepsis due to accumulation of bile in
the peritoneal cavity and this is especially true if the injury is
several days old. In either case ERCP is the first-line investiga-
tion. Next a CT scan is performed. In patients with complete
occlusion of the bile duct(s) the bile ducts will be dilated and no
biloma will be seen. Percutaneous transhepatic cholangiogra-
phy (PTC) is performed next to delineate the proximal ducts
and to provide external drainage of bile. In patients with tran-
section of bile duct without occlusion the ducts will be decom-
pressed and a biloma or bile ascites is usually present. Our
approach for such patients is to drain the biloma and wait for
several weeks to perform the PTC.
Bile Fistula
The first-line investigation is a fistulogram. Subsequent man-
agement depends upon anatomical findings.
Other Symptoms
Occasionally patients with bile ascites may complain only of
vague symptoms such as malaise, constipation, or distension.
This is because hepatic bile is relatively nonirritating. Hemato-
bilia due to an arterial pseudoaneurysm is a rare but very dan-
gerous presentation.
The MRI or CT should be evaluated in all cases for the pres-
ence of vascular injury Some have advocated MRI as the best
first investigation of a biliary injury since it can show bile
ducts, blood vessels, and fluid collections in a single investiga-
tion. There is theoretical merit in this argument, but in our
experience MRI often lacks the detail required to make detailed
plans regarding reconstruction.
management of biliary injuries
Management of Injuries Recognized at the Initial Operation
Intraoperative recognition of biliary injury is usually an indi-
cation for conversion. When appropriate expertise for repair
of injury is not available, closed suction drains should be
367
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
placed in the right upper quadrant laparoscopically and the
patient referred.
Type A injuries, recognized at the time of surgery, are
repaired by suture of the cystic duct and drainage. If the anat-
omy has been clearly demonstrated through dissection or
cholangiography, laparoscopic repair by ligature loop or suture
is sometimes possible. Type D injuries are repaired by closure
of the defect using fine absorbable sutures over a T-tube and
placement of a closed suction drain, in the vicinity of the
repair. This usually requires conversion to an open procedure.
When the Type D injury is thermal in origin, or when the
injury involves more than 50% of the circumference of the
duct the preferred treatment is Roux-en-Y hepaticojejunos-
tomy, applying the principles of anastomosis given below.
Type E injuries recognized intraoperatively should be repaired
by hepaticojejunostomy. Choledocho-choledochotomy should
be avoided because of considerations of blood supply and ten-
sion. Choledocho-duodenostomy has the theoretical disad-
vantage of tension on the anastomosis as does a loop
hepaticojejunostomy.
Management of Biliary Injuries Diagnosed Postoperatively
The approach depends on type of injury, on type of initial
management and its result, and on time elapsed since the ini-
tial operation or repair.
Type A injuries: The treatment is endoscopic sphincterotomy
with placement of a stent or a nasobiliary catheter.
Type B and C Injuries: Symptomatic patients with B injuries
require hepatico-jejunostomy or hepatic resection if biliary-
enteric anastomosis is not possible. In asymptomatic patients,
treatment is not recommended when the volume of liver
affected is small or if the injury was remote and the isolated
portion has atrophied. Type C injuries require drainage of the
bile collections and biliary-enteric anastomosis, hepatic resec-
tion or ligation of the duct.
Type D Injuries: Treatment by endoscopic sphincterotomy
and stent is the treatment of choice in the postoperative period.
Type E injuries: The best chance for lasting repair is the ini-
tial repair. Strictures and sometimes clip occlusions may be
treated by dilatation and stents placed either by ERCP. In our
experience non-surgical therapy is most likely to be successful
when the strictures are mild, appear months to years after sur-
gery, or are of short length. Lillimoe reported 64% success rate
with interventional techniques (36). Failures tended to occur
when E3 or E4 lesions were treated, when a fistula was present
or when a stricture occurred shortly after a hepaticojejunos-
tomy had been done. Non-surgical therapy is most likely to be
successful in cases in which operative repair is rather easy and
non-surgical treatment often requires multiple endoscopic
procedures. The age and health of the patient as well as the
likelihood of good long-term outcome should be considered
when choosing therapy for a stricture.
Timing of Surgery
Factors favoring immediate repair are early referral, stable
patient, lack of right upper quadrant bile collections, and sim-
pler injuries, which can be rapidly diagnosed and are unlikely
to involve vascular injury. Many patients are referred between
368
1 and 6 weeks after the primary operation when local inflam-
mation may be expected to be great. In these patients percuta-
neous tubes are inserted to relieve obstruction from affected
segments, to drain subhepatic collections and control sepsis.
Repair is performed when inflammation has settled, usually
about 3 months after the last operation. This delayed approach
is sometimes used even when the patient is referred within the
first week, especially in complex injuries and those in which
either a thermal etiology or a concomitant ischemic injury is
suspected (14,16). Immediate repair may also be undertaken
when the injury is diagnosed months after surgery, for instance,
after failure of stenting of a stenosis or late failure of a biliary-
enteric anastomosis.
Preoperative Preparation
The complete extent of the injury must be diagnosed preopera-
tively. Failure to do so may result in exclusion of bile ducts from
the repair. The percutaneous transhepatic tubes placed to
assure biliary drainage from all liver segments also serve as
guides to the position of the injured ducts at surgery (Fig. 40.10).
Our policy is to perform conciliation between CT and PTC
studies to be sure that all ducts in the liver are accounted for.
Operative Technique
Success depends upon fulfilling six principles of repair, i.e., to
construct anastomoses, which are well vascularized, tension
free, mucosa-to-mucosa, widely patent, precisely constructed,
and that drain all parts of the liver. Most experts in this field
recommend hepatico-jejunostomy in preference to either
choledocho-choledochotomy or choledocho-duodenostomy,
since a tension free anastomosis is always possible with hepati-
cojejunostomy. Whenever possible, we prefer to construct
side-to-side anastomoses to avoid dissection behind bile ducts,
which may affect their blood supply (37). Often the anastomosis
Figure 40.10 An E4 injury in which the confluence of the right and left hepatic
ducts has been resected. Note the wide separation of the ducts indication a
very high injury. Also note multiple clips. Preoperative placement of percuta-
neous transhepatic tubes facilitated identification of anatomy at surgery.
 BILE DUCT INJURIES AND BENIGN BILIARY STRICTURES
is done to the extrahepatic portion of the left hepatic duct after
it is lowered by dividing the hilar plate (Hepp-Couinaud
approach) (38). This approach is particularly suitable for inju-
ries at or just below the bifurcation (Types E2, E3). Right ducts
do not lend themselves to this approach as well, since they have
a short extrahepatic length. Sometimes the end of the right
duct is used. We have described an approach to isolated right
hepatic duct injuries (Fig. 40.11) (39). Dissection of the left
duct provides a guide to the coronal plane in which the intra-
hepatic right hepatic ducts will be found and these may be
exposed by removing liver tissue. Exposure is also facilitated
by dividing the bridge of tissue between segments 3 and 4, by
fully opening the gallbladder fossa which often collapses with
adherence of it walls. If these maneuvers are not sufficient
resecting part of segment 4b and/or 5 will open the upper
porta hepatis as described by Mercado (40).
When ductal reconstruction to a part of the liver is impos-
sible then resection should be performed (41). Occasionally
prior failure of reconstruction leads to secondary biliary cir-
rhosis and end-stage liver failure. Then liver transplantation is
required (17,41). In almost all examples of this outcome, high
reconstructions have been attempted by surgeons lacking
experience in these difficult procedures or there has been
a combined biliary/vascular injury. Treatment of failed
repairs with metallic stents gives very poor results in the long
term with 50% of treated patient suffering from repeated
cholangitis.
Outcome of Treatment
Most surgical series of biliary reconstruction cite very good
short-term results. However, it is well established from older
literature describing ductal injury during open cholecystec-
tomy that there is a progressive re-stenosis rate. Two-thirds of
recurrences are diagnosed in the first two years after repair but
re-stenosis has been described after 10 years. In reports of
more than 50 repairs, the re-stenosis rate varies from 4% to
21% and the need for operative re-repair from 1% to
9.5% (13,16,40,42–51). Postoperative complications are com-
mon. The experience from our center in 113 repairs followed
Step 1
A. Identify left
duct by Hepp-
Couinaud
Gallbladder
technique
plate
B. Find right portal pedicle and divide gallbladder plate
(A)
Figure 40.11 (A) Technique for identifying isolated right ducts. Step 1: Finding and dividing cystic plate to expose right pedicle. (B) Technique for identifying
isolated right ducts. Step 2: Elevating right portal pedicle, identifying and incising right duct.
for a median of 4.9 years is a 4.5% rate of poor outcomes requir-
ing interventional treatment but no requirement for operative
re-repair (37).
Comparison among surgical series is difficult because of
lack of standard reporting variables and effect of differences in
the severity of injuries treated in different series. Injuries above
the confluence involving several bile ducts have a worse prog-
nosis than injuries of the common hepatic duct and the pro-
portion of severe injuries in a series will affect outcome.
Reporting of treatment failure is not uniform. Length of fol-
low-up is another obvious variable affecting outcome and is
not uniform among series. Several authors have reported that
quality of life (52–54) and lifespan (8) are adversely affected by
a biliary injury.
post-transplantation biliary strictures
The incidence of biliary strictures is 5% to 15% after whole
liver transplantation and higher after right-lobe live donor
surgery. Technical problems that lead to anastomotic stricture,
ischemia and rejection are the etiologic factors (55). Today
management is by endoscopic means, which is usually success-
ful in the anastomotic type of stricture (56) and less so in the
other types. Avoidance strategies focus mainly on prevention
of ischemia at the lower end of duct to duct anastomoses and
at the hilum in live donor transplantation.
noniatrogenic bile duct strictures
Biliary Strictures Secondary to Pancreatitis
Severe acute pancreatitis and chronic pancreatitis may pro-
duce benign biliary strictures in the intrapancreatic segment
of the common bile duct. That associated with acute pancre-
atitis usually resolves with the attack. The pancreatitis may be
diffuse or focal in the head of the pancreas. Alcoholic chronic
pancreatitis that produces a dense scarring of the gland is a
common type of this stricture however other types of chronic
pancreatitis including what appears to be an autoimmune
variant have been increasingly recognized as being etiologic.
Sometimes the bile duct narrowing is due to compression
by a pseudocyst rather than fibrosis. In these cases relief of
Step 2
C. Core or lift
liver off right
Portal pedicle
D. Open bile
duct on
anterior surface
(B)
369
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
compression by treatment or more rarely by spontaneous
resolution of the pseudocyst may be relieve the stenosis.
Presenting symptoms are jaundice with or without pain.
Diagnosis has classically been made by CAT scan combined
with ERCP, but more recently MRI and MRCP has been
increasingly used, as it is less invasive. ERCP permits brushings
and these may diagnose malignancy. Characteristically, the
stricture is of the long smooth “rat-tail” type. One of the con-
tinuing conundrums in pancreatic surgery is the differentia-
tion between benign and malignant causes of intrapancreatic
bile duct stricture. Focal pancreatitis can produce a mass in the
head of the pancreas, cause jaundice and thereby mimic can-
cer. Cancer is more likely arising in the chronically inflamed
gland. The cancers are often scirrhous making diagnosis by
needle biopsy more difficult especially in an already chroni-
cally inflamed gland. EUS-guided FNA and core biopsies are
very helpful in making the diagnosis and the CA19-9 level is
also helpful. Occasionally laparoscopic US-guided biopsy may
be useful.
Treatment depends upon whether biliary stricture is an iso-
lated problem or whether it is part of a more general problem
such as unremitting pancreatic pain, whether a pseudocyst is
present, or whether cancer is a serious consideration. For iso-
lated strictures biliary enteric anastomosis was the standard
treatment; however, dilatation with multiple endoscopically
placed stents can be successful (57) and may be used first, sur-
gery being reserved for patients who fail this treatment (58).
When caused by pseudocyst compression treatment may sim-
ply require drainage of the cyst, which now can often be
accomplished endoscopically. Treatment may be part of a pro-
cedure to treat chronic pancreatitis such as the Frey or Beger
procedures. These relieve the obstruction by removal of the
surrounding compressive scar or by adding biliary enteric
anastomosis. Pylorus-preserving or standard Whipple proce-
dures, which relieve the biliary obstruction by resection are
sometimes used when cancer is suspected. Metallic stents
should never be used in this or other benign strictures as they
eventually clog and result in the need for a Whipple procedure.
Stricture due to Noniatrogenic Bile Duct Injuries
Noniatrogenic bile duct injuries are usually caused by non-
penetrating trauma and are often a part of wider injuries (59).
Isolated bile duct injury due to penetrating trauma may occur
but more often it is not isolated and is usually fatal as the
hepatic artery and portal vein are also injured. The injury is
often missed and diagnosis is delayed. The principles of com-
plete diagnosis and repair enunciated above apply to these inju-
ries as well. Combined biliary and arterial injuries may occur
and the surgeon must be aware that the bile duct may be devas-
cularized to a higher level than the laceration or transection
Strictures due to Calculous Disease
Oriental cholangiohepatitis is a disease associated with biliary
parasite infestation leading to the development of intrahepatic
and extrahepatic bile duct stones, usually of the brown pig-
ment type. Recurrent pyogenic infections are common and
these lead to strictures. Treatment is by a combination of ther-
apies, including eradication of the parasites, removal of the
370
stones, dilatation of the strictures, and occasionally local liver
resection. Sometimes much of the therapy can be accom-
plished percutaneously. At other times operative removal of
stones and hepaticojejunostomy is required; the Roux loop
may be place in proximity to the skin to permit later percuta-
neous access.
Choledocholithiasis occurring in western countries may
lead to biliary strictures through repeated bouts of cholangitis
or local stone ulceration and resultant stricture formation
often near the lower end of the bile duct, although today this is
very rare. Endoscopic sphincterotomy (ES) is the treatment for
low strictures and biliary enteric anastomoses are used when is
unsuccessful or not applicable. Large stones within the gall-
bladder may cause biliary obstruction by external compres-
sion (Mirizzi’s syndrome).
Sclerosing Cholangitis
Sclerosing cholangitis is an idiopathic disease, probably auto-
immune in type, frequently associated with ulcerative colitis,
that causes biliary strictures, which are usually both intrahe-
patic and extrahepatic and multiple. Stones are not usually
present. Degeneration to cancer may occur and these cancers
are difficult to diagnose early. Treatment of symptomatic
localized strictures in the larger bile ducts is usually endo-
scopic (60). Resection of the confluence has been advocated
when the major area of stricturing is localized to that area
(61). Many of these patients require orthotopic liver trans-
plantation as the definitive procedure surgical procedure and
this is done when end-stage liver disease appears or when can-
cer is suspected. Prior surgery on the bile ducts may make
OLT more difficult.
Benign Inflammatory Pseudotumors
This inflammatory process of unknown etiology was first
described by Stamatakis et al. (62) and has several synonyms.
The masses consist of chronic inflammatory cells and fibrosis.
Benign inflammatory tumors appear to occur most frequently
in extrahepatic upper ducts, but also occur intrahepatically (63),
and less commonly in lower ducts.
Benign inflammatory tumors mimic malignant biliary
obstructions at the hilum, causing jaundice. Patients tend to be
younger with a median age of 50 but the tumors cannot be
differentiated from cancer on the basis of presentation or liver
function tests. CA19-9 serum levels are normal or slightly ele-
vated (64) unless cholangitis is present. A mass at the hilum is
commonly present on axial imaging but vascular invasion/
encasement has not been described with this process. Currently
they are treated as cholangiocarcinomas and resected.
references
1. Keus F dJJ, Gooszen HG, van Laarhoven CJHM. Laparoscopic versus open
cholecystectomy for patients with symptomatic cholecystolithiasis. The
Cochrane Library 2008, Issue 2 2008: 1–133.
2. Adamsen S, Hansen OH, Funch-Jensen P, Schulze S, Stage JG, Wara P. Bile
duct injury during laparoscopic cholecystectomy: a prospective nation-
wide series. J Am Coll Surg 1997; 184: 571–8.
3. Russell JC, Walsh SJ, Mattie AS, Lynch JT. Bile duct injuries, 1989–1993. A
statewide experience. Connecticut Laparoscopic Cholecystectomy Registry.
Arch Surg 1996; 131: 382–8.
 BILE DUCT INJURIES AND BENIGN BILIARY STRICTURES
4. Merrie AE, Booth MW, Shah A, Pettigrew RA, McCall JL. Bile duct imag-
ing and injury: a regional audit of laparoscopic cholecystectomy. Austr
NZ J Surg 1997; 67: 706–11.
5. Solheim K, Buanes T. Bile duct injury in laparoscopic cholecystectomy. Int
Surg 1995; 80: 361–4.
6. Richardson MC, Bell G, Fullarton GM. Incidence and nature of bile duct
injuries following laparoscopic cholecystectomy: an audit of 5913 cases.
West of Scotland Laparoscopic Cholecystectomy Audit Group [see com-
ments]. BrJ Surg 1996; 83: 1356–60.
7. Wherry DC, Rob CG, Marohn MR, Rich NM. An external audit of laparo-
scopic cholecystectomy performed in medical treatment facilities of the
department of Defense. Ann Surg 1994; 220: 626–34.
8. Flum DR, Cheadle A, Prela C, et al. Bile duct injury during cholecystec-
tomy and survival in medicare beneficiaries. JAMA 2003; 290: 2168–73.
9. Waage A, Nilsson M, Waage A, Nilsson M. Iatrogenic bile duct injury: a
population-based study of 152 776 cholecystectomies in the Swedish
Inpatient Registry. Arch Surg 2006; 141: 1207–13.
10. Bismuth H. Postoperative strictures of the bile duct. In: Blumgart LH, ed.
The Biliary Tract. Edinburgh: Churchill Livingston; 1982: 209–18.
11. Bismuth H, Majno P. Biliary strictures: classification based on the princi-
ples of surgical treatment. World J Surg 2001; 25: 1241–4.
12. Boerma D, Rauws EA, Keulemans YC, et al. Impaired quality of life 5 years
after bile duct injury during laparoscopic cholecystectomy: a prospective
analysis.[see comment]. Ann Surg 2001; 234: 750–7.
13. Stewart L, Way LW. Bile duct injuries during laparoscopic cholecystec-
tomy: Factors that influence the results of treatment. Arch Surg 1995;
1995: 1123–9.
14. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary
injury during laparoscopic cholecystectomy [see comments]. [Review]
[111 refs]. J Am Coll Surg 1995; 180: 101–25.
15. Koffron A, Ferrario M, Parsons W, et al. Failed primary management of
iatrogenic biliary injury: incidence and significance of concomitant
hepatic arterial disruption. Surgery 2001; 130: 722–8; discussion 8–31.
16. Alves A, Farges O, Nicolet J, et al. Incidence and consequence of an hepatic
artery injury in patients with postcholecystectomy bile duct strictures.
Ann Surg 2003; 238: 93–6.
17. Thomson BN, Parks RW, Madhavan KK, Garden OJ, Thomson BNJ. Liver
resection and transplantation in the management of iatrogenic biliary
injury. World J Surg 2007; 31: 2363–9.
18. Gurusamy KS, Samraj K. Early versus delayed laparoscopic cholecystec-
tomy for acute cholecystitis. Cochrane Database Syst Rev 2006: CD005440.
19. Strasberg SM, Eagon CJ, Drebin JA. The “hidden cystic duct” syndrome
and the infundibular technique of laparoscopic cholecystectomy—the
danger of the false infundibulum. J Am Coll Surg 2000; 191: 661–7.
20. Brodsky A, Matter I, Sabo E, et al. Laparoscopic cholecystectomy for acute
cholecystitis: can the need for conversion and the probability of complica-
tions be predicted? A prospective study. Surg Endosc 2000; 14: 755–60.
21. Hadad SM, Vaidya JS, Baker L, et al. Delay from symptom onset increases
the conversion rate in laparoscopic cholecystectomy for acute cholecysti-
tis. World J Surg 2007; 31: 1298–01; discussion 302–3.
22. Halachmi S, DiCastro N, Matter I, et al. Laparoscopic cholecystectomy for
acute cholecystitis: how do fever and leucocytosis relate to conversion and
complications? Euro J Surg 2000; 166: 136–40.
23. Lim KR, Ibrahim S, Tan NC, et al. Risk factors for conversion to open
surgery in patients with acute cholecystitis undergoing interval laparo-
scopic cholecystectomy. Ann Acad Med, Singapore 2007; 36: 631–5.
24. Lo CM, Fan ST, Liu CL, Lai EC, Wong J. Early decision for conversion of
laparoscopic to open cholecystectomy for treatment of acute cholecystitis.
Am J Surg 1997; 173: 513–7.
25. Yamashita Y, Takada T, Kawarada Y, et al. Surgical treatment of patients
with acute cholecystitis: Tokyo Guidelines. J Hepato-Biliary-Pancreatic
Surg 2007; 14: 91–7.
26. Strasberg SM, Strasberg SM. Clinical practice. Acute calculous cholecysti-
tis. New Engl J Med 2008; 358: 2804–11.
27. Meyers WC, Peterseim DS, Pappas TN, et al. Low insertion of hepatic seg-
mental duct VII-VIII is an important cause of major biliary injury or mis-
diagnosis [see comment]. Am J Surg 1996; 171: 187–91.
28. Kune G, Sali A. The Practice of Biliary Surgery. 2nd edn. Oxford: Black-
well Scientific Publications; 1980.
29. Davidoff AM, Pappas TN, Murray EA, et al. Mechanisms of major biliary
injury during laparoscopic cholecystectomy . Ann Surg 1992; 215: 196–202.
30. Fletcher DR, Hobbs MS, Tan P, et al. Complications of cholecystectomy:
risks of the laparoscopic approach and protective effects of operative
cholangiography: a population-based study. Ann Surg 1999; 229: 449–57.
31. Flum DR, Dellinger EP, Cheadle A, et al. Intraoperative cholangiography
and risk of common bile duct injury during cholecystectomy. JAMA 2003;
289: 1639–44.
32. Hugh TB, Hugh TB. New strategies to prevent laparoscopic bile duct
injury--surgeons can learn from pilots. Surgery 2002; 132: 826–35.
33. Way LW, Stewart L, Gantert W, et al. Causes and prevention of laparo-
scopic bile duct injuries: analysis of 252 cases from a human factors and
cognitive psychology perspective [see comment]. Ann Surg 2003; 237:
460–9.
34. Heistermann HP, Tobusch A, Palmes D. [Prevention of bile duct injuries
after laparoscopic cholecystectomy. “The critical view of safety”]. Zentral-
blatt fur Chirurgie 2006; 131: 460–5.
35. Yegiyants S, Collins JC, Yegiyants S, Collins JC. Operative strategy can
reduce the incidence of major bile duct injury in laparoscopic cholecys-
tectomy. Am Surg 2008; 74: 985–7.
36. Lillemoe KD, Martin SA, Cameron JL, et al. Major bile duct injuries dur-
ing laparoscopic cholecystectomy. Follow-up after combined surgical and
radiologic management. Ann Surg 1997; 225: 459–68; discussion 68–71.
37. Winslow ER, Fialkowski EA, Linehan DC, et al. “Sideways”: results of repair of
biliary injuries using a policy of side-to-side hepatico-jejunostomy. Ann Surg
249: 426–34, 2009
38. Hepp J. Hepaticojejunostomy using the left biliary trunk for iatrogenic
biliary lesions: the French connection. World J Surg 1985; 9: 507–11.
39. Strasberg SM, Picus DD, Drebin JA. Results of a new strategy for recon-
struction of biliary injuries having an isolated right-sided component. J
Gastrointest Surg 2001; 5: 266–74.
40. Mercado MA, Chan C, Orozco H, et al. Long-term evaluation of biliary
reconstruction after partial resection of segments IV and V in iatrogenic
injuries. J Gastrointest Surg 2006; 10: 77–82.
41. Laurent A, Sauvanet A, Farges O, et al. Major hepatectomy for the treat-
ment of complex bile duct injury. Ann Surg 2008; 248: 77–83.
42. Kaman L, Sanyal S, Behera A, et al. Comparison of major bile duct injuries
following laparoscopic cholecystectomy and open cholecystectomy. ANZ
J Surg 2006; 76: 788–91.
43. Murr MM, Gigot JF, Nagorney DM, et al. Long-term results of biliary
reconstruction after laparoscopic bile duct injuries. Arch Surg 1999; 134:
604–9; discussion 9–10.
44. Mercado MA, Chan C, Orozco H, et al. To stent or not to stent bilioenteric
anastomosis after iatrogenic injury: a dilemma not answered? Arch Surg
2002; 137: 60–3.
45. Wudel LJ, Jr., Wright JK, Pinson CW, et al. Bile duct injury following lapa-
roscopic cholecystectomy: a cause for continued concern. Am Surg 2001;
67: 557–63; discussion 63–4.
46. Tocchi A, Costa G, Lepre L, Liotta G, Mazzoni G, Sita A. The long-term
outcome of hepaticojejunostomy in the treatment of benign bile duct
strictures. Ann Surg 1996; 224: 162–7.
47. Walsh RM, Henderson JM, Vogt DP, et al. Long-term outcome of biliary
reconstruction for bile duct injuries from laparoscopic cholecystectomies.
Surgery 2007; 142: 450–6; discussion 6–7.
48. Chapman WC, Halevy A, Blumgart LH, Benjamin IS. Postcholecystec-
tomy bile duct strictures. Management and outcome in 130 patients. Arch
Surg 1995; 130: 597–602; discussion 4.
49. de Reuver PR, Grossmann I, Busch OR, et al. Referral pattern and timing
of repair are risk factors for complications after reconstructive surgery for
bile duct injury. Ann Surg 2007; 245: 763–70.
50. Lillemoe KD, Melton GB, Cameron JL, et al. Postoperative bile duct
strictures: management and outcome in the 1990s. Ann Surg 2000; 232:
430–41.
51. Pottakkat B, Sikora SS, Kumar A, et al. Recurrent bile duct stricture: causes
and long-term results of surgical management. J Hepato-Biliary-Pancre-
atic Surg 2007; 14: 171–6.
52. de Reuver PR, Sprangers MA, Rauws EA, et al. Impact of bile duct injury
after laparoscopic cholecystectomy on quality of life: a longitudinal study
after multidisciplinary treatment. Endoscopy 2008; 40: 637–43.
371
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
53. Moore DE, Feurer ID, Holzman MD, et al. Long-term detrimental effect
of bile duct injury on health-related quality of life. Arch Surg 2004; 139:
476–81; discussion 81–2.
54. Melton GB, Lillemoe KD, Cameron JL, et al. Major bile duct injuries asso-
ciated with laparoscopic cholecystectomy: effect of surgical repair on
quality of life. Ann Surg 2002; 235: 888–95.
55. Sharma S, Gurakar A, Jabbour N, et al. Biliary strictures following liver
transplantation: past, present and preventive strategies. Liver Transplan-
tation 2008; 14: 759–69.
56. Barriga J, Thompson R, Shokouh-Amiri H, et al. Biliary strictures after
liver transplantation. Predictive factors for response to endoscopic man-
agement and long-term outcome. Am J Med Sci 2008; 335: 439–43.
57. Pozsar J, Sahin P, Laszlo F, et al. Medium-term results of endoscopic treatment
of common bile duct strictures in chronic calcifying pancreatitis with increas-
ing numbers of stents.[see comment]. J Clin Gastroenterol 2004; 38: 118–23.
58. Judah JR, Draganov PV, Judah JR, Draganov PV. Endoscopic therapy of
benign biliary strictures. World J Gastroenterol 2007; 13: 3531–9.
372
59. Sawaya DE Jr., Johnson LW, Sittig K, McDonald JC, Zibari GB. Iatrogenic
and noniatrogenic extrahepatic biliary tract injuries: a multi-institutional
review. Am Surg 2001; 67: 473–7.
60. Johnson GK, Saeian K, Geenen JE, et al. Primary sclerosing cholangitis
treated by endoscopic biliary dilation: review and long-term follow-up
evaluation. Curr Gastroenterol Rep 2006; 8: 147–55.
61. Pawlik TM, Olbrecht VA, Pitt HA, et al. Primary sclerosing cholangitis:
role of extrahepatic biliary resection. J Am Coll Surg 2008; 206: 822–30;
discussion 30–2.
62. Stamatakis JD, Howard ER, Williams R. Benign inflammatory tumour of
the common bile duct. Br J Surg 1979; 66: 257–8.
63. Schmid A, Janig D, Bohuszlavizki A, Henne-Bruns D. Inflammatory
pseudotumor of the liver presenting as incidentaloma: report of a
case and review of the literature. Hepatogastroenterol 1996; 43:
1009–14.
64. Koea J, Holden A, Chau K, et al. Differential diagnosis of stenosing lesions
at the hepatic hilus. World J Surg 2004; 28: 466–70.
41 Gallstones and common bile duct stones—surgical
and non-surgical approaches
Matthew P. Dearing and Michael Rhodes
introduction
About 10% to 15% of the adult Western population has
gallstones (1,2). This equates to 7.5 million Britons and
20 million Americans with gallstones, with between 1% and
4% a year developing symptoms (2,3). Cholecystectomy is not
recommended in asymptomatic patients (4). However, symp-
tomatic gallstone disease is one of the most common condi-
tions in the United Kingdom requiring surgery (5,6). Up to
35% of patients with gallstones will ultimately become symp-
tomatic, requiring cholecystectomy (7). In England, 49,077
cholecystectomies were performed between April 2005 and
March 2006 (3). It is estimated that over half a million chole-
cystectomies are performed each year in the United States (5).
Gallstones are seen in all age groups but incidence increases
with age, with over one-third of the population over the age of
70 years affected (3,5). The development of gallstones is a multi-
factorial process, but has been shown to be associated with family
history, pregnancy, obesity, rapid weight loss (such as after bar-
iatric surgery), hemolytic anemias, parenteral nutrition, loss of
bile salts (as seen in terminal ileitis and after terminal ileal resec-
tion), and diabetes mellitus (via the metabolic syndrome) (8).
classification of gallstones
There are three common types of gallstone.
1. Cholesterol (20%)
2. Bile Pigment (5%)
3. Mixed (75%)
In western populations the consumption of a diet which is
high in cholesterol and fat leads to the supersaturation of bile,
with resultant precipitation and crystal growth (Fig. 41.1).
Pure cholesterol stones are often solitary or exist as clusters of
“mulberries” (9). Bile pigment stone are multiple, irregular,
small, black, and fragile. They are seen in patients with chronic
hemolysis (hereditary spherocytosis and sickle cell disease)
and cirrhosis, where there is an increase in bilirubin (10).
Mixed stones, composed of varying proportions of the above
ingredients, are usually multiple.
presentations of gallstone disease
Gallstones are responsible for a wide range of clinical prob-
lems. The most common of these are biliary colic (56%) and
acute cholecystitis (36%) (11).
Biliary Colic
This arises when a gallstone impacts in the neck of the gall-
bladder leading to obstruction of the cystic duct. Sustained
gallbladder contraction, produces a rise in pressure within the
gallbladder, leading to the pain perceived as biliary colic (6).
This is typically centered in the right upper quadrant, or epigastrium,
with radiation to the right lower chest or the lower pole of the scap-
ula. This can be explained by the origin of the gallbladder from
the lower thoracic segments, and transmission of visceral sensa-
tion through splanchnic nerves to the lower thoracic spinal cord.
Some pain afferents may travel within the right phrenic nerve
and peritoneum below the right diaphragm, accounting for the
radiation of pain to the right shoulder tip. The pain of biliary
colic often has a slower periodicity than ureteric colic, lasting
between 30 minutes and 2 hours, but sometimes persisting for
up to 8 hours. Although it is a commonly held belief that the
consumption of fatty food is likely to provoke an attack, there is
little evidence to support this (6). The pain may resolve sponta-
neously but often requires parenteral analgesia and anti-emetics.
Acute Cholecystitis
This is characterized by the presence of right upper quadrant or
epigastric pain lasting for more than 8 hours, accompanied by
systemic signs of infection such as fever and leukocytosis. The
condition arises after impaction of a stone in the neck of the
gallbladder or cystic duct, leading to sustained high pressure in
the gallbladder. This leads to a reduction in the blood flow to
the mucosa with subsequent ischemic injury (6). As a result of
this, a chemical cholecystitis develops with inflammatory infil-
trate and edema of the gallbladder wall. In the first 48 hours it
is unusual for bacterial infection to occur but the incidence of
infection after 1 week is in the order of 70% (6). Traditionally
patients were admitted to hospital for a period of intense med-
ical therapy—analgesia, intra-venous fluid rehydration and
broad-spectrum antibiotics, with cholecystectomy deferred for
6 to 12 weeks (12). This used to be common practice across the
United Kingdom. In one survey, 88% of surgeons reported
routinely managing patients in this manner (13). However, it
has been shown that early surgery (laparoscopic or open) is
preferable to delayed surgery and is not associated with any
additional morbidity or mortality (12–14). Laparoscopic
cholecystectomy, widely accepted as the gold standard of
treatment, has been shown to be safe and effective in acute
cholecystitis, with shortened length of hospital stay (15).
empyema
The contents of the gallbladder become purulent, as a result of
bacterial proliferation and exudation of neutrophils. The
resultant collection of pus is termed an empyema. The adja-
cent omentum often becomes involved in the inflammatory
process encasing the gallbladder and leading to the develop-
ment of large tender mass in the right upper quadrant. The
patient will be systemically unwell with a high swinging tem-
perature and leukocytosis. Treatment involves controlling the
sepsis with broad-spectrum antibiotics and percutaneous
ultrasound-guided drainage, prior to definitive surgery. Most
373
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Decreased cholesterol 7
alpha-hydroxylase
Liver XXX
Increased cholesterol
secretion Decreased bile salt
Gall
Bile
bladder
supersaturated
with
cholesterol
Cholesterol
Nidus for gallstone
gallstone
formation
Figure 41.1 Pathogenesis of formation of cholesterol stones.
patients can be managed in this way, although in severe cases
the inflammatory process produces patchy necrosis of the gall-
bladder wall, which can result in perforation. Often the omen-
tum is adherent around the gallbladder and this contains the
perforation, leading to the formation of a peri-cholecystic
abscess. In a small proportion of patients, usually the elderly,
the perforation is not contained and generalized peritonitis
develops with associated high morbidity and mortality (16).
mucocele
In this situation the obstructed gallbladder remains free of
infection. Although the mucosa remains inflamed, it continues
to function, absorbing water from bile and secreting mucus. The
gallbladder fills with clear or bile-stained mucus. The patient
will often report an episode of severe pain, consistent with
cholecystitis. The symptoms may resolve partly, but there will be
some persisting right upper quadrant pain and tenderness.
cholecystenteric fistula and gallstone
ileus
A cholecystenteric fistula develops when a gallstones fistulates
directly into the stomach, duodenum, or colon following
adherence of the gallbladder to these structures. This occurs as
a result of pressure necrosis. Whilst this can be seen after an
episode of acute cholecystitis it often follows a period of silent
inflammation (3). If the stones are small, as is often the case,
they will not obstruct the bowel. However, larger stones can
cause obstruction at certain sites. First, at the ileo-caecal valve
causing small bowel obstruction, or within the duodenum
causing gastroduodenal obstruction (Bouveret’s syndrome).
The diagnosis can sometimes be made with plain radiographs.
374
These may demonstrate small bowel obstruction, a gallstone
in the bowel lumen and gas in the biliary tree. Often the
diagnosis is made at laparotomy. These conditions are rare but
important causes of bowel obstruction, particularly in the
elderly, where gallstones and cholecystenteric fistula are more
common. Gallstones are implicated in 20% of cases of small
bowel obstruction where there is no history of a hernia or
previous abdominal surgery (17).
obstructive jaundice
Gallstones can migrate through the cystic duct into the
common bile duct. Sometimes they will pass spontaneously
causing no symptoms. The likelihood of stones passing spon-
taneously is related to their size (18). Stones up to 8 mm in
diameter may pass without problems (19,20). When a stone
impacts at the lower end of the common bile duct this can lead
to obstructive jaundice. The impacted stone prevents the
normal flow of bile resulting in biliary colic as the gallbladder
contracts against the obstruction. The jaundice may be
transient, resolving in 24 to 48 hours, as the stone either
disimpacts and floats free in the bile duct or passes into the
duodenum (6). If the stone remains impacted then the jaun-
dice will persist and deepen. The diagnosis is based on analysis
of the liver function tests, showing a characteristic rise in
alkaline phosphatase and only minor derangement of trans-
aminases, together with finding dilated extra-hepatic bile
ducts on ultrasound. This can be confirmed with magnetic
resonance cholangiopancreatography, endoscopic ultrasound,
or ERCP (21). The prevalence of asymptomatic bile duct
stones has been estimated between 5.2% and 12% (22–24).
Common bile duct stones have been found in between 10%
and 18% of patients undergoing cholecystectomy (25).
acute cholangitis
Acute cholangitis results when bacterial infection develops
within a partially or completely obstructed biliary system.
Stasis leads to an increase in the resident bacterial flora, which
are often found when gallstones are present in the biliary tract.
Classically the condition presents with Charcot’s Triad of
symptoms—right upper quadrant pain, rigors, and jaundice.
Ascending infection of the biliary tree can lead to septicemia
and multiple hepatic abscesses. One-fifth of patients present-
ing with cholangitis have a bacteremia, with gram negative
organisms mainly responsible (26). Treatment is with broad
spectrum antibiotics, such as second generation cephalospo-
rins or ciprofloxacin. ERCP is performed at an early stage
allowing both confirmation of the diagnosis and decompres-
sion of the bile ducts. Biliary stents can be placed to encourage
further drainage prior to definitive treatment.
acute pancreatitis
Gallstones are responsible for up to 60% of all cases of pancre-
atitis. Between 4% and 8% of patients with gallstones will
develop acute pancreatitis due to migratory stones (27). Small
stones, with mean diameter of 4 mm, are more likely to cause
pancreatitis than larger stones (28).
The condition develops when a small gallstone, traveling from
gallbladder to the bowel, impacts in the biliopancreatic duct
 GALLSTONES AND COMMON BILE DUCT STONES
(the common channel) of the duodenal ampulla. Transitory
obstruction of the duct leads to reflux of duodenal and/or biliary
fluid into the pancreatic duct. This initiates premature activation
of enzymes in the pancreas, leading to pancreatitis (29,30).
Patients with pancreatitis present with central or epigastric
abdominal pain. Classically this is constant, radiating to the
back and relieved by leaning forwards. Profuse vomiting is
common. The diagnosis can be confirmed by significantly
elevated serum amylase or lipase.
There are several scoring systems used to predict the severity
of pancreatitis, including the Ranson system, the modified
Imrie system, Apache II score, and Balthazar grading system.
They are based on organ dysfunction and local complications
(31,32)). Most patients will have a self-limiting disease but in
severe cases the mortality can be high. Overall mortality
remains around 10% (33).
mirrizi's syndrome
This occurs when a gallstone, impacted in the neck of the gall-
bladder, causes inflammation to the surrounding tissue
thereby compressing the adjacent bile duct. The stone induces
fibrosis leading to obliteration of the cystic duct. Ongoing
inflammation results in adherence of the gallbladder to the
common hepatic duct, causing partial obstruction and jaun-
dice. Mirrizi’s syndrome has been classified into two types. In
type 1, there is no communication between the gallbladder
and the bile duct. In type 2, the gallstone has eroded into the
bile duct, resulting in a cholecyst–choledochal fistula.
biliary dyspepsia
This represents a set of vague abdominal symptoms which
have been attributed to gallstones. These include non-specific
upper abdominal pain, nausea, belching, and food intolerance.
These symptoms have been found to occur with equal
frequency in patients with or without gallstones (34). In fact,
symptoms other than typical biliary colic are rarely due to
gallstones (6). Cholecystectomy in these situations is often
ineffective with up to 30% of patients continuing to suffer
dyspeptic symptoms (35,36).
management of gallstone disease
Non-surgical Management of Gallstones
Analgesia for Biliary Colic/Cholecystitis
In the acute setting the initial management involves analgesia.
This is best achieved with diclofenac and opioids (morphine
and pethidine). Antiemetics are often required as nausea and
vomiting are prominent symptoms.
Drug Dissolution Therapy
This involves the use of medications, such as methyl tert butyl
ether (MTBE) and ursodeoxycholic acid (UCDA) to dissolve
cholesterol back into bile. They are of use in the treatment of
cholesterol gallstones but are not able to achieve dissolution in
calcified or pigment stones. This restricts their use to around
10% to 20% of patients. MTBE is directly instilled into the gall-
bladder via endoscopic transpapillary catheterization (37). The
early results suggested this to be an effective treatment, achiev-
ing complete dissolution of stones in 80% to 90% of patients
with cholesterol stones (38). However, stones were found to
recur in up to 70% of patients over 5-year follow-up (39).
UCDA has a role in the prevention of gallstones, although it
does not appear to be of use once stones have developed
(40,41)). Miller and colleagues looked at the formation of gall-
stones in patients following obesity surgery (an established
risk factor for developing stones). They found significantly
lower gallstone formation in patients treated with UCDA
compared to placebo (3% vs. 22% at 12 months and 8% vs.
30% at 24 months) (40). However, Venneman et al. found that
UCDA was not beneficial in patients with symptomatic
gallstones (41).
Ezetimibe, a potent cholesterol absorption inhibitor, has
recently been found to be effective in reducing biliary cholesterol
content. This offers the potential for promising new strategies in
the prevention and treatment of cholesterol gallstones (42).
Percutaneous Cholecystostomy
In critically ill or high-risk patients with biliary sepsis, percu-
taneous cholecystostomy allows decompression of the
inflamed gallbladder, with resolution of sepsis. Patients can
then undergo definitive surgery once their overall condition
has improved. A retrospective review of 55 patients treated by
percutaneous transhepatic cholecystostomy reported success-
ful biliary drainage in 98%, with 95% of patients recovering
well (43). Percutaneous cholecystostomy can be performed
under ultrasound or fluoroscopic guidance. The gallbladder
can be entered using the Seldinger technique with tract dilata-
tion and catheter placement via guide wire or by means of the
direct trocar technique (44). The choice of tract depends on
the anatomy and whether stone extraction is planned. The
transhepatic route is associated with less risk of bile leakage,
but the transperitoneal approach is preferable for stone
removal through a larger tract (43).
Surgical Management of Gallstones
Cholecystectomy
Cholecystectomy was first performed by Langenbuch in 1882.
It has been the accepted treatment for symptomatic gallstones
for over a century. Laparoscopic cholecystectomy has revolu-
tionized the surgical management of gallstones, replacing the
standard “open” cholecystectomy as the gold standard of
treatment (45).
Open Cholecystectomy
The main indication for open cholecystectomy is failure of the
laparoscopic approach. This is often due to inflammation
around the cystic duct or artery which makes dissection and
definition of Calot’s triangle difficult. In some cases dense
adhesions from previous abdominal surgery necessitate con-
version to open surgery. Open cholecystectomy is also per-
formed when there is a suspicion of gallbladder cancer as there
is well-documented evidence of laparoscopic port site recur-
rence (46–49).
Traditionally, open cholecystectomy was performed through
an oblique right subcostal incision. The incision should be
centered over the fundus of the gallbladder, allowing optimal
access. The gallbladder should be removed using a fundus-first
375
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 41.2 Laparoscopic cholecystectomy. The gallbladder fundus is grasped
and pushed cephalad.
Figure 41.3 Dissection of Calot’s triangle—identification of the cystic duct.
technique. During dissection, the gallbladder neck is retracted
to the patient’s right. This stretches the peritoneum overlying
the cystic duct and common duct, facilitating safe dissection.
The cystic duct, cleared of peritoneum, can be cannulated in
order to perform operative cholangiography. Following this
the duct can be clipped and ligated. The cystic artery should be
clipped and ligated similarly. The gallbladder can be removed
from the liver bed using diathermy. The rectus sheath should
be closed in 2 layers with continuous monofilament suture.
Laparoscopic Cholecystectomy
Laparoscopic cholecystectomy, which was first performed in
1985 (50), is well established as the preferred method of treat-
ment (45). These procedures are routinely performed as day
cases (51) and during the index admission for cholecystitis (12).
This has been shown to be both safe and efficacious. The stan-
dard procedure involves four ports and will be described below.
Operative Technique
The patient is positioned supine on the operating table. The
pneumoperitoneum is established via an open longitudinal
376
Figure 41.4 A window is created behind the cystic duct and artery.
incision below the umbilicus, followed by insertion of a blunt
10 mm trocar and insufflation of carbon dioxide. This tech-
nique is preferable to the use of the Veress needle which has a
higher incidence of bowel and vascular injuries (52). Further
ports can then be inserted under direct vision. Two 5 mm
ports are placed in the right flank (in the anterior axillary and
midclavicular lines) and a further 10 mm port is placed in the
midline about 5 cm below the xiphisternum.
The usual setup requires the surgeon to stand on the patient’s
left side with the monitor positioned on the right. The gall-
bladder fundus is grasped atraumatically and pushed cephalad
(Fig. 41.2). The assistant is required to hold the grasper with
the left hand, maintaining traction, and the camera with the
right hand. Adhesions can be taken down with either blunt or
sharp dissection. Another grasper, inserted via the medial
5 mm port, is used to apply lateral and caudal traction to
Hartmann’s pouch. This allows Calot’s triangle to be identi-
fied. The peritoneum overlying Calot’s triangle is opened with
diathermy. The cystic duct and artery are carefully dissected
and identified (Fig. 41.3). This can be done with either blunt
dissection or with cautious and sparing use of the diathermy
hook. By moving the gallbladder medially the surgeon can
continue the dissection, developing a window behind the
cystic artery (Fig. 41.4).
Having identified the cystic duct, cholangiography can be
performed. Although this is not routinely performed in all
cases it should be available, particularly if bile duct stones are
suspected or there is difficulty in defining the biliary anatomy.
Scissors are used to open the cystic duct and a 4 Fr catheter is
inserted and held in place with a clip. Contrast media is
injected via the catheter and real-time images are obtained
using the image intensifier. A normal cholangiogram must
demonstrate flow of contrast in the main bile duct and right
and left hepatic ducts. There must be flow distally into the
duodenum, and no stones present in the duct.
After obtaining a cholangiogram and removing the catheter,
the cystic duct and artery can be clipped and divided (Fig.
41.5). The gallbladder can then be removed with the diathermy
hook. The gallbladder fossa is inspected thoroughly at the end
 GALLSTONES AND COMMON BILE DUCT STONES
Figure 41.5 The cystic duct is clipped and divided.
of the procedure for bleeding and bile leaks, as are the cystic
duct and artery clips. The area can be gently irrigated with
saline and then suctioned. The camera is moved to the top port
and the gallbladder is grasped via the umbilical port and deliv-
ered. The linea alba can be closed with absorbable sutures and
the skin with steristrips or sutures.
Future Developments
Advances in surgical technology and innovation have made
possible the advent of 2 port (53) and single port laparoscopic
cholecystectomy (54) and the development of NOTES—natu-
ral orifice transluminal endoscopic surgery (55). This will allow
the surgeon to undertake major intraperitoneal surgery with-
out the need for skin incisions, with access to the peritoneal
cavity via the mouth (via the stomach), the rectum and the
vagina, using flexible endoscopes. There is, to date, no research
published on resections in humans but the first transvaginal
cholecystectomy in a porcine model was carried out in 2005
(55). Progress in this area is likely to be rapid since the set up of
working groups, dedicated to advancing the concept (56).
management of common bile duct stones
Non-surgical Management
Drug Dissolution Therapy
As previously discussed, ursodeoxycholic acid (UCDA) has
been used to dissolve cholesterol gallstones (28). However, at
present there are no large randomized controlled trials to
demonstrate that UCDA is of benefit in the treatment of bile
duct stones (28). Much of the work done to evaluate the use of
UCDA has involved patients with gallstones rather than bile
duct stones (57). UCDA has been used, in combination with
endoscopic retrograde cholangiography (ERC) and stent
insertion, in the management of difficult to extract bile duct
stones. In one study, Johnson and colleagues demonstrated
that 90% of patients treated with both UCDA and stent inser-
tion had ductal clearance at repeat ERC compared to none of
the patients in the stent alone group (58). However, further
work is needed to define the role of UCDA in the management
of bile duct stones.
Endoscopic Removal of Bile Duct Stones/Biliary Stenting
Endoscopic retrograde cholangiography (ERC) is highly sensi-
tive in the detection of common bile duct stones, with rates of
over 90% reported (28). It also permits therapeutic removal of
stones at the same time. After cannulation of the papilla,
spincterotomy can be performed with diathermy. This allows
small stones to be extracted using a Dormia basket or balloon
catheter. Endoscopic balloon dilatation of the sphincter can
also be performed. However, balloon dilation of the papilla
should be avoided in most patients because of the increased
risk of post procedure pancreatitis, compared to biliary
sphincterotomy (28). These techniques are effective in
removing 90% to 95% of bile duct stones (28).
Short-term biliary stenting can be used in the management
of retained common bile duct stones, permitting adequate
biliary drainage prior to further endoscopy or surgery. The use
of biliary stents as the sole treatment of common bile duct
stones is recommended only for high risk patients or those
with limited life expectancy (72).
Lithotripsy
Mechanical lithotripsy can be used to break up larger
stones. Several studies have reported on the efficacy of the
technique, with bile duct clearance rates of between 68%
and 98% (59,60). The wide variation in the success rates
can be attributed to the size of the stone. Over 90% of
stones with a diameter of 10 mm or less can be cleared,
whereas only 68% of stones with a diameter over 28 mm
can be removed (61). Laser lithotripsy can also be used in
the treatment of retained bile duct stones, with reported
success rates of between 64% and 97% (62–64). Extracor-
poreal shockwave lithotripsy and electrohydraulic litho-
tripsy have been used to treat large, retained bile duct stones
and bile clearance rates of 83% (65–67) and 74% (68) have
been reported.
Surgical Management
Open Choledocholithotomy
The common bile duct is accessed via a supraduodenal
approach. A cholangiogram can be performed via the cystic
duct to delineate the anatomy and determine the site and
number of stones. Following cholecystectomy and mobiliza-
tion of the duodenum (kocher’s maneuver), the lower com-
mon bile duct can be accessed and choledochotomy performed.
Gentle palpation of the duct permits stones to be milked into
the choledochotomy. Choledochoscopy can then be per-
formed, with removal of stones by Dormia basket or Fogarty
catheter. The bile duct can be closed primarily or over a T-tube.
T-tube drainage used to be standard practice after bile duct
exploration, but a large retrospective audit published recently
found that there was a lower biliary complication rate after
primary closure of the duct (69). A T-tube may be inserted if
there is evidence of cholangitis, multiple stones, or a large
duct. A further cholangiogram can be done at this stage to
check for retained stones and confirm that contrast can be
seen flowing into the duodenum. A drain should be placed
after choledochotomy for 24 to 48 hours. It can be removed if
there is no bile drainage.
377
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Laparoscopic Common Bile Duct Stone Removal
Between 70% and 95% of bile duct stones can be removed
using the laparoscopic approach (70,71)). Laparoscopic access
is achieved as described earlier. An operative cholangiogram
can be performed via the cystic duct and small stones can be
removed without the need to open the main bile duct. How-
ever, this approach will not be successful in all patients. The
cystic duct may have a very tortuous anatomical course with
prominent spiral valves or a small diameter which prevent
stone extraction. In cases of multiple or large stones or where
proximal duct stones have been identified on the cholangio-
gram, it may be necessary to perform a choledochotomy in the
distal bile duct. Choledochoscopy can then be performed
using a flexible choledochoscope. The stones can be extracted
using a Dormia basket or Fogarty catheter. The choledochot-
omy can be primarily closed or a T-tube inserted if conditions
are not favorable for primary closure.
key points
10% to 15% of the adult Western population have gall-
stones. Between 1% and 4% of patients a year develop
symptoms.
Cholecystectomy is not recommended for asymptomatic
gallstones (4)—Grade A.
Cholecystectomy is recommended for all patients with
symptomatic gallbladder stones and CBDS (except where
surgery is considered inappropriate). Grade A.
Laparoscopic cholecystectomy is the gold standard of
treatment for symptomatic gallstone disease (45)—Grade A.
Laparoscopic cholecystectomy is safe and effective in the
management of acute cholecystitis (12,14))—Grade A.
Cholecystectomy during the index admission for cholecysti-
tis is recommended (12) – Grade A.
Symptomatic patients with suspected ductal stones should
undergo stone extraction where possible—Grade B.
ERCP is not recommended solely as a diagnostic test, it
should only be done in patients for whom an intervention
is planned. Grade B
Biliary sphincterotomy and endoscopic stone extraction are
recommended for patients with bile duct stones post
cholecystectomy.
Biliary stenting should only be used as a sole treatment in
patients with limited life expectancy or very high-surgical
risk. Grade A.
Patients with ductal stones undergoing laparoscopic
cholecystectomy may be managed by laparoscopic com-
mon bile duct exploration at the time of surgery, or
undergo peri-operative ERCP. Transcystic and transductal
exploration of the common bile duct are both recom-
mended approaches for removal of stones. Grade A.
In patients with bile duct stones that have not been extracted,
short term use of a biliary stent is recommended, followed
by further endoscopy or surgery. Grade B.
If duct clearance is not achieved by minimally invasive
methods then open surgical exploration is recommended
as an important treatment option. Grade B.
378
references
1. NIH Consensus Statement on gallstones and laparoscopic cholecystec-
tomy. National Institute of Health Consensus Development Conference
Statement Sep 14–16, 1992.
2. Halldestam I, Enell EL, Kullman E, et al. Development of symptoms and
complications in individuals with asymptomatic gallstones. Br J Surg
2004; 91(6): 734–8.
3. Sanders G, Kingsnorth AN. Gallstones. BMJ 2007; 335: 295–9.
4. Gurusamy KS, Samraj K. Cholecystectomy versus no cholecystectomy in
patients with silent gallstones. Cochrane Database Syst Rev 2007. CD 006230.
5. Geibel J, Longo W. Cholelithiasis: evolving standards for diagnosis and
management. World J Gastroenterol 2006 May 28; 12(20): 3162–7.
6. Johnson CD. Gallstones. Surg J 21: 5 May 2003.
7. Schirmer BD, Winters KL, Edlich RF. Cholelithiasis and cholecystitis.
J Long Term Eff Med Implants 2005; 15: 329–38.
8. Shaffer EA. Gallstone disease: epidemiology of gallbladder stone disease.
Best Pract Res Clin Gastrenterol 2006; 20: 981–96.
9. Ellis H, Calne R, Watson C. Lecture Notes on General Surgery, 9th edn.
256–64.
10. Kumar P, Clark M. Clinical Medicine, 5th edn. Edinburgh: W B Saunders,
2002: 981–6.
11. Glasgow RE, Cho M, Hatter MM, et al. The spectrum and cost of compli-
cated gallstone disease in California. Arch Surg 2000; 135: 1021–5.
12. Papi C, Catarci M, D’Ambrosio L, et al. Timing of cholecystectomy for
acute calculous cholecystitis: a meta-analysis. Am J of Gastroenterol 2004;
99(1): 147–55.
13. Cameron IC, Chadwick C, Phillips J, et al. Current practice in the
management of acute cholecystitis. Br J Surg 2000; 87: 366–7.
14. Gurusamy KS, Samraj K. Cholecystectomy for acute cholecystitis.
Cochrane Database Syst Rev 2006 CD 005440.
15. Keus F, deJong JA, Gooszen HG, et al. Laparoscopic versus open cholecys-
tectomy for patients with symptomatic cholecystolithiasis. Cochrane
Database Syst Rev 2006 CD 006231.
16. Stefandis D, Kirinek KR, Bingener J. Gallbladder perforation: risk factors
and outcome. J Surg Res. 2006; 131(2): 204–8.
17. Clavien PA, Richon J. Gallstone ileus. Br J Surg 1990; 77(7): 737–42.
18. Fisher EJ, Sherman S. The interface of ERCP and laparoscopic cholecyste-
comy. Gastrointest Endosc Clin N Arm 1996; 6(1): 57–80.
19. Chung RS, Chad V, Eisenstat M. Choledocholithiasis treated with
endoscopic stenting of the papilla followed by stent guided sphincterot-
omy. Gastrointest Endosc 1997; 45: 121–30.
20. Frossard JL, Hadengue A, Amouyal G, et al. Choledochlithiasis: a prospec-
tive study of common bile duct stone migration. Gastrointest Endosc
2000; 51(2): 175–9.
21. Beckingham IJ. MRCP versus ERCP in the diagnosis of choledochlithiasis.
Eur J Gastro Hepatol 2003; 15(7): 809–13.
22. Murison MS, Gartell PC, McGinn FP. Does selective preoperative cholan-
giography result in missed bile duct stones? J R Coll Surg Edin 1993;
38(4): 220–4.
23. Rosseland AR, Stomsaker TB. Asymptomatic common bile duct stones.
Eur J Gastr Hepatol 2000; 12(11): 1171–3.
24. Sarli L, Pietra N, Franze A, et al. Routine intravenous cholangiography;
selective ERCP and endoscopic treatment of bile duct stones before
laparoscopic cholecystectomy. Gastrointest Endosc 1999; 50(2): 200–8.
25. Martin DJ, Vernon DR, Toouli J. Cochrane Database of Systematic Review
2006 CD 003327.
26. Leung JW, Ling TK, Chan RL, et al. Antibiotics, biliary sepsis and bile duct
stones. Gastrointest Endosc 1994; 40(6): 716–21.
27. Ayub K, Imada R, Slavis J. ERCP in gallstone associated pancreatitis.
Cochrane Database of Systematic Review 2004; CD 003630.
28. Caddy GR, Tham TC. Gallstone disease: Symptoms, diagnosis and
endoscopic management of common bile duct stones. Best Prac Res
Clin Gastr 2006; 20(6): 1085–101.
29. Mayer AD, McMahon MJ, Benson EA, et al. Operations on the biliary
tract in patients with acute pancreatitis; aims, indications and timing.
Ann R Coll Surg Engl 1984; 66: 179–83.
30. Neoptolemos JP, Hall AW, Finlay DF, et al. The urgent diagnosis of
gallstones in acute pancreatitis: a prospective study of 3 methods. Br J
Surg 1984; 71: 230–3.
 GALLSTONES AND COMMON BILE DUCT STONES
31. Banks PA. A new classification system for acute pancreatitis. Am J Gastro-
enterol 1994; 89(2): 151–2.
32. Bradley EL. A clinically based system for acute pancreatitis. Summary of
the international symposium on acute pancreatitis. Arch Surg 1993;
128(5): 586–90..
33. Toh SK, Phillips S, Johnson CD. A prospective audit against national
standards of the presentation and management of acute pancreatitis in
the South of England. Gut 2000; 46(2): 239–43.
34. Price WH. Gallbladder dyspepsia. Br Med J 1963 Jul 20; 2(5350) 138–41.
35. Black NA, Thompson E, Sanderson CF. Symptoms and health status
before and 6 weeks after cholecystectomy. Gut 1994; 35(9): 1301–5.
36. Ferster LF, Lonborg R, Thirlby RE. Am J Surg 1995; 169(5): 533–8.
37. Uchida N, Nakatsu T, Hirabayashi S, et al. J Gastroenterol Aug 1994; 29: 4.
38. Thistle JU, May GR, Bender CE, et al. Dissolution of cholesterol gallstones
b Methyl tert butyl ether administered by percutaneous transhepatic
catheter. N Engl J Med 1989; 320: 633–9.
39. Hellstern A, Leuschner U, Benjaminov A, et al. Dissolution of gallbladder
stones with methyl tert butyl ether and stone recurrence. A European
Survey. Dig Dis Sci 1998; 43: 911.
40. Miller K, Hell E, Lang B, et al. Gallstone formation prophylaxis after
gastric restriction procedures for weight loss, a randomized double-blind
placebo controlled trial. Ann Surg 2003; 238: 697–702.
41. Venneman NG, Besselink MG, Keulemans VC, et al. Ursodeoxycholic acid
exerts no beneficial effect in patients with symptomic gallstones awaiting
cholecystectomy. Hepatology 2006; 43: 1276–83.
42. Wang HH, Portincasa P, Mendez-Sanchez N, et al. Effect of ezetimibe on
the prevention and dissolution of cholesterol gallstones. Gastroenterology
2008 Jun; 134(7): 2101–10.
43. Spira RM, Nissan A, Zamir O, et al. Percutaneous transhepatic cholecys-
tostomy and delayed cholecystectomy in critically ill patients with acute
calculous cholecystitis. Am J Surg; 183: 62–6.
44. Borloff A, Chen MY, Ott DJ, et al. Gallbladder stones: imaging and
intervention. Radiographics 2000; 20(3): 751–66.
45. Bittner R. The standard of laparoscopic cholecystectomy. Langenbecks
Arch Surg 2000; 389: 157–63.
46. Clair DG, Lautz DB, Brooks DC. Rapid development of umbilical
metastases after laparoscopic cholecystectomy for unsuspected gallblad-
der cancer. Surgery 1993; 113: 355–8.
47. Landen SM. Laparoscopic surgery and tumour seeding. Surgery 1993;
114: 131–2.
48. Fligelstone L, Rhodes M, Flook D, et al. Tumour inoculation during
laparoscopy. Lancet 1993; 342: 368–9.
49. Kim HJ, Roy T. Unexpected gallbladder cancer with cutaneous seeding
after laparoscopic cholecystectomy. South Med J 1994; 87: 817–20.
50. Muhe E. The first cholecystectomy through the laparoscope. Langenbecks
Arch Surg 1986; 369: 804.
51. Gurusamy KS, Junnakar S, Farouk M, et al. Meta-analysis of randomised
controlled trials on the safety and effectiveness of day-case laparoscopic
cholecystectomy. Br J Surg 2008; 95: 161–8.
52. Osborne DA, Alexander G, Boe B, et al. Laparoscopic cholecystectomy –
past, present and future. Surg Technol Int 2006; 15: 81–5.
53. Bonjer HJ, Hazebroek EJ, Kazemier G, et al. open versus closed establish-
ment of pneumoperitoneum in laparoscopic surgery. Br J Surg 1997; 84:
599–602.
54. Romanelli JK, Mark L, Omotosho PA. Single port laparoscopic cholecys-
tectomy with the Triport system, a case report. Surg Innov 2008; 15(3)
223–8.
55. Park PO, Bergstrom M, Ikeda K, et al. Experimental studies of transgastric
gallbladder surgery: cholecystectomy and cholecystogastric anastomosis.
Gastrointest Endosc 2005; 61: 601–6.
56. Rattner D, Kalloo A. ASGE/SAGES. Working group on natural orifice
transluminal endoscopic surgery. Oct 2005. Surg Endosc 2006; 20:
329–33.
57. Danziger RG, Hoffman AF, Schoenfield P, et al. Dissolution of cholesterol
gallstones by chendeoxycholic acid. N Engl J Med 1972; 286(1): 1–8.
58. Johnson GK, Geenen JE, Venu RP, et al. Treatment of non-extractable
CBD stones with combination ursodeoxycholic acid and endoprosthesis.
Gastrointest Endosc 1993; 39(4): 528–32.
59. Chung WH, Chu CH, Wang TE, et al. Outcome of simple use of mechan-
ical lithotripsy of difficult common bile duct stones. World J Gastroen-
terol 2005; 11(4): 593–6.
60. Garg PK, Tandon RK, Akuja V, et al. Predictors of unsuccessful mechanica
lithotripsy and endoscopic clearance of large bile duct stones. Gastroin-
test Endosc 2004; 59(6): 601–5.
61. Cipolletta C, Costamagna G, Bianco MA, et al. Endoscopic mechanical
lithotripsy of difficult bile duct stones. Br J Surg1997; 84(10): 1407–9.
62. Brambs HJ, Duda SH, Rieber A, et al. Treatment of bile duct stones: value
of laser lithotripsy delivered by percutaneous endoscopy. Eur J Radiol
1996; 6(5): 734–40.
63. Harris VJ, Sherman S, Trevotola S, et al. Complex biliary stones: treatment
with a small choledochoscope and laser lithotripsy. Radiology 1996;
199(1): 71–7.
64. Born P, Neuhaus H. Laser lithotripsy of refrctory bile duct stones after
failure of endoscopic shockwave lithotripsy. Gastroenterol 1995; 33(4):
202–8.
65. Sauerbruch T, Delius M, Paumgartner G, et al. Fragmentation of gall-
stones by endoscopic shockwaves. N Engl J Med 1986; 314: 818–22.
66. Sackmann M, Holl J, Sanffer G, et al. Endoscopic shockwave lithotripsy
for clearance of bile duct stones. Gastrointest Endosc 2001; 53(1):
27–32.
67. Ellis RD, Jenkins AP, Thompson RP, et al. Clearance of refractory bile
duct stones with endoscopic shockwave lithotripsy. Gut 2000; 47(5)
728–31.
68. Arya N, Nelles E, Haber GB, et al. EHL in 111 patients: a safe and effective
therapy for difficult bile duct stones. Am J Gastroenterol 2004; 99(12):
2330–4.
69. Ahmed I, Pradhan C, Beckingham IJ, et al. Is T Tube necessary after
common bile duct exploration. World J Surg 2008; 32: 1485–88.
70. Rhodes M, Sussman L, Cohen, et al. Randomized trial of laparoscopic
exploration of common bile duct versus postoperative ERCP for common
bile duct stones. Lancet 1998 Jan 17; 351: 159–61.
71. Cuschieri A, Croce E, Faggioni A, et al. EAES ductal stone study: prelimi-
nary findings of multi-centre prospective randomized trial comparing
2 stage versus single stage management. Surg Endosc 1996 Dec; 10(2):
1130–5.
72. Williams EJ, Green J, Beckingham I, et al. Guidelines on the management
of common bile duct stones. British Society of Gastroenterology. Gut
2008 Jul; 57(7): 1004–21.
379
42 Adenocarcinoma of the pancreas
André L. Mihaljevic, Jörg Kleeff, and Helmut Friess
introduction
The most frequent type of pancreatic adenocarcinoma,
pancreatic ductal adenocarcinoma (PDAC), accounts for more
than 85% of all pancreatic malignancies (1). Other malignant
pancreatic tumors include intraductal papillary mucinous car-
cinomas, mucinous cystadenocarcinomas, acinar cell cancers,
as well as endocrine cancers. These rare tumors will not be dis-
cussed in this chapter. PDAC is characterized by late presenta-
tion, aggressive local tumor growth, early lymphogenic and
hematogenic spread, and poor prognosis.
epidemiology
PDAC is the tenth most common type of cancer in the United
States and the United Kingdom but accounts for the fourth
and sixth most frequent type of cancer-related death in these
countries (2–4), respectively. Due to its aggressive nature, the
number of new cases per year (an estimated 37,680 in the U.S.
in 2008 and 7,632 in the UK in 2005) almost equals the num-
ber of deaths per year (34,290 in the U.S. and 7315 in the UK)
(3–6). PDAC has an overall median survival of less than
6 months and one of the lowest overall 5-year survival rates of
any malignant disease with 0.4% to 5% (7,8). Furthermore,
these dismal figures seem to have improved little compared to
the 1950s (5). The incidence rate peaks between 65 and
75 years of age (9) and only 15% to 20% of patients initially
present with localized disease suitable for potential curative
surgical resection.
etiology and risk factors
Numerous risk factors have been implicated in the develop-
ment of PDAC. Studies have focused not only on identifying
modifiable risk factors like diet and life-style habits, but also
tried to elucidate hereditary and genetic risk factors.
Diet as a risk factor for pancreatic cancer has been investi-
gated in multiple studies yielding contradicting results (10–16).
Currently, no specific diet can be recommended to reduce the
risk of PDAC (evidence grade 2b, recommendation C). An
overview of the available data is given in Table 42.1. Obesity,
however, seems to pose a risk factor for the development of
pancreatic cancer (17,18). In a metaanalysis of six case–control
and eight cohort studies, a body-mass index of 30 was associ-
ated with an increase in the relative risk of 1.19 compared to
normal weighing subjects (19). Consequently, an increase in
physical activity seems to lower the risk for pancreatic cancer
(18,20,21). Another well-documented risk factor is smoking
which seems to roughly double the risk for pancreatic cancer
(22–26). Individual genetic factors appear to influence this
association (27–29) and even passive smoking has been linked
to an increased risk in one population-based study (30). Alco-
hol, albeit one of the leading causes of chronic pancreatitis, does
not seem to increase the risk for pancreatic cancer (31–34),
380
although an association between excessive drinking and
pancreatic cancer cannot be ruled out (35). Furthermore, it
should be mentioned that alcohol is one of the leading causes
of sporadic chronic pancreatitis which increases the risk for
pancreatic cancer 2.3- to 25-fold (36–40). Finally, diabetes
mellitus poses an increased risk for the development of pan-
creatic cancer. In one population-based study, the risk was
increased up to eightfold (41), although other studies showed
smaller increases in the relative risk (13,42–46)
Familial background is an important, non-modifiable risk
factor. First-degree relatives of PDAC patients have an approx-
imately two- to three-fold increased risk to develop the disease
themselves depending on the age of the affected family mem-
ber (47,48). Familial predisposition seems to account for
approximately 1.9% to 5% of all PDAC cases (1,49,50) and
occurs in three clinical settings: (1) familial pancreatic cancer
syndrome (FPC), (2) hereditary pancreatitis and cystic fibro-
sis, and (3) hereditary tumor syndromes involving the pan-
creas such as the Peutz–Jeghers syndrome.
In FPC, two or more first-degree relatives are affected by
PDCA while other hereditary causes (familial tumor syndromes,
cystic fibrosis, and hereditary pancreatitis) have been ruled out
(51). FPC is believed to account for 70% of all hereditary pan-
creatic cancer cases (51) and the increase in risk is dependent on
the number of affected individuals in a family (52). Individuals
from FPC families with two affected first-degree relatives have a
relative risk of about 6.4%, those with three or more affected
first-degree relatives of 32% (48). Importantly, in FPC families,
patients from younger generations are, on average, affected
10 years earlier than their parents (genetic anticipation) (53).
The genetic alterations causing FPC remain elusive and up till
now potential genetic defects have been identified in only a
number of FPC families including mutations in the Palladin
(54) or BRCA2 gene (55–57).
Two hereditary syndromes causing chronic pancreatitis are
also associated with an increased risk for PDAC: hereditary
pancreatitis and cystic fibrosis. Hereditary pancreatitis is an
autosomal dominant disorder characterized by recurrent epi-
sodes of acute pancreatitis at a young age eventually leading to
chronic pancreatitis. It is associated with a 50- to 70-fold
increased risk for PDAC (38,58). Approximately 70% of
hereditary pancreatitis cases are caused by loss-of-function
mutations in the protease serine 1 (PRSS1) (59) blocking the
trypsine inactivation in pancreatic acinar cells and leading to
autodigestion. Less frequently, mutations in the SPINK1 gene,
coding for the serine protease inhibitor Kazal-type 1, were
found to be associated with hereditary pancreatitis (60). Cystic
fibrosis, the most frequent hereditary metabolic disorder in
Caucasians, on the other hand, is an autosomal-recessive dis-
ease caused by mutations in the CFTR gene (cystic fibrosis
transmembrane regulator) and is characterized by viscous
 ADENOCARCINOMA OF THE PANCREAS

Table 42.1 Influence of Dietary Factors on the Development of Pancreatic Cancer.

Grade of evidence and
Dietary factor Influence on risk recommendation References
Dietary fiber No proven benefit 3, C (12,248,249)
Fruit/vegetables No proven benefit 2b, C (250)
Vitamin C Potential benefit 3, D (12,251)
Low fat low cholesterol No proven benefit 2b, B (15,14)
Grilled/smoked meat Potential risk 3, C (252–254)
Low sugar No proven benefit 2b, B (254–256)
Fish No proven benefit 2b, B (15,14)
Tea No proven benefit 2b, B (257,258)
Coffee No proven risk 2b, B (25,31,259)
Alcohol No proven risk 3, C (25,31,260,34)

mucus production in exocrine glands. Several studies have
analyzed the association between cystic fibrosis and PDAC
showing a 2.3- to 32-fold increase in relative risk (61,62).
Finally, a number of hereditary tumor syndromes are associ-
ated with an increased risk for PDAC. Table 42.2 gives an over-
view of hereditary pancreatic cancer disorders.
symptoms and clinical presentation
Symptoms of PDAC include back pain, painless obstructive
jaundice, weight loss, loss of appetite, and fatigue and are
largely unspecific. Associated conditions include endocrine
(new-onset diabetes mellitus) as well as exocrine pancreatic
insufficiency (maldigestion, steatorrhea) or an unexplained
attack of acute pancreatitis. Clinical features such as persistent
back pain, ascites, supraclavicular lymphadenopathy, or a pal-
pable abdominal mass may indicate advanced tumor disease.
No data exist regarding which clinical symptom or combi-
nation of symptoms should trigger further diagnostic mea-
sures. New onset epigastric or back pain is the most frequent
symptom of PDAC. Based on expert opinion (evidence grade
4, recommendation D), a clinical approach based on age and
coexisting symptoms has been proposed for patients present-
ing with new onset back pain (Table 42.3) (63).
Painless jaundice in PDAC patients is caused by obstruction
of the intrapancreatic common bile duct. It is a classical fea-
ture of PDAC since 80% to 90% of tumors are located in the
head of the gland (64). Painless jaundice should always trigger
further diagnostic measures to rule out pancreatic or common
bile duct malignancies since they account for over 20% of
cases in patients over 60 years of age (evidence grade 2b, rec-
ommendation B) (65–67). Conversely, the less frequent tumors
of the pancreatic tail rarely cause jaundice and are typically
diagnosed at a later stage.
Late-onset diabetes mellitus (>50 year of age) may be caused
by PDAC (68). Conversely, diabetes mellitus seems to be a risk
factor for pancreatic cancer (see Etiology and Risk Factors).
Eighty percent of PDAC patients exhibit diabetes mellitus or
an impaired glucose tolerance at the time of diagnosis (69).
Furthermore, a population-based study suggests that PDAC
will be detected in about 1% of diabetics over 50 years who
had their diabetes diagnosed within 3 years of cancer diagno-
sis. Most (56%) of these patients had been diagnosed with dia-
betes within 6 months of cancer detection (70). Others have
argued that the lack of efficient diagnostic tools to detect
pancreatic cancer early does not warrant further diagnostic
measures in patients with late-onset diabetes as their sole
symptom (63).
Although PDAC contributes only marginally to the overall
number of acute pancreatitis cases, idiopathic acute pancreati-
tis in patients over 50 of age justifies further diagnostic work-
up, since up to 5% of PDAC patients are present with idiopathic
pancreatitis as their first clinical manifestation (63,71).
diagnosis and staging
The diagnostic work-up in patients with suspected pancreatic
cancer should verify the diagnosis and determine surgical
resectability. Pathological tumor staging follows the UICC
staging system (Table 42.4); however, for further clinical deci-
sion making it suffices to group the tumor into one of the
following simple categories:
1. Resectable tumors without distant metastasis
2. Locally advanced tumors, borderline resectable, no
distant metastasis
3. Locally advanced tumors, unresectable, no distant
metastasis
4. Tumors with distant metastasis
The following questions must be answered during the diag-
nostic work-up in order to correctly classify the tumor:
1. Presence or absence of distant metastasis (hepatic
and/or peritoneal)
2. Patency of the superior mesenteric vein (SMV), the
splenic vein, the portal confluence, and the portal
vein
3. Patency of the superior mesenteric artery (SMA),
the coeliac axis, the hepatic artery, and the gastro-
duodenal artery
4. Presence of aberrant vascular anatomy
5. Tumor invasion into neighboring organs per
continuitatem
Table 42.5 gives an overview of how tumor infiltration
translates into surgical resectability. The diagnostic work-up
should follow a logical order, be as little time consuming as
possible, and start with simple, inexpensive measures followed
by more invasive procedures (Fig. 42.1).

381
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 42.2 Overview of Hereditary Pancreatic Cancer Disorders.

Cumulative risk for PDAC
Clinical presentation Gene till the age of 70 (Ref. 268)
1. Familial pancreatic cancer Two or more first-degree relatives with PDAC Not known, 40%
BRCA2 (6–17%,
(57,56,55))
2. Hereditary forms of CP
Hereditary pancreatitis Recurrent acute pancreatitis in young patients PRSS1 40%
SPINK1
Cystic fibrosis Exocrine pancreas insufficiency CFTR <5%
DIOS
COPD
Biliary cirrhosis
Reduced fertility
3. Hereditary tumor syndromes
Peutz–Jeghers Intestinal hamartomatous polyps STK11 36%
Mucocutaneous pigment spots
FAMM/MPCS FAMM: multiple dysplastic naevi/melanoma in two or CDKN2A 17%
more first-degree relatives
25% of FAMM families show association with PDAC
MPCS: melanoma and PDAC
FBOC Breast cancer BRCA1/2 3–8%
Ovarian cancer
HNPCC Early-onset right-sided colorectal cancer MLH1, MSH2, <5%
Carcinoma of the pancreas, hepatobiliary tract, MSH6, PMS2
endometrium, ovary, stomach, small bowel, brain,
upper uroepithelial tract
FAP Multiple colonic polyps and colon cancer APC <5%
Duodenal tumors
Desmoids and others
LiFraumeni Breast cancer, TP53 <5%
Sarcoma,
leukemia
Brain tumors and others
Familial pancreatic cancer syndrome (FPC), hereditary pancreatitis and cystic fibrosis as well as hereditary tumor syndromes with PDAC association are listed.
The causative genes are listed as well as the cumulative risk to develop PDAC the age of 70. Abbreviations: DIOS, distal intestinal obstruction syndrome; COPD,
chronic obstructive pulmonary disease; STK11, serine-threonine protein kinase 11; PDAC, pancreatic ductal adenocarcinoma; FPC, familial pancreatic cancer;
BRCA1/2, breast-cancer gene 1/2; PRSS1, Protease Serine 1; SPINK1, serine protease inhibitor Kazal-type 1; CFTR, cystic fibrosis transmembrane regulator;
FAMM, familial atypical multiple mole melanoma syndrome; MPCS, melanoma pancreatic cancer syndrome; CDKN2A, cyclin-dependent kinase inhibitor 2A;
HNPCC, hereditary non-polyposis colon cancer; FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; FBOC, familial breast and ovarian
cancer syndrome; MLH1, MutL homolog 1; MSH2/6, MutS homolog 2/6; PMS2, postmeiotic segregation 2; TP53, tumor protein 53.

Following the initial suspicion of a pancreatic malig-
nancy after taking the patients’ history and conducting a
thorough physical exam, a laboratory work-up and a trans-
abdominal ultrasound are the first steps to be taken. Labo-
ratory values should include amylase and lipase, cholestasis
parameters (γGT, direct and indirect bilirubin, alkaline
phosphatase), the transaminases ALT and AST, a blood
count to evaluate tumor anemia, coagulation parameters,
and the tumor marker carbohydrate antigen 19-9 (CA19-
9). None of these parameters are specific for pancreatic
cancer and none can be used as a screening tool. The
tumor-associated antigen CA19-9 specifically has been
tested in two large studies and found to be ineffective as a
screening tool in asymptomatic patients because of its low
positive predictive value (72,73). Furthermore, controver-
sies exist regarding the correct cut-off value for CA19-9.
However, in the context of suspected pancreatic malig-
nancy, CA19-9 remains a valuable adjunct since in combi-
nation with computed tomography (CT) a positive
predictive value of 99% can be achieved when levels are
over 120 U/ml (74). In addition, high levels of CA19-9
(over 150 U/ml) were shown to serve as an indicator for
irresectability with a positive predicitive value of 88% and
might justify further staging procedures (75). Finally,
CA19-9 can be used as a parameter of therapeutic response
and as an indicator of recurrence in patients
with PDAC.
Transabdominal ultrasonography is a fast and cost-effective
measure and provides valuable information. The presence of
ascites, hepatic metastasis as well as dilated intrahepatic and
extrahepatic bile ducts can be evaluated with high accuracy,
whereas the visualization of the primary tumor is achieved

382
 ADENOCARCINOMA OF THE PANCREAS

(81) that is difficult to distinguish from the actual tumor on

Table 42.3 Age- and Symptom Oriented Approach to New
CT imaging which may lead to the false positive diagnosis of
Onset Epigastric or Back Pain Based on Expert Opinion
irresectability. Using a cut-off value of 180° of vascular involve-
(Evidence Grade 4, Recommendation D)
ment on CT yielded a sensitivity of 84% and a specificity of
Level of 98% for unresectable disease in one study (82), but recent data
suspicion Age Symptoms Work-up suggest that greater tumor involvement of arteries is necessary
Low <50 Pain only a
US if pain to accurately identify arterial invasion (83). Furthermore,
persists enlargement of lymph nodes on CT is a poor indicator for
Medium <50 Pain plus US, (CT) metastasis and irresectability (84). Finally, the sensitivity of CT
Loss of appetite/loss of imaging to detect hepatic metastasis varies depending on the
weight/fatigue
size of the lesion, but is considered to range between 38% and
>50 Pain onlya
73% (76).
High >50 Pain plus US, EUS,
Loss of appetite/loss of (CT) MRI should be performed with a field volume of at least
weight/fatigue 1.5 T, with sections of 5 mm and T1 and T2 weighted as well
a
as MRCP images. In this setting, MRI/MRCP yields similar
Epigastric pain that radiates to the back and persists at night should trigger
further investigations independent of age. accuracy in diagnosis and staging of PDAC than CT imaging
Abbreviations: US, abdominal ultrasound; EUS, endoscopic ultrasound; CT, and might be superior in the diagnosis of hepatic lesions (85–
computed tomography. 87). As with endoscopic retrograde cholangio-pancreaticogra-
phy (ERCP), a double-duct sign (obstruction of both the
pancreatic and the bile ducts) strongly suggests pancreatic
malignancies (88). Recent reports foster the hope that special
MRI sequences may be superior to other imaging techniques
Table 42.4 UICC Staging of Pancreatic Cancer (Seventh in detecting early PDAC lesions (89).
Edition, 2010) EUS is highly sensitive in the diagnosis of pancreatic cancer
M0 M1 as well as in the evaluation of vascular involvement (90). It has
a sensitivity of 95%, a specificity of 80%, a positive predictive
N0 N1 N0/N1
value of 95%, and a negative predictive value of 80% for pan-
Tis 0 ø IV creatic tumors in experienced hands (91–93). It was reported
T1 IA IIB to be superior to CT imaging in detecting small tumors
T2 IB IIB
(93,94), but less effective in assessing vascular involvement
T3 IIA IIB
T4 III III and distant metastasis (91,95). Furthermore, EUS is a sensitive
(over 90%) and highly specific (over 90%) method to obtain
Abbreviations: Tis: carcinoma in situ; T1, tumor limited to the pancreas
<2 cm; T2, tumor limited to the pancreas >2 cm; T3: tumor extending fine-needle aspirates (FNA) for pathological analysis (96–99).
beyond the pancreas but without involvement of the coeliac axis or the In most cases, however, a histological verification before sur-
superior mesenteric artery; T4, tumor involving coeliac axis or superior gery is not necessary since any potentially malignant lesions of
mesenteric artery; N0, no regional lymph node metastasis; N1, regional
lymph node metastasis; M0, no distant metastasis; M1, distant metastasis. the pancreas should be resected (evidence level 2; recommen-
dation B) (63). Histological verification should, therefore, only
be sought if the result would influence further treatment,
which is particularly important in the palliative setting.
In order to complete staging procedures, a chest X-ray or
with less sensitivity (95% in tumors greater than 3 cm, 81% in thoracic CT scan should be performed to rule out potential
tumors 1–3 cm, and 50% in tumors less than 1 cm) (76). pulmonary metastasis. Further diagnostic procedures that
Subsequently, a qualified imaging procedure should be per- may be employed in specific clinical settings include ERCP,
formed to clarify local resectability and the presence of poten- positron emission tomography with CT (PET-CT), and diag-
tial metastasis. CT is now widely regarded as the “gold nostic laparoscopy.
standard” for this purpose although based on local experience PET-CT does not play a role in the routine evaluation of
and availability, magnetic resonance imaging (MRI) with pancreatic cancers, although it may be used in the context of
magnetic resonance cholangiopancreaticography (MRCP) or equivocal radiographic findings, detection of occult metasta-
endoluminal ultrasound (EUS) may be applied without com- sis, or in the case of recurrent disease (100,101).
promising sensitivity and specificity (evidence grade 3, recom- Similarly, diagnostic laparoscopy may detect peritoneal carci-
mendation C). CT diagnostic should be performed with a nosis and occult organ metastasis not previously visible on
multidetector row CT (MDCT) with arterial and portal venous imaging studies. Early studies demonstrated a 15% to 25% inci-
phases of contrast enhancement and a maximum section dence of such lesions when compared with preoperative imag-
thickness of 3 mm. In this setting, MDCT will accurately pre- ing studies (102–104) leading to the routine employment of
dict respectability in 80% to 90% of cases (77–79), but sensi- diagnostic laparoscopy in some centers. Advances in the accu-
tivity drops below 80% when tumors are smaller than 2 cm racy of imaging techniques, however, reduced the incidence of
(80). It should be mentioned, however, that PDAC induces a newly diagnosed lesions detected by diagnostic laparoscopy to
heavy desmoplastic reaction in the surrounding stroma tissue 5% to 15% (105–107). In addition, diagnostic laparoscopy

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Table 42.5 Criteria for Categorizing PDAC According to Respectability into Resectable, Borderline and Locally Irresectable
Tumors as Well as Tumors with Distant Metastases
Resectable Borderline Local irresectability Distant metastasis
Venous involvement
Splenic vein ✓✗ ✓✗ ✓✗ ✓✗
Portal vein-SMV confluence ✗ ✓ ✗ (short segment) ✓(long segment and/or ✓✗
major tumor thrombosis)
Arterial involvement
Superior mesenteric artery (SMA) ✗ ✓ ✗ (not circumferential) ✓(circumferential/long ✓✗
segment)
Coeliac axis ✗ (✗) ✓ ✓✗
Common hepatic artery ✗ ✓ ✗ (short segment) ✓(encasement) ✓✗
Gastroduodenal artery ✓✗ ✓✗ ✓✗ ✓✗
Involvement of neighboring organs
Duodenum ✓✗ ✓✗ ✓✗ ✓✗
Stomach ✓ ✗ (pylorus or ✓✗ ✓✗ ✓✗
antrum)
Colon ✗ ✓✗ ✓✗ ✓✗
Spleen ✗ ✓✗ ✓✗ ✓✗
Kidney / adrenal gland ✗ ✓✗ ✓✗ ✓✗
Spine ✗ ✗ ✓ ✓✗
Distant metastasis ✗ ✗ ✗ ✓
✗: must be absent. ✓ : must be present. ✓✗ : may or may not be present (in brackets the maximum extent of involvement). For locally irresectabe tumors: one
✓-criterion is enough to classify the tumor as locally irresectable. Abbreviations: SMV: superior mesenteric vein.

History
physical exam

Labs
transabd. US

MDCT or
MRI/MRCP or
EUS

(ERCP)
(PET)
(diag. laparoscopy)

Locally Metastatic
Resectable Borderline
irresectable disease

Figure 42.1 Preoperative diagnosis pathway in patients with pancreatic cancer. The aim is to determine surgical respectability. Abbreviations: US, ultrasonography;
MDCT, multidetector-computed tomography; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreaticography; EUS, endoluminal
ultrasound; ERCP, endoscopic retrograde cholangiopancreaticography; PET, positron emission tomography.

384
 ADENOCARCINOMA OF THE PANCREAS
cannot clarify the question of local resectability, which can
ultimately be assessed only by laparotomy and exploration.
Therefore, diagnostic laparoscopy should be confined to spe-
cific clinical settings in which tumor spread is likely but could
not been verified by routine procedures (evidence grade IV, rec-
ommendation D). These include (1) tumors larger than 5 cm,
(2) high levels of CA19-9 preoperatively (over 680 U/ml) (108),
and (3) tumors of the body and tail of the pancreas (107).
ERCP is not regularly used to diagnose pancreatic cancer
since its accuracy does not exceed that of less invasive imaging
techniques, its association with a significant complication rate
of 5% to 10% (109,110) and its failure to visualize the tumor
and its relation to surrounding organs. Furthermore, brush
biopsies taken from suspect parts of the duct system for cyto-
logical analysis have a low sensitivity (59.8%), albeit high spec-
ificity (98.1%) (111), and are thus inferior to EUS-FNA (see
above). ERCP should therefore be confined to clinical settings
in which a direct visualization of the ampullary region is nec-
essary (e.g., in suspected intraductal papillary mucinous neo-
plasm, IPMN, in which mucin excretion from the ampulla is
almost diagnostic) or in which a preoperative decompression
of the common bile duct is necessary (see below).
Finally, a thorough assessment of any relevant co-morbidity
(cardiac, pulmonary, renal, etc.) must precede any decision
concerning further treatment.
preoperative biliary drainage
Whether or not preoperative biliary drainage (PBD) by ERCP
and stenting or by percutaneous cholangio-drainage (PTCD)
should be sought prior to resection remains a matter of debate.
While some studies have reported increased morbidity rates
following pancreaticoduodenectomy after PBD (112) others
could not verify this association except an increase in the rate
of postoperative wound infections (113–116). However, PBD
was significantly associated with an increase in the rate of bili-
ary infections (112,117), and this seemed to directly translate
into an increase in overall morbidity (118). However, most of
these studies have been retrospective. A metaanalysis of five
randomized controlled trials and 18 cohort studies evaluating
PBD versus no PBD in jaundiced patients undergoing surgical
resection showed no difference in overall mortality, but a sig-
nificantly reduced overall morbidity in the non-PBD group
(114). Interestingly, in the randomized controlled trials post-
operative morbidity was actually significantly lower in the PBD
group, a difference, however, that was reversed by the signifi-
cant number of preoperative complications associated with
PBD (around 27%) (119,120). A recent multicenter, random-
ized controlled trial confirmed these findings insofar as the
early-surgery group (no PBD) had significantly less serious
complications than the PBD group while overall mortality did
not significantly differ (269). In this study both pre- and post-
operative morbidity was higher in the PBD group. PBD
should therefore be avoided prior to surgery (evidence 1a,
recommendation A). PBD may be used in specific clinical
situations in which immediate surgery is not feasible (e.g.,
during neoadjuvant treatment) or in the case of cholangitis.
Furthermore, most surgeons would recommend to have plas-
tic rather than metal stents placed in these settings, since the
latter are difficult to extract during surgery and may harm the
bile duct (Evidence grade IV; recommendation D).
management
Management of PDAC depends on the clinical tumor stage
(Fig. 42.2):
1. Patients with resectable tumors should undergo sur-
gery as soon as possible followed by adjuvant che-
motherapy.
2. Patients with borderline tumors should undergo
exploration and resection if possible. If resection
is not possible the decision to perform a (dou-
ble) bypass operation (gastrojejunostomy and/or
hepaticojejunostomy) must be made. The patient
can then either be enrolled in a neoadjuvant treat-
ment protocol to achieve respectability or undergo
palliative care.
3. Patients with locally advanced, unresectable tumors
can be enrolled in a neoadjuvant treatment trial or
be treated palliatively.
4. Patients with distant metastasis should be offered
palliative treatment.
The rational to perform surgical resection whenever possi-
ble is the vastly improved prognosis and quality of life follow-
ing a macroscopic complete (R0/R1) removal of the tumor
(see below). It should be mentioned that age should not be a
contraindication for surgery since several studies have demon-
strated comparable outcomes between young and old patient
cohorts (evidence grade 4, recommendation D) (121–123).
surgical resection
The objective of surgical management of PDAC is the mac-
roscopic complete resection of the primary tumor, com-
plete regional lymphadenectomy, and reconstruction of the
gastrointestinal tract. Depending on the localization of the
tumor this goal can be achieved either by left (distal) pan-
createctomy, pancreatoduodenectomy (PD) or by total
pancreatectomy. A standard PD (Kausch–Whipple opera-
tion) (124) involves resection of the pancreatic head, the
duodenum, the distal common bile duct, the distal stom-
ach, the gall bladder, and regional lymph nodes. A variant of
this standard PD procedure preserves the stomach and is
thus termed pylorus-preserving pancreatoduodenectomy
(ppPD, Traverso-Longmire operation) (125). Resections as
well as the extent of lymphadenectomy (standard and
extended) have been defined in order to allow for better
comparison of data (126,127). For details concerning the
surgical resection procedures see the chapter on pancreatic
resection in this book.
Standard Versus Pylorus-Preserving
Pancreatoduodenectomy
The question whether standard or pylorus-preserving pan-
creatoduodenectomy (PD vs. ppPD) is superior in the treat-
ment of PDAC has been a matter of debate for some time. The
main areas of concern were the oncological completeness of
the ppPD procedure as well as the potential physiological side
385
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

III IV
I II
Local Metastatic
Resectable Borderline
irresectability disease

Histology Histology
Laparotomy
-CT/US/EUS: biopsy -CT/US/EUS: biopsy

Resection
-PD
Neoadjuvant Palliative CTx
-ppPD Irresectable
-Left resection
(R)CTx supportive care
-total pancreatecotmy

Adjuvant CTx (Double bypass) Resectable Irresectable

Neoadjuvant Palliative CTx

Laparotomy
(R)CTx supportive care

Figure 42.2 Treatment of PDAC dependent on clinical tumor stage. Abbreviations: CTx, chemotherapy; RCTx, radio-chemotherapy; EUS, endoluminal
ultrasound; US, ultrasound; PD, pancreaticoduodenectomy; ppPD, pylorus-preserving pancreaticoduodenectomy.

effects of the distal gastrectomy performed during PD. A
number of series have compared the two procedures; how-
ever, results were inconclusive or conflicting (128–131). A
recent meta-analysis of seven randomized controlled trials
including a total of 496 patients, however, found no difference
between the two procedures concerning in-hospital mortality,
overall survival, and overall morbidity. Merely intra-operative
blood loss and operation time were significantly reduced in
the ppPD procedure (132). Although the authors pointed out
that the analyzed studies were of clinical and methodological
heterogeneity, currently both procedures seem to be equally
appropriate in treating tumors of the pancreatic head (evi-
dence grade Ia, recommendation A).
Pancreatic–Enteric Anastomosis
One of the most common and feared complications of pancre-
atic surgery is the development of a pancreatic fistula which
was historically associated with mortality rates of up to 40%
(133–135). Mortality rates have dropped significantly with the
advent of CT-guided drainage, modern antibiotic regimes,
and nutritional support, but the question which anastomotic
techniques are associated with the lowest possible leakage rate
remains.
Several studies have investigated whether pancreaticogas-
trostomy might be superior to the traditional pancreaticojeju-
nostomy. A recent meta-analysis of three randomized
controlled trials and 13 nonrandomized observational studies
found no significant differences between the two procedures
regarding overall postoperative complications, pancreatic fis-
tula, intra-abdominal fluid collection, or mortality when ana-
lyzing the randomized controlled trials (136). On the contrary,
analysis of the 13 nonrandomized observational studies
showed significant results in favor of pancreaticogastrostomy,
a result which was most likely due to publication bias. There-
fore, neither pancreaticogastrostomy nor pancreaticojejunos-
tomy seems to be superior in reconstruction after PD (evidence
grade Ia; recommendation A).
Further areas of research concern technical aspects of the
pancreaticojejunostomy. Specifically the question whether the
anastomosis should be performed with invagination (end of
the pancreas invaginated into either the end or the side of the
jejunum) or whether a duct-to-mucosa approach leads to less
pancreatic fistulas has been investigated. All have been proven
to be safe and feasible with no clear advantage of one over the
other (137,138). Similarly, the use of anastomotic stents has
failed to affect fistula rates (137,139).

386
 ADENOCARCINOMA OF THE PANCREAS
Most pancreatic surgeons would argue that the texture of
the pancreatic gland remnant influences postoperative fistula
rates with a soft pancreatic tissue promoting pancreatic leak-
age. PDAC with its strong desmoplastic reaction would there-
fore favor anastomotic stability in comparison to ampullary or
primary duodenal neoplasms (evidence grade IV).
Extended Lymphadenectomy
Given the high incidence of lymph node metastasis in PDAC
the idea of an extended lymphadenectomy to improve progno-
sis seems reasonable. Standard lymphadenectomy during PD
or ppPD comprises of the lymph nodes on the right side of the
hepatoduodenal ligament, along the hepatic artery, the portal
vein, and the cranial part of the SMV. Figure 42.3 gives an over-
view of the lymph nodes involved in PDAC according to the
Japanese Pancreatic Society classification (140). According to
this classification, standard lymphadenectomy should remove
the lymph node stations 12, 13, 17, as well as partly 14.
Studies comparing standard lymphadenectomy to extended
lymphadenectomy procedures have not been standardized in
respect to the extent and localization of lymph node groups
resected. Three randomized controlled trials have been pub-
lished on this question (141–143) and all of them have failed
to show a significant benefit on survival from extended lymph-
adenectomy. One study, however, reported a significantly
higher postoperative morbidity rate, mainly dumping syn-
drome and debilitating diarrhoea, in the extended lymphade-
nectomy group (141). A recent long-term (5 year) follow-up
of this study seems to confirm the initial data. A nonsignificant
trend toward improved survival in the radical lymphadenec-
tomy group can be accounted for by the higher incidence of
microscopically margin positive resections in the standard
resection group (144). These results were confirmed in a recent
metanalysis (145). Therefore, extended lymphadenectomy
cannot be recommended in the surgical treatment of PDAC
(evidence grade Ia, recommendation A).
Extended Resections
Partial resection of the portal vein, the SMV, and/or the venous
confluence is by now a well-established procedure in special-
ized centers. It is indicated if it results in complete macroscopic
tumor resection (R0/R1) since R-status is an important prog-
nostic factor (see below). In experienced hands it does not
seem to increase operative morbidity or mortality (146–148)
and has been shown to result in similar long-term survival
rates compared to standard surgical resections (147,149–151).
Technical options include primary end-to-end anastomosis,
reconstruction with a vein patch, autologous interposition
graft, or with an alloplastic vascular graft (152).
The success of major venous resection has lead to even more
aggressive resections involving the arterial system as well.
Studies showing a benefit for such extended resections, how-
ever, are sparse and consists mostly of small single-center
cohorts and are at present far from being an established
treatment option (148,153–157). In these studies, mortality
rates between 0% and 17% (i.e., higher than during standard
pancreatic resections), with median survival rates between
12.2 and 22 months were reported. The improved median
survival in these patients in comparison to palliative therapy
has led some surgeons to advocate for arterial resection in
selected cases. Reconstruction after hepatic artery resection
can be achieved by reinsertion of the artery into the abdominal
aorta. In the case of pancreatic left resections, reconstruction
may not be necessary if the retrograde flow along the pancre-
aticoduodenal and gastroduodenal arteries is sufficient for
liver perfusion. The SMA may be reconstructed using an end-
to-end anastomosis or a venous or synthetic graft.
The complete resection of distant metastasis has been
reported only in a limited number of highly selected patients
at specialized centers and did not improve median survival
compared to palliative therapy alone (median survival
5.9–13.8 months) (158,159).
Improved survival rates in patients undergoing complete
surgical resection have raised the interest in downstaging pan-
creatic tumors that seem irresectable at presentation by means
of neoadjuvant therapy.
neoadjuvant treatment
Currently, no randomized controlled trial comparing neoad-
juvant therapy (radiochemotherapy or chemotherapy alone)
with direct resection for locally advanced pancreatic cancer
exists. A number of phase I/II trials or retrospective studies,
however, have demonstrated that neoadjuvant treatment is
safe and may result in down-sizing in a number of cases result-
ing in resection rates as high as 51% for tumors that deemed
unresectable at presentation (160–162). These patients might
benefit from the improved prognosis of an R0/R1 resection,
although data to confirm this notion are lacking. Due to the
lack of evidence, however, neoadjuvant treatment for pancre-
atic cancer should be confined to clinical trials.
In this context, it should be pointed out that specialized,
high-volume centers have markedly improved resection rates
compared to low-volume centers (over 50%), i.e., patients that
might be classified as unresectable in one hospital might
undergo successful resection at a specialized center (163,164).
mortality and morbidity
Mortality after pancreatic resection has decreased dramatically
from over 30% in the 1970s to below 4% in specialized centers
today (165–176). At the same time, the hospital stay decreased
from a median of 16 days to currently 8 to 10 days at special-
ized units (177). Several studies have stressed the significant
improvement in mortality in high-volume centers compared
to low-volume hospitals (see Table 42.6 for a selected list).
Long-term follow-up studies have demonstrated that this
translates into an increased overall survival (171,178). This
volume–outcome relationship seems to be proportional to the
number of pancreatic resections performed (179). In high-
volume centers more patients die from systemic than from
surgical complications (180). Therefore, strong evidence exists
that pancreatic surgery should be performed at specialized
high-volume centers (evidence grade II, recommendation B).
While mortality decreased significantly within the last years,
morbidity rates remain high and range between 30% and
40% (181,182). As for mortality, morbidity rates seem to be
significantly reduced in high-volume centers (183). Most
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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Group Lymph nodes

1 Right cardial
2 Left cardial
3 Along the lesser curvature of the stomach
4 Along the greater curvature of the stomach
5 Suprapyloric
6 Infrapyloric
7 Along the left gastric artery
8 Along the common hepatic artery
9 Around the celiac artery
10 Splenic hilum
11 Along the splenic artery
12 In the hepatoduodenal ligament
12h Hepatic hilum
12a1 Superior to hepatic artery
12a2 Inferior to hepatic artery
12p1 Superior to portal vein
12p2 Inferior to portal vein
12b1 Superior to bile duct
12b2 Inferior to bile duct
12c Around cystic duct
13 Posterior pancreatoduodenal nodes
13a Superior to ampulla of Vater
13b Inferior to ampulla of Vater
14 Along the superior mesenteric artery
14a Origin of the SMA
14b Origin of the pancreatoduodenal artery
14c Origin of the middle colic artery
14d Origin of the jejunal arteries
15 Along the middle colic artery;
16 Around the abdominal aorta
16a1 Above the origin of the coeliac axis
16a2 Between coeliac axis and left renal artery
16b1 Between left renal artery and IMA
16b2 Between IMA and aortic bifurcation
17 On the anterior surface of the pancreatic head
17a Superior to ampulla of Vater
17b Inferior to ampulla of Vater
18 Along the inferior margin of the pancreatic body/tail

Figure 42.3 Japanese Pancreatic Society lymph node groups (140). Only the lymph node groups relevant for pancreatic surgery are shown in the figure, while the
table lists all abdominal lymph node groups. 13 and 17 are first-order lymph nodes. 6, 8, 12 and partly 9 are second-order lymph nodes. 10, 11, 15, 16, 18 and partly
9 are third-order lmyph nodes. Abbreviations: SMA, superior mesenteric artery; IMA, inferior mesenteric artery. Opaque numbers indicate posteriorly
positioned lymph nodes.

388
 ADENOCARCINOMA OF THE PANCREAS

Table 42.6 Comparison of In-Hospital Mortality Between High- and Low-Volume Centers. Criteria for High- and Low-Volume
Centers Vary Between Different Studies and are Listed as Cases Per Year
Cases per year In-hospital mortality (%)
Year Low-volume High-volume Low-volume High-volume References
Netherlands 1994–1998 <5 ≥25 16 0.86 (165)
USA 1994–1999 <1 >16 16.3 3.8 (170)
USA 1992–1995 <1 >5 16 4 (169)
California and Florida, USA 1988–1998 ≤1 ≥10 9.5 3.3 (172)
New York, U.S. 1984–1991 <10 >81 21.8 4 (173)
Ontario 1998–1995 <3 >6 14.4 3.4 (174)
Maryland, USA 1984–1995 <20 ≥20 14.2 1.8 (167)
USA 1984–1993 1–5 >11 12.9 5.8 (175)
Maryland, USA 1988–1993 ≤1 >4 19 2.2 (168)
Maryland, USA 1990–1995 <5 >20 19 1 (176)

complications are surgical but frequently they can be handled
by pharmaceutical, radiological, and/or endoscopic inter-
ventions. Complications that require reoperation are still
associated with high-mortality rates between 23% and 67%
(184–186). The most common surgical complications in order
of frequency are (the percentages given indicate the frequen-
cies reported at two specialized high-volume centers and
should be regarded as minimum numbers) (181,187):
● Delayed gastric emptying (DGE) 9% to 15%
● Postoperative pancreatic fistula (POPF) 5%
● Wound infection 3% to 8%
● Intraabdominal abscess 1% to 4%
● Postpancreatectomy hemorrhage (PPH) 1% to 3%
The reported incidence rates for these complications vary
widely since up to recently standardized definitions for these
entities were lacking. In order to facilitate the reporting and
comparison of morbidity data between different institu-
tions, consensus definitions and classifications have been
achieved recently and should be used in all future reports
( Table 42.7).
Delayed Gastric Emptying (DGE)
DGE has been reported in 14% to 70% of cases without
application of a standardized definition (186,188,180), but
seems to be considerably lower in specialized centers
(9–15%) (181,187). DGE is graded according to an interna-
tional consensus definition ( Table 42.7). A number of stud-
ies have demonstrated an association between DGE and
other postpancreatectomy complications like intraabdomi-
nal abscesses or pancreatic fistulas (186). A relationship
between DGE and the pylorus preserving Whipple proce-
dure reported in one trial (189) could not be verified in
consecutive randomized trials (128,190). However, the
route of reconstruction, i.e., antecolic versus retrocolic gas-
trojejunostomy is associated with a significant lower DGE
rate (191). Furthermore, early initiation of enteral feeding
via an intraoperatively placed jejunal feeding tube after
Whipple resections resulted in significantly higher rates
of DGE as compared to patients not receiving early
enteral nutrition (267). Intravenous erythromycin has
been reported to alleviate the symptoms of DGE in up to
37% of patients (192).
Postoperative Pancreatic Fistula (POPF)
As for DGE, the rate of POPF in reports varies depending on
the definition used and the experience of the team, but is
approximately 5% in specialized centers (181,187). POPF is
a feared complication since it is associated with a significant
mortality rate of up to 28% secondary to sepsis and hemor-
rhage (189,193,194). An early sign of POPF may be a persis-
tently elevated CRP level after postoperative day 4 (187).
Surgical risk factors for POPF have been discussed in section
Pancreatic-Enteric Anastomosis. Recently, POPF have been
defined and graded according to their clinical relevance
( Table 42.7) (195). It should be mentioned that imaging
studies are not necessary for diagnosis, although helpful in
deciding further treatment options. Treatment should be
tailored to the grade of POPF (all recommendations are
grade D):
Grade A fistulas have little or no clinical impact. The patient
does well and can continue to be fed orally. Neither antibiotics
nor total parenteral nutrition or somatostatin analogs are
indicated. Most surgeons would leave the intraoperatively
placed drains in situ and remove them slowly.
Grade B fistulas require an adaption of the clinical manage-
ment. Pancreatic fluid should be drained effectively. If this
cannot be achieved via the intraoperative drains visualization
by radiologic imaging and effective percutaneous drainage of
any pancreatic fluid collection should be sought. Frequently,
the patient is kept with nil by mouth and has to be supported
by parenteral or enteral nutrition. Frequently, grade B fistulas
are associated with fever and leucocytosis in which case antibi-
otics should be applied.
Grade C fistulas constitute a worrisome clinical setting and
demand immediate action since clinical stability of the patient
is often compromised. Patients should be transferred to an ICU
or at least intermediate care unit for better observation. The
patient is kept with nil by mouth and is supported by parenteral
or enteral nutrition. Intravenous antibiotics as well as soma-
tostatin analogs are usually instituted. Radiologic imaging
should be sought quickly and any peripancreatic fluid collection

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 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 42.7 Consensus definitions and grading of three common complications following pancreatic surgery
Delayed Gastric Emptying (DGE) (261)
Grade A Grade B Grade C
Nasogastric tube 4–7 days or reinsertion > POD 3 8–14 days or einsertion > POD 7 >14 days or reinsertion >POD 14
NPO till POD 7 14 21
Nausea/vomiting Present or absent Present Present
Postoperative Pancreatic Fistula (POPF) (195)
Definition: Output via an operatively placed drain (or a subsequently placed, percutaneous drain) of any measurable volume of drain fluid
on or after postoperative day 3, with an amylase content greater than three times the upper normal serum value
Grade A Grade B Grade C
Clinical condition Well Often well Ill appearing/bad
Specific treatmenta No Yes/no Yes
CT/US findings Negative Negative/positive Positive
Persistent drainage No Usually yes Yes
>3 weeks
Reoperation No No Yes
Death related to POPF No No Possible
Signs of infection No Yes Yes
Sepsis No No Yes
Postpancreatectomy Hemorrhage (PPH) (200)
Time of onset (early <24 hr, late >24 hr) Location: intraluminal vs. extraluminal Severity: mild vs. severe b
Grade A Grade B Grade C
Time of onset, location, Early, mild, intra-/extraluminal Early, severe, intra-/extraluminal or Late, severe, intra-/extraluminal
severity and clinical late, mild, intra-/extraluminal
impact
Clinical condition Well Often well, intermediate, very rarely Severely impaired, life-threatening
life-threatening
Diagnostic consequence Observation, blood count, US, if abservation, blood count, US, CT, Angiography, CT, endoscopy,
necessary CT angiography, endoscopy
Therapeutic consequence None transfusion, ICU, therap. endoscopy, Localization of bleeding,
embolization, relaparotomy angiography and embolization,
endoscopy, relaparotomy, ICU
a
Partial (peripheral) or total parenteral nutrition, antibiotics, enteral nutrition, somatostatin analog and/or minimal invasive drainage; bFor the definition of
mild and severe PPH see text. Abbreviations: delayed gastric emptying (DGE) (261), postoperative pancreatic fistula (POPF) (195), and postpancreatectomy
hemorrhage (PPH) (200). CT, computed tomography; US, ultrasound; POD, postoperative day; NPO, nothing by mouth.

should be adequately drained percutaneously. Deteriorating
clinical status (e.g., sepsis and organ dysfunction) may require
re-exploration in order to attempt either to repair the site of
leakage, convert to alternative means of pancreatic–enteric
anastomosis (e.g., conversion of pancreaticojejunostomy to
pancreaticogastrostomy), or to resect the pancreatic remnant.
Intraabdominal Abscess
Intraabdominal abscesses have been reported in 1% to 12% of
patients following pancreatic resection (186,188,180,196). The
usual cause is a persistent leak from the pancreatojejunostomy
(see pancreatic fistula) or any other anastomosis. Intraabdom-
inal abscesses following pancreatic surgery typically present as
subhepatic or left subdiaphragmatic collections (182) and can
usually be managed by CT-guided percutaneous drainage and
intravenous antibiotic application (197).
Postpancreatectomy Hemorrhage (PPH)
PPH occurs in 1% to 8% of pancreatic resections and acc-
ounts for approximately 11% to 38% of overall mortality
(189,198,199). Again the variation seems to be in part due to a
lack of a uniform definition, which has recently been achieved
(Table 42.7) (200). PPH should henceforth be classified
according to: (1) time of onset, (2) location and cause, and (3)
severity.
Early onset PPH (<24 hours) seems to be due to insufficient
intraoperative hemostasis or an underlying coagulopathy
while late PPH (>24 hours) may occur from: (a) erosion of
(peripancratic) vessels due to pancreatic fistulas or intraab-
dominal drains, (b) gastric or duodenal ulcers, (c) anastomotic
suture lines, (d) the resected area, (e) intraabdominal abscesses,
or (f) the formation and rupture of pseudoaneurysms in the
peripancreatic vasculature (201–203).
It is important to distinguish between intraluminal and
extraluminal PPH with markedly different clinical presenta-
tion. While the former is characterized by melena, hemateme-
sis, or blood flow from the nasogastric tube, the latter is more
often characterized by hemorrhage from the abdominal
drains.
The severity of the PPH should be determined clinically.

390
 ADENOCARCINOMA OF THE PANCREAS
Mild PPH is defined as:
● Small or medium volume blood loss, decrease in
hemoglobin level by <3 g/dl
● Mild clinical impairment of the patient, no therapeutic
consequence, or at most the need for noninvasive treat-
ment with volume resuscitation or blood transfusions
(2–3 units packed cells within 24 hr of end of operation
or 1–3 units if later than 24 hr after operation)
● No need for reoperation or interventional angio-
graphic embolization; endoscopic treatment of anas-
tomotic bleeding may occur provided the other
conditions apply
Severe PPH on the other hand is defined as:
● Large volume blood loss (drop of hemoglobin level
by >3 g/dl)
● Clinically significant impairment (e.g., tachycardia,
hypotension, oliguria, hypovolemic shock), need for
blood transfusion (>3 units packed cells)
● Need for invasive treatment (interventional angio-
graphic embolization, or relaparotomy
Time of onset, localization, and severity allow an exact clas-
sification of PPH into three grades and thus define further
diagnostic and therapeutic measures (Table 42.7).
postoperative treatment
In addition to the management of complications, standard
postoperative treatment should include nutritional support
which is vital since many patients suffer from tumor cachexia
going into the surgery and the return of normal bowl function
may be delayed because of postoperative complications like
DGE. However, early total parenteral nutrition after pancreatic
resection was associated with an increased risk of complication
(204). Enteral feeding is recommended after pancreatic resec-
tion whenever possible, however, early initiation of enteral
feeding via an intraoperatively placed jejunal feeding tube after
Whipple resections resulted in significantly higher rates of
DGE as compared to patients not receiving early enteral nutri-
tion in one study (267). Another study evaluating continuous
enteral feeding to cyclic enteral nutrition after ppPD showed
significant benefits for the latter with earlier commencement of
normal oral diet and shorter hospital stay (205).
Increasingly, components of fast-track surgery are
applied to pancreatectomized patients including early
postoperative mobilisation, oral diet, and modern forms of
analgesia (206). Intraoperatively placed drains for example
can be removed on the second postoperative day if incon-
spicuous to avoid bacterial contamination of the abdomi-
nal cavity (207,208).
The benefit of prophylactic application of somatostatin ana-
logs to prevent pancreas-specific complications has been con-
troversial with some studies arguing for and some against it. A
recent meta-analysis of 10 randomized trials including
1918 patients showed no benefit of somatostatin analogs to
reduce mortality, but did show a significant reduction in mor-
bidity in the treatment group (209). The external validity of
the analysis was, however, limited by the lack of any standard-
ized definition for pancreatic fistulas between different trials
(see above). As a result a meaningful subgroup analysis was not
possible to elucidate which patients benefit from prophylactic
application. Therefore, currently, prophylactic use of soma-
tostatin analogs cannot be recommended indiscriminately.
adjuvant treatment
Two recent randomized controlled trails (CONKO-1 (210);
ESPAC-1 (211)) as well as one meta-analysis (212) have
demonstrated a significant benefit of adjuvant chemother-
apy on outcome following pancreatic cancer resection com-
pared to observation. Therefore, all patients undergoing
curative resection should receive adjuvant chemotherapy
(evidence grade 1b, recommendation A). The current data
suggest that tumor-specific risk factors like grading or
T-stage as well as age (even >80) are no contraindication for
adjuvant chemotherapy (210,211). Poor postoperative per-
formance status should be regarded as only a relative con-
traindication since in the trial of Oettle et al. even patients
with Karnofsky index ≥50 were included (210). Currently,
both 5-FU/folic acid (211) and gemcitabine (210) chemo-
therapy schemes are accepted after curative resection. A
direct comparison of gemcitabine with 5-FU/folinic acid
was recently conducted in the randomized, multicenter
ESPAC-3 trial (270). Both groups had comparable overall
survival rates after a median of 34.2 months of follow-up.
While the treatment-related serious adverse events were sig-
nificantly more frequent in the 5-FU/folinic acid group
compared to gemcitabine, this did not translate into a differ-
ence in overall quality of life, which was comparable between
the two groups. Based on the data from the currently avail-
able studies, adjuvant chemotherapy should be initiated
within 6 weeks of surgery and be applied for 6 months.
Table 42.8 lists all available randomized controlled trials of
adjuvant treatment after resection of pancreatic carcinoma.
Furthermore, based on subgroup analysis of the CONKO-1
trial (210), patients receiving a gemcitabine-based adjuvant
chemotherapy demonstrated a significantly longer disease-free
survival compared to observation alone after R1 resection of
pancreatic cancer. Therefore, even in the setting of an R1 resec-
tion postoperative chemotherapy has been proven beneficial
(evidence grade 1b, recommendation A).
In contrast, the evidence for a combination of radioche-
motherapy with chemotherapy is less clear, although this
treatment is common in the United States (213). Most adju-
vant trials have been underpowered and the randomized
controlled ESPAC-1 (211) trial as well as one meta-analysis
(212) failed to show any benefit for radiochemotherapy
( Table 42.8). Radiochemotherapy actually seemed to have a
detrimental, albeit nonsignificant, effect on outcome.
Therefore, currently, radiochemotherapy cannot be recom-
mended as adjuvant treatment for PDAC outside trials (evi-
dence grade 1b, recommendation A). Shortly data of the
randomized controlled CAPRI trial (combination of radio-,
chemo- and immunotherapy) (214) should be available to
see if the promising data from previous reports on this
combination can be confirmed (215).
391
392
Table 42.8 Randomized Controlled Trials for Adjuvant Treatment after Resection for Pancreatic Cancer
Median survival Overall 2-year Hazard ratio
Year Treatment Comparison (months) survival rate (95% CI), p-value Conclusion Ref.
Chemotherapy
ESPAC-1a 1994–2000 2x2 factorial design CTx vs. no CT 20.1 39.7 0.71 (0.55, 0.92) Significant increase in survival (211)
2x(20 Gy in 15.5 30.0 p = 0.009) for CT (P = 0.009) in 289
10 fractions+500 mg/m2 eligible patients
5FU/FA days 1–3)
(20 mg/m2 FA+425 mg/m2
5FU days 1–5) x 6 cycles
CONKO-1 1998–2004 6 cycles of gemcitabine every CTx vs. OBS 13.4 34% NN Median disease-free survival was (210)
4 weeks. Each cycle consisted 6.9 20.5% 13.4 months in the gemcitabine
of 3 weekly infusions of i.v. estimated group (95% CI, 11.4–15.3) and
gemcitabine 1000 mg/m2 overall 3-year 6.9 months in the control group
followed by a 1-week pause. survival (95% CI, 6.1–7.8; p = 0.001,
log-rank). Estimated disease-
free survival at 3 and 5 years
was 23.5% and 16.5% in the
gemcitabine group, and 7.5%
and 5.5% in the control group.
ESPAC-3 2000–2007 Fluorouracil (425 mg/m2 Fluorouracil/ 23.0(fluorouracil) 48.1% vs. 49.1% 0.94 (0.81–1.08) No significant difference in (270)
intravenous bolus injection folinic acid vs. 23.6 p=0.39 overall survival between the two
given 1–5 days every 28 days) vs. (gemcitabine) groups.
plus folinic acid (20 mg/m2, gemcitabine Treatment-related serious adverse
intravenous bolus injection ) events were more frequent in
or gemcitabine (1000 mg/m2 the fluorouracil group.
intravenous infusion once a Both groups had comparable
week for 3 of every overall QoL.
4 weeks) for 6 months
Takade et al. 1986–1992 6 mg/m2 mytomycin C day1 CTx vs. OBS 12.8 24.2 1.18 (0.84, 1.66) Significant survival benefit in (262)
+310 mg/m2 5FU days 1–5 12.4 29.6 p = 0.33 gallbladder cancer patients.
and days 15–20 followed by No difference in 158 eligible
100 mg/m2 oral 5FU daily to pancreatic cancer patients.
recurrence No difference in 48 eligible
ampullary cancer patients
Bakkevold et al. 1984–1987 AMF (40 mg/m2 doxorubicin, CTx vs. OBS 17.7 30.6% 0.80 (0.42, 1.53) Significant increase in median (263)
SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

6 mg/m2 mytomycin 10.4 24.3% p = 0.48 survival (23 vs. 11 mo,

C,500 mg/m2 5FU) once P1/40.02) in 60 pancreatic and
every 3 weeks for six courses ampullary patients combined
(Continued)
 Table 42.8 (Continued) Randomized Controlled Trials for Adjuvant Treatment after Resection for Pancreatic Cancer
Median survival Overall 2-year Hazard ratio
Year Treatment Comparison (months) survival rate (95% CI), p-value Conclusion Ref.
Radiochemotherapy
ESPAC-1a 1994–2000 2x2 factorial design RCTx vs. No 15.9 28.5 1.28 (0.99, 1.66) Non-significant decrease in (211)
2x (20 Gy in RCTx 17.9 41.4 p = 0.053 survival for RCTx (P=0.053) in
10 fractions+500 mg/m2 289 patients.
5FU/FA days 1–3)
(20 mg/m2 FA+425 mg/m2
5FU days 1–5) x 6 cycles
EORTC 1987–1995 2x (20 Gy in 10 RCTx vs. No 17.5 35.7 0.70 (0.46, 1.06) Non significant increase in (264)
fractions+25 mg/kg 5FU/FA RCTx 12.6 23.2 p = 0.088 median survival
days 1–5) (25 vs. 19 mo, P=0.21) in 207
eligible patients
Non significant increase in
median survival in 114 eligible
pancreatic (17 vs. 13 mo, P =
0.099)
RTOG 97-04 1998–2002 CTx with either 5FU (i.v. RCTx + 20.5 31% 0.82 (0.65, 1.03) The addition of gemcitabine to (265)
250 mg/m2 per day) or gemcit. vs. 16.9 22% p = 0.09 adjuvant fluorouracil-based
gemcitabine (1000 mg/m2 RCTx + 5FU 3-year survival chemoradiation was associated
once per week) for 3 weeks with a survival benefit for
prior to and for 12 weeks patients with resected pancre-
after chemoradiation. atic cancer, although this
ADENOCARCINOMA OF THE PANCREAS

Chemoradiation with 50.4 Gy improvement was not statisti-

+ 5FU (250 mg/m2 per day) cally significant
GITSG 1974–1982 2x (20 Gy in 10 fractions + RCTx vs. OBS 20.0 42% 0.54 (0.27, 1.05) Significant increase in median (266)
500 mg/m2 5FU days 1–3) + 10.9 15% p = 0.035 survival (20 vs. 11 mo, p =
weekly 5FU to recurrence 0.035) in 43 eligible patients
Trials addressing chemotherapy (CTx) and radiochemotherapy (RCTx) are listed. aThe ESPAC-1 trial had a factorial 2x2 design, meaning that patients were initially randomized into one of the four groups: observation,
chemotherapy, radiochemotherapy, or a combination of both. Comparisons were made between (1) patients receiving chemotherapy (chemotherapy alone or radiochemotherapy + chemotherapy) and those not
receiving it (observation or radiochemotherapy only) or (2) patients receiving radiation therapy (radiochemotherapy or radiochemotherapy + chemotherapy) and those not receiving it (observation or chemotherapy
alone). Abbreviations: OBS, observation; NN, not reported.

393
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
prognosis
Curative surgical resection in patients with PDAC is the single
most important factor influencing survival and the quality of
life (216). Advanced age (>80 years) is no contraindication for
resection which can be performed with similar mortality and
morbidity rates and offers the same advantages than in the
young (217). Although mortality rates for pancreatic surgery
decreased significantly in the last years (see above) the overall
5-year survival rate for all patients with PDAC remains dismal
(around 5%) (7,8). This number can be explained in part by
the low incidence of resectable PDAC at presentation, but
might also reflect a failure of adequate treatment. A recent
nationwide study in the United States including over
9,500 patients with early, potentially resectable (stage I,
T1/2N0M0) PDAC demonstrated that 71% of these patients
did not undergo resection, mostly because they were not
offered surgery (218).
Following curative resection and adjuvant chemotherapy,
patients have a 5-year survival rate of 20% to 25% and a
median survival of 17 to 28 months (181,201,210,211,217,219–
223). Even after 5 years, recurrence does occur meaning that
true long-term survivors are rare (224,225). These numbers,
however, compare favorable to the devastating prognosis of
patients with inoperable, locally advanced, or metastatic dis-
ease that have a median survival of 8 to 12 and 3 to 6 months,
respectively (226). In certain subgroups (R0 resection, nega-
tive lymph node status, and specialized center), the 5-year sur-
vival might actually be as high as 40% (227).
Multiple pre-, intra-, and postoperative factors influencing
prognosis have been studied, but consistently negative resec-
tion margins (R0), negative lymph node status (N0), favorable
tumor grading, primary tumor size under 2 cm, and absence
of perineural invasion have been identified as favorable prog-
nostic markers. Tumor size under 2 cm seems to improve
median survival dramatically from an average of 14 months to
35.5 months and significantly improves 5-year survival
(201,228–232). Similarly, a positive lymph node status (N1)
has been demonstrated to be a negative prognostic factor
(181,233–235), a finding confirmed by data from the ESPAC-1
trial (211,212). Finally, poor tumor grading significantly wors-
ens median as well as overall survival in a number of studies
(181,223,236), as does perineural invasion (237–239), although
in the latter case a significant association could not be verified
in other studies (231,240).
Similarly, the results concerning the influence of micro-
scopic tumor-free resection margins (R0) on prognosis have
been ambiguous. While a number of studies have demon-
strated a significant improvement in median as well as 5-year
survival following R0 resection as compared to R1 resection
(181,227,236,241) others have failed to confirm this associa-
tion (240,242–244). This observation is confirmed by data
from the ESPAC-1 trial in which only tumor grade and lymph
node status were identified as significant prognostic factors
(245). The reason for this apparent disparity is that the patho-
logical handling and reporting of pancreatic specimens vary
widely between different institutions and guidelines concern-
ing this matter have not been standardized (246). Conse-
quently, the rate of R0 resections dropped from 86% to 24%
394
after implementation of a standardized pathological examina-
tion protocol (246,247).
conclusion
All patients with PDAC should be evaluated for potential sur-
gical resection given the improved prognosis and quality of life
following resection compared to palliative treatment only. In
case of questionable local respectability determined by the
radiologist, an experienced pancreatic surgeon should evalu-
ate the radiographic images to determine whether a tumor is
resectable or not. Surgery can nowadays be carried out with
low mortality and acceptable morbidity rates at high-volume
specialized centers. Extended resections are justified if this
results in macroscopic complete resection of the tumor. Surgi-
cal resection as the mainstay of treatment should be comple-
mented by adjuvant chemotherapy in order to improve
survival in patients suffering from PDAC.
references
1. Alexakis N, Halloran C, Raraty M, et al. Current standards of surgery for
pancreatic cancer. Br J Surg 2004; 91(11): 1410–27.
2. Jemal A, Siegel R, Ward E, et al. Cancer Statistics. CA Cancer J Clin 2007;
57(1): 43–66.
3. Cancer Research UK: UK cancer mortality statistics for males. 2005.
[Available from: http://info.cancerresearchuk.org/cancerstats/mortality/
males/?a=5441]
4. Cancer Research UK: UK cancer mortality statistics for females. 2005.
[Available from: http://info.cancerresearchuk.org/cancerstats/mortality/
females/?a=5441]
5. SEER Cancer Statistics Review 1975–2005. Available from: http://seer.
cancer.gov/cgi-bin/csr/1975_2005/search.pl#results
6. Cancer Research UK: UK cancer incidence statistics by country. 2005.
Available from: http://info.cancerresearchuk.org/cancerstats/incidence/
site/?a=5441
7. Bramhall SR, Allum WH, Jones AG, et al. Treatment and survival in
13,560 patients with pancreatic cancer, and incidence of the disease, in the
West Midlands: an epidemiological study. Br J Surg 1995; 82(1): 111–5.
8. Hedberg M, Borgström A, Genell S, Janzon L. Survival following pancre-
atic carcinoma: a follow-up study of all cases recorded in Malmö,
Sweden, 1977–1991. Br J Surg 1998; 85(12): 1641–4.
9. Lankisch PG, Assmus C, Maisonneuve P, Lowenfels AB. Epidemiology of
pancreatic diseases in Lüneburg County. A study in a defined german
population. Pancreatology 2002; 2(5): 469–77.
10. Glade MJ. Food, nutrition, and the prevention of cancer: a global perspec-
tive. American Institute for Cancer Research/World Cancer Research Fund,
American Institute for Cancer Research, 1997. Nutrition 1999; 15(6): 523–6.
11. Soler M, Chatenoud L, La Vecchia C, et al. Diet, alcohol, coffee and pan-
creatic cancer: final results from an Italian study. Eur J Cancer Prev 1998;
7(6): 455–60.
12. Ji BT, Chow WH, Gridley G, et al. Dietary factors and the risk of pancre-
atic cancer: a case-control study in Shanghai China. Cancer Epidemiol
Biomarkers Prev 1995; 4(8): 885–93.
13. Chow WH, Gridley G, Nyrén O, et al. Risk of pancreatic cancer following
diabetes mellitus: a nationwide cohort study in Sweden. J Natl Cancer
Inst 1995; 87(12): 930–1.
14. Nöthlings U, Wilkens LR, Murphy SP, et al. Meat and fat intake as risk
factors for pancreatic cancer: the multiethnic cohort study. J Natl Cancer
Inst 2005; 97(19): 1458–65.
15. Michaud DS, Giovannucci E, Willett WC, et al. Dietary meat, dairy prod-
ucts, fat, and cholesterol and pancreatic cancer risk in a prospective
study. Am J Epidemiol 2003; 157(12): 1115–25.
16. Michaud DS, Skinner HG, Wu K, et al. Dietary patterns and pancreatic
cancer risk in men and women. J Natl Cancer Inst 2005; 97(7): 518–24.
17. Patel AV, Rodriguez C, Bernstein L, et al. Obesity, recreational physical
activity, and risk of pancreatic cancer in a large U.S. Cohort. Cancer
Epidemiol Biomarkers Prev 2005; 14(2): 459–66.
 ADENOCARCINOMA OF THE PANCREAS
18. Michaud DS, Giovannucci E, Willett WC, et al. Physical activity, obesity,
height, and the risk of pancreatic cancer. JAMA 2001; 286(8): 921–9.
19. Berrington de Gonzalez A, Sweetland S, Spencer E. A meta-analysis
of obesity and the risk of pancreatic cancer. Br J Cancer 2003; 89(3):
519–23.
20. Berrington de González A, Spencer EA, Bueno-de-Mesquita HB, et al.
Anthropometry, physical activity, and the risk of pancreatic cancer in the
European prospective investigation into cancer and nutrition. Cancer
Epidemiol Biomarkers Prev 2006; 15(5): 879–85.
21. Stolzenberg-Solomon RZ, Pietinen P, Taylor PR, et al. prospective study
of medical conditions, anthropometry, physical activity, and pancreatic
cancer in male smokers (Finland). Cancer Causes Control 2002; 13(5):
417–26.
22. Qiu D, Kurosawa M, Lin Y, et al. Overview of the epidemiology of pan-
creatic cancer focusing on the JACC Study. J Epidemiol 2005; 15(Suppl
2): S157–67.
23. Larsson SC, Permert J, Håkansson N, et al. Overall obesity, abdominal
adiposity, diabetes and cigarette smoking in relation to the risk of pan-
creatic cancer in two Swedish population-based cohorts. Br J Cancer
2005; 93(11): 1310–5.
24. Coughlin SS, Calle EE, Patel AV, Thun MJ. Predictors of pancreatic can-
cer mortality among a large cohort of United States adults. Cancer
Causes Control 2000; 11(10): 915–23.
25. Lin Y, Tamakoshi A, Kawamura T, et al. A prospective cohort study of
cigarette smoking and pancreatic cancer in Japan. Cancer Causes Con-
trol 2002; 13(3): 249–54.
26. Yun YH, Jung KW, Bae J, et al. Cigarette smoking and cancer incidence
risk in adult men: National Health Insurance Corporation Study. Cancer
Detect Prev 2005; 29(1): 15–24.
27. Duell EJ, Holly EA, Bracci PM, et al. A population-based, case-control
study of polymorphisms in carcinogen-metabolizing genes, smoking,
and pancreatic adenocarcinoma risk. J Natl Cancer Inst 2002; 94(4):
297–306.
28. Miyasaka K, Kawanami T, Shimokata H, et al. Inactive aldehyde dehydro-
genase-2 increased the risk of pancreatic cancer among smokers in a
Japanese male population. Pancreas 2005; 30(2): 95–8.
29. Wang L, Miao X, Tan W, et al. Genetic polymorphisms in methylenetet-
rahydrofolate reductase and thymidylate synthase and risk of pancreatic
cancer. Clin Gastroenterol Hepatol 2005; 3(8): 743–51.
30. Villeneuve PJ, Johnson KC, Mao Y, Hanley AJ. Environmental tobacco
smoke and the risk of pancreatic cancer: findings from a Canadian pop-
ulation-based case-control study. Can J Public Health 2004; 95(1): 32–7.
31. Michaud DS, Giovannucci E, Willett WC, et al. Coffee and alcohol con-
sumption and the risk of pancreatic cancer in two prospective United
States cohorts. Cancer Epidemiol Biomarkers Prev 2001; 10(5): 429–37.
32. Lin Y, Tamakoshi A, Kawamura T, et al. Risk of pancreatic cancer in rela-
tion to alcohol drinking, coffee consumption and medical history: find-
ings from the Japan collaborative cohort study for evaluation of cancer
risk. Int J Cancer 2002; 99(5): 742–6.
33. Silverman DT, Schiffman M, Everhart J, et al. Diabetes mellitus, other
medical conditions and familial history of cancer as risk factors for pan-
creatic cancer. Br J Cancer 1999; 80(11): 1830–7.
34. Brown LM. Epidemiology of alcohol-associated cancers. Alcohol 2005;
35(3): 161–8.
35. Ye W, Lagergren J, Weiderpass E, et al. Alcohol abuse and the risk of pan-
creatic cancer. Gut 2002; 51(2): 236–9.
36. Bansal P, Sonnenberg A. Pancreatitis is a risk factor for pancreatic cancer.
Gastroenterology 1995; 109(1): 247–51.
37. Karlson BM, Ekbom A, Josefsson S, et al. The risk of pancreatic cancer
following pancreatitis: an association due to confounding? Gastroenter-
ology 1997; 113(2): 587–92.
38. Lowenfels AB, Maisonneuve P. Risk factors for pancreatic cancer. J Cell
Biochem 2005; 95(4): 649–56.
39. Talamini G, Falconi M, Bassi C, et al. Incidence of cancer in the course of
chronic pancreatitis. Am J Gastroenterol 1999; 94(5): 1253–60.
40. Howes N, Neoptolemos JP. Risk of pancreatic ductal adenocarcinoma in
chronic pancreatitis. Gut 2002; 51(6): 765–6.
41. Chari ST. Detecting early pancreatic cancer: problems and prospects.
Semin Oncol 2007; 34(4): 284–94.
42. Coughlin SS, Calle EE, Teras LR, et al. Diabetes mellitus as a predictor of
cancer mortality in a large cohort of US adults. Am J Epidemiol 2004;
159(12): 1160–7.
43. Huxley R, Ansary-Moghaddam A, Berrington de González A, et al. Type-
II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Can-
cer 2005; 92(11): 2076–83.
44. Stolzenberg-Solomon RZ, Graubard BI, Chari S, et al. Insulin, glucose,
insulin resistance, and pancreatic cancer in male smokers. JAMA 2005;
294(22): 2872–8.
45. Wideroff L, Gridley G, Mellemkjaer L, et al. Cancer incidence in a popu-
lation-based cohort of patients hospitalized with diabetes mellitus in
Denmark. J Natl Cancer Inst 1997; 89(18): 1360–5.
46. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic can-
cer. A meta-analysis. JAMA 1995; 273(20): 1605–9.
47. McWilliams RR, Rabe KG, Olswold C, et al. Risk of malignancy in first-
degree relatives of patients with pancreatic carcinoma. Cancer 2005;
104(2): 388–94.
48. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic
cancer in familial pancreatic cancer kindreds. Cancer Res 2004; 64(7):
2634–8.
49. Bartsch DK, Kress R, Sina-Frey M, et al. Prevalence of familial pancreatic
cancer in Germany. Int J Cancer 2004; 110(6): 902–6.
50. Hemminki K, Li X. Familial and second primary pancreatic cancers: a
nationwide epidemiologic study from Sweden. Int J Cancer 2003; 103(4):
525–30.
51. Brand RE, Lerch MM, Rubinstein WS, et al. Advances in counselling and
surveillance of patients at risk for pancreatic cancer. Gut 2007; 56(10):
1460–9.
52. Tersmette AC, Petersen GM, Offerhaus GJ, et al. Increased risk of inci-
dent pancreatic cancer among first-degree relatives of patients with
familial pancreatic cancer. Clin Cancer Res 2001; 7(3): 738–44.
53. McFaul CD, Greenhalf W, Earl J, et al. Anticipation in familial pancreatic
cancer. Gut 2006; 55(2): 252–8.
54. Pogue-Geile KL, Chen R, Bronner MP, et al. Palladin mutation causes
familial pancreatic cancer and suggests a new cancer mechanism. PLoS
Med 2006; 3(12): e516.
55. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes
MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer:
deleterious BRCA2 mutations in 17%. Cancer Res 2002; 62(13):
3789–93.
56. Hahn SA, Greenhalf B, Ellis I, et al. BRCA2 germline mutations in famil-
ial pancreatic carcinoma. J Natl Cancer Inst 2003; 95(3): 214–21.
57. Couch FJ, Johnson MR, Rabe KG, et al. The prevalence of BRCA2 muta-
tions in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev
2007; 16(2): 342–6.
58. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk
of pancreatic cancer. International Pancreatitis Study Group. N Engl J
Med 1993; 328(20): 1433–7.
59. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is
caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;
14(2): 141–5.
60. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the
serine protease inhibitor, Kazal type 1 are associated with chronic pan-
creatitis. Nat Genet 2000; 25(2): 213–6.
61. Maisonneuve P, FitzSimmons SC, Neglia JP, et al. Cancer risk in non-
transplanted and transplanted cystic fibrosis patients: a 10-year study.
J Natl Cancer Inst 2003; 95(5): 381–7.
62. Neglia JP, FitzSimmons SC, Maisonneuve P, et al. The risk of cancer
among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study
Group. N Engl J Med 1995; 332(8): 494–9.
63. Adler G, Seufferlein T, Bischoff SC, et al. [S3-Guidelines “Exocrine pan-
creatic cancer” 2007]. Z Gastroenterol 2007; 45(6): 487–523.
64. Solcia E, Capella C, Kloppel G. Tumors of the Pancreas. Washington, DC:
Armed Forces Institute of Pathology, 1997.
65. Björnsson E, Ismael S, Nejdet S, Kilander A. Severe jaundice in Sweden in
the new millennium: causes, investigations, treatment and prognosis.
Scand J Gastroenterol 2003; 38(1): 86–94.
66. Reisman Y, Gips CH, Lavelle SM, Wilson JH. Clinical presentation of
(subclinical) jaundice--the Euricterus project in The Netherlands.
395
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
United Dutch Hospitals and Euricterus Project Management Group.
Hepatogastroenterology 1996; 43(11): 1190–5.
67. Watanabe I, Sasaki S, Konishi M, et al. Onset symptoms and tumor loca-
tions as prognostic factors of pancreatic cancer. Pancreas 2004; 28(2):
160–5.
68. Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a poten-
tial clue to the early diagnosis of pancreatic cancer. Lancet Oncol 2009;
10(1): 88–95.
69. Wang F, Herrington M, Larsson J, Permert J. The relationship between
diabetes and pancreatic cancer. Mol Cancer 2003; 2: 4.
70. Chari ST, Leibson CL, Rabe KG, et al. Probability of pancreatic cancer
following diabetes: a population-based study. Gastroenterology 2005;
129(2): 504–11.
71. Gambill EE. Pancreatitis associated with pancreatic carcinoma: a study
of 26 cases. Mayo Clin Proc 1971; 46(3): 174–7.
72. Homma T, Tsuchiya R. The study of the mass screening of persons
without symptoms and of the screening of outpatients with gastroin-
testinal complaints or icterus for pancreatic cancer in Japan, using
CA19-9 and elastase-1 or ultrasonography. Int J Pancreatol 1991; 9:
119–24.
73. Kim J, Lee KT, Lee JK, et al. Clinical usefulness of carbohydrate antigen
19-9 as a screening test for pancreatic cancer in an asymptomatic popu-
lation. J Gastroenterol Hepatol 2004; 19(2): 182–6.
74. Ritts RE, Nagorney DM, Jacobsen DJ, et al. Comparison of preoperative
serum CA19-9 levels with results of diagnostic imaging modalities in
patients undergoing laparotomy for suspected pancreatic or gallbladder
disease. Pancreas 1994; 9(6): 707–16.
75. Schlieman MG, Ho HS, Bold RJ. Utility of tumor markers in determining
resectability of pancreatic cancer. Arch Surg 2003; 138(9): 951–5; discus-
sion 955–6.
76. Balci NC, Semelka RC. Radiologic diagnosis and staging of pancreatic
ductal adenocarcinoma. Eur J Radiol 2001; 38(2): 105–12.
77. McCarthy MJ, Evans J, Sagar G, Neoptolemos JP. Prediction of resect-
ability of pancreatic malignancy by computed tomography. Br J Surg
1998; 85(3): 320–5.
78. Chong M, Freeny PC, Schmiedl UP. Pancreatic arterial anatomy: depic-
tion with dual-phase helical CT. Radiology 1998; 208(2): 537–42.
79. Vedantham S, Lu DS, Reber HA, Kadell B. Small peripancreatic veins:
improved assessment in pancreatic cancer patients using thin-section
pancreatic phase helical CT. AJR 1998; 170(2): 377–83.
80. Bronstein YL, Loyer EM, Kaur H, et al. Detection of small pancreatic
tumors with multiphasic helical CT. AJR 2004; 182(3): 619–23.
81. Erkan M, Michalski CW, Rieder S, et al. The activated stroma index is a
novel and independent prognostic marker in pancreatic ductal adeno-
carcinoma. Clin Gastroenterol Hepatol 2008; 6(10): 1155–61.
82. Lu DS, Reber HA, Krasny RM, et al. Local staging of pancreatic cancer:
criteria for unresectability of major vessels as revealed by pancreatic-
phase, thin-section helical CT. AJR 1997; 168(6): 1439–43.
83. Li H, Zeng MS, Zhou KR, et al. Pancreatic adenocarcinoma: the different
CT criteria for peripancreatic major arterial and venous invasion.
J Comput Assist Tomogr 2005; 29(2): 170–5.
84. Roche CJ, Hughes ML, Garvey CJ, et al. CT and pathologic assessment of
prospective nodal staging in patients with ductal adenocarcinoma of the
head of the pancreas. AJR; 180(2): 475–80.
85. Ichikawa T, Haradome H, Hachiya J, et al. Pancreatic ductal adenocarci-
noma: preoperative assessment with helical CT versus dynamic MR
imaging. Radiology 1997; 202(3): 655–62.
86. Megibow AJ, Zhou XH, Rotterdam H, et al. Pancreatic adenocarci-
noma: CT versus MR imaging in the evaluation of resectability—
report of the Radiology Diagnostic Oncology Group. Radiology 1995;
195(2): 327–32.
87. Arslan A, Buanes T, Geitung JT. Pancreatic carcinoma: MR, MR angiog-
raphy and dynamic helical CT in the evaluation of vascular invasion. Eur
J Radiol 2001; 38(2): 151–9.
88. Fayad LM, Mitchell DG. Magnetic resonance imaging of pancreatic ade-
nocarcinoma. Int J Gastrointest Cancer 2001; 30(1–2): 19–25.
89. Reiser-Erkan C, Gaa J, Kleeff J. T1 pancreatic cancer with lymph node
metastasis and perineural invasion of the celiac trunk. Clin Gastroen-
terol Hepatol 2008; 6(11): e41–2.
396
90. Rösch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endo-
crine tumors by endoscopic ultrasonography. N Engl J Med 1992;
326(26): 1721–6.
91. Rösch T, Dittler HJ, Strobel K, et al. Endoscopic ultrasound criteria
for vascular invasion in the staging of cancer of the head of the pancreas:
a blind reevaluation of videotapes. Gastrointest Endosc 2000; 52(4):
469–77.
92. Volmar KE, Vollmer RT, Routbort MJ, Creager AJ. Pancreatic and bile
duct brushing cytology in 1000 cases: review of findings and comparison
of preparation methods. Cancer 2006; 108(4): 231–8.
93. Mertz HR, Sechopoulos P, Delbeke D, Leach SD. EUS, PET, and CT scan-
ning for evaluation of pancreatic adenocarcinoma. Gastrointest Endosc
2000; 52(3): 367–71.
94. Howard TJ, Chin AC, Streib EW, et al. Value of helical computed tomog-
raphy, angiography, and endoscopic ultrasound in determining resect-
ability of periampullary carcinoma. Am J Surg 1997; 174(3): 237–41.
95. Aslanian H, Salem R, Lee J, et al. EUS diagnosis of vascular invasion in
pancreatic cancer: surgical and histologic correlates. Am J Gastroenterol
2005; 100(6): 1381–5.
96. Raut CP, Grau AM, Staerkel GA, et al. Diagnostic accuracy of endoscopic
ultrasound-guided fine-needle aspiration in patients with presumed
pancreatic cancer. J Gastrointest Surg 2003; 7(1): 118–26; discussion
127–8.
97. Agarwal B, Abu-Hamda E, Molke KL, et al. Endoscopic ultrasound-
guided fine needle aspiration and multidetector spiral CT in the diagno-
sis of pancreatic cancer. Am J Gastroenterol 2004; 99(5): 844–50.
98. Varadarajulu S, Tamhane A, Eloubeidi MA. Yield of EUS-guided FNA of
pancreatic masses in the presence or the absence of chronic pancreatitis.
Gastrointest Endosc 2005; 62(5): 728–36; quiz 751, 753.
99. Klapman JB, Chang KJ, Lee JG, Nguyen P. Negative predictive value
of endoscopic ultrasound in a large series of patients with a clinical
suspicion of pancreatic cancer. Am J Gastroenterol 2005; 100(12):
2658–61.
100. Shreve PD. Focal fluorine-18 fluorodeoxyglucose accumulation in
inflammatory pancreatic disease. Eur J Nucl Med 1998; 25(3): 259–64.
101. Sendler A, Avril N, Helmberger H, et al. Preoperative evaluation of pan-
creatic masses with positron emission tomography using 18F-fluorode-
oxyglucose: diagnostic limitations. World J Surg 2000; 24(9): 1121–9.
102. Warshaw AL, Tepper JE, Shipley WU. Laparoscopy in the staging and
planning of therapy for pancreatic cancer. Am J Surg 1986; 151(1):
76–80.
103. Warshaw AL, Gu ZY, Wittenberg J, Waltman AC. Preoperative staging
and assessment of resectability of pancreatic cancer. Arch Surg 1990;
125(2): 230–3.
104. Conlon KC, Dougherty E, Klimstra DS, et al. The value of minimal access
surgery in the staging of patients with potentially resectable peripancre-
atic malignancy. Ann Surg 1996; 223(2): 134–40.
105. Friess H, Kleeff J, Silva JC, et al. The role of diagnostic laparoscopy in
pancreatic and periampullary malignancies. J Am Coll Surg 1998; 186(6):
675–82.
106. Barreiro CJ, Lillemoe KD, Koniaris LG, et al. Diagnostic laparoscopy for
periampullary and pancreatic cancer: what is the true benefit? J Gastro-
intest Surg 2002; 6(1): 75–81.
107. Pisters PW, Lee JE, Vauthey JN, et al. Laparoscopy in the staging of pan-
creatic cancer. Br J Surg 2001; 88(3): 325–37.
108. Katz A, Hanlon A, Lanciano R, et al. Prognostic value of CA 19-9 levels in
patients with carcinoma of the pancreas treated with radiotherapy. Int J
Radiat Oncol Biol Phys 1998; 41(2): 393–6.
109. Mallery JS, Baron TH, Dominitz JA, et al. Complications of ERCP. Gas-
trointest Endosc 2003; 57(6): 633–8.
110. Freeman ML. Adverse outcomes of endoscopic retrograde cholangio-
pancreatography: avoidance and management. Gastrointest Endosc Clin
N Am 2003; 13(4): 775–98, xi.
111. Stewart CJ, Mills PR, Carter R, et al. Brush cytology in the assessment of
pancreatico-biliary strictures: a review of 406 cases. J Clin Pathol 2001;
54(6): 449–55.
112. Povoski SP, Karpeh MS, Conlon KC, et al. Association of preoperative
biliary drainage with postoperative outcome following pancreaticoduo-
denectomy. Ann Surg 1999; 230(2): 131–42.
 ADENOCARCINOMA OF THE PANCREAS
113. Pisters PW, Hudec WA, Hess KR, et al. Effect of preoperative biliary
decompression on pancreaticoduodenectomy-associated morbidity in
300 consecutive patients. Ann Surg 2001; 234(1): 47–55.
114. Sewnath ME, Karsten TM, Prins MH, et al. A meta-analysis on the effi-
cacy of preoperative biliary drainage for tumors causing obstructive
jaundice. Ann Surg 2002; 236(1): 17–27.
115. Sohn TA, Yeo CJ, Cameron JL, et al. Do preoperative biliary stents
increase postpancreaticoduodenectomy complications? J Gastrointest
Surg 2000; 4(3): 258–67; discussion 267–8.
116. Martignoni ME, Wagner M, Krähenbühl L, et al. Effect of preoperative
biliary drainage on surgical outcome after pancreatoduodenectomy. Am
J Surg 2001; 181(1): 52–9; discussion 87.
117. Schwarz RE. Technical considerations to maintain a low frequency of
postoperative biliary stent-associated infections. J Hepatobiliary Pan-
creat Surg 2002; 9(1): 93–7.
118. Jagannath P, Dhir V, Shrikhande S, et al. Effect of preoperative biliary
stenting on immediate outcome after pancreaticoduodenectomy. Br J
Surg 2005; 92(3): 356–61.
119. Lai EC, Mok FP, Fan ST, et al. Preoperative endoscopic drainage for
malignant obstructive jaundice. Br J Surg 1994; 81(8): 1195–8.
120. Pitt HA, Gomes AS, Lois JF, et al. Does preoperative percutaneous biliary
drainage reduce operative risk or increase hospital cost? Ann Surg 1985;
201(5): 545–53.
121. Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative
resection for pancreatic ductal adenocarcinoma. Clinicopathologic anal-
ysis of 5-year survivors. Ann Surg 1996; 223(3): 273–9.
122. Kim HJ, Czischke K, Brennan MF, Conlon KC. Does neoadjuvant chemo-
radiation downstage locally advanced pancreatic cancer? J Gastrointest
Surg 2002; 6(5): 763–9.
123. Espat NJ, Brennan MF, Conlon KC. Patients with laparoscopically staged
unresectable pancreatic adenocarcinoma do not require subsequent
surgical biliary or gastric bypass. J Am Coll Surg 1999; 188(6): 649–55;
discussion 655–7.
124. Whipple AO, Parsons WB, Mullins CR. Treatment of Carcinoma of the
Ampulla of Vater. Ann Surg 1935; 102(4): 763–79.
125. Traverso LW, Longmire WP. Preservation of the pylorus in pancreatico-
duodenectomy. Surg Gynecol Obstet 1978; 146(6): 959–62.
126. Jones L, Russell C, Mosca F, et al. Standard Kausch-Whipple pancreato-
duodenectomy. Dig Surg 1999; 16(4): 297–304.
127. Pedrazzoli S, Beger HG, Obertop H, et al. A surgical and pathological
based classification of resective treatment of pancreatic cancer. Summary
of an international workshop on surgical procedures in pancreatic can-
cer. Dig Surg 1999; 16(4): 337–45.
128. Seiler CA, Wagner M, Sadowski C, et al. Randomized prospective trial of
pylorus-preserving vs. Classic duodenopancreatectomy (Whipple proce-
dure): initial clinical results. J Gastrointest Surg 2000; 4(5): 443–52.
129. Williamson RC, Bliouras N, Cooper MJ, Davies ER. Gastric emptying
and enterogastric reflux after conservative and conventional pancreato-
duodenectomy. Surgery 1993; 114(1): 82–6.
130. Zerbi A, Balzano G, Patuzzo R, et al. Comparison between pylorus-pre-
serving and Whipple pancreatoduodenectomy. Br J Surg 1995; 82(7):
975–9.
131. Mosca F, Giulianotti PC, Balestracci T, et al. Long-term survival in pan-
creatic cancer: pylorus-preserving versus Whipple pancreatoduodenec-
tomy. Surgery 1997; 122(3): 553–66.
132. Diener MK, Heukaufer C, Schwarzer G, et al. Pancreaticoduodenectomy
(classic Whipple) versus pylorus-preserving pancreaticoduodenectomy
(pp Whipple) for surgical treatment of periampullary and pancreatic
carcinoma. Cochrane Database Syst Rev 2008; (2): CD006053.
133. Lerut JP, Gianello PR, Otte JB, Kestens PJ. Pancreaticoduodenal resec-
tion. Surgical experience and evaluation of risk factors in 103 patients.
Ann Surg 1984; 199(4): 432–7.
134. Herter FP, Cooperman AM, Ahlborn TN, Antinori C. Surgical experience
with pancreatic and periampullary cancer. Ann Surg 1982; 195(3): 274–81.
135. Aston SJ, Longmire WP. Pancreaticoduodenal resection. Twenty years’
experience. Arch Surg 1973; 106(6): 813–7.
136. Wente MN, Shrikhande SV, Müller MW, et al. Pancreaticojejunostomy
versus pancreaticogastrostomy: systematic review and meta-analysis. Am
J Surg 2007; 193(2): 171–83.
137. Sikora SS, Posner MC. Management of the pancreatic stump following
pancreaticoduodenectomy. Br J Surg 1995; 82(12): 1590–7.
138. Bassi C, Falconi M, Molinari E, et al. Duct-to-mucosa versus end-to-side
pancreaticojejunostomy reconstruction after pancreaticoduodenec-
tomy: results of a prospective randomized trial. Surgery 2003; 134(5):
766–71.
139. Balcom JH, Rattner DW, Warshaw AL, et al. Ten-year experience with
733 pancreatic resections: changing indications, older patients, and
decreasing length of hospitalization. Arch Surg 2001; 136(4): 391–8.
140. Japanese Pancreatic Society. Classification of Pancreatic Carcinoma, 2nd
edn. Tokyo: Kanehara, 2003.
141. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with
or without distal gastrectomy and extended retroperitoneal lymphade-
nectomy for periampullary adenocarcinoma, part 2: randomized con-
trolled trial evaluating survival, morbidity, and mortality. Ann Surg
2002; 236(3): 355–66; discussion 366–8.
142. Pedrazzoli S, DiCarlo V, Dionigi R, et al. Standard versus extended
lymphadenectomy associated with pancreatoduodenectomy in the sur-
gical treatment of adenocarcinoma of the head of the pancreas: a multi-
center, prospective, randomized study. Lymphadenectomy Study Group.
Ann Surg 1998; 228(4): 508–17.
143. Farnell MB, Pearson RK, Sarr MG, et al. A prospective randomized trial
comparing standard pancreatoduodenectomy with pancreatoduodenec-
tomy with extended lymphadenectomy in resectable pancreatic head
adenocarcinoma. Surgery 2005; 138(4): 618–28; discussion 628–30.
144. Riall TS, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with
or without distal gastrectomy and extended retroperitoneal lymphade-
nectomy for periampullary adenocarcinoma—part 3: update on 5-year
survival. J Gastrointest Surg 2005; 9(9): 1191–204; discussion 1204–6.
145. Michalski CW, Kleeff J, Wente MN, et al. Systematic review and meta-
analysis of standard and extended lymphadenectomy in pancreaticoduo-
denectomy for pancreatic cancer. Br J Surg 2007; 94(3): 265–73.
146. Leach SD, Lee JE, Charnsangavej C, et al. Survival following pancreatico-
duodenectomy with resection of the superior mesenteric-portal vein
confluence for adenocarcinoma of the pancreatic head. Br J Surg 1998;
85(5): 611–7.
147. Bachellier P, Nakano H, Oussoultzoglou PD, et al. Is pancreaticoduode-
nectomy with mesentericoportal venous resection safe and worthwhile?
Am J Surg 2001; 182(2): 120–9.
148. Nakao A, Takeda S, Inoue S, et al. Indications and techniques of extended
resection for pancreatic cancer. World J Surg 2006; 30(6): 976–82; discus-
sion 983–4.
149. Sasson AR, Hoffman JP, Ross EA, et al. En bloc resection for locally
advanced cancer of the pancreas: is it worthwhile? J Gastrointest Surg
6(2): 147–57; discussion 157–8.
150. Nakagohri T, Kinoshita T, Konishi M, et al. Survival benefits of portal
vein resection for pancreatic cancer. Am J Surg 2003; 186(2): 149–53.
151. van Geenen RC, ten Kate FJ, de Wit LT, et al. Segmental resection and
wedge excision of the portal or superior mesenteric vein during pancre-
atoduodenectomy. Surgery 2001; 129(2): 158–63.
152. Weitz J, Kienle P, Schmidt J, et al. Portal vein resection for advanced pan-
creatic head cancer. J Am Coll Surg 2007; 204(4): 712–6.
153. Stitzenberg KB, Watson JC, Roberts A, et al. Survival after pancreatec-
tomy with major arterial resection and reconstruction. Ann Surg Oncol
2008; 15(5): 1399–406.
154. Yekebas EF, Bogoevski D, Cataldegirmen G, et al. En bloc vascular resec-
tion for locally advanced pancreatic malignancies infiltrating major
blood vessels: perioperative outcome and long-term survival in
136 patients. Ann Surg 2008; 247(2): 300–9.
155. Hirano S, Kondo S, Hara T, et al. Distal pancreatectomy with en bloc
celiac axis resection for locally advanced pancreatic body cancer: long-
term results. Ann Surg 2007; 246(1): 46–51.
156. Gagandeep S, Artinyan A, Jabbour N, et al. Extended pancreatectomy
with resection of the celiac axis: the modified Appleby operation. Am J
Surg 2006; 192(3): 330–5.
157. Kondo S, Katoh H, Hirano S, et al. Results of radical distal pancreatec-
tomy with en bloc resection of the celiac artery for locally advanced
cancer of the pancreatic body. Langenbecks Arch Surg 2003; 388(2):
101–6.
397
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
158. Shrikhande SV, Kleeff J, Reiser C, et al. Pancreatic resection for M1 pan-
creatic ductal adenocarcinoma. Ann Surg Oncol 2007; 14(1): 118–27.
159. Gleisner AL, Assumpcao L, Cameron JL, et al. Is resection of periampul-
lary or pancreatic adenocarcinoma with synchronous hepatic metastasis
justified? Cancer 2007; 110(11): 2484–92.
160. Allendorf JD, Lauerman M, Bill A, et al. Neoadjuvant chemotherapy and
radiation for patients with locally unresectable pancreatic adenocarci-
noma: feasibility, efficacy, and survival. J Gastrointest Surg 2008; 12(1):
91–100.
161. Krempien R, Muenter MW, Harms W, Debus J. Neoadjuvant chemora-
diation in patients with pancreatic adenocarcinoma. HPB (Oxford)
2006; 8(1): 22–8.
162. Kleeff J, Friess H, Büchler MW. Neoadjuvant therapy for pancreatic
cancer. Br J Surg 2007; 94(3): 261–2.
163. Sohn TA, Lillemoe KD, Cameron JL, et al. Reexploration for periampul-
lary carcinoma: resectability, perioperative results, pathology, and long-
term outcome. Ann Surg 1999; 229(3): 393–400.
164. Michalski CW, Kleeff J, Bachmann J, et al. Second-look operation for
unresectable pancreatic ductal adenocarcinoma at a high-volume center.
Ann Surg Oncol 2008; 15(1): 186–92.
165. Gouma DJ, van Geenen RC, van Gulik TM, et al. Rates of complications
and death after pancreaticoduodenectomy: risk factors and the impact of
hospital volume. Ann Surg 2000; 232(6): 786–95.
166. Gordon TA, Bowman HM, Bass EB, et al. Complex gastrointestinal sur-
gery: impact of provider experience on clinical and economic outcomes.
J Am Coll Surg 1999; 189(1): 46–56.
167. Gordon TA, Bowman HM, Tielsch JM, et al. Statewide regionalization of
pancreaticoduodenectomy and its effect on in-hospital mortality. Ann
Surg 1998; 228(1): 71–8.
168. Gordon TA, Burleyson GP, Tielsch JM, Cameron JL. The effects of
regionalization on cost and outcome for one general high-risk surgical
procedure. Ann Surg 1995; 221(1): 43–9.
169. Birkmeyer JD, Finlayson SR, Tosteson AN, et al. Effect of hospital volume
on in-hospital mortality with pancreaticoduodenectomy. Surgery 1999;
125(3): 250–6.
170. Birkmeyer JD, Siewers AE, Finlayson EVA, et al. Hospital volume and
surgical mortality in the United States. N Engl J Med 2002; 346(15):
1128–37.
171. Birkmeyer JD, Sun Y, Wong SL, Stukel TA. Hospital volume and late sur-
vival after cancer surgery. Ann Surg 2007; 245(5): 777–83.
172. Ho V, Heslin MJ. Effect of hospital volume and experience on in-hospital
mortality for pancreaticoduodenectomy. Ann Surg 2003; 237(4): 509–14.
173. Lieberman MD, Kilburn H, Lindsey M, Brennan MF. Relation of periop-
erative deaths to hospital volume among patients undergoing pancreatic
resection for malignancy. Ann Surg 1995; 222(5): 638–45.
174. Simunovic M, To T, Theriault M, Langer B. Relation between hospital
surgical volume and outcome for pancreatic resection for neoplasm in a
publicly funded health care system. CMAJ 1999; 160(5): 643–8.
175. Begg CB, Cramer LD, Hoskins WJ, Brennan MF. Impact of hospital vol-
ume on operative mortality for major cancer surgery. JAMA 1998;
280(20): 1747–51.
176. Sosa JA, Bowman HM, Gordon TA, et al. Importance of hospital volume
in the overall management of pancreatic cancer. Ann Surg 1998; 228(3):
429–38.
177. Welsch T, Büchler MW, Schmidt J. Surgery for pancreatic cancer.
Z Gastroenterol 2008; 46(12): 1393–403.
178. Fong Y, Gonen M, Rubin D, et al. Long-term survival is superior after
resection for cancer in high-volume centers. Ann Surg 2005; 242(4):
540–4; discussion 544–7.
179. van Heek NT, Kuhlmann KFD, Scholten RJ, et al. Hospital volume and
mortality after pancreatic resection: a systematic review and an evalua-
tion of intervention in the Netherlands. Ann Surg 2005; 242(6): 781–8,
discussion 788–90.
180. Büchler MW, Wagner M, Schmied BM, et al. Changes in morbidity after
pancreatic resection: toward the end of completion pancreatectomy.
Arch Surg 2003; 138(12): 1310–4; discussion 1315.
181. Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduodenec-
tomies for pancreatic cancer: A single-institution experience. J Gastroin-
test Surg 2006; 10(9): 1199–210; discussion 1210–1.
398
182. Berberat PO, Friess H, Kleeff J, et al. Prevention and treatment of com-
plications in pancreatic cancer surgery. Dig Surg 1999; 16(4): 327–36.
183. Dimick JB, Pronovost PJ, Cowan JA, et al. Variation in postoperative
complication rates after high-risk surgery in the United States. Surgery
2003; 134(4): 534–40; discussion 540–1.
184. Cunningham JD, Weyant MT, Levitt M, et al. Complications requiring
reoperation following pancreatectomy. Int J Pancreatol 1998; 24(1):
23–9.
185. Farley DR, Schwall G, Trede M. Completion pancreatectomy for surgical
complications after pancreaticoduodenectomy. Br J Surg 1996; 83(2):
176–9.
186. Halloran CM, Ghaneh P, Bosonnet L, et al. Complications of pancreatic
cancer resection. Dig Surg 2002; 19(2): 138–46.
187. Welsch T, Frommhold K, Hinz U, et al. Persisting elevation of C-reactive
protein after pancreatic resections can indicate developing inflammatory
complications. Surgery 2008; 143(1): 20–8.
188. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancre-
aticoduodenectomies in the 1990s: pathology, complications, and
outcomes. Ann Surg 1997; 226(3): 248–57; discussion 257–60.
189. van Berge Henegouwen MI, van Gulik TM, DeWit LT, et al. Delayed gas-
tric emptying after standard pancreaticoduodenectomy versus pylorus-
preserving pancreaticoduodenectomy: an analysis of 200 consecutive
patients. J Am Coll Surg 1997; 185(4): 373–9.
190. Tran KTC, Smeenk HG, van Eijck CHJ, et al. Pylorus preserving pancre-
aticoduodenectomy versus standard Whipple procedure: a prospective,
randomized, multicenter analysis of 170 patients with pancreatic and
periampullary tumors. Ann Surg 2004; 240(5): 738–45.
191. Hartel M, Wente MN, Hinz U, et al. Effect of antecolic reconstruction on
delayed gastric emptying after the pylorus-preserving Whipple proce-
dure. Arch Surg 2005; 140(11): 1094–9.
192. Yeo CJ, Barry MK, Sauter PK, et al. Erythromycin accelerates gastric emp-
tying after pancreaticoduodenectomy. A prospective, randomized, pla-
cebo-controlled trial. Ann Surg 1993; 218(3): 229–37; discussion 237–8.
193. Böttger TC, Junginger T. Factors influencing morbidity and mortality
after pancreaticoduodenectomy: critical analysis of 221 resections.
World J Surg 1999; 23(2): 164–71; discussion 171–2.
194. Cullen JJ, Sarr MG, Ilstrup DM. Pancreatic anastomotic leak after pan-
creaticoduodenectomy: incidence, significance, and management. Am J
Surg 1994; 168(4): 295–8.
195. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula:
an international study group (ISGPF) definition. Surgery 2005; 138(1):
8–13.
196. Bassi C, Falconi M, Salvia R, et al. Management of complications after
pancreaticoduodenectomy in a high volume centre: results on 150 con-
secutive patients. Dig Surg 2001; 18(6): 453–7; discussion 458.
197. Sohn TA, Yeo CJ, Cameron JL, et al. Pancreaticoduodenectomy: role of
interventional radiologists in managing patients and complications.
J Gastrointest Surg 2003; 7(2): 209–19.
198. Tien Y, Lee P, Yang C, et al. Risk factors of massive bleeding related to
pancreatic leak after pancreaticoduodenectomy. J Am Coll Surg 2005;
201(4): 554–9.
199. Trede M, Schwall G. The complications of pancreatectomy. Ann Surg
1988; 207(1): 39–47.
200. Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage
(PPH): an International Study Group of Pancreatic Surgery (ISGPS)
definition. Surgery 2007; 142(1): 20–5.
201. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy for
cancer of the head of the pancreas. 201 patients. Ann Surg 1995; 221(6):
721–31; discussion 731–3.
202. Shimizu Y, Yasui K, Fuwa N, et al. Late complication in patients undergo-
ing pancreatic resection with intraoperative radiation therapy: gastroin-
testinal bleeding with occlusion of the portal system. J Gastroenterol
Hepatol 2005; 20(8): 1235–40.
203. de Castro SMM, Busch ORC, Gouma DJ. Management of bleeding and
leakage after pancreatic surgery. Best Pract Res Clin Gastroenterol 2004;
18(5): 847–64.
204. Brennan MF, Pisters PW, Posner M, et al. A prospective randomized trial
of total parenteral nutrition after major pancreatic resection for malig-
nancy. Ann Surg 1994; 220(4): 436–41; discussion 441–4.
 ADENOCARCINOMA OF THE PANCREAS
205. van Berge Henegouwen MI, Akkermans LM, van Gulik TM, et al. Pro-
spective, randomized trial on the effect of cyclic versus continuous
enteral nutrition on postoperative gastric function after pylorus-
preserving pancreatoduodenectomy. Ann Surg 1997; 226(6): 677–85;
discussion 685–7.
206. Berberat PO, Ingold H, Gulbinas A, et al. Fast track-different implica-
tions in pancreatic surgery. J Gastrointest Surg 2007; 11(7): 880–7.
207. Büchler MW, Friess H. Evidence forward, drainage on retreat: still we
ignore and drain!? Ann Surg 2006; 244(1): 8–9.
208. Kawai M, Tani M, Terasawa H, et al. Early removal of prophylactic drains
reduces the risk of intra-abdominal infections in patients with pancre-
atic head resection: prospective study for 104 consecutive patients. Ann
Surg 2006; 244(1): 1–7.
209. Connor S, Alexakis N, Garden OJ, et al. Meta-analysis of the value of
somatostatin and its analogues in reducing complications associated
with pancreatic surgery. Br J Surg 2005; 92(9): 1059–67.
210. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gem-
citabine vs observation in patients undergoing curative-intent resection
of pancreatic cancer: a randomized controlled trial. JAMA 2007; 297(3):
267–77.
211. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of
chemoradiotherapy and chemotherapy after resection of pancreatic can-
cer. N Engl J Med 2004; 350(12): 1200–10.
212. Stocken DD, Büchler MW, Dervenis C, et al. Meta-analysis of ran-
domised adjuvant therapy trials for pancreatic cancer. Br J Cancer 2005;
92(8): 1372–81.
213. Sener SF, Fremgen A, Menck HR, Winchester DP. Pancreatic cancer: a
report of treatment and survival trends for 100,313 patients diagnosed
from 1985–1995, using the National Cancer Database. J Am Coll Surg
1999; 189(1): 1–7.
214. Knaebel HP, Märten A, Schmidt J, et al. Phase III trial of postoperative
cisplatin, interferon alpha-2b, and 5-FU combined with external radia-
tion treatment versus 5-FU alone for patients with resected pancreatic
adenocarcinoma—CapRI: study protocol [ISRCTN62866759]. BMC
Cancer 2005; 5: 37.
215. Picozzi VJ, Kozarek RA, Traverso LW. Interferon-based adjuvant chemo-
radiation therapy after pancreaticoduodenectomy for pancreatic adeno-
carcinoma. Am J Surg 2003; 185(5): 476–80.
216. Crippa S, Domínguez I, Rodríguez JR, et al. Quality of life in pancreatic
cancer: analysis by stage and treatment. J Gastrointest Surg 2008; 12(5):
783–93; discussion 793–4.
217. Makary MA, Winter JM, Cameron JL, et al. Pancreaticoduodenectomy in
the very elderly. J Gastrointest Surg 2006; 10(3): 347–56.
218. Bilimoria KY, Bentrem DJ, Ko CY, et al. National failure to operate on
early stage pancreatic cancer. Ann Surg 2007; 246(2): 173–80.
219. Lüttges J, Vogel I, Menke M, et al. The retroperitoneal resection margin
and vessel involvement are important factors determining survival after
pancreaticoduodenectomy for ductal adenocarcinoma of the head of the
pancreas. Virchows Arch 1998; 433(3): 237–42.
220. Delcore R, Rodriguez FJ, Forster J, et al. Significance of lymph node
metastases in patients with pancreatic cancer undergoing curative resec-
tion. Am J Surg 1996; 172(5): 463–8; discussion 468–9.
221. Millikan KW, Deziel DJ, Silverstein JC, et al. Prognostic factors associated
with resectable adenocarcinoma of the head of the pancreas. Am Surg
1999; 65(7): 618–23; discussion 623–4.
222. Raut CP, Tseng JF, Sun CC, et al. Impact of resection status on pattern of
failure and survival after pancreaticoduodenectomy for pancreatic ade-
nocarcinoma. Ann Surg 2007; 246(1): 52–60.
223. Benassai G, Mastrorilli M, Quarto G, et al. Survival after pancreaticoduo-
denectomy for ductal adenocarcinoma of the head of the pancreas. Chir
Ital 2000; 52(3): 263–70.
224. Schnelldorfer T, Ware AL, Sarr MG, et al. Long-term survival after pan-
creatoduodenectomy for pancreatic adenocarcinoma: is cure possible?
Ann Surg 2008; 247(3): 456–62.
225. Carpelan-Holmström M, Nordling S, Pukkala E, et al. Does anyone sur-
vive pancreatic ductal adenocarcinoma? A nationwide study re-evaluat-
ing the data of the Finnish Cancer Registry. Gut 2005; 54(3): 385–7.
226. Evans DB, Abbruzzese JL, Willett CG. Cancer of the pancreas. In: DeVita
VT, Hellman S, Rosenberg SA, eds. Cancer—Principles and Practice of
Oncology, 6th edn. Philadelphia: Lippincott Williams and Wilkins, 2001:
1126–61.
227. Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive
pancreaticoduodenectomies. Ann Surg 2006; 244(1): 10–5.
228. Lim JE, Chien MW, Earle CC. Prognostic factors following curative
resection for pancreatic adenocarcinoma: a population-based, linked
database analysis of 396 patients. Ann Surg 2003; 237(1): 74–85.
229. Meyer W, Jurowich C, Reichel M, et al. Pathomorphological and histo-
logical prognostic factors in curatively resected ductal adenocarcinoma
of the pancreas. Surg Today 2000; 30(7): 582–7.
230. Bouvet M, Gamagami RA, Gilpin EA, et al. Factors influencing survival
after resection for periampullary neoplasms. Am J Surg 2000; 180(1): 13–7.
231. Cameron JL, Crist DW, Sitzmann JV, et al. Factors influencing survival
after pancreaticoduodenectomy for pancreatic cancer. Am J Surg 1991;
161(1): 120–4; discussion 124–5.
232. Allema JH, Reinders ME, van Gulik TM, et al. Prognostic factors for sur-
vival after pancreaticoduodenectomy for patients with carcinoma of the
pancreatic head region. Cancer 1995; 75(8): 2069–76.
233. Welsch T, Kleeff J, Friess H. Molecular pathogenesis of pancreatic cancer:
advances and challenges. Curr Mol Med 2007; 7(5): 504–21.
234. Wagner M, Redaelli C, Lietz M, et al. Curative resection is the single most
important factor determining outcome in patients with pancreatic ade-
nocarcinoma. Br J Surg 2004; 91(5): 586–94.
235. Pawlik TM, Gleisner AL, Cameron JL, et al. Prognostic relevance of
lymph node ratio following pancreaticoduodenectomy for pancreatic
cancer. Surgery 2007; 141(5): 610–8.
236. Kuhlmann KFD, de Castro SMM, Wesseling JG, et al. Surgical treatment
of pancreatic adenocarcinoma; actual survival and prognostic factors in
343 patients. Eur J Cancer 2004; 40(4): 549–58.
237. Shimada K, Sakamoto Y, Sano T, Kosuge T. Prognostic factors after distal
pancreatectomy with extended lymphadenectomy for invasive pancre-
atic adenocarcinoma of the body and tail. Surgery 2006; 139(3): 288–95.
238. Takahashi T, Niino N, Ishikura H, et al. Predictive factors for long-term
survival in patients with pancreatic carcinoma. Hepatogastroenterology
1997; 44(17): 1463–8.
239. Ozaki H, Hiraoka T, Mizumoto R, et al. The prognostic significance of
lymph node metastasis and intrapancreatic perineural invasion in pan-
creatic cancer after curative resection. Surg Today 1999; 29(1): 16–22.
240. Cleary SP, Gryfe R, Guindi M, et al. Prognostic factors in resected pancre-
atic adenocarcinoma: analysis of actual 5-year survivors. J Am Coll Surg
2004; 198(5): 722–31.
241. Han S, Jang J, Kim S, et al. Analysis of long-term survivors after surgical
resection for pancreatic cancer. Pancreas 2006; 32(3): 271–5.
242. Connor S, Bosonnet L, Ghaneh P, et al. Survival of patients with periam-
pullary carcinoma is predicted by lymph node 8a but not by lymph node
16b1 status. Br J Surg 2004; 91(12): 1592–9.
243. Tseng JF, Raut CP, Lee JE, et al. Pancreaticoduodenectomy with vascular
resection: margin status and survival duration. J Gastrointest Surg 2004;
8(8): 935–49; discussion 949–50.
244. Geer RJ, Brennan MF. Prognostic indicators for survival after resection of
pancreatic adenocarcinoma. Am J Surg 1993; 165(1): 68–72; discussion
72–3.
245. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection mar-
gins on survival for patients with pancreatic cancer treated by adjuvant
chemoradiation and/or chemotherapy in the ESPAC-1 randomized con-
trolled trial. Ann Surg 2001; 234(6): 758–68.
246. Verbeke CS, Leitch D, Menon KV, et al. Redefining the R1 resection in
pancreatic cancer. Br J Surg 2006; 93(10): 1232–7.
247. Esposito I, Kleeff J, Bergmann F, et al. Most pancreatic cancer resections
are R1 resections. Ann Surg Oncol 2008; 15(6): 1651–60.
248. Bueno de Mesquita HB, Maisonneuve P, et al. Intake of foods and nutri-
ents and cancer of the exocrine pancreas: a population-based case-
control study in the Netherlands. Int J Cancer 1991; 48(4): 540–9.
249. Lyon JL, Slattery ML, Mahoney AW, Robison LM. Dietary intake as a risk
factor for cancer of the exocrine pancreas. Cancer Epidemiol Biomarkers
Prev 1993; 2(6): 513–8.
250. Larsson SC, Håkansson N, Näslund I, et al. Fruit and vegetable consump-
tion in relation to pancreatic cancer risk: a prospective study. Cancer
Epidemiol Biomarkers Prev 2006; 15(2): 301–5.
399
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
251. Lin Y, Tamakoshi A, Hayakawa T, et al. Nutritional factors and risk of
pancreatic cancer: a population-based case-control study based on direct
interview in Japan. J Gastroenterol 2005; 40(3): 297–301.
252. Anderson KE, Sinha R, Kulldorff M, et al. Meat intake and cooking tech-
niques: associations with pancreatic cancer. Mutat Res 2002; 506–507:
225–31.
253. Anderson KE, Kadlubar FF, Kulldorff M, et al. Dietary intake of hetero-
cyclic amines and benzo(a)pyrene: associations with pancreatic cancer.
Cancer Epidemiol Biomarkers Prev 2005; 14(9): 2261–5.
254. Ghadirian P, Baillargeon J, Simard A, Perret C. Food habits and pancre-
atic cancer: a case-control study of the Francophone community in
Montreal, Canada. Cancer Epidemiol Biomarkers Prev 1995; 4(8): 895–9.
255. Michaud DS, Liu S, Giovannucci E, et al. Dietary sugar, glycemic load,
and pancreatic cancer risk in a prospective study. J Natl Cancer Inst 2002;
94(17): 1293–300.
256. Silvera SAN, Rohan TE, Jain M, et al. Glycemic index, glycemic load, and
pancreatic cancer risk (Canada). Cancer Causes Control 2005; 16(4): 431–6.
257. Harnack LJ, Anderson KE, Zheng W, et al. Smoking, alcohol, coffee, and tea
intake and incidence of cancer of the exocrine pancreas: the Iowa Women’s
Health Study. Cancer Epidemiol Biomarkers Prev 1997; 6(12): 1081–6.
258. La Vecchia C, Negri E, Franceschi S, D’, et al. Tea consumption and cancer
risk. Nutr Cancer 1992; 17(1): 27–31.
259. Tavani A, La Vecchia C. Coffee and cancer: a review of epidemiological
studies, 1990–1999. Eur J Cancer Prev 2000; 9(4): 241–56.
260. Silverman DT. Risk factors for pancreatic cancer: a case-control study
based on direct interviews. Teratog Carcinog Mutagen 2001; 21(1):
7–25.
261. Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE)
after pancreatic surgery: a suggested definition by the International Study
Group of Pancreatic Surgery (ISGPS). Surgery 2007; 142(5): 761–8.
400
262. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemo-
therapy useful for gallbladder carcinoma? A phase III multicenter pro-
spective randomized controlled trial in patients with resected
pancreaticobiliary carcinoma. Cancer 2002; 95(8): 1685–95.
263. Bakkevold KE, Arnesjø B, Dahl O, Kambestad B. Adjuvant combination
chemotherapy (AMF) following radical resection of carcinoma of the
pancreas and papilla of Vater--results of a controlled, prospective, ran-
domised multicentre study. Eur J Cancer 1993; 29A(5): 698–703.
264. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and
5-fluorouracil after curative resection of cancer of the pancreas and peri-
ampullary region: phase III trial of the EORTC gastrointestinal tract can-
cer cooperative group. Ann Surg 1999; 230(6): 776–82; discussion 782–4.
265. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine
chemotherapy before and after fluorouracil-based chemoradiation fol-
lowing resection of pancreatic adenocarcinoma: a randomized con-
trolled trial. JAMA 2008; 299(9): 1019–26.
266. Further evidence of effective adjuvant combined radiation and chemo-
therapy following curative resection of pancreatic cancer. Gastrointesti-
nal Tumor Study Group. Cancer 1987; 59(12): 2006–10.
267. Martignoni, ME, Friess H, Sell F, et al. Enteral nutrition prolongs delayed
gastric emptying in patients after Whipple resection. Am J Surg 2000;
180(1) (July): 18–23.
268. Habbe N, Langer P, Bartsch DK. Hereditäres Pankreaskarzinom. Chirurg
2008; 79: 1029–37.
269. van der Gaag NA, Rauws EA, van Eijck CH, et al. Preoperative biliary
drainage for cancer of the head of the pancreas. N Engl J Med 2010; 362:
129–37.
270. Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemotherapy
with fluorouracil plus folinic acid vs. gemcitabine following pancreatic
cancer resection: a randomized controlled trial. JAMA 2010; 304: 1073–81.
43 Palliation of pancreas cancer
Michael G. House and Keith D. Lillemoe
The surgical management of pancreatic adenocarcinoma is
focused largely on complete tumor extirpation in patients with
resectable tumors. Unfortunately, the majority of patients with
pancreatic adenocarcinoma have advanced stage disease at the
time of diagnosis and are not eligible for resection. Detectable
metastases and/or extensive locoregional disease is frequently
recognized during preoperative staging, thus consideration for
a potentially curative resection is appropriate in less than one-
fourth of all patients with pancreatic adenocarcinoma (1–4).
Even though high-resolution cross-sectional imaging and other
dedicated staging modalities (e.g., pancreatic endoscopic
ultrasound) have obviated the need for routine operative
exploration to assess resectability in most patients, occult
metastases or celiac/mesenteric vascular invasion precluding
complete resection will be discovered at the time of exploration
in approximately 20% of patients with localized, apparently
resectable tumors on preoperative imaging (5,6).
Symptom palliation becomes the goal of therapy for the
majority of patients with pancreatic adenocarcinoma whose
disease is not amenable to a potentially curative resection.
Depending on individual performance status and medical
co-morbidities, the life expectancy for all patients with unre-
sectable cancer is typically less than 1 year. Patients with
nonmetastatic, locally advanced cancer experience a median
survival on the order of 9 to 12 months, whereas metastatic
pancreatic adenocarcinoma is typically associated with a
median survival of less than 6 months (1,7–10). Adequate
palliation of biliary and duodenal obstruction, and most
importantly control of cancer-related pain, has been shown to
improve quality of life (10–18). Therefore, every attempt,
whether nonoperative or operative, should be made to palliate
obstruction and relieve pain in virtually all patients with unre-
sectable pancreatic cancer who have a reasonable life expec-
tancy. Contrarily, the benefits of palliative treatments must be
weighed against the potential morbidity associated with them.
Therefore, it is difficult to advocate prophylactic palliative
procedures for asymptomatic patients, many of whom are at
uncertain risk for developing symptoms prior to death.
Operative treatment has served as the traditional modality
for palliating the symptoms associated with locally advanced
pancreatic cancer. However, nonoperative therapies offered by
endoscopists and interventional radiologists have proved to be
reliable and durable in select patients with biliary and/or
duodenal obstruction (19,20). A decision to pursue operative
versus nonoperative palliation typically arises in two clinical
scenarios. For patients undergoing open exploration for
equivocal radiographic signs of unresectability, operative pal-
liation is almost always indicated for those found to have
nonmetastatic (or low-volume metastatic), locally unresect-
able disease intraoperatively. In experienced hands, operative
biliary and gastric bypass procedures should not add
considerable morbidity to the actual laparotomy and
exploration (12,18,21). For patients with unequivocal evidence
of unresectable or metastatic disease during preoperative
evaluation, endoluminal methods for biliary and gastroduo-
denal stenting should be attempted when clinical findings of
obstruction are present or imminent. Operative bypass
procedures should be reserved for treatment failures of
nonoperative methods (i.e., endoscopic or percutaneous) in
patients who otherwise have reasonable life expectancy.
indications for palliation of pancreatic
cancer
The majority of pancreatic adenocarcinomas arise in the head
of the pancreas and possess a desmoplastic biology. Not
surprisingly, 80% of patients with pancreatic adenocarcinoma
will seek medical attention for symptoms related to jaundice
secondary to mechanical obstruction of the intrapancreatic
portion of the distal common bile duct (16,22). Obstructive
jaundice is the most common presenting symptom for patients
with periampullary cancer, and if left untreated, it can be
accompanied by refractory pruritus, anorexia, malabsorptive
diarrhea, and liver failure. Although nausea and vomiting are
common symptoms among patients with pancreatic cancer,
possibly as a result of disease infiltration of autonomic nerve
plexuses that causes gastric noncompliance and poor
emptying, only a minority of patients will develop mechanical
obstruction of the duodenum, either at the time of diagnosis
(i.e., less than 5%) or during disease progression (i.e., 10–30%)
(21–23). The development of gastric outlet obstruction only
adds to the progressive malnutrition potentiated by the
jaundiced state. Each of these conditions, particularly when
combined, can lead to rapid generalized wasting and dimin-
ished quality of life. For these reasons, decompression of
biliary obstruction and relief of duodenal obstruction lead to
a dramatic improvement in the overall medical condition that
contributes to a prolongation of comfortable survival.
Diagnostic laparoscopy, either routinely or selectively, has
become an integral part of the staging of many patients with
pancreatic cancer. In most situations when unresectable
disease is found at laparoscopy, as either liver metastasis or
peritoneal implants, life expectancy is quite short and opera-
tive palliation is not generally indicated. In a series of
155 patients from Memorial Sloan-Kettering Cancer Center
who were found to have unresectable pancreatic adenocarci-
noma at the time of staging laparoscopy, only 2% required an
open procedure to palliate biliary or gastric obstruction dur-
ing their remaining lifetime (24). Jaundiced patients without
gastric outlet obstruction, who are found to have metastatic
disease at the time of staging laparoscopy, can be palliated
successfully with biliary stenting alone in most circumstances.
Laparoscopic biliary bypass is an option and surgical series,
401
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
involving limited numbers of patients, have shown satisfactory
short- and long-term results from this approach (25–29).
Patients with gastric outlet obstruction, who are determined
to have unresectable disease at the time of staging laparoscopy,
should be considered for laparoscopic gastrojejunostomy,
especially when there are anatomic constraints that will limit
the success of endoluminal gastroduodenal stenting.
If unresectable disease is discovered at the time of laparot-
omy, both a biliary–enteric bypass and a gastrojejunostomy
should be performed regardless of existing symptoms. At least
three meta-analyses of surgical series have suggested that 15%
to 25% of patients found to be unresectable at the time of lap-
arotomy and not provided with a gastrojejunostomy will even-
tually develop symptomatic duodenal obstruction (22,23).
Two prospective randomized trials have also provided Level Ib
evidence that supports performing a biliary–enteric bypass
and a gastrojejunostomy for patients who are determined to
have unresectable disease at the time of laparotomy (12,18).
nonoperative techniques for biliary
decompression
For jaundiced patients with unequivocally unresectable pan-
creatic cancer on preoperative evaluation, nonsurgical pallia-
tion is generally indicated except for the most terminally ill
patients. Since its clinical inception in 1980, the use of endo-
scopically placed biliary endoprostheses has continued to
evolve and now serves as the predominant modality for palli-
ating obstructive jaundice in patients who are not candidates
for curative resection. Endoscopic attempts at biliary drainage
fail in less than 10% of patients, usually as the result of tumor
infiltration into the duodenal wall that prevents access to the
ampulla (30,31). A Cochrane review of endoscopic stents for
the relief of distal biliary obstruction has provided Level Ia evi-
dence that metal biliary stents, compared to plastic stents, have
a lower risk of recurrent obstruction with no increased risk of
complications (32). Obviously, the cost-effectiveness of metal
stents over plastic stents is most apparent for patients with
longer survival (33–36). In the uncommon event that endo-
scopic management is unsuccessful, percutaneous transhe-
patic access should be gained to allow external biliary drainage.
In most cases, the initial external drainage procedure can be
converted later to internal biliary drainage with a stainless steel
alloy biliary stent (e.g., Wallstent; Boston Scientific, Natick,
MA, USA) (19).
Most symptomatic patients with preoperatively confirmed
unresectable disease can be palliated adequately with nonop-
erative techniques, thus there is little role for surgical palliation
for a large subgroup of patients with pancreatic cancer. How-
ever, there remains an important role for operative palliation
in patients undergoing attempted resection.
operative techniques for biliary
decompression
Despite advances in diagnostic radiography, open surgical
exploration continues to serve as the standard for determining
local tumor resectability. Thus, operative palliation of existing
or potential biliary obstruction remains a major issue in the
management of unresectable pancreatic cancer. Patients, who
402
are found to be unresectable at the time of laparotomy, should
be provided with appropriate operative palliation. This point
is obvious for patients who require transection of the bile duct
as part of the operation to determine resectability. However,
for patients who have existing metallic biliary stents and do
not require division of the bile duct to assess resectability, a
decision to perform a biliary bypass must factor the patient’s
expected lifespan, the reported durability of metallic stents,
and potential operative complications associated with biliary–
enteric bypass. Unfortunately, there are no randomized data
comparing operative versus nonoperative biliary decompres-
sion procedures using metallic biliary stents exclusively.
After the abdomen is entered and assessed for metastatic
disease, the duodenum is extensively mobilized out of the ret-
roperitoneum to determine involvement of the superior mes-
enteric artery and to exclude the rare presence of aortic or
caval invasion. Accurate assessment of tumor resectability in
patients with equivocal radiographic findings usually necessi-
tates a cholecystectomy and transection of the common bile or
hepatic duct to facilitate identification and dissection of the
portal vein. With extensive Kocherization of the third portion
of the duodenum, the superior mesenteric vein (SMV) can be
identified anteriorly and dissected along its surface under the
neck of the pancreas to its connection with the portal vein. If
extensive tumor encasement of the SMV or portal vein is dis-
covered and the chance for a margin-negative resection is
unlikely even with a major vein resection and reconstruction,
a palliative double (biliary and gastric) bypass procedure
should be considered at this point in the operation. If tissue
confirmation of pancreatic adenocarcinoma was not obtained
preoperatively, a transduodenal core needle biopsy of the pan-
creatic head should be obtained.
Even though an operative biliary bypass can be accom-
plished with cholecystojejunostomy or choledochoduodenos-
tomy, these two options are associated with overall inferior
short- and long-term results and generally should be avoided
(8,37–39). Our preferred approach uses hepatico- or choledo-
chojejunostomy for internal drainage. Biliary bypass can be
accomplished with either a simple jejunal loop or a Roux-en-Y
limb (Fig. 43.1). While a loop anastomosis requires slightly less
operative time, the use of a defunctionalized Roux-en-Y jeju-
nal limb is associated with less anastomotic tension and facili-
tates the management of potential biliary leaks. The incidence
of postoperative cholangitis also seems to be reduced with
Roux limb drainage.
nonoperative techniques for gastric
decompression
Duodenal or gastric outlet obstruction has traditionally been
managed by surgery, but there has been increased experience
with endoluminal approaches to relieve gastric and duodenal
obstruction over the past several years (40–42). In the past,
endoscopic options included tube gastrostomy with jejunal
extension for nutritional access; however, the development of
self-expanding enteral stents has provided a reliable tool for
palliating duodenal obstruction in patients who do not require
surgical exploration to determine resectability (Fig. 43.2).
Despite early success with enteral stents in small series,
 PALLIATION OF PANCREAS CANCER
complications can arise and include mucosal ulceration, duo-
denal perforation, stent migration, and tumor ingrowth lead-
ing to recurrent obstruction (43,44). Patients with reasonable
life expectancy, who fail endoscopic attempts at palliation or
develop complications related to endoluminal stenting, may
require an operative gastrojejunostomy.
Figure 43.1 Illustration of one operative technique for a palliative double
bypass procedure for unresectable pancreatic cancer. Here, the hepaticojeju-
nostomy (HJ) is shown as an end-to-side anastomosis with a retrocolic
Roux-en-Y jejunal limb. The gastrojejunostomy (GJ) is depicted as a retrocolic
side-to-side anastomosis between the most dependent aspect of the stomach
and an isoperistaltic loop of proximal jejunum just beyond the ligament of
Treitz.
(A)
Figure 43.2 Coronal section of a representative CT scan showing a metallic endostent providing adequate relief of duodenal obstruction from a pancreatic
head cancer (A). Plain film radiography demonstrating the long-term patency of palliative metallic biliary and duodenal stents which can be deployed serially as
combined or separate endoscopic procedures (B).
operative techniques for gastric
decompression
Historically, most surgeons advocated an antecolic gastrojeju-
nostomy due to concerns of placing the anastomosis in prox-
imity to the tumor bed; however, there is now strong evidence
that a retrocolic, isoperistaltic gastrojejunostomy is associated
with a lower incidence of postoperative delayed gastric empty-
ing and even late-occurring gastric outlet obstruction (45).
The anastomosis should be fashioned with either a hand-sewn
or a stapled technique at the most dependent aspect of the
greater curvature of the stomach with a loop of jejunum
approximately 20 to 30 cm from the ligament of Treitz. The
posterior gastrojejunostomy should be delivered below the
transverse mesocolon and tacked in place. Vagotomy is gener-
ally avoided during palliative gastrojejunostomy to prevent
delayed gastric emptying.
palliation of pain
The last step of surgical palliation for unresectable pancreatic
cancer includes chemical splanchnicectomy which can be read-
ily accomplished with the injection of 20 ml of 50% alcohol on
each side of the aorta at the level of the celiac axis at the time of
laparotomy (Fig. 43.3). Chemical splanchnicectomy can be
performed similarly at the time of staging laparoscopy or other
laparoscopic palliative procedures (46). Celiac plexus blocks
under endoscopic ultrasound or computed tomography guid-
ance have also been described, and thoracic splanchnicectomy
although used infrequently can provide adequate pain relief for
patients with unresectable pancreatic cancer (47,48).
Long-term, pain related to pancreatic cancer is perhaps the
most debilitating symptom associated with this disease and
can lead to the deterioration of quality of life rather quickly.
While only 30% to 40% of patients with pancreatic cancer
report moderate to severe pain at the time of diagnosis, over
80% of patients with advanced cancer experience severe pain
prior to death (49–52). A single institution prospective ran-
domized controlled trial (Level Ib) has demonstrated that
chemical splanchnicectomy can achieve acute pain relief in
over 80% of patients and can prevent the subsequent onset of
(B)
403
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

pain for up to 6 months postoperatively (53). Furthermore,

patients with severe preoperative pain who undergo a pallia-
tive chemical splanchnicectomy experience a significant
improvement in overall survival (Fig. 43.4).

Comparisons Between Operative Versus Nonoperative

Figure 43.3 A chemical splanchnicectomy can be accomplished by injecting
20 ml of 50% alcohol into the celiac ganglia on each side of the aorta (A) at the
level of the celiac axis (CA). The use of a 22 gauge or smaller caliber spinal
needle ensures containment of the injection wheal within the retroperitoneum.
Techniques
Several prospective randomized studies have compared opera-
tive versus nonoperative procedures to palliate patients with
malignant obstruction of the distal common bile duct
(Table 43.1) (54–56). The findings of these individual studies,
which have been corroborated by a larger meta-analysis (Level
Ia), show no difference in patient survival based on treatment
approach (20,30). Compared to nonoperative techniques
which carry a lower short-term morbidity, mortality, hospital
stay, and cost; the major advantage of operative biliary bypass
is the lower incidence of late complications, namely recurrent
jaundice and cholangitis (20,30). The relative benefits of oper-
ative palliation for biliary obstruction are most apparent for
patients with low operative risk and reasonable life expectancy
(e.g., greater than 6 months). It is often difficult to estimate the
lifespan of an individual patient with a determined burden of
tumor, and recent developments in palliative chemotherapy
may further affect the natural history of advanced stage pan-
creatic cancer.
Similarly, meta-analyses of relatively small-scale random-
ized prospective and comparative studies of endoscopic

Table 43.1 Randomized Trials of Operative Versus Nonoperative Palliation of Malignant Biliary Obstruction
Treatment Major complications Need for reintervention
Study Year No. of patients failure (%)a (%) (%)
Shepherd et al. 1988
Surgery 25 8 56 8
Stent 23 9 30 43
Andersen et al. 1989
Surgery 25 4 20 8
Stent 25 4 36 52
Smith et al. 2004
Surgery 101 7 29 2
Stent 100 5 11 36
Overall
Surgery 151 7 32 4
Stent 148 5 18 40
a
Inadequate biliary decompression.

Table 43.2 Randomized Trials of Operative Versus Nonoperative Palliation of Malignant Gastroduodenal Obstruction
Study Year No. of patients Treatment success (%)a Major complications (%)
Mehta et al. 2006
Laparoscopic GJ 14 93 57
Stent 13 85 0
Fiori et al. 2004
Open GJ 9 89 11
Stent 9 100 0
Overall
Surgery 23 91 39
Stent 22 91 0
a
Oral intake by 2 weeks post-procedure.

404
 PALLIATION OF PANCREAS CANCER
100
Alcohol pain (n = 20)
80 Saline pain (n = 14)
60
%
40
p = 0.0001
20
0
0 3 6 9 12 15 18 21 24 27 30 33
Months of survival
Figure 43.4 In a prospective, randomized, double-blind study by Lillemoe
et al. (53), chemical splanchnicectomy (alcohol) in patients with unresectable
pancreatic cancer and preoperative pain resulted in a significant reduction in
pain at 2-, 4-, and 6-month follow-up and a significant improvement in over-
all survival compared to placebo (saline) injection.
stenting versus surgical gastrojejunostomy have shown that
while endoscopic stenting for the palliation of malignant gas-
troduodenal obstruction is associated with higher early clini-
cal success (i.e., shorter time to oral intake and shorter length
of hospital stay), operative gastric bypass procedures are pref-
erable in patients with a prolonged prognosis who are likely to
benefit from the reliable durability of surgical palliation that is
less likely to require reintervention (Table 43.2) (41,57–59).
summary
Based on the existing clinical evidence, we advocate operative
biliary decompression, gastric bypass, and chemical splanch-
nicectomy for all patients who undergo laparotomy without
an indwelling metallic biliary stent and are found to have
locally unresectable pancreatic carcinoma in the periampul-
lary region. Even though this has not been studied directly, the
durability of operative palliation should influence patients’
quality of life positively by decreasing the need for reinterven-
tions and future hospitalizations. Symptomatic patients with
preoperatively confirmed locally unresectable cancer or meta-
static disease can be palliated reliably with nonoperative tech-
niques. Such patients should be offered surgical palliation only
when nonoperative procedures are unsuccessful and they have
a reasonable life expectancy. To take advantage of the long-
term benefits of surgical palliation, operative bypass proce-
dures must be performed with acceptable morbidity.
references
1. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004 Mar
27; 363(9414): 1049–57.
2. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base
report on pancreatic cancer. Cancer 1995 Nov 1; 76(9): 1671–7.
3. Schneider G, Siveke JT, Eckel F, Schmid RM. Pancreatic cancer: basic and
clinical aspects. Gastroenterology 2005 May; 128(6): 1606–25.
4. Wray CJ, Ahmad SA, Matthews JB, Lowy AM. Surgery for pancreatic
cancer: recent controversies and current practice. Gastroenterology 2005
May; 128(6): 1626–41.
5. House MG, Yeo CJ, Cameron JL, et al. Predicting resectability of periam-
pullary cancer with three-dimensional computed tomography. J Gastroin-
test Surg 2004 Mar–Apr; 8(3): 280–8.
6. Soriano A, Castells A, Ayuso C, et al. Preoperative staging and tumor resect-
ability assessment of pancreatic cancer: prospective study comparing
endoscopic ultrasonography, helical computed tomography, magnetic
resonance imaging, and angiography. Am J Gastroenterol 2004 Mar;
99(3): 492–501.
7. de Rooij PD, Rogatko A, Brennan MF. Evaluation of palliative surgical pro-
cedures in unresectable pancreatic cancer. Br J Surg 1991 Sep; 78(9): 1053–8.
8. Di Fronzo LA, Cymerman J, Egrari S, O’Connell TX. Unresectable pancre-
atic carcinoma: correlating length of survival with choice of palliative
bypass. Am Surg 1999 Oct; 65(10): 955–8.
9. Gouma DJ, Nieveen van Dijkum EJ, van Geenen RC, van Gulik TM,
Obertop H. Are there indications for palliative resection in pancreatic
cancer? World J Surg 1999 Sep; 23(9): 954–9.
10. Moore MJ. Pancreatic cancer: what the oncologist can offer for palliation.
Can J Gastroenterol 2002 Feb; 16(2): 121–4.
36
11. Cubiella J, Castells A, Fondevila C, et al. Prognostic factors in nonresect-
able pancreatic adenocarcinoma: a rationale to design therapeutic trials.
Am J Gastroenterol 1999 May; 94(5): 1271–8.
12. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojeju-
nostomy indicated for unresectable periampullary cancer? A prospective
randomized trial. Ann Surg 1999 Sep; 230(3): 322–8; discussion 8–30.
13. Lillemoe KD, Cameron JL, Yeo CJ, et al. Pancreaticoduodenectomy. Does
it have a role in the palliation of pancreatic cancer? Ann Surg 1996 Jun;
223(6): 718–25; discussion 25–8.
14. Nieveen van Dijkum EJ, Kuhlmann KF, Terwee CB, et al. Quality of life
after curative or palliative surgical treatment of pancreatic and
periampullary carcinoma. Br J Surg 2005 Apr; 92(4): 471–7.
15. Ridwelski K, Meyer F, Ebert M, Malfertheiner P, Lippert H. Prognostic
parameters determining survival in pancreatic carcinoma and, in
particular, after palliative treatment. Dig Dis 2001; 19(1): 85–92.
16. van den Bosch RP, van der Schelling GP, Klinkenbijl JH, et al. Guidelines
for the application of surgery and endoprostheses in the palliation of
obstructive jaundice in advanced cancer of the pancreas. Ann Surg 1994
Jan; 219(1): 18–24.
17. van der Schelling GP, van den Bosch RP, Klinkenbij JH, Mulder PG, Jeekel
J. Is there a place for gastroenterostomy in patients with advanced cancer
of the head of the pancreas? World J Surg 1993 Jan–Feb; 17(1): 128–32;
discussion 32–3.
18. Van Heek NT, De Castro SM, van Eijck CH, et al. The need for a prophy-
lactic gastrojejunostomy for unresectable periampullary cancer: a pro-
spective randomized multicenter trial with special focus on assessment of
quality of life. Ann Surg 2003 Dec; 238(6): 894–902; discussion5.
19. Costamagna G, Pandolfi M. Endoscopic stenting for biliary and pancre-
atic malignancies. J Clin Gastroenterol 2004 Jan; 38(1): 59–67.
20. Taylor MC, McLeod RS, Langer B. Biliary stenting versus bypass surgery
for the palliation of malignant distal bile duct obstruction: a meta-
analysis. Liver Transpl 2000 May; 6(3): 302–8.
21. Sarr MG, Cameron JL. Surgical management of unresectable carcinoma
of the pancreas. Surgery 1982 Feb; 91(2): 123–33.
22. Singh SM, Longmire WP Jr., Reber HA. Surgical palliation for pancreatic
cancer. The UCLA experience. Ann Surg 1990 Aug; 212(2): 132–9.
23. Watanapa P, Williamson RC. Surgical palliation for pancreatic cancer:
developments during the past two decades. Br J Surg 1992 Jan; 79(1): 8–20.
24. Espat NJ, Brennan MF, Conlon KC. Patients with laparoscopically staged
unresectable pancreatic adenocarcinoma do not require subsequent sur-
gical biliary or gastric bypass. J Am Coll Surg 1999 Jun; 188(6): 649–55;
discussion 55–7.
25. Gentileschi P, Kini S, Gagner M. Palliative laparoscopic hepatico- and gastro-
jejunostomy for advanced pancreatic cancer. JSLS 2002 Oct–Dec; 6(4): 331–8.
26. Hamade AM, Al-Bahrani AZ, Owera AM, et al. Therapeutic, prophylactic,
and preresection applications of laparoscopic gastric and biliary bypass
for patients with periampullary malignancy. Surg Endosc 2005 Oct;
19(10): 1333–40.
27. Nieveen van Dijkum EJ, Romijn MG, Terwee CB, et al. Laparoscopic
staging and subsequent palliation in patients with peripancreatic carci-
noma. Ann Surg 2003 Jan; 237(1): 66–73.
28. Rhodes M, Nathanson L, Fielding G. Laparoscopic biliary and gastric
bypass: a useful adjunct in the treatment of carcinoma of the pancreas.
Gut 1995 May; 36(5): 778–80.
29. Rothlin MA, Schob O, Weber M. Laparoscopic gastro- and hepaticojeju-
nostomy for palliation of pancreatic cancer: a case controlled study. Surg
Endosc 1999 Nov; 13(11): 1065–9.
405
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
30. Moss AC, Morris E, Leyden J, MacMathuna P. Malignant distal biliary
obstruction: a systematic review and meta-analysis of endoscopic and
surgical bypass results. Cancer Treat Rev 2007 Apr; 33(2): 213–21.
31. Naggar E, Krag E, Matzen P. Endoscopically inserted biliary endoprosthe-
sis in malignant obstructive jaundice. A survey of the literature. Liver
1990 Dec; 10(6): 321–4.
32. Moss AC, Morris E, MacMathuna P. Palliative biliary stents for obstructing
pancreatic carcinoma. Cochrane Database Syst Rev 2006(2): CD004200.
33. Arguedas MR, Heudebert GH, Stinnett AA, Wilcox CM. Biliary stents in
malignant obstructive jaundice due to pancreatic carcinoma: a cost-effec-
tiveness analysis. Am J Gastroenterol 2002 Apr; 97(4): 898–904.
34. Kaassis M, Boyer J, Dumas R, et al. Plastic or metal stents for malignant
stricture of the common bile duct? Results of a randomized prospective
study. Gastrointest Endosc 2003 Feb; 57(2): 178–82.
35. Prat F, Chapat O, Ducot B , et al. A randomized trial of endoscopic drain-
age methods for inoperable malignant strictures of the common bile duct.
Gastrointest Endosc 1998 Jan; 47(1): 1–7.
36. Yeoh KG, Zimmerman MJ, Cunningham JT, Cotton PB. Comparative costs
of metal versus plastic biliary stent strategies for malignant obstructive jaun-
dice by decision analysis. Gastrointest Endosc 1999 Apr; 49(4 Pt 1): 466–71.
37. DiFronzo LA, Egrari S, O’Connell TX. Choledochoduodenostomy for pallia-
tion in unresectable pancreatic cancer. Arch Surg 1998 Aug; 133(8): 820–5.
38. Sarfeh IJ, Rypins EB, Jakowatz JG, Juler GL. A prospective, randomized
clinical investigation of cholecystoenterostomy and choledochoenteros-
tomy. Am J Surg 1988 Mar; 155(3): 411–4.
39. Urbach DR, Bell CM, Swanstrom LL, Hansen PD. Cohort study of surgi-
cal bypass to the gallbladder or bile duct for the palliation of jaundice due
to pancreatic cancer. Ann Surg 2003 Jan; 237(1): 86–93.
40. Holt AP, Patel M, Ahmed MM. Palliation of patients with malignant gas-
troduodenal obstruction with self-expanding metallic stents: the treat-
ment of choice? Gastrointest Endosc 2004 Dec; 60(6): 1010–7.
41. Jeurnink SM, van Eijck CH, Steyerberg EW, Kuipers EJ, Siersema PD.
Stent versus gastrojejunostomy for the palliation of gastric outlet obstruc-
tion: a systematic review. BMC Gastroenterol 2007; 7: 18.
42. Kozarek RA, Ball TJ, Patterson DJ. Metallic self-expanding stent applica-
tion in the upper gastrointestinal tract: caveats and concerns. Gastrointest
Endosc 1992 Jan–Feb; 38(1): 1–6.
43. Espinel J, Vivas S, Munoz F, Jorquera F, Olcoz JL. Palliative treatment of
malignant obstruction of gastric outlet using an endoscopically placed
enteral Wallstent. Dig Dis Sci 2001 Nov; 46(11): 2322–4.
44. Lopera JE, Brazzini A, Gonzales A, Castaneda-Zuniga WR. Gastroduode-
nal stent placement: current status. Radiographics 2004 Nov–Dec; 24(6):
1561–73.
406
45. Sohn TA, Lillemoe KD, Cameron JL, et al. Surgical palliation of unresect-
able periampullary adenocarcinoma in the 1990s. J Am Coll Surg 1999
Jun; 188(6): 658–66; discussion 66–9.
46. Strong VE, Dalal KM, Malhotra VT, et al. Initial report of laparoscopic
celiac plexus block for pain relief in patients with unresectable pancreatic
cancer. J Am Coll Surg 2006 Jul; 203(1): 129–31.
47. Gress F, Schmitt C, Sherman S, Ikenberry S, Lehman G. A prospective
randomized comparison of endoscopic ultrasound- and computed
tomography-guided celiac plexus block for managing chronic pancreati-
tis pain. Am J Gastroenterol 1999 Apr; 94(4): 900–5.
48. Pietrabissa A, Vistoli F, Carobbi A, et al. Thoracoscopic splanchnicectomy
for pain relief in unresectable pancreatic cancer. Arch Surg 2000 Mar;
135(3): 332–5.
49. Kalser MH, Barkin J, MacIntyre JM. Pancreatic cancer. Assessment of
prognosis by clinical presentation. Cancer 1985 Jul 15; 56(2): 397–402.
50. Lichtenstein DR, Carr-Locke DL. Endoscopic palliation for unresectable
pancreatic carcinoma. Surg Clin N Am 1995 Oct; 75(5): 969–88.
51. House MG, Choti MA. Palliative therapy for pancreatic/biliary cancer.
Surg Oncol Clin N Am 2004 Jul; 13(3): 491–503, ix.
52. Kelsen DP, Portenoy RK, Thaler HT, et al. Pain and depression in patients with
newly diagnosed pancreas cancer. J Clin Oncol 1995 Mar; 13(3): 748–55.
53. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicec-
tomy in patients with unresectable pancreatic cancer. A prospective ran-
domized trial. Ann Surg 1993 May; 217(5): 447–55; discussion 56–7.
54. Andersen JR, Sorensen SM, Kruse A, Rokkjaer M, Matzen P. Randomised
trial of endoscopic endoprosthesis versus operative bypass in malignant
obstructive jaundice. Gut 1989 Aug; 30(8): 1132–5.
55. Shepherd HA, Royle G, Ross AP,et al. Endoscopic biliary endoprosthesis
in the palliation of malignant obstruction of the distal common bile duct:
a randomized trial. Br J Surg 1988 Dec; 75(12): 1166–8.
56. Smith AC, Dowsett JF, Russell RC, Hatfield AR, Cotton PB. Randomised
trial of endoscopic stenting versus surgical bypass in malignant low bile-
duct obstruction. Lancet 1994 Dec 17; 344(8938): 1655–60.
57. Fiori E, Lamazza A, Volpino P, Burza A, Paparelli C, et al. Palliative man-
agement of malignant antro-pyloric strictures. Gastroenterostomy vs.
endoscopic stenting. A randomized prospective trial. Anticancer Res 2004
Jan–Feb; 24(1): 269–71.
58. Mehta S, Hindmarsh A, Cheong E, et al. Prospective randomized trial of
laparoscopic gastrojejunostomy versus duodenal stenting for malignant
gastric outflow obstruction. Surg Endosc 2006 Feb; 20(2): 239–42.
59. Hosono S, Ohtani H, Arimoto Y, Kanamiya Y. Endoscopic stenting versus
surgical gastroenterostomy for palliation of malignant gastroduodenal
obstruction: a meta-analysis. J Gastroenterol 2007 Apr; 42(4): 283–90.
44 Cystic tumors of the pancreas
Peter J. Allen and Murray F. Brennan
introduction
A cystic tumor of the pancreas is a radiographic finding that
has a broad histologic differential. This differential includes
non-neoplastic pseudocysts, benign neoplastic cysts (serous
cysts), pre-malignant cysts (mucinous cysts), and cystic lesions
with invasive carcinoma (Table 44.1) (1). The current ability to
determine the histologic diagnosis of these lesions without
resection is improving but limited (2,3). Serum testing, radio-
graphic imaging, endoscopic ultrasound, cyst fluid cytology,
and cyst fluid marker analysis (CEA) have a combined overall
accuracy of approximately 70% to 85% (4). This diagnostic
limitation can make treatment decisions difficult: resection
may provide the only form of cure in those patients with high-
risk mucinous cysts or very early invasive disease; however,
resection has a major morbidity rate of approximately 20%
and mortality rate of 2% to 10%. Resection of benign cysts will
expose the asymptomatic patient to all the risks of resection
without identified benefit.
As cross-sectional imaging improves this diagnostic and
treatment dilemma will become more common. The
increased use of high-quality cross-sectional imaging has
resulted in an increasing number of patients identified with
small (<3 cm) asymptomatic cysts, and the ability to deter-
mine histology in these patients is even more difficult (5–7).
The natural history of these small, incidentally discovered
lesions is unknown. Even in a patient with a small and
asymptomatic pre-malignant cyst (mucinous) the future risk
of progression to malignancy has not been determined with
respect to both frequency and duration. The decision to
resect a small, asymptomatic mucinous lesion, particularly in
someone who is elderly or with significant comorbidities,
must take into account the fact that the natural history of
that lesion is unknown.
clinical scenarios—presentation
and diagnostic evaluation
The clinical scenarios below are from three patients with cystic
lesions of the pancreas treated at our institution over the past
5 years. The presentation and diagnostic evaluation are pre-
sented. Treatment decisions and rationale are provided in the
last section of this chapter.
Scenario 1. Otherwise healthy 66-year-old female who
underwent CT imaging of the abdomen for left lower quad-
rant abdominal pain. Symptoms resolved without treatment
and imaging revealed no evidence of diverticulitis or other
left abdominal/pelvic pathology. Imaging did reveal 4.5 cm
cystic lesion in pancreatic tail (Fig. 44.1). Review of CT
revealed imaging characteristic of serous cystadenoma
(microcystic, central calcification). No further diagnostic testing
was performed.
Scenario 2. Otherwise healthy 63-year-old female with
episode of severe bronchitis who underwent CT imaging of
the chest. No significant pulmonary abnormality noted on
CT; however, cystic lesion noted in the tail of the pancreas.
Dedicated pancreatic imaging revealed 3.2 cm cyst in the tail
of the pancreas and mild diffuse main pancreatic ductal
dilatation (Fig. 44.2). No further diagnostic testing was
performed.
Scenario 3. Otherwise healthy 60-year-old female with non-
specific abdominal pains who underwent CT imaging of the
abdomen. A 1.5-cm cyst noted in the body of the pancreas
(Fig. 44.3). Review of imaging reveals no solid component to
the cyst and no main pancreatic ductal dilatation. An upper
endoscopy with endoscopic ultrasound was performed which
confirmed the CT-imaging findings. Fine needle aspiration
was performed with cytology revealing non-diagnostic mate-
rial. Cyst fluid CEA was 2853 ng/ml.
pathologic sub-types and clinical behavior
Although the differential diagnosis of a cystic lesion of the
pancreas is broad, over 85% of resected lesions will represent
serous or mucinous cysts (8). This section will focus on these
more common lesions.
Pancreatic Pseudocyst
The most common cystic lesion of the pancreas is the
non-neoplastic inflammatory pseudocyst that develops as a
complication of pancreatitis (4,9). A pancreatic pseudocyst is a
fluid collection that arises in or adjacent to the pancreas but
lacks an epithelial lining. Pseudocysts have been reported to
develop in 15% to 50% of patients who experience acute
pancreatitis (9,10). Because of this, some studies have reported
that pseudocysts represent 75% to 85% of all cystic lesions of
the pancreas (9,10). Pseudocysts are a well-characterized
complication of pancreatitis and are not the focus of this
chapter. Pseudocysts are managed expectantly or with percuta-
neous, endoscopic, or operative drainage.
Serous Cystadenoma
Serous cystadenoma of the pancreas was first characterized in
detail by Compagno and Oertel in 1978 (11,12). In this report
they described the gross (microcystic) and microscopic (glyco-
gen rich) characteristics of SCA and differentiated the
appearance and behavior of these lesions from mucinous cysts
of the pancreas. Serous cystadenomas may range in diameter
from 1 cm to over 20 cm and are grossly characterized by thick
fibrous walls and septa, innumerable small cysts (<1 cm in
diameter) containing thin clear fluid, and often a calcified cen-
tral scar which may or may not contain focal hemorrhage
(Fig. 44.4). Microscopically these lesions are characterized by
407
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

a bland cuboidal epithelial cell lining which is typically The more common clinical problem with serous cystade-
devoid of nuclear polymorphism or mitotic activity (Fig. 44.4). noma is local growth and the subsequent development of
Glycogen is abundant in the cytoplasm and can occasionally symptoms such as pain or jaundice. The presence of symp-
be detected within the amorphous cystic material. toms (pain) appears to be related to the size of the lesion as
In general SCA are considered to be benign as there are fewer studies describing patients with larger tumors tend to have a
than 10 cases of metastatic serous cystadenocarcinoma within greater percentage of patients with symptoms. Compagno and
the world’s literature (13). Many of the case reports that Oertel’s study in 1978 of 34 cases of serous cystadenoma
describe “malignant” SCAs describe local invasion rather than reported an average tumor diameter of 10.8 cm, and 71% were
metastatic spread, and therefore the true incidence of malig- symptomatic (11). In a previous report from our institution
nancy within serous cystadenomas is certainly less than 1%. the average tumor diameter of patients with resected serous
Within our institutional database there are currently over lesions was 4.9 cm, and 35% were symptomatic (14).
120 patients who have undergone resection for serous cystad- Because the exact size at which a serous lesion will become
enoma, and not a single case of metastatic spread has been symptomatic is unknown, and because the growth rate of
documented. serous cystadenomas has not been defined, the appropriate
management of the young patient with an asymptomatic ser-
ous lesion is yet to be determined. Tseng et al. reported a
Table 44.1 Kloppel’s Classification of Cystic Neoplasms growth rate of 0.6 cm/year for patients with serous cystade-
of the Pancreas noma (15). In Tseng’s report, serial radiography was obtained
Kloppel’s classification
Epithelial tumors Serous cystadenoma
Mucinous cystadenoma
Cystadenocarcinoma
Intraductal papillary mucinous
tumor
Pseudopapillary and solid tumor
Teratoma
Acinous cystadenocarcinoma
Adenosquamous carcinoma
Mucinous cystic adenocarcinoma
Non-epithelial tumors Cystic islet cell tumor
Vascular tumor
Lymphangioma
Hemangiopericytoma
Leiomyosarcoma
Lymphoma
Pseudotumors Single cyst
Polycystic disease Figure 44.2 Cystic lesion in the tail of the pancreas (solid arrow) and dilated
Exclusively pancreatic main pancreatic duct (broken arrow) in an otherwise healthy 63-year-old
With hepatorenal disease female.
Von Hippel–Lindau disease

Figure 44.1 Cystic lesion in the tail of the pancreas (arrow) in otherwise Figure 44.3 Cystic lesion in the body of the pancreas (arrow) in an otherwise
healthy 66-year-old female. healthy 60-year-old female.

408
 CYSTIC TUMORS OF THE PANCREAS

for a group of 24 patients who had a median radiographic
follow-up of 23 months. There was a significant difference in
growth rates between patients with tumors <4 cm at presen-
tation (0.48 cm/year) and patients with lesions ≥4 cm
(1.98 cm/year). Because of the observed increased rate of
growth in larger lesions, this report recommended resection
for asymptomatic patients with serous cystadenomas >4 cm.
We have previously reported a similar overall growth rate of
approximately 0.5 cm/year, but have not found any associa-
tion between the size of the lesion and the rate of growth. We
feel that asymptomatic patients can be safely followed with
the possible exception of those patients who have large lesions
that are marginally resectable.
Intraductal Papillary Mucinous Neoplasm (IPMN)
Intraductal papillary mucinous neoplasms (IPMN) are muci-
nous cystic tumors of the pancreas which were first classified
into a unified diagnosis by the World Health Organization in
1996 (16). Prior to this these neoplasms were described under
a variety of names including mucinous ductal ectasia, papil-
lary carcinoma, and villous adenoma. Because of the lack of a
unifying diagnosis, older reports evaluating mucinous cysts of
the pancreas may actually represent a combination of both
IPMN and mucinous cystic neoplasm (MCN) which is a dis-
tinct histopathologic entity.
Grossly, IPMNs are characterized by ductal dilatation and
mucin production (Fig. 44.5). IPMN is considered a “whole
gland” process; however, radiographically apparent disease
may be evident in the main pancreatic duct alone, the
branch ducts alone, or both. Microscopically, IPMN lesions
are characterized by papillary projections of columnar-
lined epithelium with varying degrees of dysplasia (Fig.
44.5). Mucin is typically abundant both within the cyto-
plasm of the lining epithelial cells as well as within the acel-
lular fluid matrix. Current nomenclature (WHO) divides
these lesions into the categories of adenoma, borderline (low-
grade dysplasia), high-grade dysplasia (carcinoma in situ),
and carcinoma.

(A) (B)

Figure 44.4 Gross and microscopic characteristics of serous cystadenoma. Arrow notes central scar.

BD

PD

(A) (B)

Figure 44.5 Gross and microscopic characteristics of main duct IPMN. Abbreviations: PD, pancreatic duct; BD, bile duct.

409
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Invasive malignancy is well documented for this group of
lesions. Several large series of resected IPMN have been
reported in the literature (17,18). In a series from Johns
Hopkins of 136 patients who underwent resection for IPMN
there was invasive carcinoma identified in 38% of patients and
an additional 55% of patients had in situ carcinoma (18).
Similar results have been reported from our institution (17).
D’Angelica et al. reported on 62 patients with resected IPMN
of the pancreas, and in this series the prevalence of invasive
carcinoma was 48% (n = 30), and the prevalence of in situ
carcinoma was 27% (n = 17). The presence of malignancy has
been found to be associated with the presence of main duct
disease (vs. branch duct), as well as with the radiographic
characteristics of a solid component and cyst size (14,18–20).
Recent reports from the Massachusetts General Hospital, as
well as from our own institution, have failed to identify inva-
sive malignancy in small (<3 cm) branch duct IPMNs of the
pancreas (14,20).
The frequency and length of time it takes for IPMN to prog-
ress to malignancy are unknown. Increased age has been
reported to be associated with malignancy in IPMN in several
studies (18,19). Because of this association, a report from
Johns Hopkins concluded that the lag time from adenoma to
carcinoma in IPMN was approximately 5 years (18). In a
recent study from our institution we also found that patients
with IPMN adenoma were significantly younger than those
with carcinoma (65 vs. 74 years, p = 0.02). We feel that this
finding likely represents the course of progression from benign
to malignant; however, the timing of this progression and if it
occurs in even the majority of lesions remain unknown.
Within our institutional cyst registry we have identified
approximately 20 patients with small IPMNs of the pancreas
who have been followed radiographically over a period of 5 to
120 months. None of these patients have been noted to have
significant growth of the lesions or other evidence of the
development of malignancy.
Initial reports with limited follow-up suggested a signifi-
cantly improved survival for patients with malignant IPMN as
compared to patients with conventional pancreatic adeno-
carcinoma (19,21). These differences have become smaller as
PD
Cyst
(A)
Figure 44.6 Gross and microscopic characteristics of MCN. Abbreviation: PS, pancreatic duct.
410
series with longer follow-up are reported; however, there does
appear to be a biologic spectrum in the aggressiveness of
invasive IPMN (17,22). The rate of nodal positivity is typi-
cally lower (33% to 54%) than what is seen after resection for
conventional pancreatic adenocarcinoma, and some histo-
pathologic sub-types, such as colloid papillary mucinous
carcinoma, appear to have a more favorable long-term out-
come (17). After resection for non-invasive IPMN distant
recurrence should not occur; however, these patients have
been found to be at risk for recurrence within the pancreatic
remnant. A study from the Mayo clinic reported an 8% gland
recurrence rate after partial pancreatectomy for non-invasive
IPMN with a median follow-up of 37 months (22). These
results are similar to those observed at our institution and
highlight the need to follow patients for a long term after resec-
tion of non-invasive IPMN for the development of disease
within the pancreatic remnant (23).
Mucinous Cystic Neoplasm
Current histopathologic data support the distinction between
IPMN and MCN of the pancreas (12,24,25). MCNs are much
less common than IPMN, and are defined as tumors that lack
communication with the pancreatic ductal system, contain a
mucin-producing columnar epithelium, and are supported by
ovarian-like stroma. The ovarian stroma is a unique and defin-
ing feature of MCNs of the pancreas, is the presumed reason
that MCNs are almost exclusively identified in women, and is
a characteristic that pancreatic MCNs share with mucinous
cysts of the ovary and liver (24,26). These lesions are most
commonly located in the body and tail and can range in size
from 2 to 25 cm (12,24). Grossly these tumors are round with
a smooth surface and fibrous pseudocapsule (Fig. 44.6).
MCNs may also progress to a malignant process and the
reported malignancy rate in most large series has ranged
between 10% and 50% (12,24,27). This rate may be underesti-
mated as both benign and malignant epithelium may coexist
within the same cyst and thus extensive histologic sampling
and assessment are necessary. Factors found associated with
the presence of malignancy in MCN of the pancreas have
included the presence of septations, mural nodularity, and cyst
(B)
 CYSTIC TUMORS OF THE PANCREAS
size (14,24). Because these tumors are uncommon the natural
history of mucinous cystadenocarcinoma has not been well
defined. Patients with extension of malignancy beyond the
tumor capsule have been shown to be at risk for recurrence
and death from disease (24).
diagnostic evaluation
High-quality cross-sectional imaging is essential for the evalu-
ation of patients with cystic lesions of the pancreas. Multi-
detector CT (MdCT) allows thin section scanning of the
pancreas and has become the most common method for assess-
ing pancreatic cysts (28). MdCT has the ability to provide excel-
lent visualization of septa, mural nodules, and calcifications.
MdCT also allows excellent visualization and characterization
of the pancreatic parenchyma. Evaluation of the parenchyma
adjacent to the cyst is critical as we have recently reported on
several patients with pancreatic adenocarcinoma who pre-
sented with isolated small retention cysts adjacent to a radio-
graphically occult malignancy (14). MRCP also provides
excellent characterization of cyst morphology (4). MRCP
may also allow for the ability to diagnose branch duct IPMN
through identification of communication between the cyst
and the pancreatic duct (29).
Endoscopic evaluation with endoscopic ultrasound (EUS)
has played an increasingly important role in the evaluation of
pancreatic cysts. In general, endoscopy with or without endo-
scopic retrograde cholangiopancreatography (ERCP) has a
limited role in the evaluation of pancreatic cysts; however,
these tests may have indications in the evaluation of suspected
IPMN. Endoscopic ultrasound (EUS) with or without cyst
aspiration is highly operator dependent, but the information
gained from EUS by an experienced gastroenterologist can be
very valuable. EUS can provide detailed images of the cyst wall
as well as internal cyst architecture and can be used to per-
form fine needle aspiration biopsy. The fluid obtained by EUS
FNA can be used both for cytologic analysis as well as for
various tumor marker analyses.
The diagnostic utility of cyst fluid analysis has been studied
extensively (4,30–32). A variety of tumor markers including
CA19-9, CEA, CA15-3, M1 mucin, and amylase have been
evaluated. The most consistent results have been reported for
cyst fluid CEA levels. In a prospective study by Brugge et al. of
112 patients with cystic lesions, an elevated cyst fluid CEA level
(>192 ng/ml) was the best predictor of a mucinous lesion and
accurately identified these lesions in 79% of cases (3). Elevated
CEA levels and the presence of extracellular mucin have been
shown to have a positive predictive value for mucinous lesions
as high as 85% (4,33,34). The degree to which the cyst fluid
CEA level is elevated has not been found to be predictive of
malignancy within mucinous cysts. Serous cystadenomas and
retention cysts have been shown to have almost uniformly
undetectable cyst fluid CEA levels (4,34,35).
The ability of cyst fluid cytology to differentiate between
serous versus mucinous cysts as well to identify malignancy
within the mucinous sub-group is limited. Most studies have
shown accuracy rates of cyst fluid cytology in the range of 50%
and thus cytology is probably inferior to cyst fluid CEA alone
in discriminating between serous and mucinous cysts (3).
The limitations to cyst fluid cytology are the result of the
typically small volume and low cellular content of the aspi-
rates, and the contamination of the samples with mucin and
mucin-producing cells from the stomach or duodenum
through which the needle is passed.
The typical radiographic appearance of a serous cystade-
noma is of a spherical lesion, with multiple small cysts, and
central calcification. Because of the fibrous nature of these
lesions a solid component is often described, and in the setting
of other findings that are characteristic for SCA should not be
viewed as concerning for malignancy. Like all cystic lesions,
some SCA will present with atypical radiographic findings.
Oligocystic SCA is a recently identified variant of SCA with a
radiographic appearance that is indistinguishable from MCN
or branch-duct IPMN (Fig. 44.5) (36).
The radiographic appearance of IPMN is dependent on
whether the lesion is predominantly involving the main duct,
branch ducts, or both. Main duct IPMN will characteristically
present with diffuse ductal dilatation. Any solid component or
focal mass within these lesions should be viewed as concerning
for malignancy. Branch duct IPMN may be unilocular or mul-
tilocular and there is by definition no dilation of the main
pancreatic duct. In the absence of septations, solid compo-
nent, or mural nodularity these lesions may be indistinguish-
able from MCN, retention cysts, small cystic endocrine tumors,
or even pseudocysts.
Any macrocystic lesion in the tail of the pancreas in a female
patient should be suspected as an MCN. These lesions are typ-
ically several centimeters in diameter, solitary, and there should
not be dilation of the main pancreatic duct. Peripheral calcifi-
cations, described as eggshell calcifications may be present.
Any mural nodularity or solid component should be viewed as
concerning for malignancy.
treatment recommendations
Because of the frequent inability to determine histology with-
out resection, and because of the unknown natural history of
some cystic sub-types, many authors have recommended rou-
tine resection of all pancreatic cysts (2,37,38). These authors
argue that because the preoperative distinction between
benign and malignant is unreliable, and because the potential
adverse consequences of not resecting a pre-malignant or
malignant cyst are significant, all medically fit patients should
undergo resection. Although this approach provides a guaran-
tee to patients that no pre-malignant or malignant lesions will
be observed, it exposes patients with benign lesions to the risks
of pancreatectomy.
Several recent reports, including a study from our own insti-
tution, have recommended a more selective approach to resec-
tion (39–41). Proponents of this approach argue that with
current imaging techniques, and with an improved under-
standing of the various histologic entities, a group of patients
can be identified who have an extremely low risk of malig-
nancy. Most reports evaluating this approach have recom-
mended non-operative management (radiographic follow-up)
for selected patients with small, incidentally discovered cysts
of the pancreas that do not have a solid component or other
concerning clinical or radiographic features of malignancy
411
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
such as main pancreatic ductal dilatation (14,39,40). This
approach avoids the risks of operation in patients with benign
lesions, but with current limitations in non-resectional diag-
nosis cannot guarantee that a malignancy is not mistakenly
being observed.
In some instances the histopathology of a given cyst can be
determined with a high level of certainty without resection. In
these instances treatment recommendations can be made
based on the known natural history of the specific histologic
entity. In other circumstances, typically patients with small
cysts, the exact histopathology of the lesion cannot be deter-
mined without resection. In these instances treatment recom-
mendations must be based on the radiographic characteristics
and the inferred histopathology once the diagnostic work-up
is complete.
Serous Cystadenoma
When diagnostic evaluation identifies a patient with a serous
cystadenoma, resection should be reserved for the symptom-
atic patient or in a healthy patient in whom significant growth
has been observed. In the asymptomatic patient the risk of
mortality from resection exceeds the risk of malignancy. As
noted above, data from our institution as well as others con-
firm the non-metastatic nature of serous cystadenomas. How-
ever, these lesions can become symptomatic and resection
remains indicated in the presence of symptoms.
Intraductal Papillary Mucinous Neoplasm (IPMN)
and Mucinous Cystic Neoplasm (MCN)
Resection has been previously recommended for all patients
with IPMN of the pancreas. These recommendations should
in general be considered because of the previously reported
high rate of malignancy within these lesions as well as the abil-
ity of non-invasive IPMN to progress to invasive malignancy.
When cross-sectional imaging and endoscopic studies are
characteristic of main duct IPMN, and/or when there are any
concerning radiographic features such as a solid component,
septations, or size >3 cm our standard approach is to perform
resection (14).
The most difficult clinical scenario is the management of
the patient who presents with a small branch duct IPMN,
particularly when it arises in the head of the pancreas of a
50-year-old patient. A recent review of our institutional
experience with these lesions identified the size of the lesion
to be associated with the presence of malignancy as well as
with the decision to recommend operative or non-operative
management (14). We have not identified invasive malig-
nancy in any mucinous lesion less than 3 cm in diameter in
the absence of solid component, symptoms, or main ductal
dilatation. Multiple other studies have also not shown inva-
sive disease in small (<3 cm) mucinous cysts of the pancreas
and a recent consensus statement supported a non-operative
approach in patients with small mucinous cysts of this
nature (42). Our typical follow-up schedule for patients
undergoing non-operative management consists of high-
quality cross-sectional imaging every 6 months for 2 years
and then annually thereafter. Resection is typically per-
formed when there is any significant growth in the lesion, or
412
the development of a solid component, or other concerning
features of malignancy.
clinical scenarios: treatment
Scenario 1. The radiographic features of this lesion are charac-
teristic of serous cystadenoma and therefore no further diag-
nostic evaluation was performed. Radiographic follow-up was
recommended because the patient was asymptomatic and the
lesion was not marginally resectable. The patient has now been
imaged (MRCP) annually for 4 years and there has been no
growth of the lesion and the patient remains asymptomatic.
Scenario 2. The radiographic features of this lesion are
characteristic of combined branch and main duct IPMN,
because of this no further testing was performed. Because of
the main duct dilation operative resection was recommended.
The risks and benefits of several resectional procedures (distal
pancreatectomy, total pancreatectomy) were discussed in
detail with the patient. Because the majority of the cystic dis-
ease was in the pancreatic tail and because the pancreatic head
was relatively spared a laparoscopic spleen-sparing distal pan-
createctomy was performed. The patient had low-grade dys-
plasia within the resected specimen. Follow-up at 2 years
reveals no evidence of progressive disease within the head of
the gland.
Scenario 3. EUS was performed because of the radiographic
ambiguity of the lesion and the young age of the patient. The
CEA within the aspirated fluid was characteristic of a muci-
nous lesion and this patient almost certainly has a small branch
duct IPMN. Radiographic follow-up has been recommended
and the patient has had no significant change within this lesion
after 2 years.
summary
In summary, many institutions are now reporting a selective
approach to resection in patients with cystic lesions of the
pancreas. Routine resection of all pancreatic cysts is currently
impractical, and given the large numbers of patients being
identified with <2 cm lesions this approach would result in a
mortality rate that is much higher than the rate of malignancy.
Most studies that have advocated a selective approach have
reported the radiographic characteristics of main duct dilata-
tion, a solid component, cyst size, and symptoms to be associ-
ated with treatment recommendations. In the absence of these
findings we feel that radiographic follow-up is warranted. In
the young patient with a small mucinous tumor the additional
factors are the likelihood of progression to malignancy and the
patient anxiety about radiographic follow-up. No data are
available for the former.
Efforts should be made to improve the ability to distinguish
histopathologic sub-types without resection. The current
challenges are to improve the sensitivity and specificity for the
identification of mucinous sub-type, to better characterize the
progression of IPMN and mucinous cystic tumors, and to
develop better methods for identifying the presence of in situ
or invasive disease in these patients. Continued improvements
in cross-sectional imaging and endoscopic techniques, and
further investigation into markers in the serum and cyst fluid,
should allow better stratification of mucinous sub-types.
 CYSTIC TUMORS OF THE PANCREAS
references
1. Kloppel G, Kosmahl M. Cystic lesions and neoplasms of the pancreas. The
features are becoming clearer. Pancreatology 2001; 1: 648–55.
2. Ooi LL, Ho GH, Chew SP, et al. Cystic tumours of the pancreas: a diag-
nostic dilemma. Aust N Z J Surg 1998; 68: 844–6.
3. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of
pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst
study. Gastroenterology 2004; 126: 1330–6.
4. Brugge WR, Lauwers GY, Sahani D, et al. Cystic neoplasms of the pancreas.
N Engl J Med 2004; 351: 1218–26.
5. Gorin AD, Sackier JM. Incidental detection of cystic neoplasms of the
pancreas. Md Med J 1997; 46: 79–82.
6. Fernandez-Del CC, Targarona J, Thayer SP, et al. Incidental pancreatic
cysts: clinicopathologic characteristics and comparison with symptom-
atic patients. Arch Surg 2003; 138: 427–3.
7. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancre-
atic cysts on MDCT. AJR 2008; 191: 802–7.
8. Le Borgne J., De Calan L., Partensky C. Cystadenomas and cystadenocar-
cinomas of the pancreas: a multiinstitutional retrospective study of 398
cases. French Surgical Association. Ann Surg 1999; 230: 152–61.
9. Grace PA, Williamson RC. Modern management of pancreatic pseudo-
cysts. Br J Surg 1993; 80: 573–81.
10. O’Malley VP, Cannon JP, Postier RG. Pancreatic pseudocysts: cause,
therapy, and results. Am J Surg 1985; 150: 680–2.
11. Compagno J, Oertel JE. Microcystic adenomas of the pancreas (glycogen-
rich cystadenomas): a clinicopathologic study of 34 cases. Am J Clin
Pathol 1978; 69: 289–98.
12. Compagno J, Oertel JE. Mucinous cystic neoplasms of the pancreas with
overt and latent malignancy (cystadenocarcinoma and cystadenoma).
A clinicopathologic study of 41 cases. Am J Clin Pathol 1978; 69: 573–80.
13. Matsumoto T, Hirano S, Yada K, et al. Malignant serous cystic neoplasm
of the pancreas: report of a case and review of the literature. J Clin Gastro-
enterol 2005; 39: 253–6.
14. Allen PJ, D’Angelica M, Gonen M, et al. A selective approach to the resec-
tion of cystic lesions of the pancreas: results from 539 consecutive
patients. Ann Surg 2006; 244: 572–82.
15. Tseng JF, Warshaw AL, Sahani DV, et al. Serous cystadenoma of the pan-
creas: tumor growth rates and recommendations for treatment. Ann Surg
2005; 242: 413–9.
16. Kloppel G, Solcia E, Longnecker DS. World Health Organization Interna-
tional Classification of Tumors. Berlin: Springer, 1996.
17. D’Angelica M, Brennan MF, Suriawinata AA, et al. Intraductal papillary
mucinous neoplasms of the pancreas: an analysis of clinicopathologic fea-
tures and outcome. Ann Surg 2004; 239: 400–8.
18. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neo-
plasms of the pancreas: an updated experience. Ann Surg 2004; 239: 788–97.
19. Salvia R, Fernandez-Del CC, Bassi C, et al. Main-duct intraductal papil-
lary mucinous neoplasms of the pancreas: clinical predictors of malig-
nancy and long-term survival following resection. Ann Surg 2004; 239:
678–85.
20. Sahani DV, Saokar A, Hahn PF, et al. Pancreatic cysts 3 cm or smaller: how
aggressive should treatment be? Radiology 2006; 238: 912–19.
21. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neo-
plasms of the pancreas: an increasingly recognized clinicopathologic
entity. Ann Surg 2001; 234: 313–21.
22. Chari ST, Yadav D, Smyrk TC, et al. Study of recurrence after surgical
resection of intraductal papillary mucinous neoplasm of the pancreas.
Gastroenterology 2002; 123: 1500–7.
23. White R, D’Angelica M, Tang L, et al. The fate of the remnant pancreas
following resection of non-invasive intraductal papillary mucinous neo-
plasm. J Am Coll Surg 2007; 204(5): 987–93.
24. Zamboni G, Scarpa A, Bogina G, et al. Mucinous cystic tumors of the
pancreas: clinicopathological features, prognosis, and relationship to
other mucinous cystic tumors. Am J Surg Pathol 1999; 23: 410–22.
25. Yamada M, Kozuka S, Yamao K, et al. Mucin-producing tumor of the pan-
creas. Cancer 1991; 68: 159–68.
26. Erdogan D, Lamers WH, Offerhaus GJ, et al. Cystadenomas with ovarian
stroma in liver and pancreas: an evolving concept. Dig Surg 2006; 23:
186–91.
27. Warshaw AL, Compton CC, Lewandrowski K, et al. Cystic tumors of the
pancreas. New clinical, radiologic, and pathologic observations in
67 patients. Ann Surg 1990; 212: 432–43.
28. Sahani DV, Kadavigere R, Saokar A, et al. Cystic pancreatic lesions: a sim-
ple imaging-based classification system for guiding management. Radio-
graphics 2005; 25: 1471–84.
29. Koito K, Namieno T, Ichimura T, et al. Mucin-producing pancreatic
tumors: comparison of MR cholangiopancreatography with endoscopic
retrograde cholangiopancreatography. Radiology 1998; 208: 231–7.
30. Sand JA, Hyoty MK, Mattila J, et al. Clinical assessment compared with
cyst fluid analysis in the differential diagnosis of cystic lesions in the pan-
creas. Surgery 1996; 119: 275–80.
31. Hammel PR, Forgue-Lafitte ME, Levy P, et al. Detection of gastric mucins
(M1 antigens) in cyst fluid for the diagnosis of cystic lesions of the
pancreas. Int J Cancer 1997; 74: 286–90.
32. Hammel P, Levy P, Voitot H, et al. Preoperative cyst fluid analysis is
useful for the differential diagnosis of cystic lesions of the pancreas.
Gastroenterology 1995; 108: 1230–5.
33. Walsh RM, Henderson JM, Vogt DP, et al. Prospective preoperative deter-
mination of mucinous pancreatic cystic neoplasms. Surgery 2002; 132:
628–33.
34. Lewandrowski KB, Southern JF, Pins MR, et al. Cyst fluid analysis in the
differential diagnosis of pancreatic cysts. A comparison of pseudocysts,
serous cystadenomas, mucinous cystic neoplasms, and mucinous cystad-
enocarcinoma. Ann Surg 1993; 217: 41–7.
35. van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the
differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gas-
trointest Endosc 2005; 62: 383–9.
36. Goh BK, Tan YM, Yap WM, et al. Pancreatic serous oligocystic adenomas:
clinicopathologic features and a comparison with serous microcys-
tic adenomas and mucinous cystic neoplasms. World J Surg 2006; 30:
1553–9.
37. Horvath KD, Chabot JA. An aggressive resectional approach to cystic
neoplasms of the pancreas. Am J Surg 1999; 178: 269–74.
38. Siech M, Tripp K, Schmidt-Rohlfing B, et al. Cystic tumours of the
pancreas: diagnostic accuracy, pathologic observations and surgical
consequences. Langenbecks Arch Surg 1998; 383: 56–61.
39. Spinelli KS, Fromwiller TE, Daniel RA, et al. Cystic pancreatic neoplasms:
observe or operate. Ann Surg 2004; 239: 651–7.
40. Walsh RM, Vogt DP, Henderson JM, et al. Natural history of indetermi-
nate pancreatic cysts. Surgery 2005; 138: 665–70.
41. Allen PJ, Jaques DP, D’Angelica M, et al. Cystic lesions of the pancreas:
selection criteria for operative and nonoperative management in
209 patients. J Gastrointest Surg 2003; 7: 970–7.
42. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for
management of intraductal papillary mucinous neoplasms and mucinous
cystic neoplasms of the pancreas. Pancreatology 2006; 6: 17–32.
413
45 Neuroendocrine pancreatic tumors
Steven N. Hochwald and Kevin Conlon
introduction
Pancreatic endocrine tumors are benign or malignant epithelial
tumors that show evidence of endocrine cell differentiation.
Pancreatic endocrine tumors are uncommon, representing
<5% of pancreatic tumors in surgical series (1,2). Clinically
silent endocrine tumors have been detected in 0.3% to 1.6% of
unselected autopsies in which only a few sections of the pan-
creas were examined, and in up to 10% of autopsies the whole
pancreas was systematically investigated both grossly and
microscopically. Most tumors from these series are small (less
than 1 cm), in elderly patients (mean age of 70 years), and
benign (clinically silent microadenomas).
Pancreatic endocrine tumors can be broadly classified as
functional or non-functional. Despite changing trends, the
majority of clinically relevant pancreatic endocrine tumors are
functional (3). The proportion of non-functioning tumors, in
series of islet cell neoplasms, has varied over time, ranging
between 15% and 53% of cases (4–7). While the definition of
non-functional has been inconsistent in many reports,
increased use of more sophisticated imaging modalities has
allowed clinically silent intra-abdominal masses to be identi-
fied incidentally and many series report an increased incidence
of non-functioning neoplasms (8,9). Overall, the reported
35% to 50% incidence of non-functioning endocrine tumors
suggest that non-functional tumors are at least as common as
insulinomas and more common than all of the remaining pan-
creatic endocrine tumor types (2).
Functional endocrine tumors of the pancreas are peptide-
secreting neoplasms leading to clinical presentation with a
defined syndrome related to the effects of an abnormally ele-
vated plasma peptide level. These peptides may or may not
occur naturally in the pancreas and a given tumor may secrete
multiple peptides. It is on the basis of the primary functional
peptide hormone secreted that each tumor is named; e.g., gas-
trinoma, insulinoma.
Non-functioning islet cell tumors are pancreatic neoplasms
with endocrine differentiation in the absence of a clinical syn-
drome of hormone hyperfunction. Despite the presence of
hormones in tumor cells at immunohistochemistry, many of
these tumors lack evidence of increased serum hormonal lev-
els. Tumors releasing increased amounts of hormone in the
blood stream without evidence of a hyperfunctional syndrome
are also often reported as non-functioning tumors. Several
explanations can be given for why these non-functioning
tumors are hormonally silent. One reason is that the principal
hormone secreted by the tumor may cause no specific clinical
signs, although it is released in excess. In some situations, the
tumor makes a functionally inert hormone, which is recog-
nized by an antibody directed against a functional hormone.
As the specificity of antibodies improves, such false positives
should disappear. A second possibility is that the amount of
414
hormone produced may be too small to cause symptoms.
Third, the tumor may secrete a precursor hormone that is
functionally inert or the hormonal product of the tumor may
not yet be identified.
Pancreatic endocrine tumors may occur at any age, although
they are rare in children. The age range in one series of
125 patients was 3 months to 80 years, with a mean of 51 years
(10). There have been no described significant differences in
incidence by sex.
No differences in histologic pattern have been found in non-
functioning as compared to functioning tumors. During
embryogenesis pancreatic islets are known to form mostly
through cellular buds originating from intralobular ductules.
Although this process normally ends before birth, it may per-
sist or reappear in many proliferative diseases of the endocrine
pancreas, including pancreatic involvement of type I MEN
syndrome or solitary endocrine tumors arising in the adult
pancreas (2). Since islet cells often have hormone co-expression
during early fetal development, it is thought that the origin of
pancreatic endocrine tumors is from multipotent cells in duct-
ular epithelium, which can differentiate toward the various cell
lines found in these tumors (11,12).
Clinically, functional and non-functional tumors present in
diverse manners with varied treatment dilemmas. Presenta-
tion in functional tumors is usually due to symptoms from the
hypersecretion of a particular hormone, while in non-
functional tumors it is usually due to an effect of the tumor
mass. We will separately discuss the treatment challenges of
these two tumor types, but attempts will be made to identify
where therapeutic algorithms may overlap for these tumors.
functional islet cell tumors
Functional tumors vary with regard to size, location, age dis-
tribution, sex distribution, propensity for malignancy, and
metastatic potential in accordance with the individual tumor
type (Table 45.1) (13). As with most endocrine tumors, the
clinical morbidity and mortality associated with the tumor are
due to hormone hypersecretion. Most tumors are slow grow-
ing and well differentiated.
insulinoma
Insulinoma is a neoplasm that arises from the pancreatic insu-
lin-producing beta-cells. Unlike other gastrointestinal endo-
crine tumors, which are malignant in more than 60% of cases,
90% of insulinomas are benign, solitary growths that occur
almost exclusively within the pancreatic parenchyma
(Table 45.1). They occur throughout the head, body, and tail of
the pancreas with equal frequency (14). Three percent are in
the uncinate and 2% to 3% are ectopic. Ectopic insulinomas
are usually found in the duodenal mucosa, the hilum of the
spleen, or in the gastrocolic ligament (13).
 NEUROENDOCRINE PANCREATIC TUMORS

The well-known symptoms associated with hypoglycemia
and inappropriate hyperinsulinism occur in a fasting state.
The symptoms of headache, blurred vision, incoherence, con-
vulsions, and coma are due to the deleterious effect of hypo-
glycemia on cerebral function. The symptoms of sweating,
weakness, hunger, palpitation, and trembling are homeostatic
responses to hypoglycemia, involving secretion of catechol-
amines (15). The development of these symptoms and the
presence of fasting hypoglycemia (glucose <40 mg/dl) and
hyperinsulinism (>5 U/ml) during a supervised 72-hour in-
hospital fast have been the gold standard in establishing the
diagnosis (16). In fact, a 72-hour fast is rarely needed, since
one-third of patients develop symptoms within only 12 hours,
at least 80% within 24 hours, 90% in 48 hours, and 100% in
72 hours (17). Elevated plasma levels of C peptide and
proinsulin are confirmatory.
Once the biochemical diagnosis of insulinoma has been
achieved, diagnostic testing should be performed in an effort
at tumor localization. The preoperative localization of insuli-
nomas has received a tremendous amount of attention in
recent years. However, as of yet, no single technique has been
accepted that is accurate, independent of operator expertise,
safe, non-invasive, and inexpensive. A multitude of localiza-
tion modalities has been devised with a wide disparity in
reported success rates and expenses (Table 45.2) (17).
Imaging for suspected islet cell tumors is important in the
preoperative period for planning therapy. Metastases must be
identified preoperatively so that the operative approach can be
determined or unnecessary surgery can be abandoned. Non-
invasive imaging studies most frequently utilized include CT
and MRI and are considered standard radiological modalities
for imaging of suspected insulinomas. Because results with
dynamic CT for localization of insulinomas have been poor
(Table 45.2), spiral CT has replaced dynamic CT for pancreatic
imaging in most centers (Fig. 45.1). In one report, nine of 11
tumors could be located using two-phase spiral CT (18). How-
ever, the sensitivity of spiral CT in tumor localization remains
to be determined in larger numbers of patients (17). Pancre-
atic endocrine tumors typically have a low signal intensity on
T1-weighted MR images. They demonstrate high signal inten-
sity on T2-weighted images. MRI with gadolinium contrast is
more sensitive for the detection of vascular tumors than is CT
with standard intravenous iodinated contrast agents and may
therefore permit detection of insulinomas that cannot be
identified on CT (19,20). MRI is likely to become more impor-
tant for localization of insulinomas, but its role is not yet
established.
Other modalities that have been utilized in the localization
of insulinomas include somatostatin receptor scintigraphy
and endoscopic ultrasound. The sensitivity of somatostatin
receptor scintigraphy for the detection of islet cell tumors
should be independent of tumor size and depends only on
tumor expression and cellular and total number of somatosta-
tin receptors. Unfortunately, tumors with low somatostatin
receptor density may not be imaged. Only 60% to 70% of
insulinomas have been found to express this receptor (21,22)
and, therefore, the sensitivity of somatostatin receptor scintig-
raphy is approximately 50% (23).
Endoscopic ultrasound, in experienced hands, may be quite
sensitive in localization of insulinomas. In one review, seven of

Table 45.1 Comparison of Functional Endocrine Tumors

Pancreatic associated Malignancy Metastatic
Tumor type primary (%) rate (%) rate (%) Multicentricity (%) Size MEN-1 (%)
Gastrinoma 30 60 50–80 20–40 Medium 18–41
Insulinoma 95–99 5–16 31 10 Small 4–10
Glucagonoma 100 82 >50 2–4 Large Rarely
Vi Poma 100 50 50 20 Small 4
Somatostatinoma 68 >90 75 10 Large Unknown
Source: Adapted from Ref. (13).

Table 45.2 Sensitivity (%) of Localization Modalities for Insulinoma

Transabdominal Portal venous Intraoperative
Center ultrasonography CT Angiography sampling MR imaging ultrasonography Palpation
Ann Arbor (25) 26 44 94 0
NIH (103) 26 17 35 77 25 92 64
Sweden (104) 11 43 54 63
France (105) 40 50 44 89
Italy (106) 15 60 75 100 82
Mayo Clinic (107) 59 36 53 90 90
(1982–87)
Mayo Clinic 64 26 47 16 95 90
(1980–95)
Source: Adapted from Ref. (17).

415
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
10 patients had insulinomas ranging in size from 1.5 to 2.2 cm.
Two of three missed tumors were in the head of the pancreas
(24). Despite this, endoscopic ultrasound has several disad-
vantages. It has difficulty visualizing tumors in the tail of the
pancreas. In addition, it is invasive, requiring monitored seda-
tion, and is highly operator dependent.
Invasive localization tests include arteriography and portal
venous sampling. Routine arteriography is no longer recom-
mended in the localization of insulinomas, it has been replaced
by other modalities due to its invasive and user-dependent
nature. Portal venous sampling has been considered by some
to be the single best test for localizing insulinomas (25). The
technique involves catheter placement through the liver percu-
taneously and positioned in the portal system. More than 20
blood samples are taken from different veins that drain the
pancreas and are tested for insulin to localize the insulinoma.
The false positive rate has been shown to be low and sensitivity
ranges from 63% to 94% (Table 45.2). However, this technique
is user dependent and does not localize the tumor precisely,
rather indicating a region of the pancreas that may harbor the
tumor. In addition, complications such as hemobilia and
hepatic bleeding may occur as a result of this procedure. An
invasive technique utilizing selective arteriographic injection
of calcium while measuring hepatic venous insulin levels has
yielded excellent tumor localization rates (26). This study is
becoming the invasive localizing study of choice, since it may
be less user dependent and can be performed more easily than
selective portal venous sampling.
Due to the limitations of both invasive and non-invasive
imaging in the work-up of suspected insulinomas, some cen-
ters recommend non-invasive imaging followed by surgical
exploration with the use of intraoperative ultrasound. In
selected patients, the Mayo Clinic reports a cure rate of 97.7%
using this regimen for benign insulinomas (17). The use of
intraoperative ultrasonography has enhanced the surgeon’s
ability to localize insulinomas. Additional information pro-
vided by intraoperative ultrasonography includes defining the
Figure 45.1 Spiral CT of insulinoma in body of pancreas. Arrow indicates
tumor which is enhancing with contrast material. The patient underwent an
enucleation of this tumor.
416
relationship of the tumor to the pancreatic and bile ducts and
adjacent blood vessels (17).
Our current recommendations in patients who meet bio-
chemical criteria for insulinoma are to perform preoperative
non-invasive radiologic imaging consisting of spiral CT scan-
ning or quality MR imaging. If this is negative and the patient
has no family history or signs of MEN syndrome, the patient
should go to operative exploration. At surgery, intraoperative
ultrasound should be utilized, if necessary to localize the tumor.
In general, insulinomas are usually reddish purple or white
and easily identified at operation. To confirm findings or to
help localize deep parenchymal lesions, intraoperative ultraso-
nography can be utilized. In this way, the relationship of the
pancreatic duct and other vascular structures to the tumor can
be demonstrated. Even if one tumor is found, the entire pan-
creas should be explored. Enucleation is carefully done to
avoid injury to the pancreatic duct. The tumor is enucleated by
dissecting immediately adjacent to the tumor, bluntly separat-
ing the tumor from normal pancreas using fine instruments
and a small sucker. The area is left open and is often drained.
The use of a drain is not mandatory if there is minimal disrup-
tion of pancreatic parenchyma. Distal pancreatectomy may be
necessary in larger, deeper tumors, or if the tumor involves the
pancreatic duct. For larger lesions of the pancreatic head, sub-
total pancreatectomy or a pancreaticoduodenectomy may be
required.
When an insulinoma has not been identified at the first
operation and reoperation is contemplated, referral to a center
with considerable experience is mandatory. Since insulinomas
are equally distributed throughout the pancreas, success is
proportional to the percentage of pancreas removed. There-
fore, a blind distal resection would be effective in only 50% of
cases and is not recommended. We and others would recom-
mend that the abdomen be closed and the diagnosis be recon-
firmed. Extensive preoperative localization should be
performed prior to a re-exploration (17). In one report, with
the introduction of intraoperative ultrasound, 15 of 16 reop-
erated patients have been cured of their disease (17).
Although infrequent, malignant insulinomas may be found
at exploration. The most common sites for metastasis are the
liver and adjacent lymph nodes. In the event that metastases
are found, there is a relevant role for debulking the tumor,
because a survival advantage has been demonstrated for
removing as much tumor as possible (27). In addition, debulk-
ing may assist in temporary alleviation of hypoglycemia.
Attempts at resection or debulking of hepatic metastases may
also be palliative or, rarely, curative (13).
gastrinoma
Gastrinomas are the second most common functioning islet
cells tumors of the pancreas, occurring one-half as often as
insulinomas (14). These tumors are generally small and occur
more frequently (3:2) in males than in females (28,29). Gastri-
nomas may occur from childhood into old age, but the major-
ity of cases occur between the fourth and the sixth decades of
life (13).
The Zollinger–Ellison syndrome (ZES), originally described
in 1955, includes non-insulin-producing tumors of the
 NEUROENDOCRINE PANCREATIC TUMORS
pancreas, acid hypersecretion and fulminant peptic ulcer dis-
ease (30). The more proper designation for this syndrome
today is gastrinoma, as one or more of the initially described
components of ZES may not be present. Historically, this dis-
ease was recognized following a protracted course of ulcer dis-
ease with delays in diagnosis ranging from 3 to 9 years (14). At
present, patients with gastrinoma resemble the typical peptic
ulcer patient. The most common presenting symptom of gas-
trinoma is epigastric pain and most patients will have a soli-
tary ulcer. These ulcers are often <1 cm in diameter and 75%
occur in the first portion of the duodenum. Less commonly,
patients with gastrinomas may have recurrent, multiple, and
atypically located ulcers, for example, in the distal duodenum
(14%) or jejunum (11%) (31). Perforated ulcer remains a
common complication with 7% of patients with gastrinomas
presenting with perforation of the jejunum (32). Interestingly,
as many as 20% of patients have no evidence of ulcer disease
and present with the secretory effects of the tumor (33).
Diarrhea occurs in 40% of patients with gastrinoma and is
caused by gastric acid hypersecretion that increases intestinal
transit time, leading to malabsorption. Control of stomach
acid output by either total gastrectomy or medications has
been shown to control the diarrhea in nearly all patients (34).
A significant proportion of patients with gastrinoma will
experience esophageal abnormalities including dysphagia and
esophagitis. Indeed, ulceration, stricture formation, and per-
foration have been reported in this disease (35). Medical man-
agement of esophageal disease requires strict control of acid
secretion by the stomach.
Measurement of the fasting serum concentration of gastrin
is the best single screening test for gastrinoma, as more than
99% of patients with gastrinomas will have abnormally ele-
vated levels (>100 pg/ml). Ideally, for gastrin levels to be most
accurate, all antisecretory medications should be stopped for
several days prior to testing. The second critical exam is the
determination of basal acid output (BAO). This is defined as a
BAO greater than 15 mEq/h in patients without previous sur-
gery to reduce gastric acid secretion, or greater than 5 mEq/h
in patients with prior acid-reducing operations (31). The mea-
surement of gastric acid output helps to exclude other causes
for hypergastrinemia such as gastric outlet obstruction, antral
G-cell hyperplasia, postvagotomy state, and retained antrum.
In patients with achlorhydria, such as those with pernicious
anemia and atrophic gastritis, failure of acid-induced feedback
inhibition results in elevated serum gastrin levels. Therefore,
measurement of serum gastrin levels alone in these patients
will be inaccurate 50% of the time in the diagnosis of gastri-
noma (34).
If there is any diagnostic uncertainty or if the serum gastrin
level is only moderately elevated, a secretin stimulation test is
indicated. This test involves an intravenous bolus of 2 U/kg of
secretin and then serum levels of gastrin are determined at 0,
2, 5, 10, and 20 minutes. Patients with gastrinomas have gas-
trin level elevations of 200 pg/ml or more above the fasting
value (14). A positive secretin test is very useful in the differen-
tial diagnosis of gastrinoma from antral G-cell hyperplasia.
The latter is also characterized by gastrin hypersecretion and
hyperacidity. However, gastrin secretion in antral G-cell
hyperplasia does not rise after administration of a secretin
bolus (13). The secretin test has also been used to follow
patients following surgical resection of gastrinoma to evaluate
for the presence of recurrent or persistent disease. Patients
with persistent or recurrent gastrinoma will have an abnormal
secretin test before they develop an elevated basal gastrin level
or imageable disease (36).
With the advent of potent gastric antisecretory medications,
acid hypersecretion can be effectively controlled in all patients
with gastrinoma. Therefore, for control of gastric acid output,
total gastrectomy is no longer indicated in the management of
these patients (31). Proton pump inhibitors are the medical
treatment of choice when H2-receptor antagonists have failed
because of escape or unwanted side effects. Patients with gas-
trinoma require greater doses of medication than patients
with typical peptic ulcer disease. In one study, the mean total
dose of omeprazole to control gastric acid output in 63 patients
with gastrinoma was 80 mg per day (37). Despite this, there is
concern whether prolonged high dose omeprazole is safe in
humans. Experiments in rodents have shown that prolonged
omeprazole use is associated with the development of gastric
carcinoid tumors (38). In fact, the development of diffuse
malignant gastric carcinoids has been observed in a few
patients with gastrinoma and MEN-1 maintained on omepra-
zole for prolonged time periods (37).
Precise localization of all gastrinomas is critical for defining
an appropriate therapeutic strategy. Gastrinomas are mainly
located in the gastrinoma triangle (Fig. 45.2) (39). Primary
gastrinomas can also be observed, but less frequently, in the
distal duodenum or jejunum and in other parts of the pancre-
atic gland. Ectopic gastrinomas are rare but hard to localize
preoperatively (ovaries, gallbladder). In sporadic gastrinoma,
the primary tumor is often single or associated with peripan-
creatic metastatic lymph nodes (33,40). It is thought that
primary gastrinomas can be located in lymph nodes because
resection of lymph nodes has rarely been associated with
90%
10%
Figure 45.2 Anatomic triangle in which gastrinomas are most often found.
Source: From Ref. (13).
417
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
long-term cure (33,40,41). Data indicate that about 30% of
gastrinomas are pancreatic and the others are extrapancreatic,
mainly duodenal (33,41,42). In MEN-1, the endocrine tumors
are often multiple and can be located both in the pancreatic
gland and in the duodenum (37).
The ability of imaging modalities to localize primary gastri-
noma and gastrinoma metastatic to the liver is summarized in
Tables 45.3 and 45.4. At the time of diagnosis, approximately
25% to 40% of patients will have liver metastases, therefore,
imaging studies must carefully assess the liver. Although non-
invasive modalities for tumor localization have high specificity,
their sensitivity is often low. In addition, the sensitivities of
ultrasonography and CT scanning are much lower for duode-
nal gastrinomas than for pancreatic gastrinomas and depend
on tumor size (43). Approximately 30% of gastrinomas
between 1 and 3 cm are seen on CT, while nearly all larger
tumors are imaged. CT detects 80% of pancreatic gastrinomas
but only 35% of extrapancreatic tumors. Modern MRI technol-
ogy has demonstrated improved ability to detect liver metasta-
ses with 83% sensitivity and 88% specificity (44). Despite the
widespread use of computed tomography and magnetic reso-
nance imaging, 50% of primary tumors will not be identified
on conventional preoperative imaging studies (37).
Somatostatin receptor scintigraphy (SRS) has been sug-
gested to be the non-invasive imaging study of choice to local-
ize primary and metastatic gastrinomas. Studies have
demonstrated that gastrinomas have high densities of soma-
tostatin receptors and that these can be used to image these
tumors using radiolabeled somatostatin analogs (Table 45.3)
(22,23). In a study of 35 patients, SRS detected 67% of all gas-
trinomas found at exploration, including 52% of primary gas-
trinomas found and 80% of lymph nodes containing metastatic
gastrinoma. Therefore, SRS missed approximately one-third
of all extrahepatic gastrinomas that were found at exploration.
Of note, SRS detected only 30% of duodenal gastrinomas but
detected 90% of pancreatic gastrinomas. Similar to several
Table 45.3 Sensitivity of Non-invasive Imaging Studies for
Localization of Primary and Metastatic Gastrinoma
Imaging study Extrahepatic primary (%) Liver (%)
Ultrasound 9 48
CT 31 42
MR 30 71
SRS 58 92
Source: Adapted from Ref. (57).
Table 45.4 Sensitivity of Invasive Imaging Studies for
Localization of Gastrinoma
Imaging modality Primary (%) Liver (%)
Endoscopic ultrasound 50–75 NA
Angiogram 28 62
Portal venous sampling 73 NA
Secretion angiogram 78 41
Source: Adapted from Ref. (37).
418
other studies, the investigators found that SRS was signifi-
cantly more sensitive than conventional imaging studies and,
on a lesion-by-lesion basis, was even more sensitive than all
conventional imaging studies combined. The addition of all
conventional studies to SRS detected only three (4%) addi-
tional lesions found at exploration in three patients (45).
The potential benefit of endoscopic ultrasound for preop-
erative imaging is that it can visualize small tumors and may
help distinguish the primary tumor from lymph node and
liver metastases. In a study of 22 patients, EUS had a sensitivity
of 50%, 75%, and 63% for duodenal, pancreatic, and lymph
node gastrinoma, respectively (46). Currently, studies suggest
that EUS has a sensitivity of 50% to 75% and a specificity of
95% in the localization of gastrinomas (24,46).
Techniques such as portal venous sampling of gastrin and
angiography with intra-arterial injection of secretin with
venous sampling of gastrin have been shown to have good sen-
sitivity for gastrinoma detection (Table 45.4) However, since
80% of gastrinomas are located in a relatively small anatomical
area, the gastrinoma triangle, performing a study that indi-
cates a region that may harbor a tumor does not add much
information. Secretin angiography may be indicated for selec-
tion of patients that may benefit from an aggressive approach
(e.g., pancreaticoduodenectomy) for a locally advanced or
locally recurrent gastrinoma. A secretin angiogram may be
indicated to determine whether all tumor is localized within
the planned resection (37).
In our opinion, preoperative evaluation in patients with
gastrinoma should include
1. Endoscopy to evaluate for the presence of duodenal
gastrinoma,
2. Spiral CT scan to evaluate the pancreas, lymph
nodes, and liver (consider MR imaging if CT
is not adequate or further evaluation of liver is
needed), and
3. SRS for global evaluation of tumor extent.
Despite these tests, a significant percentage of patients will
not have their tumors detected before surgery. Therefore, a
thorough surgical exploration is indicated.
All patients with sporadic gastrinoma should undergo local-
ization studies and be considered for exploratory laparotomy
for potential cure. Since gastrinomas are relatively indolent, it
has not been shown that resection of the primary tumor
extends survival. However, evidence suggests that resection of
primary gastrinoma decreases the incidence of liver metasta-
ses. Patients with liver metastases from gastrinoma will even-
tually die of disease. Therefore, it is reasonable to assume that
resection of the primary should prolong survival (37).
When exploring a patient for gastrinoma, a meticulous
intraoperative approach is necessary. Gastrinomas that were
previously missed have often subsequently been found to be in
the duodenal wall. Gastrinomas are located in more proximal
portions of the duodenum and the tumor density decreases
more distally (Fig. 45.3). Simple palpation through the bowel
wall without opening the duodenum will miss small duodenal
tumors. Endoscopic transillumination and extensive duode-
notomy have been found to improve localization of duodenal
 NEUROENDOCRINE PANCREATIC TUMORS

primaries (16). Care to identify the ampulla and the pancreatic
duct must be used when attempting to remove medial wall
gastrinomas.
Gastrinomas within the pancreatic head should be enucle-
ated and those in the body or tail of the pancreas should be
resected by either subtotal or distal pancreatectomy. Whether
tumors are actually in lymph nodes near the pancreatic head
or in the pancreas itself is determined by frozen section. If
tumor is found only in lymph nodes, other lymph nodes
should be identified and removed. A search must then be made
for a duodenal wall primary gastrinoma. Duodenal tumors
should be resected with a narrow margin of duodenum around
the tumor. Distant metastases to the liver should be resected if
all tumor can be completely and safely removed.
With increased awareness of duodenal tumors, the operative
detection rate is greater than 90% and the immediate cure rate
is between 60% and 90% (Table 45.5) (28,48,49). The long-
term cure rate is about one-half the immediate cure rate.
Patients with resectable disease have excellent survival (5 year:
70%, 10 year: 50%) but those with unresectable multiple
metastases have a 5-year survival rate of only 20% to 38%
(33,50). Removal of all tumor or surgical debulking prolongs
life expectancy in selected patients with metastatic disease
(16). Prospective studies indicate that aggressive resection of
metastatic disease in patients who have resectable disease by
radiologic criteria had a 5-year survival of 79% compared with
28% in patients with inoperable metastatic disease (50,51).
Patients who have solitary, localized metastatic disease appear
to benefit most from this aggressive approach.
The management of gastrinoma in patients with MEN-1 is
controversial (52). Neuroendocrine tumors of the pancreas
and duodenum are frequently multiple in this syndrome,
making it difficult to determine which tumor is responsible for
the clinical features. The role of surgery in these patients is not
clear as few are cured and the islet cell tumors are thought to
be less malignant than those seen in non-familial forms of the
disease. A study has shown that, even when procedures to
explore the duodenum and remove duodenal tumors were
used, complete remission was uncommon because 86% of
tumors had metastasized to lymph nodes and 43% of patients
had multiple tumors (53). Nevertheless, some authors advo-
cate an aggressive approach to these patients including
1. Performance of a distal pancreatectomy in every
patient to remove tumors in the neck, body, or tail,
2. Duodenotomy in every patient to remove small
duodenal wall tumors, and
3. Peripancreatic lymph node dissection in any MEN-1
patient with a duodenal neuroendocrine tumor or
a pancreatic tumor 2 cm in diameter or larger (54).
Using this approach in 38 patients resulted in 5-, 10-, and
15-year survival rates of 98%, 98%, and 96%, respectively.
There was no operative mortality and no patient subsequently
died of MEN-1 related disease. Two-thirds of the patients with
gastrinomas remained eugastrinemic (54). A practical
approach may be to perform imaging studies consisting of a
CT scan and SRS in patients with MEN-1 and suspected gas-
trinoma. Those patients with tumors that are large (>2 cm)
have a significant probability of metastases to the liver and the
tumors are resected according to their malignant potential.
Other patients with MEN-1 and gastrinoma may be treated
with medication to control gastric secretion.

glucagonoma
Glucagonomas are usually large tumors (>5 cm) and occur
most often in the body and tail of the pancreas and are rarely
extrapancreatic (Table 45.1) (13,16). The incidence of gluca-
gonoma is considerably less than insulinoma and gastrinoma
and is estimated to be one in 20 million to one in 30 million.
The exact incidence is unknown because glucagonomas may

Table 45.5 Results of Surgery for Localized Sporadic and

MEN-1 Gastrinoma
No. with No.
Sporadic tumor disease-
Series or MEN N found (%) free (%)
Norton et al. (33) S 73 56 (77) 37 (50)
Howard et al. (48) S 11 10 (91) 9 (82)
Thompson et al. (49) S 5 5 (100) 5 (100)
McArthur et al. (108) S 22 9 (41) 2 (9)
Melvin et al. (109) MEN 19 17 (90) 1 (5)
MacFarlane et al. (53) MEN 10 10 (100) 0 (0)
Jaskowial et al. (110) S/MENa 17 17 (100) 5 (30)b
Source: Adapted from Ref. (37).
a
Reoperation for localized recurrent gastrinoma.
Figure 45.3 Location of 24 duodenal gastrinomas in patients with Zollinger– b
Each of the five patients who were disease-free had sporadic gastrinoma.
Ellison syndrome. Seventeen tumors were in the first portion, five were in the Abbreviations: MEN, Multiple endocrine neoplasia type 1; S, sporadic.
second, and two were in the third. Source: From Ref. (47).

419
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
be underdiagnosed since they remain asymptomatic until they
grow large, and may be misdiagnosed since the symptoms of
excess glucagon can be attributed to other causes. The mean
age at diagnosis is approximately 55 years. As glucagonoma
may be associated with MEN-1 syndrome, patients and their
families should be screened for other endocrinopathies.
Patients usually present with symptoms of weight loss, glu-
cose intolerance, and migratory necrolytic dermatitis. This
rash begins as erythematous macules and papules on the face,
abdomen, groin, and extremities. Other findings which are less
common include stomatitis, glossitis, and diarrhea. Gluca-
gonoma is diagnosed by characteristic findings on biopsy of the
rash. However, serum levels of glucagon exceeding 1000 pg/ml
are diagnostic (13,16). Although several symptomatic patients
with glucagonomas have been found with glucagon concen-
trations below 1000 pg/ml, most glucagon concentrations of
this magnitude have been in asymptomatic patients with small
tumors. Glucagon concentrations can be elevated in other dis-
ease processes such as hepatic or renal insufficiency and after
excessive exercise or severe stress. Elevation can also occur
with diabetic ketoacidosis, septicemia, and the use of oral con-
traceptives.
Glucagonomas are less difficult to localize preoperatively
than other endocrine tumors of the pancreas because of their
size at presentation. The improved technology and widespread
use of CT scanning have decreased the importance of angiog-
raphy, and CT scanning is the technique of choice both to
localize the primary tumor and to demonstrate metastatic
disease.
The management of patients with a glucagonoma is
directed toward control of the tumor and its hormonally
related symptoms. When the tumor is still localized to the
pancreas, surgical resection is the optimal treatment because
it can completely reverse all clinical manifestations of the
syndrome and result in a lasting cure. Only occasionally are
these tumors amenable to enucleation. The high rate of
malignancy together with a greater than 50% rate of metas-
tases demands an aggressive resection strategy for gluca-
gonomas (13). As much tumor as possible should be removed,
including nodal metastases and lesions in the liver that can
be safely wedged out. Formal hepatic resection is indicated if
all gross tumor can be excised. Tumor debulking can provide
dramatic and rapid improvement in many glucagonoma
symptoms. A marked and prolonged decline in serum gluca-
gon is possible with palliative resection, so the hormonal
manifestations of this disorder disappear or are relieved for
many years. Repeat debulking of recurrent or metastatic
disease may also prolong survival (55).
Since these tumors are slow growing, the results of resec-
tion plus chemotherapy have resulted in 5-year survival
rates of 50% (56). Streptozotocin as a single agent has pro-
duced a biochemical response (reduction in serum hormone
levels by at least 50%) in 64% of patients treated and a
tumor response (regression of tumor size by at least 50%) in
50% of patients (57). However, most investigators have
found a lower response rate than this. Symptoms of gluca-
gonoma may be successfully controlled with the use of
somatostatin analog (58).
420
vipoma
VIPoma syndrome characterized by watery diarrhea, hypoka-
lemia, and achlorhydria (WDHA) was first described in 1958
by Vemer and Morrison (59). Vasoactive intestinal peptide was
first isolated from bovine intestine in 1970 and soon after it
was shown that extracts of peptides from tumor and plasma of
patients with WDHA produced similar symptoms in dogs
(13,60). The first report of a surgical cure was in 1978 when
excision of a VIPoma in a patient with WDHA syndrome com-
pletely relieved the symptoms as plasma VIP levels dropped to
normal (13). Since that time, 201 cases have been reported in
the literature (61).
VIPomas are predominantly in the pancreas (90%) and
extrapancreatic tumors are very rare, except in children (14).
Pancreatic VIPomas are usually solitary, small in diameter, and
in the body or tail of the pancreas 75% of the time (Table 45.1)
(61). Approximately 50% of pancreatic VIPomas are malig-
nant and one-half of these are metastatic to the liver or regional
lymph nodes at diagnosis. Less than 5% of patients with
VIPoma of the pancreas have MEN-1 (14). The tumors have a
bimodal distribution which is related to histologic type. In a
study of 62 patients, 52 had pancreatic VIPomas and 10 had
extrapancreatic ganglioneuromas. The extrapancreatic sites
(adrenal, mediastinal, retroperitoneal) occur predominantly
in the pediatric population and demonstrate a less aggressive
course, with only a 10% rate of metastasis (61).
Diagnosis includes an evaluation of the diarrhea for a secre-
tory nature. This can be confirmed with a trial of fasting for 48
to 72 hours, which will have no major effect on the diarrhea
due to VIPomas. The fecal content of potassium and sodium is
determined. The sum of twice the sodium plus the potassium
should equal isotonicity in a secretory diarrhea. All infectious
causes of diarrhea must be excluded. A fasting plasma VIP
level of more than 200 pg/ml is required to establish the diag-
nosis (14,62).
Spiral CT scanning should be used to localize VIPomas.
With small lesions, other modalities such as SRS or angiogra-
phy may occasionally be necessary to help identify tumor loca-
tion (63).
Surgical excision remains the only effective method of cure.
Preoperative restoration of extracellular volume status and
correction of electrolyte abnormalities must be accomplished.
The fluid and electrolyte imbalance should be reversed slowly
because of its chronic nature. Octreotide acetate is useful in
promptly inhibiting VIP secretion from the tumor and stop-
ping the diarrhea (55) A careful surgical exploration including
evaluation of the retroperitoneum, both adrenal glands, and
the pancreas should be performed. Surgical therapy consists of
enucleation or pancreaticoduodenectomy for pancreatic head
tumors. Body and tail tumors are best managed by distal pan-
createctomy. Complete resection of these tumors delivers full
symptomatic relief. If all apparent tumor cannot be resected or
if there is metastatic disease, surgical debulking remains a use-
ful option. VIP levels are an excellent tumor marker for recur-
rence. If there is recurrence, repeat debulking may be a viable
and therapeutic option (64).
Survival of patients with malignancy and/or metastatic dis-
ease is disappointing. The average survival is approximately 1
 NEUROENDOCRINE PANCREATIC TUMORS
year. There are few well documented chemotherapeutic agents
for the treatment of the VIPoma syndrome. The combination
of streptozotocin and 5-fluorouracil was effective in 65% of
patients studied in the Eastern Cooperative Oncology Group
(65). DTIC, human leukocyte interferon, and adriamycin in
combination with streptozotocin have been used in small
numbers of patients with variable success (65,66). Octreotide
provides symptomatic relief for most patients with metastatic
disease (67).
somatostatinoma
Somatostatinomas are among the rarest of the functional
endocrine tumors. There have been 41 males and 42 females
reported with somatostatinomas. These patients have an aver-
age age of 54 years with a range of 24 to 84 years (64). The
most common location for somatostatinomas was within the
pancreas (68%); 19% occur in the duodenum and 3% each in
the ampulla of Vater and the small bowel (Table 45.1) (68).
Most commonly, pancreatic tumors are found in the head and
body of the gland (13).
The classic somatostatinoma syndrome has been character-
ized by the triad of diabetes, diarrhea/steatorrhea and gall-
stones. Diarrhea/steatorrhea occurs in approximately
one-third of patients and results from an increase in stool
osmolarity secondary to malabsorption of fats, sugars, and
amino acids. Steatorrhea results from decreased pancreatic
exocrine secretion and the associated impairment of fat
absorption. Excessive somatostatin inhibits the release of cho-
lecystokinin, which decreases gallbladder contraction and
leads to malabsorption and cholelithiasis. Weight loss is one of
the most common findings and is seen in about 40% of
patients and may be attributable to malabsorption. Diabetes
occurs in 25% of patients and may occur secondary to greater
suppression of insulin secretion over glucagon release by
somatostatin as well as indirectly by somatostatin suppression
of gastric inhibitory peptide (13,14,68).
Somatostatinomas are often large tumors at the time of pre-
sentation and imaging studies are associated with a high
degree of accuracy. CT scanning correctly localized the
somatostatinoma in 34 of 37 patients with pancreatic tumors.
Angiography has also been used to localize difficult neoplasms
(68). The diagnosis can be established by measuring an ele-
vated fasting somatostatin level (normal, <100 pg/ml). When
evaluated preoperatively, 34 of 35 patients had elevated levels
of circulating somatostatin. Plasma somatostatin measure-
ments may also be useful in evaluating the success of treat-
ment and to follow patients for possible recurrence.
Surgical resection is the preferred treatment for patients
with somatostatinomas. Unfortunately, successful surgical
management is difficult because of the high rate of metastases
present at exploration (Table 45.1). Most tumors are large and
enucleation is usually not possible. Pancreatic resection
including a pancreaticoduodenectomy or distal pancreatec-
tomy is often necessary. Debulking a large tumor or hepatic
metastases may effectively palliate symptoms, often for pro-
longed periods of time.
As with other islet cell cancer, somatostatinomas may have
an indolent tumor biology and long-term survival can occur.
However, due to the frequent malignant behavior of this
tumor, aggressive treatment is warranted and outcome is fre-
quently poor. In one review, survival rates for these patients
were 48% at 1 year and 13% at 5 years (68). The experience
with chemotherapy in this tumor is limited but streptozotocin
and 5-FU has caused tumor regression and symptomatic
remission in some patients and is therefore a reasonable con-
sideration in the symptomatic patient with recurrent and/or
metastatic disease (69).
unusual functional islet cell tumors
Other functional islet cell tumors are exceedingly rare and
include growth hormone-releasing factor secreting tumors,
adrenocorticotropic hormone secreting tumors, parathyroid
hormone like secreting tumors, and neurotensinomas. The
treatment of choice for these rare tumors is uncertain but
appears to be primarily surgical resection. Palliative resection
(debulking) of metastatic disease is also frequently indicated
since it may provide symptom benefit. Octreotide acetate may
prove to be useful in the symptomatic treatment of many of
these tumors (13).
non-functional islet cell tumors
Non-functioning tumors are slow growing and occur most
commonly in the head of the pancreas (4,70). In surgical
series, 38% to 80% of lesions are found in the pancreatic head.
They tend to be relatively large, symptomatic, and often pres-
ent with metastatic disease. In a similar fashion to adenocarci-
noma of the pancreas, the clinical presentation of these tumors
is related to either local invasion or metastatic spread. Jaun-
dice, abdominal pain, weight loss, or the appearance of an
abdominal mass are the predominant signs and symptoms
(Table 45.6). Many authors report the presence, in a small
number of patients, of multiple non-functioning tumors scat-
tered throughout the pancreas (Table 45.7).
Lesions in the pancreatic head may induce back pain but
much less commonly than with ductal adenocarcinoma, which
displays a characteristic ability to infiltrate retroperitoneal
nerves. Often non-functional islet cell neoplasms in the body
and tail of the pancreas do not present with many symptoms
but may have a palpable mass on examination. In addition to
these findings, patients may complain of nausea, vomiting,
diarrhea, or lethargy (71). In contrast to adenocarcinoma of
the pancreas where systemic effects are seen quite early in the
presentation of the disease, patients with non-functioning islet
cell tumors can present with advanced metastatic disease and
relatively few systemic symptoms. An incidental presentation
is not uncommon. Kent and colleagues from the Mayo Clinic
noted that four (16%) of 25 non-functional tumors presented
as an incidental finding (4). Rarely, these tumors may present
with massive hemorrhage as a result of either penetration into
the gastrointestinal tract or erosion of vessels in the retroperi-
toneum (72).
It is not clear whether the interval from onset of symptoms to
diagnosis differs in patients with non-functioning neoplasms
and those with functional neoplasms. It has been suggested that
as many small functional islet cell neoplasms cause symptoms
related to hormone excess without the development of biliary
421
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 45.6 Signs and Symptoms of Non-functional Tumors at Presentation

Author N Study (yr) Jaundice (%) Abdominal pain (%) Weight loss (%) Mass (%)
Cheslyn-Curtis et al. (80) 20 1982–91 40 35 30 40
Broughan et al. (73) 21 1948–84 24 48 24 24
Kent et al. (4) 25 1960–78 28 36 – 8
Phan et al. (10) 58 1949–96 35 56 46 –

Table 45.7 Location of Non-functional Islet Cell Tumors in the Pancreas

Body and tail Multiple
Author N Study years Head No. (%) No. (%) No. (%)
Kent et al. (4) 25 1960–78 14 (56) 5 (20) 6 (24)
Dial et al. (111) 11 1963–83 7 (64) 4 (36) –
Broughan et al. (73) 19 1948–84 9 (47) 7 (37) 3 (16)
Eckhauser et al. (112) 10 1973–85 8 (80) 2 (20) –
Yeo et al. (113) 13 1985–90 5 (38) 8 (62) –
Cheslyn-Curtis et al. (80) 20 1982–91 14 (70) 5 (25) 1 (5)
Evans et al. (84) 73 1953–92 43 (59) 30 (41) –
Madura et al. (81) 14 1972–96 11 (79) 1 (14) 1 (7)
Lo et al. (7) 34 1985–96 16 (47) 16 (47) 2 (6)

or gastrointestinal obstruction due to the primary tumor, that

they present earlier (14). The duration of symptoms related to
the tumor may be at least as long or longer in patients with
functioning tumors as in non-functioning tumors. In a review
of 64 patients with islet cell carcinomas (34 non-functional, 30
functional) treated at the Mayo Clinic, the duration of symp-
toms prior to diagnosis for all patients ranged from less than 1
to 120 months (median 10 months). For functional neoplasms
the median duration of symptoms was 11 months versus
8 months for non-functional neoplasms (p > 0.1) (7). Others
have also found that the median duration of symptoms was
significantly longer for functional tumors (insulinomas:
22 months; gastrinomas: 36 months) as compared to non-
functional neoplasms (6 months) (73). It appears that most
patients with islet cell tumors undergoing surgical treatment
have a lengthy duration of symptoms. A high index of suspi-
Figure 45.4 Computed tomography of patient with large non-functioning
cion is necessary in attempting to make the diagnosis of an islet
tumor of tail of pancreas. Note area of cystic degeneration and hypodense
cell tumor of the pancreas. areas of necrosis (arrows). This patient underwent a potentially curative resec-
tion of the tumor.
diagnosis
Since the clinical presentation of non-functioning islet cell
tumors is similar to other pancreatic neoplasms, the major vascular encasement and lack of obstruction of the pancreatic
challenge is to distinguish this tumor from other forms of pan- duct as compared to adenocarcinoma of the pancreas.
creatic neoplasia, especially from the much more common For non-functioning islet cell neoplasms, CT is the radiologic
ductal adenocarcinoma. Non-functioning islet cell tumors imaging modality of choice. Like other large, hypervascular
tend to be larger than ordinary pancreatic adenocarcinomas at neoplasms, islet cell carcinomas may have internal necrotic
the time of diagnosis. Viable portions of islet cell tumors are areas. These appear on CT as hypodense zones of low attenua-
typically well vascularized and often hypervascular relative to tion, sometimes with features of cystic degeneration or necro-
the unaffected portion of the pancreas. As a result this neo- sis (Fig 45.4). Dystrophic calcification may develop within a
plastic tissue usually undergoes an appreciable degree of tumor and is observed on CT in 20% of non-functioning islet
enhancement on images made with appropriate techniques of cell tumors (75). The characteristic features on CT of non-
intravenous contrast enhancement (74). Other morphologic functioning islet cell carcinomas, including large tumor mass,
features that distinguish islet cell tumors include the lack of hyperenhancement, cystic degeneration, and calcification,

422
 NEUROENDOCRINE PANCREATIC TUMORS
Table 45.8 CT Characteristics of Pancreatic Neoplasms
Tumor type Sex (M:F) Vascularity Degree of necrosis
Adenocarcinoma 1.3:1.0 Hypovascular Little
Acinar cell 1.0:1.0 Hypovascular Much
Solid and papillary 1.0:9.0 Hypovascular Much
Islet cell 1.0:1.0 Hypervascular Variable
Serous cystadenoma 1.0:2.0 Hypovascular None
help distinguish them from ductal adenocarcinoma. Similar
features are present and identified by CT in the metastatic
lesions from these tumors. Metastases are found most often in
the liver and in regional lymph nodes. Whereas metastases
from ductal adenocarcinoma tend to be small, those from islet
cell carcinoma are often large (74).
Pancreatic tumors other than ductal adenocarcinomas can
be difficult to distinguish from non-functioning islet cell
tumors. In a study of 45 patients with 50 non-functioning islet
cell tumors, 36 of the tumors had heterogeneous areas and
over half (N = 27) had cystic degeneration visualized on CT or
MRI. Only 14 of the 50 non-functioning tumors were solid
homogeneous masses (76). Therefore, an islet cell carcinoma
could resemble atypical forms of serous or mucinous cystic
neoplasms. More likely, a partially necrotic tumor, such as
solid and papillary epithelial neoplasm, might resemble an
islet cell neoplasm with similar structure. Unlike solid and
papillary epithelial neoplasms, however, non-functioning islet
cell tumors are often associated with large metastases and they
do not typically have visible capsules. Moreover, they tend to
occur in older age groups and they do not have the predilec-
tion for female subjects (Table 45.8).
While MEN-1 syndrome has been associated with func-
tioning endocrine tumors of the pancreas, small clinically
silent endocrine tumors are often numerous in the pancreas
of patients with this syndrome. Non-functioning microade-
nomatoses of MEN-1 patients have been found mainly to be
composed of glucagon and pancreatic polypeptide produc-
ing cells. In addition to the microadenomatosis, larger, dis-
crete adenomas, mainly composed of pancreatic polypeptide
producing cells, have been found (77). Although increased
blood levels of glucagon and pancreatic polypeptide have
been frequently detected in such patients, as a rule related
clinical syndromes have not been observed. Most clinically
non-functioning pancreatic tumors in patients with
MEN-1 syndrome have benign histologic patterns and
behavior (2).
Metastatic tumors to the pancreas such as those from renal
cell carcinoma are particularly likely to have appearances
indistinguishable from those of islet cell carcinoma. In these
cases, clinical correlation should predict the nature of the
lesion.
In addition to characteristic clinical presentations and
radiologic findings, serum markers have been utilized in the
diagnosis of non-functional endocrine tumors. To be able to
detect a tumor by its secretion(s) implies that the tumor is
no longer biochemically silent. Nonetheless, such neoplasms
are not associated with any distinct clinical symptoms.
Size Enhancing capsule Calcification
Small No No
Large Variable No
Large Yes Yes—peripheral
Mod-large No Yes (25%)—internal
Large Yes Yes—central
Pancreatic polypeptideoma (PPoma) is one such tumor and
among the most common of the non-functional islet cell
tumors. Human pancreatic polypeptide is frequently associ-
ated with other hormones in pancreatic endocrine tumors
and pancreatic polypeptide cells are most often found in
glucagonomas and in non-secreting tumors (11). In a series
of eight patients with isolated pancreatic polypeptide pro-
ducing islet cell tumors, clinical features included abdomi-
nal pain (N = 4), weight loss (N = 4), diarrhea (N = 2),
gastrointestinal bleeding (N = 2), and jaundice in one
patient. Serum basal pancreatic polypeptide was elevated in
most patients with a marked response to secretin. Six of
eight patients underwent tumor resection with two patients
being not surgical candidates due to hepatic metastases (77).
After curative resection, elevated serum pancreatic polypep-
tide levels fell to normal. Contrary to most reported non-
functioning tumors, PPomas seem to have a benign course
even when of large size and producing local symptoms, as
found in six of eight cases reported above and in 10 of 10
cases reported elsewhere (11). Other markers which have
been evaluated in non-functioning islet cell tumors include
neuron-specific enolase (78). Its role in monitoring patient
course or response to therapy is not known at present.
The presence of hormones in tumor cells at immunochemi-
cal staining provides useful information for the diagnosis of
non-functioning islet cell tumors. Multiple hormones can be
produced by these neoplasms. In a series of 61 non-function-
ing tumors, pancreatic polypeptide immunoreactivity was
detected in 35% of cases, with a mean of 33% of all tumor
cells; glucagon was found in 30% of cases and 30% of cells;
somatostatin in 15% of cases and 20% of cells; serotonin in
20% of cases and 36% of cells; calcitonin in 20% of cases and
10% of cells; neurotensin in 8% of cases and 8% of cells; and
insulin in 15% of cases and 2% of cells. No gastrin or VIP
immunoreactivity was detected (79). It seems clear that tumors
producing pancreatic polypeptide, glucagon, somatostatin,
calcitonin, and serotonin are more likely to be without an
associated syndrome than are those producing clinically
powerful hormones such as insulin, gastrin, or VIP.
localization and extent of disease
There are sparse data on the accuracy of non-invasive and
invasive radiologic imaging in tumor localization and predict-
ing resectability of non-functioning islet cell tumors. With
improvements in CT scanning, angiography is no longer nec-
essary in their diagnostic work-up. In a series of 20 patients
studied between 1982 and 1991, dynamic CT localized the
tumor in 17 of 20 patient (85%). No pancreatic lesion was seen
423
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
in three patients who had obstructive jaundice. In two, the
lesions were seen with angiography and the third was found at
operation (80). In another series, dynamic CT demonstrated a
mass in nine of 13 patients (69%) while three of the patients
had no mass seen but dilated common and/or pancreatic ducts
were present (81). In a study which evaluated both functioning
and non-functioning islet cell tumors from 1949 to 1996,
dynamic CT successfully localized the tumor 76% of the time.
Angiography localized the tumor in 58% of patients and CT
plus angiography did no better at tumor localization (79%) as
compared to CT alone (76%) (10). Usually when CT shows a
pancreatic mass presumed to be a non-functional islet cell
neoplasm, arteriography is not warranted unless there is a
question of invasion of a major vascular structure. Even then,
non-invasive MR angiography has been shown to be accurate
in predicting tumor vascular involvement (82). Due to the
relatively good prognosis with islet cell neoplasms, many sur-
geons would attempt en bloc resection with vascular recon-
struction if there was vascular involvement at the time of
surgery (83). At present, the yield of new generation helical CT
scanning in localizing non-functioning islet cell tumors is not
known.
Although a study suggests that MR imaging is superior to
CT in identification of pancreatic endocrine tumors, this study
can be faulted since dynamic CT was utilized for comparison
(19). To our knowledge, no studies that compared state-of-
the-art helical CT with MR imaging have been reported in the
literature.
The role of laparoscopy in the management of patients with
non-functioning islet cell tumors is unknown. With the goal
of ruling out metastatic disease, laparoscopy would spare
patients from undergoing an unnecessary laparotomy. In
multiple series, evidence of metastatic disease has been found
at the time of surgery in more than 50% of patients and
resectability rates are low (8,73,84). Unfortunately, most of
these series have spanned long time frames and it is unknown
whether metastatic disease was visible on quality preoperative
imaging studies. A number of studies have demonstrated
improved accuracy of laparoscopy in predicting extent of dis-
ease for pancreatic adenocarcinoma (85). No study has spe-
cifically evaluated the use of laparoscopy in patients with islet
cell tumors of the pancreas. Extrapolating from data obtained
with pancreatic adenocarcinoma, it would appear that lapa-
roscopy could spare asymptomatic patients with metastatic
disease from undergoing unnecessary laparotomy (Fig. 45.5).
High-affinity somatostatin receptors have been identified
in the pancreatic islet cells (86). With this in mind, somatosta-
tin receptor scintigraphy (SRS) has been developed for
in vivo imaging of somatostatin receptor-positive tumors
(Fig. 45.6A–C). Studies with small numbers of patients have
shown accurate localization of non-functioning islet cell
tumors with SRS (22,87). In a collective review of results from
15 centers in Europe with SRS, 82% of non-functioning
tumors (N = 60) were visualized at scintigraphy (23). Investi-
gations in patients with non-functioning pancreatic tumors,
which have compared SRS with CT scanning and MRI, have
shown a similar sensitivity (60%) for both SRS and conven-
tional imaging in detecting tumors. Somatostatin receptor
424
Figure 45.5 Photograph of liver metastases of a non-functioning islet cell
tumor (arrows) detected at laparoscopy. The primary tumor was in the head of
the pancreas. The preoperative CT scan did not reveal metastatic disease.
scintigraphy was superior in detecting intra-abdominal and
bony metastases. Conversely, tumor masses shown by conven-
tional scanning techniques were missed by SRS in several
patients. Since large tumor masses were missed by SRS in some
cases, it is felt that the low density of somatostatin receptors on
some tumors may be the major factor causing false negative
results (88). Since somatostatin receptors appear to be present
in similar concentrations in non-functioning and functioning
tumors, SRS should be of equal accuracy in detecting both
types of tumors. The advantage of radionuclide scintigraphy is
that adenocarcinoma of the pancreas does not take up the
tracer and therefore false positive rates are low (23). The disad-
vantage of this methodology is that the absence of tracer
uptake by a tumor does not rule out an islet cell tumor. With
rapid improvements in conventional imaging modalities (e.g.,
CT and MRI) in the visualization of the pancreas, liver and
other intra-abdominal organs, the benefit of SRS in islet cell
tumor identification may decrease.
The capacity to take up and decarboxylate amine precursors
such as 5-hydroxytryptophan (5-HTP) and l-dihydroxyphe-
nylalanine (l-DOPA) and store their amine precursors is char-
acteristic of neuroendocrine cells and tumors. Utilizing this
concept, positron emission tomography (PET) has been evalu-
ated in the diagnosis of pancreatic endocrine tumors. In a
study utilizing l-DOPA, the ability to detect the pancreatic
tumor and possible metastases was evaluated in 22 patients
with islet cell tumors. In the six patients with non-functioning
islet cell tumors, there was relatively lower uptake of l-DOPA
and in two cases the primary tumor as well as the metastases
were not identified with PET, despite the fact that they were
large and clearly visible with CT (89). At present, with few
available data, it appears that for localization of non-function-
ing endocrine tumors and their metastases, there is no general
advantage of PET compared with CT. A larger patient popula-
tion is needed to determine the usefulness of l-DOPA and
5-HTP as tracers for visualization of the various subgroups of
pancreatic endocrine tumors.
 NEUROENDOCRINE PANCREATIC TUMORS

(A) (B)

(C)
Figure 45.6 (A) CT scan of patient with cirrhosis and large non-functioning tumor of tail of pancreas (arrow). (B) Another image of the liver of the same patient
shows a cystic lesion in the liver (arrow), which was suspicious for metastatic disease. (C) Octreotide scan of the same patient. Top panel demonstrates two intense
areas of uptake in the left abdomen corresponding with the tumor and the spleen (arrowheads). In the bottom panel, the large cyst in the liver is visualized and
there is no uptake within this cyst in the liver (arrowhead). At operation, these findings were confirmed, no liver metastases were identified and the patient under-
went a distal pancreatectomy with splenectomy.

treatment: curative surgery
for the primary tumor
Operative resection is the only potentially curative form of
therapy for patients with pancreatic islet cell tumors. Opera-
tion can be performed to resect local disease and to prevent the
development of distant metastases or local recurrence. Patients
with non-functional islet cell tumors may have similar clinical
symptoms to ductal adenocarcinoma of the pancreas. How-
ever, in contrast to ductal adenocarcinoma, survival rates fol-
lowing surgical resection are quite good, and aggressive
surgical therapy is indicated for non-functional neoplasms.
Even though these tumors tend to be slow growing, they often
present when the tumor mass is quite large. In some studies
mean tumor size is 8 to 10 cm at presentation (73,80). Despite
this, with surgical resection, actuarial 5-year survival rates
range from 44% to 63% with a median survival of 30 months
to 4.8 years (Table 45.9). Surgical therapy should not be denied
to patients on the basis of tumor size alone.
While ductal adenocarcinoma tends to directly encompass
and invade adjacent structures early in its disease course, non-
functioning islet cell tumors more often displace structures
without actual invasion. The large tumor bulk may cause near
obstruction of blood vessels via a compressive effect which can
be relieved by tumor resection. For instance, tumors in the tail
of the pancreas can compress the splenic vein leading to spleno-
megaly and even varices (Fig. 45.7A,B). Nevertheless, these
tumors can be frequently resected with negative margins. Simi-
larly, tumors in the head of the pancreas can compress the supe-
rior mesenteric vein. Again, in the absence of known metastatic
disease, every attempt should be made at tumor resection.
Tumors in the head of the pancreas should usually be treated
by pancreaticoduodenectomy, while tumors in the body and
tail should be treated with distal pancreatectomy. Extension of
tumor from the pancreas into surrounding organs such as the
stomach and colon should be resected en bloc. If the tumor is
small (<2 cm) and located in the tail of the pancreas consider-
ation should be given to distal pancreatectomy with splenic
preservation. In patients with significant co-morbid condi-
tions or for small lesions in the head of the pancreas,
enucleation can be entertained.
With endocrine tumors, some authors have advocated that
surgical removal of involved lymph nodes should be performed

425
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 45.9 Rates of Curative Resection and Survival in Non-functional Islet Cell Tumors
Author N Study years Tumor sizea (cm) Curative resection (%) Survival allb Curativec
Kent et al. (4) 25 1960–78 >5d 9 (36) 44% – (actuarial 5-yr)
Broughan et al. (73) 21 1948–84 10 12 (57) 63% – (actuarial 5-yr)
Thompson et al. (8) 27 1965–84 – 10 (37) 58% – (actuarial 3-yr)
Venkatesh et al. (102) 43 1950–87 – 22 (51) 40 – months (mean)
Cheslyn-Curtis et al. (80) 20 1982–91 8 10 (50) 30 42 months (median)
Evans et al. (84) 73 1953–92 – 19 (26) 4.8 6.8 yr (median)
Legaspi and Brennan (71) 33 1983–88 – 12 (36) 76% 100% (actuarial 3-yr)
Lo et al. (7) 34 1985–96 6.2 12 (35) – –
Phan et al. (10) 58 1949–96 5.1 46 (79) 52% – (actuarial 5-yr)
a
Mean or median tumor size.
b
Survival in entire study group: curative and non-curative resections.
c
Survival in curatively resected patients.
d
18 of 25 tumors >5 cm in size.

(A) (B)
Figure 45.7 (A) Large tumor in the tail of the pancreas with splenic vein obstruction and varices (arrows). This tumor was resected with negative margins.
(B) Intraoperative picture of varices encountered at the time of resection (arrows).

as it may improve survival. Patients with malignant endocrine
tumors whose disease is confined to regional lymph nodes
have a greater chance of benefit by removal of tumor than
patients who have distant metastases. Therefore, regional
nodes which are involved with tumor should be resected as
completely as possible in an attempt to eliminate all disease
and decrease the probability of distant metastases (90). With
non-functioning islet cell tumors, in the absence of metastases,
it is controversial whether nodal disease outside the field of
dissection should be resected. However, utilizing the data from
neuroendocrine tumors of the small bowel in which extensive
lymphadenectomy is recommended, it can be concluded that
for non-functional islet cell neoplasms reasonable attempts
should be made to remove all nodal disease.
treatment: curative surgery
for metastatic disease
There are few data available on the role for attempted curative
resections of metastatic non-functional islet cell tumors. Since
these tumors may follow a relatively indolent clinical course, a
case to resect anatomically localized and surgically resectable
metastases within the liver can be made. Of course, for this to
be in the best interest of the patient, the primary disease and
metastases must be completely resected. No data exist to vali-
date this approach. It should only be considered if the meta-
static lesion can be resected with acceptable morbidity and
mortality.
Patients with unresected hepatic metastases from gastroin-
testinal neuroendocrine tumors have been reported to have
5-year survival rates of between 13% and 43% (64). In an
effort to improve survival and even cure patients who have
failed other forms of therapy, liver transplantation has been
applied in these patients. Reports of liver transplantation for
metastatic neuroendocrine tumors have been confined to
small numbers of patients and short follow-up, typically less
than 3 years from the time of transplantation (91). In the best
results published to date, 12 patients (five pancreatic islet cell
tumors) received transplants at a single center. Long-term sur-
vival was achieved in most patients with a median survival of
55 months (92). However, in a multicenter report from France
of 16 cases of liver transplantation for metastatic pancreatic
islet cell tumors, the 4-year survival was 8%. The authors con-
cluded that liver transplantation was not indicated for meta-
static pancreatic islet cell tumors (93). Despite some

426
 NEUROENDOCRINE PANCREATIC TUMORS
Table 45.10 Surgical Palliation and Survival in Non-functional Islet Cell Tumors
Author N Palliative procedure no. (%)
Kent et al. (4) 25 3 (12)
Prinz et al. (96) 8 4 (50)
Dial et al. (111) 11 2 (18)
Eckhauser et al. (112) 11 2 (18)
Evans et al. (84) 73 12 (16)
Cheslyn-Curtis et al. (80) 20 7 (35)
a
Biliary and gastric bypass.
Abbreviations: AWD, alive with disease; DOD, dead of disease.
encouraging results from individual groups, until larger
numbers of patients and longer follow-up are accumulated, or
until the supply of donor livers increases, liver transplantation
for metastatic pancreatic islet cell carcinomas should be
applied with great caution.
treatment: palliative surgery
Palliative resections of the primary tumor in the presence of
metastatic disease have been performed in non-functioning
islet cell tumors. In the series from M.D. Anderson, nine distal
pancreatectomies and three pancreaticoduodenectomies were
performed in the presence of liver metastases (84). One peri-
operative death occurred in a patient who underwent distal
pancreatectomy. Five of the 12 patients died of disease at a
median of 3.7 years. Uncontrolled local tumor recurrence con-
tributed to the cause of death in only one of the five patients.
Overall, the median survival was 4.5 years (Table 45.10). These
results can be compared to 22 patients who had metastatic dis-
ease at diagnosis and did not undergo resection of the primary
tumor. Sixteen of the 22 died of disease at a median of 3.2
years. The cause of death in one patient was gastrointestinal
hemorrhage caused by progression of the primary tumor in
the pancreatic head. The other 15 patients died of liver metas-
tases. The authors determined that the trend toward improved
median survival in patients undergoing resection of their pri-
mary tumor in the presence of metastases could probably be
explained by the smaller tumor volume in this group at the
time of surgery.
In a second study, resection for palliation of local tumor
symptoms was performed in two patients with non-function-
ing tumors. Complete relief of symptoms was achieved in both
patients. One patient died 76 months after palliative resection
and the other patient was still alive with disease at 10 months
(94). In the asymptomatic patient who has metastases from
non-functioning islet cell tumor, due to prolonged survival
regardless of primary tumor resection, it is difficult to justify
primary tumor resection. In our opinion, in the absence of
compelling data, resection of the primary tumor in the
Type Survival
Biliary bypass (N = 2) 7 yr (mean)
Unknown (N = 1)
Double bypass (N = 3)a 4.5 yr (mean)
Biliary bypass (N = 1)
Biliary bypass (N = 2) 1.5 yr (AWD)
8 yr (AWD)
Double bypass (N = 2) 13 mo (AWD)
26 mo (DOD)
Distal pancreatectomy (N = 9) 4.5 yr (median)
Pancreaticoduodenectomy (N = 3)
Distal pancreatectomy (N = 2) 16 mo (median)
Biliary bypass (N = 3)
Pancreaticoduodenectomy (N = 2)
presence of liver metastases should be considered only in
the presence of debilitating symptoms (e.g., pain) or in the
presence of complications (e.g., bleeding).
Resection of metastases for palliation of symptoms has been
reported more often in functioning than in non-functional
islet cell carcinomas. It may play a more important role in alle-
viating the effects of excess production of endocrine hormones
in functioning tumors. For non-functioning tumors it is rarely
indicated, especially when other less invasive modalities can be
utilized for treatment of symptoms due to metastatic tumor
growth.
Hepatic artery embolization has been performed to palliate
symptoms from metastatic disease. In a study of 22 patients
with metastatic functional or non-functioning neoplasms,
sequential hepatic artery embolization was performed.
Patients underwent a median of four embolizations. Partial
remission was achieved in 12 patients. Hormonal syndromes
were frequently relieved. Moderately toxic reactions were
incurred after each embolization, but they were brief. Median
survival was 33.7 months (95). Sequential hepatic artery occlu-
sion with microembolic material may provide prolonged pal-
liation for selected symptomatic patients with islet cell
carcinoma metastatic to the liver.
Palliative biliary and/or enteric bypasses for patients pre-
senting with unresectable disease and biliary or gastric outlet
obstruction have been performed (Table 45.10). Prinz et al.
(96) reported four of eight patients with unresectable tumors
who underwent either a biliary bypass and gastrojejunostomy
or a biliary bypass alone. The mean survival in these four
patients was 4.5 years. For patients with obstructive jaundice
secondary to a locally unresectable non-functioning islet cell
neoplasm, operative biliary bypass should be strongly consid-
ered. The superiority of operative biliary bypass for long-term
management of malignant biliary obstruction justifies this
approach in patients who have islet cell tumors and potential
for prolonged survival. Duodenal bypass via a gastrojejunos-
tomy for lesions in the head of the pancreas should also be
considered in these patients.
427
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
treatment: chemotherapy
Recommended chemotherapy for advanced islet cell tumors is
based on the results of a multicenter randomized trial. In this
trial, 105 patients were randomized to receive one of three regi-
mens: streptozotocin plus fluorouracil, streptozotocin plus
doxorubicin, or chlorozotocin alone. Patients with either non-
functioning or functioning islet cell tumors were included in
this study. Streptozotocin plus doxorubicin was superior to
streptozotocin plus fluorouracil in terms of the rate of tumor
regression, measured objectively (69% vs. 45%, p = 0.05,
respectively), and the median length of time to tumor progres-
sion (20 vs. 6.9 months, p = 0.001, respectively). Streptozotocin
plus doxorubicin also had a significant advantage in terms of
survival (median 2.2 vs. 1.4 years, p = 0.004) (97). This regimen
is now considered the standard treatment for advanced islet cell
tumors, but should be considered in the context of each indi-
vidual patient, as some may have prolonged survival untreated,
and response to treatment is greater than the effect on overall
survival.
treatment: radiation therapy
The reported experience with radiation therapy in patients
with islet cell carcinoma has been scarce. Torrisi et al. (98)
treated three patients with locally advanced islet cell carci-
noma. Objective responses were seen in two patients, whereas
the third patient had a prolonged stabilization of the tumor. In
addition, case reports of locally advanced islet cell tumors that
have had complete responses to radiation therapy exist (99). It
would appear that selected patients may be palliated by radio-
therapy. Radiation has, however, been reserved in the main for
the treatment of pain from localized bone metastases.
treatment: octreotide
Octreotide is a synthetic octapeptide with structure and activ-
ities similar to those of the native hormone somatostatin, but
with significantly longer half-life and duration of action that
the native substance. Octreotide has been reported to be effec-
tive in controlling the hormone-induced symptoms of patients
with functional islet cell tumors (100). Although rare reports
of tumor regression to octreotide have been published, the
drug has been primarily utilized to ameliorate the symptoms
from hormonal excess in patients with functional islet cell
tumors. In a study which included 13 patients with advanced,
incurable non-functional islet cell tumors, octreotide was
administered via subcutaneous injection. No patient experi-
enced a major objective response. Of the 21 patients with
functional tumors, 15 demonstrated either a symptomatic
improvement or an objective decrease in hormone level.
Octreotide is useful in controlling symptoms due to hormonal
excess in functional islet cell tumors. There is no evidence that
octreotide would benefit patients with non-functional islet cell
tumors.
prognosis
Evans et al. (84) found that patients who underwent curative
resection of their primary tumor in the absence of metastases
had a 72% 5-year survival with a median survival of 6.8 years.
This was in sharp contrast to patients who presented with
428
distant metastases and who did not undergo resection. These
patients had a 38% 5-year survival with a median survival of
3.3 years. In addition, among patients with localized disease at
presentation, the survival was significantly better in patients
who were able to undergo tumor resection as compared to
those who did not. Therefore, important predictors of survival
are the ability to undergo curative resection and the degree of
local spread.
It is unclear whether non-functional tumors have a worse
prognosis than functional islet cell tumors. Several studies
have shown that the survival of patients with non-functional
tumors is poorer than for those with functional tumors. In a
report from the Cleveland Clinic, actuarial 10-year survival
was 55% for non-functioning tumors while it was 92% for
insulinomas and 68% for gastrinomas (73). In a study from
Johns Hopkins, median survival was 121 months in functional
tumors while it was 96 months in non-functional neoplasms
(p < 0.025) (10). In an early report from the Mayo Clinic, sur-
vival was statistically better at 3 years in those patients with
gastrinomas compared with patients with non-functioning
tumors, 91% versus 58% (8). However, in a later report from
the same institution, there was no survival difference between
functional and non-functional neoplasms (7). Other studies
have found no difference in survival between functioning and
non-functioning tumors (101,102).
Size of the primary tumor rather than functional status may
be a more important prognostic variable. In the study by
Phan et al. (10) the median tumor size in the non-functional
tumors was 4.0 cm as compared to 1.9 cm in the functional
neoplasms. In addition, the malignancy rates were corre-
spondingly lower in the functional tumors (47%) as com-
pared to the non-functional ones (60%). It may be that
non-functional tumors are detected at larger tumor burdens
because of the absence of an endocrine syndrome. This may
account for poorer survival with non-functioning neoplasms
seen in some studies.
Efforts have been made to develop more sophisticated mark-
ers to determine prognosis in patients with non-functioning
islet cell neoplasms. In a preliminary study of 61 non-func-
tioning tumors, vascular or perineural microinvasion and
Ki67 proliferative index were the most sensitive and specific
variables that were predictive of malignancy. These variables
were utilized in tumors lacking evidence of malignancy at the
time of surgery, to separate cases with increased risk of malig-
nancy from cases with limited risk, and were found to be
somewhat predictive of survival (79). Rigorous studies in
larger numbers of patients with islet cell neoplasms, which
examine different immunohistochemical markers, may help
identify prognostic variables in these tumors.
conclusions
Clinically, there are similarities and differences between the
various functional endocrine tumors of the pancreas. These
tumors vary with regard to size, location, age distribution, sex
distribution, propensity for malignancy, and metastatic poten-
tial in accordance with the individual tumor type. The clinical
morbidity and mortality associated with the tumor are due to
peptide hypersecretion and not to tumor mass. In addition,
 NEUROENDOCRINE PANCREATIC TUMORS
there is no correlation between tumor size and the severity of
functional manifestations.
Non-functioning islet cell tumors are pancreatic tumors
with endocrine differentiation in the absence of a clinical syn-
drome of hormone hyperfunction. These tumors are hormon-
ally silent because either the principal hormone secreted by the
tumor may cause no specific clinical signs; although it is
released in excess, the amount of hormone produced may be
too small to cause symptoms, or the tumor may secrete a pre-
cursor hormone that is functionally inert, or the hormonal
product of the tumor may not yet be identified.
Non-functioning islet cell tumors are slow growing and
occur most commonly in the head of the pancreas. Imaging
modalities such as CT scanning or MR imaging are accurate in
the localization of these tumors within the pancreas. While
false negative rates for tumor detection are high, octreotide
scintigraphy may provide additional useful information in the
evaluation for suspected metastases.
Operative resection is the only potentially curative form of
therapy for patients with functioning and non-functioning
islet cell neoplasms. In contrast to ductal adenocarcinoma of
the pancreas, survival rates following surgical resection are
quite good. Since metastatic functional and non-functional
islet cell carcinomas may follow a relatively indolent course,
anatomically localized and surgical resectable metastases
within the liver should be considered for resection. The
primary site of disease must be controlled if this is to be
considered.
The survival of patients with non-functional tumors may be
similar to those with functional neoplasms. Patients with non-
functional tumors often present with larger tumor size, which
may account for the decreased survival seen with these neo-
plasms in some series. Prognostic variables in islet cell tumors
are limited and further work evaluating immunohistochemi-
cal markers in this disease is needed.
key points
● Clinically silent endocrine tumors have been found
in up to 10% of detailed autopsy examinations.
● Functional islet cell tumors include
Insulinoma
Gastrinoma
Glucagonoma
VIPoma
Somatostatinoma.
● Localization of pancreatic endocrine tumors:
Helical CT: sensitivity 85%
MRI: sensitivity not known
Angiography: sensitivity 58%
Somatostatin receptor scintigraphy: 82%
PET scan: sensitivity not known.
● Surgical excision, usually with curative intent, is
the major objective of treatment.
● Surgical debulking of primary and metastatic
functional islet cell tumors often achieves good
palliation of symptoms.
references
1. Kimura W, Kuroda A, Morioka Y. Clinical pathology of endocrine
tumors of the pancreas. Dig Dis Sci 1991; 36: 933–42.
2. Solcia E, Sessa F, Rindi G, Bonato M, Capella C. Pancreatic endocrine
tumors: general concepts; nonfunctioning tumors and tumors with
uncommon function. In: Dayal Y, ed. Endocrine Pathology of the Gut
and Pancreas. Boca Raton: CRC Press, 1991: 105–31.
3. Solcia E, Capella C, Kloppel G. Tumors of the endocrine pancreas. In:
Anonymous Atlas of Tumor Pathology. Washington: AFIP, 1997: 145–209.
4. Kent RB, Van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors.
Ann Surg 1981; 193: 185–90.
5. Kloppel G, Heitz PU. Pancreatic endocrine tumors. Pathol Res Pract
1988; 183: 155–68.
6. Howard JN, Moss NH, Rhoads JE. Collective review: hyperinsulinism
and islet cell tumors of the pancreas. Int Abstr Surg 1950; 90: 417–55.
7. Lo CY, Van Heerden JA, Thompson GB, et al. Islet cell carcinoma of the
pancreas. World J Surg 1996; 20: 878–84
8. Thompson GB, Van Heerden JA, Grant CS, Carney A, Ilstrup DM. Islet
cell carcinomas of the pancreas: a twenty-year experience. Surgery 1988;
104: 1011–7
9. Grant CS. Surgical management of malignant islet cell tumors. World J
Surg 1993; 17: 498–503
10. Phan GQ, Yeo CJ, Hruban RH, et al. Surgical experience with pancreatic
and peripancreatic neuroendocrine tumors: review of 125 patients.
J Gastrointest Surg 1998; 2: 473–82
11. Heitz PU, Kasper M, Polak JM, Kloppel G. Pancreatic endocrine tumors:
immunocytochemical analysis of 125 tumors. Hum Pathol 1982; 13:
263–71
12. Alpert S, Hanahan D, Teitelman G. Hybrid insulin genes reveal a devel-
opment lineage for pancreatic endocrine cells and imply a relationship
with neurons. Cell 1988; 53: 295
13. Mozzell E, Stenzel P, Woltering EA, Rosch J, O’Dorisio TM. Functional
endocrine tumors of the pancreas: clinical presentation, diagnosis, and
treatment. Curr Probl Surg 1990; 27: 303–86
14. Bieligk S, Jaffe BM. Islet cell tumors of the pancreas. Surg Clin N Am
1995; 75: 1025–40
15. Friesen SR. Tumors of the endocrine pancreas. N Engl J Med 1982; 306:
580–90
16. Norton JA. Neuroendocrine tumors of the pancreas and duodenum.
Curr Probl Surg 1994; 31: 77–164
17. Grant CS. Insulinoma. Surg Oncol Clin N Am 1998; 7: 819–44
18. Van Hoe L, Gryspeerdt S, Marchal G, Baert AL, Mertens L. Helical CT for
the preoperative localization of islet cell tumors of the pancreas. AJR
1995; 165: 1437–9
19. Smelka RC, Cumming MJ, Shoenut JP, et al. Islet cell tumors: comparison
of dynamic contrast-enhanced CT and MR imaging with dynamic gado-
linium enhancement and fat suppression. Radiology 1993; 186: 799–802
20. Muller MF, Meyenberger C, Bertschinger P, Schaer R, Marincek B. Pan-
creatic tumors: evaluation with endoscopic US, CT and MR imaging.
Radiology 1994; 190: 745–51
21. Van Byck CHJ, Bruining HA, Reubi JC, et al. Use of isotope-labeled
somatostatin analogs for visualization of islet cell tumors. World J Surg
1993; 17: 444–7
22. Krenning EP, Kwekkeboom DJ, Reubi J, et al. 111In-octreotide scintigra-
phy in oncology. Metabolism 1992; 41: 83–6
23. Krenning EP, Kwekkeboom DJ, Oei HY, et al. Somatostatin-receptor
scintigraphy in gastroenteropancreatic tumors. Ann NY Acad Sci 1994;
733: 416–24
24. Thompson NW, Czako PF, Fritts LL, et al. Role of endoscopic ultrasound
in the localization of insulinomas and gastrinomas. Surgery 1994; 116:
1131–8
25. Pasieka JL, MeLeod MK, Thompson NW, et al. Surgical approach to
insulinomas: assessing the need for preoperative localization. Arch Surg
1992; 127: 442–7
26. Doppman JL, Miller DL, Chang R, et al. Intraarterial calcium stimulation
test for insulinomas. World J Surg 1993; 17: 439–43
27. Danforth DN, Gordon P, Brennan MF, et al. Metastatic insulin secreting
carcinoma of the pancreas: clinical course and role of surgery. Surgery
1984; 96: 1027–37
429
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
28. Delcore R Jr, Cheung LY, Friesen SR. Characteristics of duodenal wall
gastrinomas. Am J Surg 1990; 160: 621–4
29. Ellison EH, Wilson SD. The Zollinger–Ellison syndrome: reappraisal and
evaluation of 260 registered cases. Ann Surg 1964; 160: 512–30
30. Zollinger RM, Ellison EH. Primary peptic ulceration of the jejunum
associated with islet cell tumors of the pancreas. Ann Surg 1955; 142:
709–23
31. Meko JB, Norton JA. Management of patients with Zollinger–Ellison
syndrome. Ann Rev Med 1995; 46: 395–411
32. Waxsman I, Gardner JD, Jensen RT, Maton PN. Peptic ulcer perforation
as the presentation of Zollinger–Ellison syndrome. Dig Dis Sci 1991; 36:
19–24
33. Norton JA, Doppman JL, Jensen RT. Curative resection in Zollinger–
Ellison syndrome: results of a 10 year prospective study. Ann Surg 1992;
215: 8–18
34. Wolfe MM, Jensen RT. Zollinger–Ellison syndrome, current concepts in
diagnosis and management. New Engl J Med 1987; 317: 1200–9
35. Bondeson AG, Bondeson L, Thompson NW. Stricture and perforation of
the esophagus: overlooked threats in the Zollinger-Ellison syndrome.
World J Surg 1990; 14: 361–4
36. Pisegna J, Norton JA, Slimak GG, et al. Effects of curative gastrinoma
resection on gastric secretory function and antisecretory drug require-
ments in the Zollinger–Ellison syndrome. Gastroenterology 1992; 102:
767–78
37. Norton JA. Gastrinoma: advances in localization and treatment. Surg
Oncol Clin N Am 1998; 7: 845–61
38. Larsson H, Caisson E, Matsson H. Plasma gastrin and gastric enterochro-
maffin cell (activation and proliferation-studies with omeprazole and
ranitidine in intact and adrenalectomized rats. Gastroenterology 1986;
90: 391–9
39. Stabile BE, Morrow DJ, Passaro E Jr. The gastrinoma triangle: operative
implications. Am J Surg 1984; 147: 25–31
40. Farley DR, Van Heereden JA, Grant CS, Miller JL, Ilstrup DM. The
Zollinger–Ellison syndrome. A collective surgical experience. Ann Surg
1992; 215: 561–9
41. Fraker DL, Norton JA, Alexander R, Venzon DJ, Jensen RT. Surgery in
Zollinger–Ellison syndrome alters the natural history of gastrinoma.
Ann Surg 1994; 220: 320–30
42. Ellison EC. Forty year appraisal of gastrinoma. Back to the future. Ann
Surg 1995; 222: 511–24
43. Miller DL, Norton JA, Jensen RT. Prospective assessment of abdominal
ultrasound in patients with Zollinger–Ellison syndrome. Radiology
1991; 178: 763–7
44. Pisegna JR, Doppman JL, Norton JA, Metz DC, Jensen RT. Prospective
comparative study of ability of MR imaging and other imaging modali-
ties to localize tumors in patients with Zollinger–Ellison syndrome. Dig
Dis Sci 1993; 38: 1318–28
45. Alexander HR, Fraker DL, Norton JA, et al. Prospective study of soma-
tostatin receptor scintigraphy and its effect on operative outcome in
patients with Zollinger–Ellison syndrome. Ann Surg 1998; 228: 228–38
46. Ruszniewski P, Amouyal P, Amouyal G, et al. Localization of gastrinomas
by endoscopic ultrasonography in patients with Zollinger–Ellison syn-
drome. Surgery 1995; 117: 629–35
47. Thorn AK, Norton JA, Axiotis CA, Jensen RT. Location, incidence
and malignant potential of duodenal gastrinomas. Surgery 1991; 110:
1086–93
48. Howard TJ, Zinner MJ, Stabile BE, et al. Gastrinoma excision for cure.
Ann Surg 1990; 211: 9–14
49. Thompson NW, Vinik Al, Eckhauser FE. Microgastrinomas of the duo-
denum: a cause for failed operations of the Zollinger–Ellison syndrome.
Ann Surg 1989; 209: 396–404
50. Carty SE, Jensen RT, Norton JA. Prospective study of aggressive resection
of metastatic pancreatic endocrine tumors. Surgery 1992; 112: 1024–32
51. Norton JA, Sugarbaker PH, Doppman JL, et al. Aggressive resection of
metastatic disease in selected patients with malignant gastrinoma. Ann
Surg 1986; 203: 352–9
52. Veldhius JD, Norton JA, Wells SAJ, et al. Therapeutic controversy; surgi-
cal versus medical management of multiple endocrine neoplasia (MEN)
type 1. J Clin Endocrinol 1997; 82: 357–64
430
53. MacFarlane MP, Fraker DL, Alexander HR, et al. Prospective study of
surgical resection of duodenal and pancreatic gastrinomas in multiple
endocrine neoplasia type 1. Surgery 1995; 118: 973–80
54. Thompson NW. Management of pancreatic endocrine tumors in
patients with multiple endocrine neoplasia type 1. Surg Oncol Clin N
Am 1998; 7: 881–91
55. Modlin IM, Lewis JJ, Ahiman H, Bilchik AJ, Kumar RR. Management of
unresectable malignant endocrine tumors of the pancreas. Surg Gynecol
Obstet 1993; 176: 507–18
56. Rothmund M, Stinner B, Arnold R. Endocrine pancreatic tumors. Eur J
Surg Oncol J 1991; 17: 191–9
57. Broder LE, Carter SK. Pancreatic islet cell carcinoma: results of therapy
with streptozotocin in 52 patients. Ann Int Med 1973; 79: 101–7
58. Boden G, Ryan IG, Eisenschmid BL, et al. Treatment of inoperable gluca-
gonoma with the long acting somatostatin analogue SMS 201995. N Engl
J Med 1986; 314: 1686–9
59. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory
watery diarrhea and hypokalemia. Am J Med 1958; 25: 374–80
60. Said SI, Mutt V. Isolation from porcine-intestinal wall of a vasoactive
octacosapeptide related to secretin and glucagon. Eur J Biochem 1972;
28: 199–204
61. Friesen SR. Update on the diagnosis and treatment of rare neuroendo-
crine tumors. Surg Clin N Am 1987; 67: 379–93
62. Mekhjian HS, O’Dorisio TM. VIPoma syndrome. Semin Oncol 1987; 14:
282–91
63. Inamoto K, Yoshino F, Nakao N, et al. Angiographic diagnosis of a pan-
creatic islet tumor in a patient with the WDHA syndrome. Gastrointest
Radiol 1980; 5: 259–61
64. Delcore R, Friesen SR. Gastrointestinal neuroendocrine tumors. J Am
Coll Surg 1994; 178: 188–211
65. Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with
streptozocin plus fluorouracil in the treatment of advanced islet-cell car-
cinoma. N Engl J Med 1980; 303: 1189–94
66. O’Dorisio TM, Mekhjian HS, Gaginella TS. Medical therapy of VIPomas.
Endocrinol Metab Clin N Am 1989; 18: 545–56
67. Maton PN. Use of octreotide for control of symptoms in patients with
islet cell tumors. World J Surg 1993; 17: 504–10
68. Harris GJ, Tio F, Cruz AB. Somatostatinoma of the duodenum: case
report and review of the literature. J Surg Oncol 1987; 36: 8–16
69. Konomi K, Chijiiwa K, Katsuta T, et al. Pancreatic somatostatinoma: case
report and review of the literature. J Surg Oncol 1990; 43: 259–69
70. Thompson NW, Eckhauser FE. Malignant islet cell tumors of the pan-
creas. World J Surg 1984; 8: 940–51
71. Legaspi A, Brennan ME. Management of islet cell carcinoma. Surgery
1988; 104: 1018–23
72. Debas HT, Mulvihill SJ. Neuroendocrine gut neoplasms. Arch Surg 1994;
129: 965–72
73. Broughan TA, Leslie JD, Soto JM, Hermann RE. Pancreatic islet cell
tumors. Surgery 1986; 99: 671–8
74. Stephens DH. CT of pancreatic neoplasms. Curr Probl Daign Radiol
1997; 26: 53–108
75. Eelkema EA, Stephens DH, Ward EM, Sheedy PF. CT features of non-
functioning cell carcinoma. AJR 1984; 143: 943–8
76. Buetow PC, Parrino TV, Buck JL, et al. Islet cell tumors of the pancreas:
pathologic-imaging correlation among size, necrosis and cysts, calcifica-
tion, malignant behavior, and function. AJR 1995; 165: 1175–9
77. Strodel WE, Vinik Al, Lloyd RV, et al. Pancreatic polypeptide-producting
tumors. Arch Surg 1984; 119: 508–14
78. Prinz RA, Marangos PJ. Serum neuron-specific enolase: a serum marker
for nonfunctioning pancreatic islet cell carcinoma. Am J Surg 1983; 145:
77–81
79. La Rosa S, Sessa F, Capella C, et al. Prognostic criteria in nonfunctioning
pancreatic endocrine tumors. Virchows Arch 1996; 429: 323–33
80. Cheslyn-Curtis S, Sitaram V, Williamson RCN. Management of non-
functioning neuroendocrine tumors of the pancreas. Br J Surg 1993; 80:
625–7
81. Madura JA, Cummings OW, Wiebke EA, et al. Nonfunctioning islet cell
tumors of the pancreas: a difficult diagnosis but one worth the effort. Am
Surg 1997; 63: 573–8
 NEUROENDOCRINE PANCREATIC TUMORS
82. McFarland EG, Kaufman JA, Saini S, et al. Preoperative staging of cancer
of the pancreas: value of MR angiography versus conventional angiogra-
phy in detecting portal venous invasion. AJR 1996; 166: 37–43
83. Harrison LE, Klimstra D, Brennan MF. Portal vein resection for adeno-
carcinoma of the pancreas: a contraindication for resection. Ann Surg
1996; 224: 342–9
84. Evans DB, Skibber JM, Lee JE, et al. Nonfunctioning islet cell carcinoma
of the pancreas. Surgery 1993; 114: 1175–82
85. Conlon KC, Dougherty E, Klimstra DS, et al. The value of minimal access
surgery in the staging of patients with potentially resectable peripancre-
atic malignancy. Ann Surg 1996; 223: 134–40
86. Patel YC, Amherdt M, Orci L. Somatostatin-receptor scintigraphy in gas-
troenteropancreatic tumors. Science 1982; 217: 1155–6
87. Van Eijck CHJ, Lamberts SWJ, Lemaire LCJM, et al. The use of soma-
tostatin receptor scintigraphy in the differential diagnosis of pancreatic
duct cancers and islet cell tumors. Ann Surg 1996; 224: 119–24
88. Scherubl H, Bader M, Fett U, et al. Somatostatin-receptor imaging of
neuroendocrine gastroenteropancreatic tumors. Gastroenterology 1993;
105: 1705–9
89. Ahlstrom H, Eriksson B, Bergstrom M, Biurling P, Langstrom B, Oberg
K. Pancreatic neuroendocrine tumors: diagnosis with PET. Radiology
1995; 195: 333–7
90. Zogakis TG, Norton JA. Palliative operations for patients with unresect-
able endocrine neoplasia. Surg Clin N Am 1995; 75: 525–38
91. Makowka L, Tzakis AG, Mazzaferro V, et al. Transplantation of the liver
for metastatic endocrine tumors of the intestine and pancreas. Surg
Gynecol Obstet 1989; 168: 107–11
92. Lang H, Oldhafer KJ, Weimann A, et al. Liver transplantation for meta-
static neuroendocrine tumors. Ann Surg 1997; 225: 347–54
93. Le Treut YP, Delpero JR. Dousset B, et al. Results of liver transplantation
in the treatment of metastatic neuroendocrine tumors. Ann Surg 1997;
225: 355–64
94. McEntee GP, Nagorney DM, Kvols LK, Moertel CG, Grant CS. Cyto-
reductive hepatic surgery for neuroendocrine tumors. Surgery 1990; 108:
1091–6
95. Ajani JA, Carrasco CH, Chamsangavej C, et al. Islet cell tumors meta-
static to the liver: effective palliation by sequential hepatic artery embo-
lization. Ann Int Med 1988; 108: 340–4
96. Prinz RA, Badrinath K, Chejfec G, Freeark RJ, Greenlee HB. ‘Nonfunc-
tioning’ islet cell carcinoma of the pancreas. Am Surg 1983; 49: 345–9
97. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozo-
cin-doxorubicin, streptozocin-fluorouracil, or chlorozotocin in the
treatment of advanced islet-cell carcinoma. N Engl J Med 1992; 326:
519–23
98. Torrisi JR, Treat J, Zeman R, Dritschilo A. Radiotherapy in the manage-
ment of pancreatic islet cell tumors. Cancer 1987; 60: 1226–31
99. Tennvall J, Ljungberg O, Ahren B, Gustavsson A, Nillson LO. Radiother-
apy for unresectable endocrine pancreatic carcinoma. Eur J Surg Oncol
1992; 18: 73–6
100. Saltz L, Trochanowski B, Buckley M, et al. Octreotide as an antineoplastic
agent in the treatment of functional and nonfunctional neuroendocrine
tumors. Cancer 1993; 72: 244–8
101. White TJ, Edney JA, Thompson JS, Karrer FW, Moor BJ. Is there a prog-
nostic difference between functional and nonfunctional islet cell tumors.
Am J Surg 1994; 168: 627–30
102. Venkatesh S, Ordonez NG, Ajani J, et al. Islet cell carcinoma of the pan-
creas. Cancer 1990; 65: 354–7
103. Doherty GM, Doppman JL, Shawker TH, et al. Results of a prospective
strategy to diagnose, localize, and resect insulinomas. Surgery 1991; 110:
989–97
104. Grama D, Eriksson B, Martensson H, et al. Clinical characteristics, treat-
ment and survival in patients with pancreatic tumors causing hormonal
syndromes. World J Surg 1992; 16: 632–9
105. Menegaux F, Schmitt G, Mercadier M, Chigot JP. Pancreatic insulinomas.
Am J Surg 1992; 165: 243–8
106. Angelini L, Bezzi M, Tucci GJ, et al. The ultrasonic detection of insulinomas
during surgical exploration of the pancreas. World J Surg 1987; 11: 642–7
107. Grant CS, Van Heerden JA, Charboneau JW, et al. Insulinoma: the value
of intraoperative ultrasonography. Arch Surg 1988; 123: 843–8
108. McArthur KE, Richardson CT, Barnett CC, et al. Laparotomy and proxi-
mal gastric vagotomy in Zollinger–Ellison syndrome: results of a 16-year
prospective study. Am J Gastroenterol 1996; 91: 1104–11
109. Melvin WS, Johnson JA, Sparks J, et al. Long-term prognosis of Zollinger–
Ellison syndrome in multiple endocrine neoplasia. Surgery 1993; 114:
1183–8
110. Jaskowiak NT, Fraker DL, Alexander HR, et al. Is reoperation for gastri-
noma excision indicated in Zollinger–Ellison syndrome. Surgery 1996;
120: 1055–63
111. Dial PF, Braasch JW, Rossi RL, Lee AK, Jin G. Management of nonfunc-
tioning islet cell tumors of the pancreas. Surg Clin N Am 1985; 65: 291–9
112. Eckhauser FE, Cheung PS, Vinik Al, et al. Nonfunctioning malignant
neuroendocrine tumors of the pancreas. Surgery 1986; 100: 978–87
113. Yeo CJ, Wang BH, Anthone GJ, Cameron JL. Surgical experience with
pancreatic islet cell tumors. Arch Surg 1993; 128: 1143–8
431
46 Rare tumors of the pancreas
Jooyeun Chung, Lisa J. Harris, Hamid Abdollahi, and Charles J. Yeo
introduction
Although ductal adenocarcinoma is the most common malig-
nant neoplasm of the pancreas, there are multiple unusual
tumors of the pancreas that surgeons must keep in mind. A
thorough history and physical exam and a high-resolution
dedicated pancreatic CT scan are crucial in differentiating
these rare tumors from the more commonly seen “tumors.” At
times, MRI/MRCP, endoscopic retrograde cholangiopancrea-
tography, and endoscopic ultrasound can aid in making the
diagnosis. Here, we discuss nine rare “tumors” of the pancreas
and their distinguishing features (Table 46.1).
solid pseudopapillary neoplasm (sppn)
SPPN of the pancreas accounts for 1% to 3% of all pancreatic
neoplasms. It has a low malignant potential and is predomi-
nantly seen in young females in their 20s and 30s. SPPN is
often an incidental finding when patients undergo imaging for
other reasons or the patient may present with nonspecific gas-
trointestinal symptoms (1).
SPPN vary widely in size. The larger tumors may undergo
cystic or hemorrhagic degeneration and occasionally have
calcifications (Fig. 46.1). They are typically well circum-
scribed and surrounded by a pseudocapsule. Histologically,
the tumors show solid regions composed of nests and sheets
of uniform epithelioid cells alternating with cystic spaces and
pseudopapillae (2).
Much has been hypothesized about the pathogenesis of SPPN,
given its predilection for young females. One theory involves the
genital ridge-related cells that could have been incorporated
into the pancreas during early embryogenesis secondary to the
close proximity of the genital ridge and the pancreatic anlage
(3). There has been a case report of SPPN in a 2-year-old female
which would support the embryology theory (4). The role of sex
hormones also has been investigated. To date, the expression of
progesterone receptors has been well documented but the status
of the estrogen receptors has remained questionable. Geers et al.
reported on the differential expression of ER versus ER but this
observation warrants further investigation (5). On a molecular
level, greater than 90% of SPPN have mutations in the B-catenin
gene, resulting in the disruption of E-cadherin, a key regulator
of cell–cell junctions (6).
Although SPPN is typically larger than pancreatic adenocar-
cinoma at the time of diagnosis, it is usually resectable and R0
resection is generally curative. The overall mortality from the
neoplasm is 2% and the recurrence rate is 10% to 15%. The
cases which recur or present with metastatic disease have
nuclear pleomorphism, a high mitotic count with diffuse
infiltrate growth pattern, and vascular invasion (7). A study by
Marchado et al., which had the highest number of male
patients (7 out of 34), reported that the male patients with
SPPN were older, had higher rate of vascular invasion, and
432
were more aggressive, again raising the role of sex hormones in
the pathogenesis of SPPN (8).
acinar cell carcinoma (acc)
ACCs account for approximately 1% of all primary pancreatic
neoplasms. ACC tends to occur in the fifth to seventh decade
of life with 2:1 ratio of males to females. The presenting
symptoms are nonspecific, including abdominal pain, bloat-
ing, postprandial vomiting, or a change in bowel habits (9–11).
The neoplastic cells have a unique ability to produce pancre-
atic enzymes such as trypsin, chymotrypsin, lipase, and amy-
lase. Lipase hypersecretion syndrome, though well described
in the literature, is seen in less than 15% of patients with ACC
and is characterized by subcutaneous fat necrosis, polyarthral-
gia, and eosinophilia. Although ACC was previously thought
to be found predominantly in the head of the pancreas, a
recent review by Wisnoski et al. suggests that ACC is more
often found in the body or the tail of the pancreas (12).
ACC is usually an exophytic, well demarcated, and large
hypodense mass on CT. The larger tumors can be heterogenous
with internal calcifications or intratumoral hemorrhage
(13,14). On gross examination, these tumors are soft, fleshy,
and well-circumscribed masses. Histologically, ACCs have four
patterns of growth: acinar, solid, trabecular, and glandular with
the acinar pattern being the most common. They are often
highly cellular with minimal stroma. In addition, they have a
unique immunohistochemical staining pattern for trypsin,
lipase, amylase, phospholipase, and chymotrypsin. In one series
of 28 patients, ACC was positive for trypsin in 100% of the
cases. They typically fail to stain for synaptophysin, chromo-
granin, and other islet cell hormones, thus helping to differen-
tiate them from pancreatic neuroendocrine tumors (15).
ACC had been previously thought to be a cancer of poor
prognosis, comparable or worse than pancreatic ductal adeno-
carcinoma. However, review of the current literature for sur-
vival analysis suggests otherwise. The stage-specific survival is
significantly better for ACC than adenocarcinoma, and
resection helps to greatly improve this survival. On multivari-
ate analysis, age less than 65, well-differentiated tumor, and R0
resection were the independent prognostic factors (17).
Current survival data are summarized in Table 46.2.
adenosquamous carcinoma (asc)
ASC accounts less than 1% to 4% of pancreatic tumors. There
are many case reports but only a few series discussing ASC exist
in current literature. According to Kardon et al., which is the
largest report on ASC to date, the mean age of the patients is
65 years, the tumors vary widely in size (2–12 cm), and ASC is
predominantly located in the head of the pancreas. The clinical
symptoms are similar to ductal adenocarcinoma, including
weight loss, obstructive jaundice, and abdominal pain (18,19).
 RARE TUMORS OF THE PANCREAS

Table 46.1 Rare Tumors of the Pancreas

Percentage of
all pancreas
Type of tumor tumors Demographics Imaging Treatment Prognosis
Solid pseudopapillary 1–3% Young females Large, well circum- Resection Low malignant potential,
neoplasm scribed, cystic or cured with R0 resection
hemorrhagic
degeneration
Acinar cell carcinoma <1% 5th to 7th decade of Large, hypodense, Resection Better than
life 2:1 M:F exophytic, well adenocarcinoma
demarcated
Adenosquamous <1–4% 6th decade of life Wide range of size Resection Worse than
carcinoma adenocarcinoma
Pancreatic lymphoma <0.5% 5th to 6th decade of Well circumscribed Chemotherapy ± Better than
life M > F lesion or infiltrat- radiotherapy. adenocarcinoma
ing lesion with Occasionally
poorly defined resection
borders
Metastases to the <1% Variable Often hypervascular Different for various Variable
pancreas spherical lesions primaries
Von Hippel–Lindau Rare M=F Cysts, adenomas, and Resection if Often determined by
syndrome hypervascular neuroendocrine other VHL lesions
neuroendocrine tumor
tumors
Giant cell tumor Rare 6th decade of life Common local Resection, if Similar to adenocarci-
M=F infiltration and appropriate noma
metastases ?chemoradiation
Medullary carcinoma ?<5% 6th to 7th decade of Similar to ductal Resection Better than
life M > F adenocarcinoma adenocarcinoma if
positive for microsatel-
lite instability
Autoimmune Uncommon 6th to 7th decade of Focal enlargement of Steroid therapy Good
pancreatitis life M > F pancreas
Note: Autoimmune pancreatitis (also termed lymphoplasmacytic sclerosing pancreatitis) is not a neoplasm, but may be mistaken for a neoplastic process.

However, Kardon et al. showed a wide range in the proportion of

Figure 46.1 CT scan showing a large heterogenous mass in the tail of the
pancreas (arrow) with central calcification. The surgical specimen was
consistent with a solid pseudopapillary neoplasm.
By definition, ASC must have both histologic components of
squamous and adenocarcinoma (20). Some authors in the past
had arbitrarily set 30% as the minimum amount of squamous
carcinoma component required to diagnose ASC in a specimen.
squamous carcinoma in individual specimens. Thus, it was their
opinion that an adenocarcinoma showing any degree of malig-
nant squamous cell differentiation should be considered as ASC.
It has been hypothesized that ASC is the result of malignant
squamous metaplasia (dedifferentiation) within an adenocar-
cinoma. To further support this theory, Kardon et al. studied
K-ras oncogene mutation, which has been strongly linked to
ductal adenocarcinoma (>95% have K-ras mutation). In their
series of ASC, they found that greater than 50% of their speci-
men had K-ras mutation, even in the tumors that were almost
exclusively squamous carcinoma. However, the presence of
K-ras mutation did not have any prognostic implications.
Recent molecular studies of ASC have shed more light on the
pathogenesis of this aggressive tumor, indicating that K-ras
mutations may be crucial for the development of ASC.
ASC is a more aggressive tumor than ductal adenocarci-
noma. Kardon et al. reported average survival of 11 months for
ASC patients who underwent R0 resection versus a median
survival of 18 to 20 months for resectable adenocarcinoma.
Patients who underwent palliative procedures had short
median survival of 3.8 months. Smoot et al. found similar
survival data in their study; patients who underwent R0 resec-
tion had median survival of 14.4 months versus 4.8 months

433
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 46.2 Summary of Survival Data on Acinar Cell Carcinoma in the Current Literature
Median survival Median survival after
Author Year Number of patients Mean age (year) (month) resection (month)
Wisnoski (12) 2008 672 56 47 123
Seth (11) 2008 14 57 33
Kitagami (16) 2007 115 59.6 41
Holen (10) 2002 39 60 19

without resection (21). Obviously, a complete surgical resec-

tion is recommended for ASC whenever possible. While the
standard of care currently recommends adjuvant chemo- or
chemoradiation therapy for resected ASC patients, no trials
have proven a survival benefit in this patient cohort.

pancreatic lymphoma
Primary pancreatic lymphoma (PPL) is a rare disease,
representing less than 0.5% of all pancreatic tumors and less
than 2% of extra nodal non-Hodgkin’s lymphomas (NHL)
(22,23). PPL occurs more frequently in men than women and
usually presents in the 5th to 6th decade (median age 57.1
years) (24). The clinical presentation of PPL is often non-
specific. The most common presenting symptom is abdominal
pain (83%), followed by abdominal mass (58%), weight loss
(50%), jaundice (37%), acute pancreatitis (12%), small bowel
obstruction (12%), and diarrhea (12%) (25). The classic
B-symptoms of nodal NHL are seen in less than 2% of PPL
patients (27). Laboratory studies are often non-diagnostic.
Two different morphologic patterns of involvement are seen
on CT: a well-circumscribed mass or an infiltrating lesion with
poorly defined borders (27). Certain CT findings such as a bulky
head of pancreas tumor without significant dilation of the bile
duct or main pancreatic duct and enlarged lymph nodes below
the level of the renal vein suggest PPL over adenocarcinoma
(23,27). However, cytohistological examination of tissue,
obtained by image-guided fine needle aspiration (FNA) or
endoscopically guided FNA, is required to confirm the diagnosis
of PPL (24,28). Surgery is usually reserved for rare cases where
less invasive modalities fail to provide a tissue diagnosis.
The treatment of PPL has varied, due to the lack of prospec-
tive randomized studies to delineate management. Chemo-
therapy has been the mainstay of treatment with CHOP
(Cyclophosphamide, Adriamycin, Vincristine, Prednisone),
CVP (Cyclophosphamide, Vincristine, Prednisolone), and
MACOP-B (Methotrexate, Leucovorin, Doxorubicin, Cyclo-
phosphamide, Vincristine, Bleomycin) being used most com-
monly (26,29). Radiotherapy has been used variably, alone and
as consolidation after chemotherapy (26). Recently rituximab
has been used in combination with CHOP resulting in
improved response rates (30). Surgical resection for stage I and
II disease has been shown to increase cure rates and may be
used as part of multimodality therapy for resectable lesions
(31). In general, the outcomes for pancreatic lymphoma are
better than for ductal adenocarcinoma.
metastatic disease to the pancreas
The pancreas is the site of metastases from a wide variety of
primary neoplasms. The five most common cancers with
Figure 46.2 CT scan showing a large heterogenous mass involving the body
and the tail of the pancreas (arrow) in a 70-year-old male who had previously
undergone right upper lobectomy for lung adenocarcinoma. This mass was
found during a follow-up PET CT scan. The pathology specimen confirmed
the diagnosis of a metastasis from the lung primary.
isolated metastases to the pancreas are renal, lung, breast,
colon, and melanoma (32). Metastases to the pancreas are
usually identified during initial metastatic work-up of a pri-
mary tumor, during routine follow-up after resection of the
primary cancer, or via the presence of symptoms secondary to
the pancreatic lesion (32). On CT imaging, hypervascularity
of the lesion, absence of enlarged lymph nodes, and multicen-
tric lesions suggest metastatic disease to the pancreas over a
primary neoplasm (Fig. 46.2) (33). Treatment options (both
surgical and nonsurgical) depend on the type of primary
tumor, location of the metastasis, the extent of disease, and
the presence or absence of symptoms related to the metastatic
tumor (32).
Renal cell carcinoma (RCC) is the most common cancer
associated with isolated metastasis to the pancreas (34).
Pancreatic metastasis from RCC is usually metachronous,
occurring an average of 9.2 years after initial resection (32,35).
Most patients are asymptomatic, with lesions detected through
routine post-RCC surveillance (36,37). Surgical resection
yields a 5-year survival between 53% and 75% compared to
5% to 30% for those with unresectable lesions (32). Metastec-
tomy in patients with RCC does seem to confer a survival
benefit and should be performed in eligible patients.

434
 RARE TUMORS OF THE PANCREAS
Table 46.3 Summary of the Most Common Isolated Metastasis to the Pancreas
Primary tumor Clinical setting
Renal cell cancer Isolated pancreatic metastasis
Lung Diffuse metastatic disease
Breast Diffuse metastatic disease
Colon Direct extension from right or transverse
colon primary
Melanoma Multiple intra-abdominal metastasis
Isolated pancreatic metastases from lung cancer are rare.
These patients have a poor prognosis and most do not benefit
from metastectomy (32,38). Pancreatic metastasis from breast
cancer usually occurs in the setting of diffusely metastatic
disease; while controversial, surgical resection, in conjunction
with multimodality therapy, may improve survival (32). Pan-
creatic metastasis from colon cancer often occurs secondary
to local invasion; en bloc resection has been found to improve
prognosis and is advocated in carefully selected cases (32).
Pancreatic metastasis from malignant melanoma is generally
found in conjunction with metastasis to other intra-
abdominal organs (39). Though the data are limited with
regard to pancreatic resection for melanoma, improved sur-
vival has been documented when complete resection of all
intra-abdominal sites of metastatic melanoma can be achieved
(39,40). The different types of primary tumors metastatic to
the pancreas and their recommended treatment are summa-
rized in Table 46.3.
von hippel-lindau syndrome
A germline mutation of a tumor suppressor gene on the short
arm of chromosome 3 (3p25–26) causes a multisystem cancer
syndrome, called the Von Hippel–Lindau (VHL) syndrome
(41,42). VHL has an autosomal dominant inheritance pattern.
The penetrance of the disease is greater than 90% by 65 years
of age (43). It is found in all ethnic groups and affects both
genders equally. The prevalence of VHL disease ranges from
1:30,000 to 1:50,000 individuals (44). Affected individuals may
develop CNS and retinal hemangioblastomas, renal cysts, renal
carcinoma, pheochromocytoma, pancreatic cysts, pancreatic
neuroendocrine tumors, as well as epididymal and broad liga-
ment cystadenomas (42). In patients with a family history of
VHL, the diagnosis can be made with the finding of a single
cerebellar or retinal hemangioblastoma, RCC, or pheochro-
mocytoma. For patients without a family history, the diagnosis
requires two or more hemangioblastomas or one hemangio-
blastoma and another visceral lesion (45).
Pancreatic involvement in VHL can present in the form of
pancreatic cysts (30–70% of affected individuals), serous cyst-
adenomas (10%), or neuroendocrine tumors (11–17%)
(46–48). Pancreatic neuroendocrine tumor typically appears
on CT scan as a well circumscribed, enhancing mass in early
phase images and on EUS as a homogenous, hypoechoic mass
(46). Somatostatin receptor scintigraphy (SRS) can be used as
an adjunct in diagnosis. Surgical intervention is not required
Recommended treatment Survival benefit
Metastectomy Improved survival
Metastectomy not recommended No survival benefit
Metastectomy in conjunction with May improve survival
multimodality therapy
En bloc resection (typically pancreaticoduo- Improved survival
denectomy)
Metastectomy if complete resection of all Improved survival
intra-abdominal sites is possible
for pancreatic cysts or serous cystadenomas (43) but surgical
resection is recommended for selected neuroendocrine tumors
due to their malignant potential. The criteria for resection of
VHL neuroendocrine tumors are (1) no metastatic disease and
size greater than 3 cm in the body or tail, or greater than 2 cm
in the head or (2) patient undergoing laparotomy for other
lesions (47). Patients who do not meet criteria for resection
should be successfully followed with yearly CT scan to assess
for tumor enlargement (42). The most common sites of
metastatic neuroendocrine tumor in VHL are the liver and
peripancreatic lymph nodes; treatment consists of chemother-
apy (and duodenal or biliary stenting as needed for palliation
of space occupying lesions) (42).
giant cell tumors
Giant cell tumors of the pancreas are very rare. They appear as
two distinct histopathologies: pleomorphic giant cell carci-
noma and osteoclast-like giant cell tumor of the pancreas
(OGTP) (49). The pleomorphic giant cell variant is highly
anaplastic with pleomorphic mononucleated and multinucle-
ated giant cells (50). OGTP is rarer and has a more favorable
prognosis than the undifferentiated pleomorphic giant cell
carcinoma (51). OGTP is characterized by osteoclast-like giant
cells and mononuclear stromal cells identical to the those
found in giant cell tumors of the bone (49). The histogenesis
of this tumor continues to remain controversial, with both
epithelial and mesenchymal origins being suggested (52).
OGTP accounts for much less than 1% of all malignant neo-
plasms of the pancreas (53). The presenting symptoms include
abdominal pain, weight loss, jaundice, and occasionally a pal-
pable mass. The average age of onset is 60 years, although there
is a wide range of 30 to 80 years of age, and it affects males and
females equally. The majority of tumors are found in the head
of the pancreas. Local invasion is common at presentation.
Approximately 50% of patients have metastasis at the time of
diagnosis (49). The overall prognosis appears to be marginally
better than pancreatic adenocarcinoma, with median survival
less than 1 year (54). These cancers may arise in association
with an adenocarcinoma of the pancreas or a mucinous cystic
neoplasm (55). Although there is no definitive treatment algo-
rithm because of the rarity of the neoplasm, surgical resection
should be pursued if appropriate (51). The role for radiation
and chemotherapy is unclear. Such treatment is often used,
extrapolating from data generated in the treatment of giant
cell tumors of the bone (49).
435
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 46.3 Typical CT scan demonstrating the “sausage-like” appearance of
the body and tail of the pancreas in autoimmune pancreatitis (arrow). The
gallbladder is prominent and the intrapancreatic portion of the distal com-
mon bile duct is dilated.
medullary carcinoma
Initially described by Goggins et al. in 1998 as pancreatic
adenocarcinomas with DNA replication errors (RER+), medul-
lary carcinomas of the pancreas are poorly differentiated carci-
nomas that have been frequently grouped with conventional
ductal carcinoma of the pancreas. However, they are
histologically distinct, described by syncytial growth pattern,
expanding tumor borders, and extensive necrosis (56).
Furthermore, they have unique genetic features and tumor
pathogenesis. Although not clearly known, up to 5% of
pancreatic cancers may be medullary variants. Clinically,
patients with these tumors present in the 6th and 7th decade of
life with a slight male to female predominance and most
patients have a family history of cancer in a first degree relative.
On a molecular level, medullary carcinomas of the pancreas
were initially reported to have a wild-type K-ras gene. How-
ever, later studies have not confirmed this as a universal find-
ing. In addition, medullary cancers harbor microsatellite
instability (MSI) in about 22% cases as compared to a lack of
MSI in ductal adenocarcinomas (56). This suggested a dis-
tinct genetic pathway for medullary tumor development that
is different from pancreatic adenocarcinoma (57). MSI is
caused by mutations or methylation in such DNA repair genes
as MLH1 and MSH2 (and others), which can be inherited or
acquired (58).
Patients with MSI-positive medullary tumors are observed
to have better prognosis than those with ductal adenocarci-
noma. Bunzo et al. examined the predictive value of MSI on
prognosis of pancreatic cancer and found that MSI-positive
tumors had significant longer survival times than their MSI-
negative counterpart (59,60). Such a beneficial association of
MSI positivity with prognosis has been observed in other types
of cancers including colorectal, gastric, and ampullary cancer.
The treatment for localized disease is surgical resection. The
optimal post-resection chemotherapy remains unknown,
although this tumor’s unique molecular profile suggests a role
for specifically targeted therapy.
436
autoimmune pancreatitis (aip)
AIP, also known as lymphoplasmacytic sclerosing pancreatitis
(LPSP), is characterized by a chronic inflammation of the
pancreas with prominent lymphocytic infiltration leading to
fibrosis (61). It was initially described by Sarles et al. in 1961 as
a case of sclerosing pancreatitis with hypergammaglobu-
linemia (62,63). However, it was not until 1995 that the term
“autoimmune pancreatitis” was introduced by Yoshida et al.
(64). In the past 10 years, many clinicopathological aspects of
AIP have been clarified and the disease has become a discrete
entity. While not a neoplasm, AIP can mimic neoplasia.
There are four histologic characteristics of AIP: dense
infiltration of the pancreas with lymphoplasmacytic cells,
interstitial fibrosis, “collar like” periductal inflammation
around medium-sized interlobular ducts, and obliterative peri-
phlebitis (30). The infiltrating cells comprise CD4+ and CD8+
lymphocytes and IgG4+ plasma cells (61). On gross examina-
tion, the fibrous process in the pancreas can mimic ductal
pancreatic adenocarcinoma (65). The disease is frequently cen-
tered at the head of the gland, although the extent of disease
can vary with some reports suggesting a diffuse involvement of
the entire pancreas. The gland is gray to white in color and firm,
often described as “sausage like.” There is also an associated loss
of lobular architecture, and the inflammation can spread to
involve the common bile duct and gallbladder (66).
The two most common presenting symptoms of AIP are
jaundice (67%) and abdominal pain (35%). Patients may also
present with anorexia, weight loss, diabetes, and pancreatic
insufficiency (30,61,65). In about 20% of patients, AIP is asso-
ciated with another autoimmune disease, including Sjögren’s
syndrome, primary sclerosing cholangitis, ulcerative colitis,
and Crohn’s disease (66). AIP usually presents in the 6th and
7th decade of life and has a male predominance (65,66). Sero-
logically, patients have been found to have elevations in several
autoantibodies, including carbonic anhydrase, anti-lactoferrin,
anti-nuclear factor, and various gamma globulins, especially
IgG4 (64,67). On CT imaging, patients will frequently have
focal enlargement of the entire pancreas, most prominently in
the head (Fig. 46.3) (64,68). Other findings include a capsule-
like rim on MRI T2-weighted images and diffuse, irregular ste-
nosis of the pancreatic duct as seen by MRCP or ERCP (68).
Treatment for confirmed AIP has evolved to medical
management, with many patients having a dramatic response
to steroid therapy within 4 weeks. There are no strict rules for
dosage and duration, although most publications report doses
of prednisone starting at 30 to 40 mg/day for at least 1 to
2 weeks, with a gradual taper. There is a reported relapse rate
of between 10% and 20%, which usually responds to additional
steroids. There has been a small group of patients which have
required maintenance therapy (61,64).
Differentiating AIP from adenocarcinoma is crucial due to
the differences in treatment of these two entities. There have
been several sets of diagnostic criteria proposed for AIP
including the Japanese, the Korean, and the Mayo Clinic
criteria (Table 46.4) (69,70). Despite these criteria, there
remain a small group of patients who may come to surgical
resection to rule out the presence of neoplasia in an
abnormal gland (71). Additionally, there have been reports of
 RARE TUMORS OF THE PANCREAS

Table 46.4 Japanese, Korean, and Mayo Criteria for Diagnosis of Autoimmune Pancreatitis
Diagnostic criteria Japanese criteria
Histology Marked interlobular fibrosis and
prominent infiltration of
lymphocytes and plasma cells in
the periductal area, occasionally
with lymphoid follicles in the
pancreas
Serology High serum gamma-globulins, IgG
or IgG4, or the presence of
autoantibodies such as antinu-
clear antibodies and rheumatoid
factor
Imaging Diffuse or segmental narrowing of
the main pancreatic duct with
diffuse or localized enlargement
of the pancreas by imaging
studies such as abdominal
ultrasound, CT, and MRI
Involvement of other Not included
organs
Response to steroid Not included
therapy
Source: Modified from Refs. (69,70,71).
Korean criteria
Fibrosis and lymphoplasmocytic
infiltration
At least one of the following:
(1) Elevated levels of IgG
and/IgG4 (2)Detected
autoantibodies
(1) CT: diffuse enlargement
(swelling) of the pancreas
(2) ERCP: diffuse or segmental
narrowing of the pancreatic duct
Association with other postulated
autoimmune diseases
Dramatic resolution of narrowing
of the pancreatic duct
Mayo criteria
At least one of the following:
(1) Periductal lymphoplasmacytic
infiltrate with obliterative
phlebitis and storiform fibrosis
(2) Lymphoplasmacytic infiltrate
with storiform fibrosis showing
abundant (>10 cell/HPF)
IgG4-positive cells
Elevated serum IgG4 levels
Common: diffusely enlarged gland
with delayed (rim) enhancement;
diffusely irregular, attenuated
main pancreatic duct.
Others: focal pancreatic mass/
enlargement; focal pancreatic
duct stricture, pancreatic duct
atrophy, pancreatic calcifications;
or pancreatitis
Hilar/intrahepatic biliary strictures,
persistent distal biliary stricture,
parotid/lacrimal gland involve-
ment, mediastinal lymphadeno-
pathy, retroperitoneal fibrosis
Resolution/marked improvement
of pancreatic/extrapancreatic
manifestation with steroids

synchronous AIP and ductal adenocarcinoma, treated via
pancreatic resection (72).
references
1. Campbell F, Azadeh B. Cystic Neoplasms of the exocrine pancreas. Histo-
pathology 2008; 52: 539–51.
2. Adams AL, Seigal GP, Jhala NC. Solid pseudopapillary tumor of the pan-
creas. Adv Anat Pathol 2008; 15: 39–45.
3. Liu X, Rauch TM, Siegal GP, et al. Solid-pseudopapillary neoplasm of the
pancreas. Three cases with a literature review. Appl Immunohistochem
Mol Morpho 2006; 14: 445–53.
4. Mao C, Guvendi M, Domenico DR, et al. Papillary cystic and solid tumors
of the pancreas: a pancreatic embryonic tumor? Studies of three cases and
cumulative review of the world’s literature. Surgery 1995; 118: 821–8.
5. Geers C, Moulin P, Gigot JF, et al. Solid and pseudopapillary tumor of the
pancreas—review and new insights into pathogenesis. Am J Surg Pathol
2006; 30: 1243–9.
6. Shi C, Daniels JA, Hruban RH. Molecular characterization of pancreatic
neoplasms. Adv Anat Pathol 2008; 15: 185–95.
7. Tipton SG, Smyrk TC, Sarr MG, et al. Malignant potential of solid pseu-
dopapillary neoplasm of the pancreas. Br J Surg 2006; 93: 733–7.
8. Machado MCC, Machado MAC, Bacchella T, et al. Solid pseudopapillary
neoplasm of the pancreas: distinct patterns of onset, diagnosis, and prog-
nosis for male versus female patients. Surgery 2008; 143: 29–34.
9. Riechelmann RP, Hoff PM, Moron RA, et al. Acinar cell carcinoma of the
pancreas. Int J Gastrointest Cancer 2003; 23: 67–72.
10. Holen KD, Klimsra DS, Hummer A, et al. Clinical characteristics and out-
comes from an institutional series of acinar cell carcinoma of the pancreas
and related tumors. J Clin Oncol 2002; 20: 4673–8.
11. Seth AK, Argani P, Campbell KA, et al. Acinar cell carcinoma of the pan-
creas: an institutional series of resected patients and review of the current
literature. J Gastrointest Surg 2008; 12: 1061–7.
12. Wisnoski NC, Townsend CM Jr, Nealon WH, et al. 672 Patients with aci-
nar cell carcinoma of the pancreas: a population-based comparison to
pancreatic adenocarcinoma. Surgery 2008; 144: 141–8.
13. Tatli S, Mortele KJ, Levy AD, et al. CT and MRI features of pure acinar cell
carcinoma of the pancreas in adults. AJR 2005; 184: 511–9.
14. Chiou YY, Chiang JH, Hwang JI, et al. Acinar cell carcinoma of the pan-
creas clinical and computed tomography manifestations. J Comput Assist
Tomogr 2004; 28: 180–6.
15. Mortenson MM, Katz MHG, Tamm EP, et al. Current diagnosis and man-
agement of unusual pancreatic tumors. Am J Surg 2008; 196: 100–13.
16. Kitagami H, Kondo S, Hirano S, et al. Acinar cell carcinoma of the pan-
creas: clinical analysis of 115 patients from Pancreatic Cancer Registry of
Japan Pancreas Society. Pancreas 2007; 35: 42–6.
17. Schmidt CM, Matos JM, Bentrem DJ, et al. Acinar cell of the pancreas in
the United State: prognostic factors and comparison to ductal adenocar-
cinoma. J Gastrointest Surg 2008; 12: 2078–86.
18. Kardon DE, Thompson LDR, Przygodki RM, et al. Adenosquamous
carcinoma of the pancreas: a clinicopathologic series of 25 cases. Mod
Pathol 2001; 14: 443–51.
19. Hsu JT, Yeh CN, Chen YR, et al. Adenosquamous carcinoma of the
pancreas. Digestion 2005; 72: 104–8.

437
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
20. Rahemtullah A, Misdraji J, Pitman MB. Adenosquamous carcinoma of
the pancreas: cytologic features in 14 cases. Cancer 2003; 99: 372–8.
21. Smoot RL, Zhang L, Sebo TJ, et al. Adenosquamous carcinoma of the
pancreas: a single-institution experience comparing resection and
palliative care. J Am Coll Surg 2008; 207: 368–70.
22. Grimison PS, Chin MT, Harrison ML, et al. Primary pancreatic
lymphoma—pancreatic tumours that are potentially curable without
resection, a retrospective review of four cases. BMC Cancer 2006; 6: 117.
23. Arcari A, Anselmi E, Bernuzzi P, et al. Primary pancreatic lymphoma. A
report of five cases. Haematologica 2005; 90: e23–6.
24. Lin H, Li SD, Hu XG, et al. Primary pancreatic lymphoma: report of six
cases. World J Gastroenterol 2006; 12: 5064–7.
25. Saif MW. Primary pancreatic lymphomas. J Pancreas 2006; 7: 262–3.
26. Basu A, Patil N, Mohindra P, et al. Isolated non-Hodgkin’s lymphoma of
the pancreas: case report and review of literature. J Cancer Res Therap
2007; 3: 236–9.
27. Merkle EM, Bender GN, Brambs HJ. Imaging findings in pancreatic
lymphoma: differential aspects. AJ R 2000; 174: 671–5.
28. Ji Y, Kuang TT, Tan YS, et al. Pancreatic primary lymphoma: a case report
and review of the literature. Hepatobiliary Pancreatic Dis Int 2005; 4:
622–6.
29. Battula N, Srinivasan P, Prachalias A, et al. Primary pancreatic lymphoma:
diagnostic and therapeutic dilemma. Pancreas 2006; 33: 192–4.
30. Mortenson MM, Katz MH, Tamm EP, et al. Current diagnosis and
management of unusual pancreatic tumors. Am J Surg 2008; 196: 100–13
31. Koniaris LG, Lillemoe KD, Yeo CJ, et al. Is there a role for surgical resection
in the treatment of early-stage pancreatic lymphoma? J Am Coll Surg
2000; 190: 319–30
32. Showalter SL, Hager E, Yeo CJ. Metastatic disease to the pancreas and
spleen. Semin Oncol 2008; 35: 160–71.
33. Wente MN, Kleeff J, Esposito I, et al. Renal cancer cell metastasis into the
pancreas: a single-center experience and overview of the literature.
Pancreas 2005; 30: 218–22.
34. Volmar KE, Jones CK, Xie HB. Metastases in the pancreas from nonhema-
tologic neoplasms: report of 20 cases evaluated by fine-needle aspiration.
Diagn Cytopathol 2004; 31: 216–20.
35. Sellner F, Tykalsky N, De Santis M, et al. Solitary and multiple isolated
metastases of clear cell renal carcinoma to the pancreas: an indication for
pancreatic surgery. Ann Surg Oncol 2006; 13: 75–85.
36. Law CH, Wei AC, Hanna SS, et al. Pancreatic resection for metastatic renal
cell carcinoma: presentation, treatment, and outcome. Ann Surg Oncol
2003; 10: 922–6.
37. Zerbi A, Ortolano E, Balzano G, et al. Pancreatic metastasis from renal cell
carcinoma: which patients benefit from surgical resection? Ann Surg
Oncol 2008; 15: 1161–8.
38. Hiotis SP, Klimstra DS, Conlon KC. Results after pancreatic resection for
metastatic lesions. Ann Surg Oncol 2002; 9: 675–9.
39. Gutman H, Hess K, Kokotsakis J. Surgery for abdominal metastases of
cutaneous melanoma. World J Surg 2001; 25: 750–8.
40. Wood T, DiFranzo L, Rose DM, et al. Does complete resection of
melanoma metastatic to solid intra-abdominal organs improve survival?
Ann Surg Oncol 2001; 8: 658–62.
41. Kaelin WG. Von Hippel-Lindau disease. Annu Rev Pathol 2007; 2: 145–73.
42. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lan-
cet 2003; 361: 2059–67.
43. Shehata BM, Stockwell CA, Castellano-Sanchez AA, et al. Von Hippel-
Lindau (VHL) disease: an update on the clinico-pathologic and genetic
aspects. Adv Anat Pathol 2008; 15: 165–71.
44. Elli L, Buscarini E, Portugalli V, et al. Pancreatic involvement in von
Hippel-Lindau disease: report of two cases and review of the literature.
Am J Gastroenterol 2006; 101: 2655–8.
45. Mukhopadhyay B, Sahdev A, Monson JP, et al. Pancreatic lesions in von
Hippel-Lindau disease. Clin Endocrinol (Oxf) 2002; 57: 603–8.
46. Corcos O, Couvelard A, Giraud S, et al. Endocrine pancreatic tumors in
von Hippel-Lindau disease: clinical, histological,and genetic features.
Pancreas 2008; 37: 85–93.
47. Blansfield JA, Choyke L, Morita SY, et al. Clinical, genetic and radiographic
analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by
pancreatic neuroendocrine neoplasms(PNETs). Surgery 2007; 142: 814–8.
438
48. Delman KA, Shapiro SE, Jonasch EW, et al. Abdominal visceral lesions in
von Hippel-Lindau disease: incidence and clinical behavior of pancreatic
and adrenal lesions at a single center. World J Surg 2006; 30: 665–9.
49. Nai GA, Amico E, Gimenez VR, et al. Osteoclast-like Giant Cell tumors of
the pancreas associated with mucous-secreting adenocarcinoma: case
report and discussion of the histogenesis. Pancreatology 2005; 5: 279–84.
50. Layfield LJ, Bentz J. Giant-cell containing neoplasm of the pancreas: an
aspiration cytology study. Diagn Cytopathol 2007; 36: 238–44.
51. Joo E, Heo T, Park C, et al. A case of osteoclast-like giant cell tumor of the
pancreas with ductal adenocarcinoma: Histopatholgical, immunohisto-
chemical, ultrastructural, and molecular biologic basis. J Korean Med Sci
2005; 20: 516–520.
52. Loya AC, Ratnakar KS, Shastry RA. Combined osteoclast giant cell and
pleomorphic giant cell tumors of the pancreas: A rarity. An immunohis-
tochemical analysis and review of literature. J Pancreas 2004; 5: 220–4.
53. Sauto-Vial N, Rahili A, Karimdjee-Soihili B, et al. Hepatobiliary and
pancreatic: osteoclast-like giant cell tumor of the pancreas. J Gastroen-
terol Hepatol 2006; 21: 1072.
54. Bauditz J, Rudolph B, Wermke W. Osteoclast-like giant cell tumors of the
pancreas and liver. World J Gastroenterol 2006; 12: 7878–83.
55. Hruban RH, Fukushima N. Pancreatic adenocarcinoma: update on the
surgical pathology of carcinomas of ductal origin and PanINs. Mod
Pathol 2007; 20: 61–70.
56. Wilentz RE, Goggins M, Redston M, et al. Genetic, immunohistochemical,
and clinical features of medullary carcinoma of the pancreas. Am J Pathol
2000; 156: 1641–51.
57. Goggins M, Offerhaus GJ, Hilgers W, et al. Pancreatic adenocarcinomas
with DNA replication errors (RER+) are associated with wild type K-ras
and characteristic histopathology: poor differentiation, a syncytial growth
pattern, and pushing borders suggest RER+. Am J Pathol 1998; 152:
1501–7.
58. Jaffee EM, Hruban RH, Canto M, et al. Focus on pancreas cancer. Cancer
Cell 2002; 2: 25–8.
59. Nakata B, Wang YQ, Yashiro M, et al. Prognostic value of microsatellite
instability in resectable pancreatic cancer. Clin Cancer Res 2002; 8:
2536–40.
60. Yamamoto H, Itoh F, Nakamura H, et al. Genetic and clinical features of
human pancreatic ductal adenocarcinoma with widespread microsatellite
instability. Cancer Res 2001; 61: 3139–44.
61. Finkelberg DA, Sahani D, Deshpande V, et al. Autoimmune pancreatitis.
N Engl J Med 2006; 355: 2670–6.
62. Sarles H, Sarles JC, Muratore R, et al. Chronic inflammatory sclerosis of
the pancreas – an autonomous pancreatic disease? Am J Dig Dis 1961; 6:
688–98.
63. Klöppel G, Sipos B, Zamboni G, et al. Autoimmune pancreatitis:
histo- and immunopatholgical features. J Gastroenterol 2007; 42: 28–31.
64. Yoshida K, Takeuchi T, Watakanabe S, et al. Chronic pancreatitis caused by
autoimmune abnormality: proposal of the concept of autoimmune
pancreatitis. Dig Dis Sci 1995; 40: 1561–8.
65. Krasinskas AM, Raina A, Khalid A, et al. Autoimmune pancreatitis.
Gastroenterol Clin North Am 2007; 36: 239–57.
66. Rao AS, Palazzo F, Chung J, et al. Diagnostic and treatment modalities for
autoimmune pancreatitis. Curr Treat Opt Gastroenterol 2006; 9: 377–84.
67. Okazaki K, Uchida K, Fukui T. Recent advances in autoimmune pancre-
atitis: concept, diagnosis, and pathogenesis. J Gastroenterol 2008; 43:
409–18.
68. Kawamoto S, Siegelman SS, Hruban et al. Lymphoplasmacytic sclerosing
pancreatitis (autoimmune pancreatitis): evaluation with multidetector
CT. Radiographics 2008; 28: 157–70.
69. Otsuki M, Chung JB, Okazaki K, et al. Asian diagnostic criteria for
autoimmune pancreatitis: concensus of the Japan-Korea symposium on
autoimmune pancreatitis. J Gastroenterol 2008, 43: 403–8.
70. Kamiwasa T. Diagnostic criteria for autoimmune pancreatitis. J Clin
Gastroenterol 2008; 42: 404–7.
71. Kamisawa T, Imai M, Chen PY, et al. Strategy for differentiating autoim-
mune pancreatitis from pancreatic cancer. Pancreas 2008; 37: 62–7.
72. Witkiewicz AK, Kennedy EP, Kennyon L, et al. Synchronous autoimmune
pancreatitis and infiltrating pancreatic ductal adenocarcinoma. Mod
Pathol 2008, 39: 1548–51.
47 Acute pancreatitis
C. Ross Carter, A. Peter Wysocki, and Colin J. McKay
introduction
In the last 20 years, there are few disease processes where the
understanding and the approach to management have
changed more than that of acute pancreatitis. Acute pancre-
atitis presents a spectrum of disordered physiology, ranging
from a mild and rapidly resolving attack (80%) requiring
little more than analgesia and a short period of intravenous
fluid resuscitation, to an overwhelming system illness char-
acterized by multi-organ dysfunction refractory to aggressive
resuscitation. Various clinical and biochemical scoring sys-
tems (1–4) have been used in an attempt to differentiate
between mild or severe acute pancreatitis, but out-with the
study environment, management is reactive aimed at nor-
malizing altered physiology or the management of local
complications.
The majority of patients with severe early organ dysfunc-
tion will have pancreatic necrosis on CT scan. There is an
association between the development of necrosis and the
severity of organ dysfunction (5), although patients with
edematous pancreatitis may manifest clinical features of a
severe attack. Clinical practice has changed rapidly over the
last decades, and the previous focus on parenchymal necrosis
and particularly the role of prevention/treatment of infection
are now considered in a wider concept tending toward organ
support and less aggressive intervention. Most patients who
develop organ failure have evidence of this at the time of
admission or very shortly thereafter (6), and worsening or
persistent organ failure is associated with an adverse outcome,
and/or the development of late complications. There is no
evidence that aggressive early surgical intervention to address
the necrosis has a beneficial effect on outcome and indeed is
potentially harmful.
The majority of patients with acute pancreatitis will have a
mild clinical course and other than maintenance of fluid vol-
ume and analgesia, subsequent treatment is aimed at preven-
tion of a further attack. Early definitive treatment of
cholelithiasis is recommended by cholecystectomy or endo-
scopic sphincterotomy as recurrent mild attacks are not
uncommon (7). The main focus of this chapter is on the 15%
to 20% of patients who present with severe disease and the
options and rationale for clinical management.
etiology
Pancreatic inflammation was first reported in association
with alcohol excess in 1878 by Freidrich, and 20 years later,
Opie proposed the bile reflux theory potentially underly-
ing the most common cause of gallstones. A detailed
description of the pathophysiological mechanisms that are
thought to be involved in the initiation of an attack is
beyond the scope of this chapter. An attack may be initi-
ated by obstruction of the duct either through passage of a
gallstone or stricture (8) or an alteration in biochemical
homeostasis at a cellular level, triggering a rise in intracel-
lular calcium inducing activation of pro-enzymes within
the acinar cell, leading to activated trypsin release into the
cytosolic compartment (9). While the cellular initiation
mechanisms are an area of significant research interest, the
management of the acute attack is in general not affected
by the etiology, and the importance of identifying an etio-
logical factor lies in the potential for preventing a further
episode.
early management of the acute admission
Following a severe acute attack, there is a dynamic process
of evolution, in some cases over several months, with
changing local and systemic clinical function and morphol-
ogy, and while the mode of death in almost all cases is
multi-organ failure, the pathophysiology and therefore the
need for intervention changes with time. The majority of
patients, whether mild or severe, present with acute-onset
abdominal pain and vomiting. Most patients will settle
within 24 to 48 hours. A proportion of patients develop a
cytokine-driven systemic inflammatory response (10),
which may progress to establish multi-organ dysfunction.
The systemic nature of the disease process has been recog-
nized for over 30 years, the “predictive” biochemical scoring
systems, dating from the 1970s, reflecting altered organ
homeostasis established early organ dysfunction. The mag-
nitude of the physiological disturbance, however, does not
affect the principles of management which remains reac-
tive, dealing with maintenance of organ function. In severe
acute pancreatitis (SAP), local and systemic inflammatory
process, coupled with increases in capillary permeability
and third space losses, leads to relative hypovolemia,
reduced tissue perfusion, and oxygenation.
Initial management therefore involves aggressive fluid
resuscitation, monitoring the response through urine out-
put, intra-arterial, intravenous monitoring, and pulse
oximetry, but there are no established endpoints of resusci-
tation to confirm that tissue perfusion and oxygen delivery
have been adequately restored. Respiratory and renal sup-
ports are often required. Inotropic cardio-vascular support
should be delayed until after an adequate circulating vol-
ume has been achieved. The pattern and severity of organ
dysfunction vary considerably from patient to patient and
management can therefore only be optimized on an indi-
vidual patient basis.
In patients often with minimal prior co-morbidity, the
development of rapidly progressive or refractory organ failure
following initial presentation led to a desire, and often belief,
that specific interventions may improve outcome, over- and
above-optimized organ support. Unfortunately there are no
439
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
measures that have been shown to reduce overall mortality,
and local protocols are often biased by personal preference
rather than an evidence base.
role for specific interventions
ERCP
A small group of patients with cholangitis present with associ-
ated hyperamylasemia, organ dysfunction being driven by
biliary sepsis and the raised amylase is coincidental. This is less
common in the Western World than in the Far East. Pyrexia,
being a common feature of a delayed Systemic inflammatory
response syndrome (SIRS) response in SAP, is very unusual
within 48 hours, and when associated with rigors and jaun-
dice, an erroneous diagnosis of pancreatitis should be consid-
ered. There have now been three published randomized trials
(11–13) and four smaller studies. The most recent meta-anal-
ysis (14) has shown early endoscopic retrograde cholangio-
pancreatography (ERCP) in patients without acute cholangitis,
which did not lead to a significant reduction in the risk of
overall complications and mortality (Level 1a).
Antibiotics
Until the early peak in multiple organ dysfunction syn-
drome (MODS)–associated mortality was recognized, late
sepsis due to secondary infection of pancreatic necrosis was
thought to be the major cause of death. Infection occurs in
15% to 20% of patients with a minimum 30% pancreatic
necrosis. Secondary infection manifests as escalating sepsis
or a deterioration in organ failure scores. The early promise
of the antibiotic trials of the 1990s (15,16) led to the wide-
spread adoption of the use of prophylactic antibiotics, but
with the addition of larger, albeit still underpowered, trials
(17,18); the most recent meta-analysis concluded that pro-
phylactic antibiotics do not reduce infected pancreatic
necrosis and mortality in patients with SAP (19). In patients
with necrosis, SIRS-associated pyrexia is common and may
last for weeks in the absence of infection. Persistence of
antibiotics beyond a prophylactic time frame carries the
danger of the emergence of subsequent resistant or nosoco-
mial infections. At present the decision to use prophylactic
antibiotics is based on personal preference rather than evi-
dence base and further well-designed trials are required.
Surgical Intervention
A small proportion of patients are initially diagnosed at lapa-
rotomy and other than washout and closure no pancreatic
procedure or drainage is required. Historical attempts at
early resection/debridement were associated with prohibitive
mortality and the only randomized trial (20) was stopped
due to unacceptable mortality in the surgery group. Very
rarely, hemorrhage or intestinal ischemia may demand inter-
vention in the first week. Recent interest has focused on the
role of intra-abdominal hypertension (IAH) as a contribut-
ing factor to organ dysfunction. There are data to suggest
that raised intra-abdominal pressure may be associated with
disease severity, organ failure, and mortality in SAP (21,22).
There are, however, no data to suggest outcome improves
following surgical decompression for raised IAP in acute
440
pancreatitis, and indeed this may be harmful. At present we
cannot advocate monitoring intra-abdominal pressure out
with a clinical trial.
Nutrition
Median inpatient stay for a patient with MODS-associated
SAP is in excess of 2 months. SIRS-associated catabolism, cou-
pled with gastric stasis is common. There is universal consen-
sus that maintenance of nutritional integrity is essential, the
main consideration relating to optimum mode of delivery. Gut
rest was considered mandatory throughout the 1980s but a
total of seven studies, all delivering enteral feed distal to the
ligament of Treitz, have now shown a benefit for enteral nutri-
tion, the consistent finding being a reduction in TPN-associ-
ated side effects and reduced cost, rather than any reduction in
pancreas-specific morbidity (23–26). Three subsequent stud-
ies (27–30) have shown proximal feeding into the stomach to
be a practical alternative to jejunal feeding with no apparent
effect on the pancreatitis. Tolerance of feed therefore governs
delivery and our own approach is to allow the patient to eat
if tolerated and to use nasogastric, naso-jejunal, or total
parenteral nutrition support as required to maintain an
adequate intake.
A secondary consideration is the potential to alter the dis-
ease process through the use of immuno-modulating feeds.
Small studies from the United Kingdom (31,32) provided
some support for this contention, showing a reduction in the
inflammatory response and organ failure in those receiving
enteral support, but unfortunately small numbers limited the
validity of the conclusions. In the critical care environment
(burns, trauma, post-surgical) there have been several trials
comparing “immuno-nutrition” with standard enteral feed,
with promising results. However, the only study in acute pan-
creatitis (PROPATRIA trial (33)—The Dutch Acute Pancreati-
tis Study group), showed probiotics to be associated with
increased mortality, and enhanced feeding should at present
remain within a study context.
Specific Pharmacological Intervention
Over the last three decades there have been a number of
studies evaluating the concept of supporting the endogenous
anti-protease defense mechanisms, the inhibition of pancre-
atic enzymes, or the inflammatory response. Double-blind
randomized trials of iv aprotinin (34) (Trasylol) and gabexate
mesilate (35), including a meta-analysis (36), showed no
advantage over placebo. Intra-peritoneal aprotinin and the
use of both low- and high-dose fresh frozen plasma proved
unhelpful. The five randomized trials of octreotide have
shown no benefit (37,38), and despite initial promising results
(39) with the platelet-activating factor antagonist, Lexipafant,
a multi-center randomized controlled trial (recruiting
>1500 patients), again showed no advantage over placebo.
The potential for other agents which modify the inflamma-
tory response or to influence outcome in acute pancreatitis
has only been assessed in experimental models, and there
is currently no evidence supporting the use of any specific
agent in SAP.
 ACUTE PANCREATITIS
summary of early management
The mainstay of early management is the early recognition
and the proactive management of compromised organ func-
tion. With the exception of the cholangitic patient, there is no
role for early surgical, endoscopic, or pharmacological inter-
vention. Nutrition should be by the enteral route where pos-
sible. The use of prophylactic antibiotics remains controversial,
but when prescribed should be for a time-limited course to
prevent the selection of resistant species.
radiological assessment
Trans-abdominal ultrasound is often performed within
24 hours but in the absence of jaundice, this has little effect on
clinical management. Bowel gas and a restless patient often
compromise the examination and exclusion of cholelithiasis
may require a repeated examination in the recovery period.
Early post-admission CT may be appropriate where the diag-
nosis is in doubt or a complication suspected; however, as the
evolution of necrosis is not complete until at least 72 hours, in
some patients axial scanning is best delayed until this time.
Subsequent management and need for further radiological
assessment are determined by the clinical condition and the
trend of biochemical and organ failure scores.
management of necrosis
Until recently, sterile necrosis was considered to be a driver of
organ dysfunction, leading to a necrosectomy for patients
failing to progress after a few weeks. It was also considered
essential to identify the development of infection as early as
possible, leading to the popularization of protocol-driven
radiologically guided fine needle bacterial aspiration (40),
and “pre-emptive” necrosectomy following a positive result.
Current opinion is that outcome can be improved by the
avoidance of early major intervention, especially in patients
with organ failure, utilizing minimally invasive approaches to
sepsis control where possible. CT-guided fine needle aspira-
tion no longer plays any role in our practice.
For many years most specialist centers have addressed all
collections utilizing a single surgical technique. This dogmatic
procedure-based algorithm failed to address the changing
requirements and risk profile with maturation of the collec-
tion. The indications for intervention vary with the dynamic
evolution of pancreatic/peri-pancreatic collections (41). In the
first 4 weeks, the “solid necrotic phase,” demarcation of devi-
talized tissue is incomplete and an attempt to remove the devi-
talized tissue often incomplete and associated with bleeding.
By about 8 to 10 weeks demarcation results in formation of a
walled off fluid collection containing a variable amount of
solid necrosis. In the early weeks, achieving control of sepsis-
driven organ failure is the primary consideration, whereas fol-
lowing maturation when organ failure is rare and morbidity
low, indications include failure to thrive, SIRS, nutritional fail-
ure, gastric outlet obstruction, or pain.
The presence of proven infection within necrosis (bacte-
ria or gas on CT) was previously seen as a mandatory indi-
cation for urgent debridement, as it was believed until
recently that recovery would only occur once the necrosis
was completely removed. The observation that drainage of
the pus surrounding the necrosis often resulted in at least a
temporary improvement in organ failure challenged this
dogma; however, further sepsis was common. The impor-
tance of maintaining a sustainable drainage system was rec-
ognized in the era of major open debridement leading to
the techniques of open packing (42) and closed lavage (43).
The solid component within these collections tends to
block the lumen of small diameter drains but provided
drainage is maintained, organ failure will resolve despite
residual necrosis.
The mortality that followed an open necrosectomy was
common in the initial (72 hours) post-operative period
due to overwhelming organ failure. This post-interven-
tional escalation in organ failure is significantly less fol-
lowing all minimally invasive approaches, but often at the
cost of multiple interventions and prolonged inpatient
stay. A balanced approach is therefore able to utilize a
number of techniques dependent on the clinical condition
of the patient, the presence of sepsis, the degree of organ
failure, the position of the collection, and the maturity of
the collection.
surgical intervention in acute pancreatitis
Open Surgery
Although minimally invasive approaches have revolutionized
management in many centers, on a worldwide basis open
debridement remains a keystone of management.
Laparotomy/Debridement (Table 47.1)
The technique of pancreatic debridement involves a wide
exposure of the abdomen, usually through a bilateral subcos-
tal/rooftop or midline incision. The lesser sac is entered via
the gastrocolic omentum, or occasionally the transverse
mesocolon. Pus is aspirated from the abscess cavity, leaving
the solid component behind which is then removed by “blunt
finger” dissection. Tissue which will not come away by finger
teasing should be left in situ to demarcate and subsequent
removal at a further procedure. The procedure may also
include a cholecystectomy, operative cholangiogram, and a
feeding jejunostomy.
Prevention of recurrent sepsis led to several approaches to
the management of the debridement cavity.
With Drainage/“Closed Packing”
Simple drainage, often with multiple retro-peritoneal tube
drains, was the conventional approach, with second look lapa-
rotomies for recurrent sepsis. This technique has been modi-
fied using multiple soft Penrose drains containing cotton
gauze to pack the cavity following completion of the necrosec-
tomy, which are subsequently removed at intervals allowing
the cavity to collapse around the drains.
Laparostomy with Open Packing
The lesser sac is packed with lubricated cotton gauze, and
the abdomen left open, allowing planned re-explorations
every few days until granulation tissue forms. Enteric fistula
and secondary hemorrhage are not uncommon, and the
technique is rarely performed as a first option. Surgical
441
442
Table 47.1 Major Series of Laparotomy and Necrosectomy
Number
with Timing of
Number Mean age infected Mean intervention Mean post- ITU
of patients in yrs necrosis AII/RS/ from onset operative length pre- ITU post-
Unit, year Method in series (range) (%) CT-SI (mean days) of stay (days) Mortality operatively Morbidity Reoperations operatively
Warshaw, Necrosectomy 64 53 (30–81) 64 9/–/– 31 41 6% – – 17% 45%
1998 (44) with closed (56%) (median
packing 6 days)
Bradley, Necrosectomy 46 – 46 14/–/– 23 – 13% – – – –
1999 (45) with (100%)
scheduled
re-explora-
tions
Buchler, Necrosectomy 29 57 (28–87) 29 13/4/– 22 85 24% – 44% 26% –
2000 (46) with closed (100%)
lavage
Götzinger, Necrosectomy 340 53 (16–85) 255 16/–/– 12 (1–31) 55a 39% 90% – 79% –
2002 (47) with (75%) preoperative (mean 2.2)
scheduled organ failure
re-explora-
tions or
resection
Beger, 2005 Necrosectomy 140 58b (19–98) 140 11/5/– 20 64 27% mean 3 days 78% 51% Mean
(43) with closed (100%) (median 1) 27 days
lavage
a
Survivors.
b
Median.
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; ITU, intensive therapy unit.
SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
 ACUTE PANCREATITIS
packing and planned re-operation are, however, some-
times required to control blood loss from the retro-
peritoneum following the development of an intraoperative
coagulopathy, a lavage system being created, following
correction of the coagulopathy, at the time of interval
pack removal.
With Closed Lavage
The Ulm group popularized the use of post-operative closed
lavage and this remains the most popular method for post-
operative sepsis control following open debridement. Several
(4–6) large diameter tube drains are inserted in the lesser sac
and throughout the abdomen and the abdomen closed. Con-
tinuous lavage is then commenced, the aim being the continu-
ous removal of devitalized necrotic material and bacteria. The
lavage is continued, for around 3 to 4 weeks on average, until
the return fluid is clear, and the patient has no residual signs of
systemic sepsis.
Minimally Invasive Approaches
A number of minimally invasive techniques have been devel-
oped over the last 15 years and these are often viewed as com-
plimentary rather than exclusive. These will be initially
described and then the potential advantages/disadvantages
discussed.
Percutaneous Catheter Drainage (Table 47.2)
Interventional radiological drainage of abscesses has been
commonplace for many years. The major difficulty in the
acute pancreatitis patient is the tendency for these to
block, leading to recurrent sepsis. Utilizing simple drain-
age as the primary modality of treatment is possible, but
is extremely labor intensive and delayed surgical intervention
is commonly required.
Endoscopic Drainage (Table 47.3)
Transmural drainage of lesser sac collections was initially
performed for established pseudocyst. Baron first described
extending the role into the management of pancreatic abscess,
where the collections contained some solid component.
Endoscopic ultrasound–guided drainage can increase the
technical success rate and reduce the risk of bleeding. Small
diameter stent drainage could lead to incomplete drainage,
and the use of tract dilatation, multiple catheters, and intra-
cystic lavage became commonplace. Seifert described the
performance of a necrosectomy through the endoscopic cyst-
gastrostomy and this is becoming increasingly popular.
Potential advantages include that it can be performed without
a general anesthetic, potentially performed as a day patient
in suitable patients and the lack of an external drain, but
inadequate drainage and hemorrhage are potential hazards.
Percutaneous Necrosectomy (Table 47.4)
This combines minimally invasive drainage with closed post-
operative lavage. A CT-guided radiological drain in inserted
ideally in the left flank to promote gravitational drainage. The
drainage tract is dilated often releasing pus under pressure and
the cavity explored using a rigid urological endoscope. Loose
necrotic material can be removed in a piecemeal fashion as it is
this that tends to block the drains. A wide bore 32FG drain
(with a parallel catheter for post-operative lavage) is left within
the cavity. Continuous lavage is maintained and further proce-
dures performed when incomplete drainage is suspected. This
is probably the easiest way of maintaining adequate drainage
and sepsis control but results in a prolonged hospital stay and
commonly late pancreatic fistula.
In the 1980s Fagniez described an open minimally invasive
approach utilizing a left flank incision and blind retroperito-
neal debridement (Table 47.5). In 2001, Horvath modified
this technique using video-assistance to allow direct visual-
ization of the debridement through a 8 to 10 cm left flank
incision. This minimally invasive technique is currently being
assessed in the first randomized comparison of a minimally
invasive approach against open surgery (PANTER trial, Dutch
Acute Pancreatitis Study Group).
laparoscopy
Early attempts at laparoscopy attempted to mimic the open
debridement, but proved technically challenging and has been
superseded by the other surgical approaches. Laparoscopic
cystgastrostomy has been reported for the management of late
walled off necrosis. Initial descriptions involved intra-luminal
laparoscopy but the position of the collection relative to the
stomach is critical. Modification by performing a longitudinal
anterior gastrostomy and then addressing the posterior cyst-
gastrostomy greatly simplified the procedure and allows a one-
step approach to organized necrosis. The procedure requires a
well-formed cavity and complete separation of the necrotic
tissue, so is less appropriate for collections in an early stage of
the disease.
summary
The choice of primary procedure is determined by the rela-
tive importance of sepsis control and the stage of evolution
of the necrosis-associated peri-pancreatic collection. Opti-
mal sepsis control is obtained by percutaneous necrosec-
tomy but completion of the process takes some time and
requires multiple procedures. At the other end of the spec-
trum, where sepsis is not an issue but intervention demanded
through pressure effects or failure to thrive, a single proce-
dure laparoscopic cystgastrostomy expedites completion of
treatment, particularly where a predominant solid compo-
nent makes endoscopic clearance likely to require multiple
procedures.
Endoscopic cystgastrostomy has a role between these
extremes. In the septic patient, initial endoscopic drainage
is easy but maintenance of sepsis control often demands
repeated intervention and adjuvant radiological drainage.
A particular problem is that the first indication of a blocked
internal cystgastrostomy drainage system is a clinical esca-
lation of sepsis whereas a blocked external drain is easily
recognized and addressed. Similarly large or para-colic col-
lections are unsuitable. However, in the fluid-predominant
443
444
Table 47.2 Percutaneous Drainage of Infected necrosis
Successful Average Acute
Number with Mean timing percutaneous duration operative
infected Mean AII/ of interven- management of management
Number of necrosis RS/CT-SI tion from alone of those Number of drainage Average catheter of those with
patients in Mean age in managed for patients onset days with infected deaths in (days or exchanges per infected
Author, year series years (range) percutaneously in series (range) necrosis Technique series range) patient (range) necrosis
Freeney, 1998 34 56 (31–71) 34 –/–/8 9 (1–48) 16 Average of 3 4 25–152 3.3 17
(48) transperi-
toneal
catheters
per patient
(10–28 Fr)
Gouzi, 1999 32 53 26 –/5/E 23 20 8–16 Fr 5 43 –a 6
(49)
Baril, 2000 25 40 (17–68) 19 –a –a 19 Average of 2 14–56 0.4b 6
(50) 1.4 drains
per patient
(10–12 Fr)
Oláh, 2006 15 59 (36–78) 15b –a 12 (2–31) 3 –a 2 –a 0.1 12
(51)
Lee, 2007 (52) 31 49 23 –/4/8 10 (1–58) 15 14 Fr 1 –a –a 3
catheter
dilated to
20 Fr
combined
with
irrigation
Bruennler, 80 57 (17–79)c 80 18/–/6c >11c 42 Median of 27 37 (1–260)c 2 (1–9)c 20
2008 (53) two (18/60 man-
catheters aged without
per patient surgery)
(8–24 Fr)
with active
necrosec-
tomy in
18 patients
b b
Szentkereszty, 61 44 (25–87)d 23/4/–d >4 7d –a (10/61)d –a –a 15d
2008 (54)
SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

a
Data not stated.
b
Limited/unclear data published.
c
Median.
d
For entire reported series of patients with various diagnoses/treatments.
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; PA, pancreatic abscess; PC, post-operative collection.
 Table 47.3 Endoscopic Necrosectomy

Mean
AII/RS/
CT-SI Patients in
for Timing of series cured Number Number of
Number of Median age Number with patients intervention by endoscopic of endoscopic Post-procedure
patients in in years infected in from onset treatment deaths reinterventions length of stay
Author, year series (range) necrosis series (mean days) alone Technique in series (average) (days)
b
Seifert, 2000 (55) 3 55 (37–55) 1 (1 SN, 1 RC) –a 13–28 3 7 Fr, 10 Fr stents 0 –a 24–96
Park, 2002 (56) 9 62 (18–68) 9 12–/–/9 42 8 One or more 7-10 0 0.3 17
Fr stents 7 Fr
nasopancreatic
catheter
Seewald, 2005 (57) 5 63 (38–84) 5 –a –a 4 Transpapillary 0 28 –a
stenting 10 Fr
stent 7 Fr
nasocyst
catheter
ACUTE PANCREATITIS

Seewald, 2005 (57) 8 56 (38–80) 0 (8 PA) –a –a 7 Transpapillary 0 7 –a

stenting 10 Fr
stent 7 Fr
nasocyst
catheter
Charnley, 2006 (58) 13 53 (30–64) 11 (2 SN) 8/–/6 ?24 9 10 Fr stent 15% 3 –a
a
Lee, 2007 (52) 5 49 5 –/4/8 6 (2–12) 4 10 Fr strent 0 – –a
a
Data not stated.
b
Limited/unclear data published.
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; OPN, organized pancreatic necrosis; PA, pancreatic abscess; SN, sterile necrosis; RC, residual collection after endoscopic
treatment.

445
446
Table 47.4 Percutaneous Necrosectomy
Patients in
series cured by Median
Median Number Mean AII/RS/ Timing of retroperitoneal Median ITU number of ITU
Number of age in with CT-SI for intervention necrosectomy Number post-operative preopera- reoperations post-opera-
patients in years infected patients in from onset Without of deaths length of stay tively Early per patient tively
Author, yr series (range) necrosis series (mean days) laparotomy in series (days) (number) morbidity (range) (number)
Carter, 2000 10 45 (32–74) 10 –a 24 9 2 42 3 1 2.5 (1–4) 4
(33)
Risse, 2004 6 46b (23–78) 6 –/10/E 23 6 0 –a 0 1 2.3 (1–4) 0
(59)
Connor, 47 56 (18–85) 38 (9 SN) 9/–/9 28 28 9 64 16 43 –a Mean of 0 days
2005 (60)
Mui, 2005 9 58 (41–80) 7 (2 PA) –a –a 6 1 84c –a 2 3 (2–8) Mean of
(61) 11 days
d d
Shelat, 2007 1 51 1 –a 1 0 >50 1 –a 8
(62)
Carter2007 110 54(18–89) 107 –a 30 (11–91) 21(19%) 38% 3(1–6) 55%
a
Data not stated.
b
Mean.
c
Total hospital stay.
d
Limited/unclear data published.
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; SN, Sterile necrosis; PA, Pancreatic abscess.
SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
 Table 47.5 Retroperitoneal Laparostomy
Author, Number of Median age Number Mean Timing of Patients in Number Mean length Technique Morbidity Mean number
year patients in in years with AII/RS/ intervention series cured by of of stay (days) of reoperations
series (range) infected CT-SI from onset lumbotomy deaths per patient
necrosis (mean days) without in series
laparotomy
Fagniez, 40 46 (26–80) 18 (17 SN) –/4a/E 14a 40 13 70 10–15 cm left upper quadrant 25 2.6
1989 (63) incision anterior to 12th rib
including mobilization of
descending colon
Gambiez, 20 51 (–) 13 (7 SN) –/3/E – 13 (7 with IPN) 2 62 6 cm incision centered on 12th 6 4
1998 (64) rib debridement, 23 cm
mediastinoscope
Horvath, 6 36 (16–48) 6 –/–/7 41 (27–77) 4 0 – Percutaneous drainage, 3 2 percutaneous
2001 (65) debridement through 4–5 cm drainages
flank incision, retroperitone-
oscopy via ports placed
through lumbotomy incision,
ACUTE PANCREATITIS

CO2 insufflation
Besselink, 18 53 (29–63) 18 –/–/8 48 (0–181) – 2 100 (43–240) Various left-sided approaches – 2 (1–11)
2006 (66) with videoscopic assistance
van 15 52 (34–66) 14 (1 SN) 9/–/8 41 (15–164) 11 1 100 (45–240) 5 cm subcostal incision along 6 1
Sant- percutaneous drain, initial
voort, blind debridement followed
2007 (67) by videoscopic debridement
a
For entire reported series of patients with various diagnoses/treatments.
– data not stated, ? limited/unclear data published
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; ITU, intensive therapy unit; ASIS, anterior superior iliac spine; IPN, infected pancreatic necrosis; SN, sterile necrosis.

447
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A) (B)

(C) (D)
Figure 47.1 (A) Early phase CT (48hrs) with head necrosis and peripancreatic edema. (B) CT at 6 weeks confirming extensive loss of parenchyma with early
demarcation and no evidence of infection. (C) CT at 7 weeks with extensive gas indicating infection—clinical sepsis addressed by percutaneous necrosectomy x3.
(D) CT at 12 weeks prior to discharge.

There are no comparative data between techniques, and our

multimodal approach has evolved largely through experience,
they should be seen as complimentary, and often combined
in a single patient. There is undoubtedly a move away from
open surgery, particularly in the septic patient. The com-
plexity and need for a spectrum of interventional options
demand that these patients are cared for within an organized
multidisciplinary regional team network.

references
Figure 47.2
well-organized collection without organ failure, endoscopic
cystgastrostomy, with dilatation and limited necrosectomy
is potentially the procedure of choice.
1. Ranson JH, Rifkind KM, Roses DF, et al. Objective early identifica-
tion of severe acute pancreatitis. Am J Gastroenterol 1974; 61(6):
443–51.
2. Blamey SL, Imrie CW, O’Neill J. Prognostic factors in acute pancreatitis.
Gut 1984; 25(12), 1340–6.
3. Larvin M, McMahon MJ. APACHE-II score for assessment and monitor-
ing of acute pancreatitis. Lancet 1989; 2(8656): 201–5.
4. Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction
score: a reliable descriptor of a complex clinical outcome. Crit Care Med
1995; 23(10): 1638–52.
5. Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and
CT evaluation. Radiology 2002; 223(3): 603–13.
6. Buter A, Imrie CW, Carter CR, Evans S, McKay CJ. Dynamic nature of
early organ dysfunction determines outcome in acute pancreatitis. Br J
Surg 2002; 89(3): 298–302.

448
 ACUTE PANCREATITIS
7. Johnson CD, et al. UK guidelines for the management of acute pancreati-
tis. Gut 2005 May; 54 (Suppl 3): iii1–9.
8. Acosta JM, Ledesma CL. Gallstone migration as a cause of acute pancre-
atitis. N Engl J Med 1974; 290(9): 484–7.
9. Raraty MGT, Petersen OH, Sutton R, Neoptolemos JP. Intracellular free
ionized calcium in the pathogenesis of acute pancreatitis. Baillieres Best
Pract Clin Gastroenterol 1999; 13(2): 241–51.
10. Imrie CW, McKay CJ. The scientific basis of medical therapy of acute pan-
creatitis: could it work, and is there a role for lexipafant? Gastroenterol
Clin North Am 1999; 28(3): 591–9.
11. Neoptolemos JP, London NJ, James D, et al. Controlled trial of urgent
endoscopic retrograde cholangiopancreatography and endoscopic
sphincterotomy versus conservative treatment for acute pancreatitis due
to gallstones. Lancet 1988; 2(8618): 979–83.
12. Fan S-T, Lai ECS, Mok FPT, et al. Early treatment of acute biliary pancre-
atitis by endoscopic papillotomy. New Engl J Med 1993; 328(4): 228–32.
13. Folsch UR, Nitsche R, Ludtke R, Hilgers RA, Creutzfeldt W. Early ERCP
and papillotomy compared with conservative treatment for acute biliary
pancreatitis. New Engl J Med 1997; 336(4): 237–42.
14. Petrov MS, van Santvoort HC, Besselink MG, et al. Early endoscopic ret-
rograde cholangiopancreatography versus conservative management in
acute biliary pancreatitis without cholangitis: a meta-analysis of random-
ized trials. Ann Surg 2008; 247(2): 250–7.
15. Pederzoli P, Bassi C, Vesentini S, Campedelli A. A randomized multicenter
clinical trial of antibiotic prophylaxis of septic complications in acute
necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993;
176(5): 480–3.
16. Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic treatment
in acute necrotising pancreatitis. Lancet 1995; 346: 663–7.
17. Dellinger EP, Tellado, J.M., Soto N.E., et al Early antibiotic treatment for
severe acute necrotising pancreatitis: randomised double blind placebo
controlled study. Ann Surg 2007; 245(5), 684–5.
18. Isenmann R, Runzi M, Kron M, Kahl S, Kraus D, Jung N, et al. Prophylac-
tic antibiotic treatment in patients with predicted severe acute pancreati-
tis: a placebo-controlled, double-blind trial. Gastroenterology 2004;
126(4): 997–1004.
19. Bai Y, Gao J, Zou DW, Li ZS. Prophylactic antibiotics cannot reduce
infected pancreatic necrosis and mortality in acute necrotizing pancreati-
tis: evidence from a meta-analysis of randomized controlled trials. Am J
Gastroenterol 2008; 103(1): 104–10.
20. Meir J., Luque-de Leon E, Castillo A, Robledo F, Blanco R. Early versus late
necrosectomy in severe necrotising pancreatitis. Am J Surg 1997; 173: 71–5.
21. Al Bahrani AZ, Abid GH, Holt A, McCloy RF, Benson J, Eddleston J et al.
Clinical relevance of intra-abdominal hypertension in patients with
severe acute pancreatitis. Pancreas 2008; 36(1): 39–43.
22. Zhang WF, Ni YL, Cai L, et al. Intra-abdominal pressure monitoring in
predicting outcome of patients with severe acute pancreatitis. Hepatobili-
ary Pancreat Dis Int 2007; 6(4): 420–3.
23. Kalfarentzos F, Kehagias J, Mead N, Kokkinis K, Gogos, CA. Enteral nutri-
tion is superior to parenteral nutrition in severe acute pancreatitis: results
of a randomized prospective trial. Br J Surg 1997; 84(12): 1665–9.
24. McClave SA, Greene LM, Snider HL, et al. Comparison of the safety of
early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN:
J Parenter Enteral Nutr 1997; 21(1): 14–20.
25. Nakad A, Piessevaux H, Marot J-C, et al. Is early enteral nutrition in acute
pancreatitis dangerous? About 20 patients fed by an endoscopically placed
nasogastrojejunal tube. Pancreas 1998; 17(2): 187–93.
26. Abou-Assi S, Craig K, O’Keefe SJ. Hypocaloric jejunal feeding is better
than total parenteral nutrition in acute pancreatitis: results of a random-
ized comparative study. Am J Gastroenterol 2002; 97: 2255–62.
27. Eatock FC, Chong P, Menezes N, et al. A randomized study of early naso-
gastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gas-
troenterol 2005; 100(2): 432–9.
28. Eckerwall GE, Axelsson JB, Andersson RG. Early nasogastric feeding in
predicted severe acute pancreatitis: a clinical, randomized study. Ann Surg
2006; 244(6): 959–65.
29. Kumar A, Singh N, Prakash S, Saraya A, Joshi YK. Early enteral nutrition
in severe acute pancreatitis: a prospective randomized controlled trial
comparing nasojejunal and nasogastric routes. J Clin Gastroenterol 2006;
40(5): 431–4.
30. Windsor ACJ, Li A, Barnes E, et al. Feeding the gut in acute pancreatitis: a
randomised trial of enteral vs parenteral nutrition. Br J Surg 1996;
83(Suppl. 1): 31.
31. Windsor ACJ, Kanwar S, Li AGK, et al. Compared with parenteral nutri-
tion, enteral feeding attenuates the acute phase response and improves
disease severity in acute pancreatitis. Gut 1998; 42(3): 431–5.
32. Pearce CB, Sadek SA, Walters AM, et al. A double-blind, randomised, con-
trolled trial to study the effects of an enteral feed supplemented with glu-
tamine, arginine, and omega-3 fatty acid in predicted acute severe
pancreatitis. JOP 2006; 7(4): 361–71.
33. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis
in predicted severe acute pancreatitis: a randomised, double-blind,
placebo-controlled trial. Lancet 2008; 371(9613): 651–9.
34. Imrie CW, McKay AJ, Neill JO. Short duration megadosage IV Trasylol in
primary acute pancreatitis – a double-blind trial. Gut 1980; 21(5): 431–5.
35. Pederzoli P, Cavallini G, Falconi M, Bassi C. Gabexate mesilate vs apro-
tinin in human acute pancreatitis (GA.ME.P.A.): a prospective, random-
ized, double-blind multicenter study. Int J Pancreatol 1993; 14(2): 117–24.
36. Andriulli A, Leandro G, Clemente R, et al. Meta-analysis of somatostatin,
octreotide and gabexate mesilate in the therapy of acute pancreatitis.
Aliment Pharmacol Ther 1998; 12(3): 237–45.
37. McKay C, Baxter J, Imrie C. A randomized, controlled trial of octreotide
in the management of patients with acute pancreatitis. Int J Pancreatol
1997; 21(1): 13–9.
38. Uhl W, Buchler MW, Malfertheiner P, et al. A randomised double blind
multicentre trial of octreotide in moderate to severe acute pancreatitis.
Gut 1999; 45: 97–104.
39. McKay CJ, Curran F, Sharples C, Baxter JN, Imrie CW. Prospective
placebo-controlled randomized trial of lexipafant in predicted severe
acute pancreatitis. British J Surg 1997; 84(9): 1239–43.
40. Rau B, Pralle U, Mayer JM, Beger HG. Role of ultrasonographically guided
fine-needle aspiration cytology in the diagnosis of infected pancreatic
necrosis. British J Surg 1998; 85(2): 179–84.
41. Carter R. Percutaneous management of necrotizing pancreatitis. HPB
(Oxford) 2007; 9(3): 235–9.
42. Bradley EL III. A fifteen year experience with open drainage for infected
pancreatic necrosis. Surg Gynaecol Obstet 1993; 177: 215–22.
43. Rau B, Bothe A, Beger HG. Surgical treatment of necrotizing pancreatitis
by necrosectomy and closed lavage: changing patient characteristics and
outcome in a 19-year, single-center series. Surgery 2005; 138(1): 28–39.
44. Fernandez-Del CC, Rattner DW, Makary MA, et al. Debridement and
closed packing for the treatment of necrotizing pancreatitis. Ann Surg
1998; 228(5): 676–84.
45. Bradley EL. Operative vs. Nonoperative therapy in necrotizing pancreati-
tis. Digestion 1999; 60(Suppl 1): 19–21.
46. Buchler MW, Gloor B, Muller CA, et al. Acute necrotizing pancreatitis:
treatment strategy according to the status of infection. Ann Surg 2000;
232(5): 619–26.
47. Gotzinger P, Sautner T, Kriwanek S, et al. Surgical treatment for severe
acute pancreatitis: extent and surgical control of necrosis determine
outcome. World J Surg 2002; 26(4): 474–8.
48. Freeny PC, Hauptmann E, Althaus SJ, Traverso LW, Sinanan. Percutane-
ous CT-guided catheter drainage of infected acute necrotizing pancreatitis:
Techniques and results. AJR 1998; 170(4): 969–75.
49. Gouzi JL, Bloom E, Julio C, et al. Percutaneous drainage of infected pan-
creatic necrosis: an alternative to surgery. Chirurgie 1999; 124(1): 31–7.
50. Baril NB, Ralls PW, Wren SM, et al. Does an infected peripancreatic fluid
collection or abscess mandate operation? Ann Surg 2000; 231(3): 361–7.
51. Olah A, Belagyi T, Bartek P, Poharnok L, Romics L Jr. Alternative treat-
ment modalities of infected pancreatic necrosis. Hepatogastroenterology
2006; 53(70): 603–7.
52. Lee JK, Kwak KK, Park JK, et al. The efficacy of nonsurgical treatment of
infected pancreatic necrosis. Pancreas 2007; 34(4): 399–404.
53. Bruennler T, Langgartner J, Lang S, et al. Outcome of patients with acute,
necrotizing pancreatitis requiring drainage-does drainage size matter?
World J Gastroenterol 2008; 14(5): 725–30.
449
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
54. Szentkereszty Z, Kotan R, Posan J, Arkossy P, Sapy P. Therapeutic tactics in
the treatment of acute necrotizing pancreatitis. Hepatogastroenterology
2008; 55(81): 266–9.
55. Seifert H, Faust D, Schmitt T, et al. Transmural drainage of cystic peripan-
creatic lesions with a new large-channel echo endoscope. Endoscopy 2001
Dec; 33(12): 1022–6.
56. Park JJ, Kim SS, Koo YS, et al. Definitive treatment of pancreatic abscess by
endoscopic transmural drainage. Gastrointest Endosc 2002; 55(2): 256–62.
57. Seewald S, Groth S, Omar S, et al. Aggressive endoscopic therapy for pan-
creatic necrosis and pancreatic abscess: a new safe and effective treatment
algorithm. Gastrointest Endosc 2005; 62(1): 92–100.
58. Charnley RM, Lochan R, Gray H,et al. Endoscopic necrosectomy as
primary therapy in the management of infected pancreatic necrosis.
Endoscopy 2006; 38(9): 925–8.
59. Risse O, Auguste T, Delannoy P, et al. Percutaneous video-assisted necro-
sectomy for infected pancreatic necrosis. Gastroenterol Clin Biol 2004;
28(10 Pt 1): 868–71.
60. Connor S, Alexakis N, Raraty MG, et al. Early and late complications after
pancreatic necrosectomy. Surgery 2005; 137(5): 499–505.
450
61. Mui LM, Wong SK, Ng EK, Chan AC, Chung SC. Combined sinus tract
endoscopy and endoscopic retrograde cholangiopancreatography in man-
agement of pancreatic necrosis and abscess. Surg Endosc 2005; 19(3): 393–7.
62. Shelat VG, Diddapur RK. Minimally invasive retroperitoneal pancreatic
necrosectomy in necrotising pancreatitis. Singapore Med J 2007; 48(8):
e220–3.
63. Fagniez PL, Rotman N, Kracht M Direct retroperitoneal approach to
necrosis in severe acute pancreatitis. Br J Surg 1989; 76: 264–7.
64. Gambiez LP, Denimal FA, Porte HL, et al. Retroperitoneal approach and
endoscopic management of peripancreatic necrosis collections. Arch Surg
1998; 133(1): 66–72.
65. Horvath KD, Kao LS, Ali A, et al. Laparoscopic assisted percutaneous
drainage of infected pancreatic necrosis. Surg Endosc 2001; 15(7):
677–82.
66. Besselink MG, de Bruijn MT, Rutten JP, et al. Surgical intervention in
patients with necrotizing pancreatitis. Br J Surg 2006; 93(5): 593–9.
67. van Santvoort HC, Besselink MG, Horvath KD, et al. Videoscopic assisted
retroperitoneal debridement in infected necrotizing pancreatitis. HPB
(Oxford) 2007; 9(2): 156–9.
48 Chronic pancreatitis
Jakob R. Izbicki, OliverMann, Asad Kutup, and Kai A. Bachmann
introduction
Chronic pancreatitis (CP) is a common disorder of the gastro-
intestinal tract with enormous social and personal impact. The
prevalence of CP is 10 to 30 per 100,000 population and it
affects about eight new patients per 100,000 population per
year in the United States (1–3). Autopsy series, however, suggest
a higher prevalence of 0.04% to 5%. CP is an inflammatory
disease characterized by the progressive conversion of pancre-
atic parenchyma to fibrous tissue. The most frequent causes are
excessive alcohol consumption, cholelithiasis, autoimmune or
individual genetic predisposition, and anatomic variants such
as pancreas divisum.
In up to 20% of the patients the reasons or predisposing
factors are not identifiable. The peak of presentation of the
disease occurs in patients between 35 and 55 years of age (4).
Abdominal pain is the main symptom of CP leading to
inability to work, early retirement, and addiction to analgesics.
Severe pain attacks are the leading causes for hospitalization.
The natural course is characterized by a consecutive loss of
pancreatic parenchyma by fibrosis leading to exocrine insuf-
ficiency with maldigestion and finally in advanced stages
endocrine insufficiency.
The clinical course and histological morphological changes
that characterize the disease are extremely variable. Overall the
life expectancy is shortened by 10 to 20 years. The mortality is
increased 3.6-fold, as compared with a population without
CP (2). The annual treatment costs are approximately $17,000
per patient (2). Due to improvements in the treatment 20% to
50% of the patients live more than 20 years with chronic
inflammation of the pancreas (5,6).
Besides pain, exocrine and endocrine malfunction, mechanical
complications occur such as stricture of the bile duct, duodenal
stenosis (7), or the formation of pancreatic pseudocysts. The
process of continuing organ destruction cannot be interrupted
by abstinence from alcohol consumption, which seems to be
the causative agent in most cases. Despite thousands of reports
that have been published in the last decades dealing with this
disease, pathogenesis and pathophysiology of CP are poorly
understood and the clinical course is unpredictable. Therefore
adequate treatment of CP and its complications remain a
major challenge (8,9).
definition of cp
The classification of CP as a separate disease was described in
1946 by Comfort et al. (10). Before, the term CP has been used
for a variety of pancreatic diseases without a generally
accepted definition (11,12). Since then, different classifica-
tions of CP have been presented. According to the Marseille
Classification, CP is characterized by histological changes
persisting after the etiologic agent has been removed (13).
The Cambridge Classification (1983) defined CP as an
ongoing inflammatory disease characterized by irreversible
structural changes associated with abdominal pain and per-
manent loss of function.
In the Marseille–Rome classification of 1988, obstructive CP,
chronic inflammatory pancreatitis (with loss of exocrine paren-
chyma and replacement by fibrosis), and the chronic calcify-
ing pancreatitis were described. Recently a new classification
of CP has been suggested: probable CP is characterized by a
typical history and one or more of the following criteria: recur-
rent or persistent pseudocysts, ductal alterations, endocrine
insufficiency (abnormal glucose tolerance test), or pathological
secretin test.
Definite CP is characterized by typical history and at least
one of the following criteria: typical histology of an adequate
surgical specimen, moderate or marked ductal alterations,
pancreatic calcification, marked exocrine insufficiency defined
as steatorrhea, normalized or markedly reduced enzyme
substitution (14).
natural course of cp
In the past the main rationale for conservative approaches
derives from the assumption, that most patients with long-
standing CP will become pain free due to a progressive
“burning out” of the organ (15). Recently it was shown that
the natural course of CP is characterized by progressive loss
of pancreatic function by fibrosis of the parenchyma with
consecutive endocrine and exocrine insufficiency supple-
mentary to pain (12,16,17). After an initial period without
noticeable pain, the disease progresses into the next stage
characterized by pain and exocrine, later endocrine insuffi-
ciency. In the third stage the burn-out pancreas with global
insufficiency is found, and pain might subside. The pancre-
atic parenchyma is irreversibly converted to fibrous tissue
with diabetes and steatorrhea (18).
At time of onset of CP 8% of the patient had a at least moder-
ate endocrine insufficiency, whereas in long-term follow-up
approximately 80% had endocrine insufficiency (19,20). Studies
revealed that it takes 10 to 20 years of a progressive inflamma-
tory process to lead to exocrine insufficiency by destroying the
pancreatic parenchyma (21). Ten years after onset of CP, 50%
to 93% of the patients with CP were still suffering from
abdominal pain (17,20–22). At least 50% to 68% of the patients
with CP need surgery for management of complications or for
intractable pain (5,23).
Reduction of alcohol intake did not influence the course of
pain in chronic alcoholic pancreatitis, but continued alcohol
abuse was associated with significantly lower survival rates
(24,25). Patients that quit drinking showed improvement in
exocrine function (20,24). Endocrine insufficiency did not
alter the course of pain. For the individual patient the course
of the disease is unpredictable (20,25).
451
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
etiology pathomorphological
findings in cp
Long-term alcohol intake is associated with an increased risk
of developing CP. High caloric intake of protein and fat, smok-
ing, and lack of vitamins and trace elements have been
described as additional, predisposing risk factors (12).
Ammann and colleagues suggested that acute pancreatitis and
chronic alcoholic pancreatitis are different stages of the same
disease (17,24). CP represents the remaining damage after epi-
sodes of severe acute pancreatitis (26,27). Alcohol consump-
tion is the leading cause of CP in western countries (70–90%)
(2,4,11,14). The acinar cells are directly damaged by alcohol. A
change in microcirculatory perfusion and alterations of the
epithelial permeability lead to an imbalance in the pancreatic
juice or decreased fluids or bicarbonate secretion. Parenchymal
necrosis with hemorrhage of the pancreas may induce peril-
obular fibrosis that leads to intralobular fibrosis, ductal
obstruction, and periductal inflammation. Altered amounts of
lithostatin in the pancreatic juice can lead to formation of the
protein plugs and stones in ducts and ductuli (11,27,28).
Pathomorphological findings in CP such as inflammatory
infiltration of the pancreatic tissue, fibrosis, atrophy of the acinar
cells, calcifications, pancreatic duct stricture, and pseudocysts
can be found isolated, segmental, or diffuse throughout the
whole organ (11,12,27,28). Histomorphologically different
forms of CP can be distinguished.
The most common form, the calcifying CP is characterized
by recurrent bouts of clinically acute pancreatitis with abdom-
inal pain and development of intraductal calculi, protein
plugs, and parenchyma calcifications (2,12). Radiographically
(ERCP) these impose as chain of lakes. These alterations of
various degrees in different stages of the disease lead to pan-
creatic duct stenosis and consecutively to prestenotic dilata-
tions. Additionally epithelial alterations, inflammatory
periductal infiltrations, parenchymal atrophy, necrosis, and
fibrosis can be found (12,18,26,27,29,30).
Obstructive CP is often painless and caused by blockage of
the main pancreatic duct due to tumor or an inflammatory
process (post-acute pancreatitis) that leads to an atrophy of
the pancreatic tissue and a prestenotic dilatation. No alteration
of the ductal epithelium is found (12,18,26,30). Pancreatic
duct stones are uncommon. Periductal fibrosis and inflamma-
tory infiltration are mainly found around the larger ducts and
in the pancreatic head. Diffuse fibrotic changes occur through-
out the organ without lobular topography. Pancreatic main
duct stenosis may be caused by papillary stenosis (tumor) or
inflammation, duodenal diverticula, pancreatic tumors, con-
genital or acquired duct abnormalities (pancreas divisum), or
rarely by traumatic pancreatic duct injuries. Small duct pan-
creatitis is an extremely rare form of CP that is defined as a
throughout fibrous, inflammatory tissue with a main duct
diameter of ≤ 3 mm, (31) .
The autoimmune pancreatitis is characterized by the absence
of typical risk factors for developing CP or hereditary factors.
In the past this subtype was named primary inflammatory scle-
rosis of the pancreas, non-alcoholic duct destructive pancreati-
tis, or lymphoplasmacytic sclerosing pancreatitis (17,18,32).
The term autoimmune pancreatitis was introduced by Yoshida
452
and colleagues in 1995 (33). Autoimmune pancreatitis can present
with focal event or with multiple lesions. Pseudocysts and calculi
are rarely found. Four histological features are characteristic for
autoimmune pancreatitis. Lymphoplasmacytic infiltration,
consisting of lymphocytes and plasma cells (often with high
level of IgG4), macrophages, neutrophils, and eosinophils,
result in an intestinal fibrosis (34). Additionally periductal
inflammation and periphlebitis can lead to luminal strictures
or obliterative venulitis, respectively. Obstructive jaundice is
caused by an affection of the common bile duct (CBD) which
may extend to the gallbladder and biliary tree. An increased
level of IgG4 is a sensitive marker (35). Autoimmune pancreati-
tis is associated with other autoimmune disorders such as
ulcerative colitis, Cohn’s disease, primary sclerosing cholangitis,
Sjörgren’s syndrome, lymphocytic thyroiditis, and primary
biliary cirrhosis (36).
Hereditary CP is a rare form with an incidence of approxi-
mate 3.5 to 10 per 100,000 inhabitants (3,37). The morphologic
findings in HCP are irregular sclerosis with focal, segmental, or
diffuse destruction of the parenchyma. Different mutations
have been detected to be associated with hereditary CP, most
common R122H, an N291 mutation of the PRSS1 gene, and
mutations of the CFTR and SPINK1 gene (36,38–40). The risk
of developing pancreatic cancer is increased in HCP with
PRSS1 mutation as compared with normal population and
chronic alcoholic pancreatitis (41,42).
Rare reasons for CP besides pancreatic duct obstruction due
to tumors, strictures, diverticula, and pathoanatomical varia-
tions like pancreas divisum or annular pancreas are trauma
and genetic mutation (14). In up to 20% of the patients the
reason for CP remains unclear.
pathogenesis of pain in cp
Pain is the cardinal symptom in patients with CP. Together
with the often ongoing consumption of alcohol it is most dif-
ficultly to treat. The permanent pain reduces the quality of life,
leads to addiction of analgesics, and unemployment or early
retirement.
CP cannot be cured; therefore the aim of treatment is directed
against symptoms (e.g. pain) and complications. Pain in CP is
still only fragmentarily understood and a multifactorial nature
is assumed, including inflammation, duct obstruction, high
pancreatic tissue pressure, fibrotic encasement of sensory
nerves, and a neuropathy characterized by both increased
numbers and sizes of intrapancreatic sensory nerves and by
inflammatory injury to the nerve sheaths allowing exposure of
the neural elements to toxic substances. The pain is often
localized in the upper part of the abdomen and is frequently
nocturnal; sometimes it radiates to the back. Development of
pain in the course of the disease is seen in 85% of the patients
(43). It is described to be deep, penetrating, and debilitating
and may increase after eating (44). In the initial stage of the
disease the pain is intermittent and recurrent; later it is persis-
tent. The painless pancreatitis is found rarely in alcohol-
induced pancreatitis (<10%), while pain-free periods are seen
in late-onset idiopathic pancreatitis. Pain pattern and histo-
pathologic/radiologic findings have to be correlated in con-
sideration of therapy especially surgery. Histological picture
 CHRONIC PANCREATITIS
and diameter of the main pancreatic duct in CT scan,
MRI/MRCP, and ERCP are necessary for optimal planning of
the operation. Small duct disease requires other procedures
compared to obstruction of the main pancreatic duct and
inflammatory mass in the pancreatic head. The assessment of
pain is very difficult. Most trials in CP use classifications for
description of pre- and postoperative pain or outcome, such as
excellent (no pain), good (better), fair (nil), poor (worse) (45),
therefore no comparison between different trials is possible.
Pain relief is more common in patients that quit drinking. The
underlying mechanism for pain in CP is poorly understood.
Different concepts have been hypothesized, but none of them
can completely explain the pain in this disease. Present hypoth-
eses include increased pressure on the ductal system and
parenchyma by obstruction, neuritis, ischemia of the pancreatic
tissue and intra- and extrapancreatic causes such as pseudocysts
and CBDs or duodenal stenosis. The impact of the mentioned
factors for the pathogenesis of the pain remains unclear and
may vary between the patients. A higher intraductal pressure
was measured in patients with CP compared to controls (46).
The reason for increased pressure can be postinflammatory
scarring of the pancreatic (main and side) ducts, pancreatic
duct stones or strictures, or hemosuccus pancreaticus that
leads to obstruction. Other reasons are pancreatic abscess,
ascites, bile duct stenosis, or duodenal stenosis. The patients
that were found to have a reduced intraductal pressure had a
better pain relief compared to patients with higher intra-
ductal pressure in the follow-up (46,47). Additionally it had
been reported that phenotypic modification of primary sen-
sory neurons may play a role in production of persisting pain
(48). Focal release and uptake of mediators in the peptidergic
nerves were changed by initial pancreatic inflammation. Pre-
vious trials revealed that number and diameter of the pancre-
atic nerves, as well as activity are significantly increased in CP
(49,50). A correlation between pain and expression of growth-
associated protein (43) and level of methionine–enkephalin
was detected (50). It is hypothesized that the increases in pres-
sure facilitate the intox of pain mediators into the nerves and
result in a neuritis and therefore causing the pain in CP.
Another hypothesis is that pancreatic ischemia is responsible
for the pain. The ischemia activates the xanthine oxygenase,
leading to the production of toxic oxygen metabolites. An
increased level of cytochrome P450 in CP was found in several
trials (51,52), but treatment with an inhibitor of the xanthine
oxygenase did not reduce the pain.
complications of cp
In the course of CP, several complications with less or more
life-threatening potential may occur. In 12% of the patients
that underwent surgery for CP, duodenal obstruction was
detected; additionally it was found to be associated with CBD
stenosis (53). Duodenal obstruction can also occur secondarily
to pancreatic pseudocysts (54). The patients typically suffer
from nausea, vomiting, upper abdominal pain, and weight
loss. If duodenal obstruction does not resolve within 1 to
2 weeks of conservative therapy, an irreversible duodenal
obstruction should be considered and therefore interventional/
surgical treatment is indicated.
Causal for the development of CBD stenosis is the close
anatomical relationship of the distal common to the head of
the pancreas; hereby the risk of CBD stricture is increased in
patients with enlarged pancreatic head. In patients with CP bile
duct stricture is found in 5% to 9% and in up to 35% after surgi-
cal procedures for CP (55–58). Patients with CBD stricture can
present asymptomatic with elevated liver enzymes, alkaline
phosphatase, or bilirubin or being septic with cholangitis. In
patients with CBD strictures secondary to CP interventional,
i.e., surgical therapy is indicated. Ruling out a local malignancy
is of greatest importance in patients with duodenal or CBD
obstruction.
Pancreatic ascites is found in approximately 4% of patients
with CP and in 6% to 14% of those with pancreatic pseudocysts
and is defined as massive accumulation of pancreatic fluid in
the peritoneal cavity. The level of amylase in the ascitic fluid is
typically above 1000 IU/L and the ascitic fluid to serum amy-
lase ratio is approximately 6.0 (59,60). In those patients an
endoscopic retrograde pancreatography (ERCP) should be
performed to localize the site of leakage and to perform endo-
scopic stenting of the leak (61). Additional treatment with
somatostatin or octreotide together with diuretics and repeated
paracentesis may be beneficial for some patients (62,63). In
patients with persistent or recurrent accumulation of ascites
and/or sudden deterioration of clinical status surgery is
indicated (64).
Pancreaticopleural fistulas, result from a disruption of the
pancreatic duct or leakage from a pseudocyst, are rare, but
associated with a significant morbidity and mortality (65,66).
Three main types of thoracic manifestations include mediasti-
nal pseudocysts, pancreaticopleural fistulas, and pancreatico-
bronchial fistulas (67,68). Once a pancreaticopleural fistula is
suspected, the concentration of amylase in the pleural effusion
should be measured. Conservative treatment has an efficacy of
30% to 60%, a recurrence rate of 15%, and a mortality rate of
12% (69). If conservative therapy fails, endoscopic shincter-
otomy or stenting and surgical procedures should be consid-
ered aiming to reduce the hypertension intraductal or within
pseudocyst, because the hypertension inhibits the spontaneous
closure of fistula.
Extrahepatic portal hypertension is a less common compli-
cation of CP; it may be confined to either the superior mesen-
teric or the splenic venous branch or may involve the whole
splenomesentericoportal axis (70). It is defined as extrahepatic
hypertension of the portal venous system in the absence of liver
cirrhosis. The pathogenesis of extrahepatic portal hypertension
in CP may include several factors. The inflammatory process is
capable of causing initial damage to vascular walls and gener-
ating venous spasm, venous stasis, and thrombosis (71).
A fibrosis of the pancreas can lead to progressive constriction
of the splenomesentericoportal axis. Other reasons are consid-
erable pancreatic head enlargement or compression by pan-
creatic pseudocysts or inflammatory swelling of the gland
(72,73). At present an extrahepatic portal hypertension per se
seems not to be an indication for surgical intervention in CP,
because there was no evidence of hemorrhage (74) even
though a potential risk of esophageal or gastric varices exists (75).
Additionally it has to be mentioned that those patients have a
453
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
considerable increased surgical risk. If the varices start to
bleed, therapeutic options include interventional measures
such as sclerotherapy, variceal ligation, and interventional
(TIPSS) or surgical portosystemic shunting procedures
(72,76). In patients with thrombosis of the portal vein with
cavernous transformation, a trans-section of the pancreatic
parenchyma above the portal vein as required for the Beger
procedure and pancreatoduodenectomy should be avoided by
all means as this carries unpredictable risks.
conservative and interventional
treatment of cp
The treatment of CP and its complications remain a major
challenge (11). The most distressing symptom is intractable
pain with consecutive abuse of analgesics. Medical therapies
such as abstinence from alcohol, dietary alterations, analgesics
(such as non-steroidal anti-inflammatory drugs, paracetamol,
prednisolone, dextropropoxiphene, and tricylic antidepres-
siva and later on opioids), oral enzyme supplements, and
somatostatin analoga offer improvement of the symptoms for
some patients. However, abstaining from excessive alcohol
consumption does not interrupt the progression of organ
destruction, exocrine and endocrine insufficiency, and the
presence of pain (8,17).
Therefore different interventional techniques have been
presented for management of CP and especially the pain
associated with the disease. Endoscopic treatment in patients
with CP was established in the last decades. The aim of this
intervention is to alleviate outflow obstructions of the pan-
creatic duct and the CBD (16). Endoscopy has its established
role in the management of pancreatic complications, espe-
cially drainage of pancreatic pseudocysts by cystic-enteric
drainage. Additionally percutaneous catheter drainage is
available as a temporizing measure in poor surgical patients
with complicated or infected pancreatic pseudocysts. For
pain control, endosonography guided or percutaneous celiac
nerve block with alcohol or steroids and thoracoscopic
splanchnicectomy have been described. Pain relief and rate of
responders range from 20% to 87%, but the data on the
results are rare. No prospective randomized trial is available
at present. However, it was pointed out, that this is a symp-
tomatic therapy (16). These procedures can be repeated as
needed, but they are associated with severe complications and
symptoms and usually recurrence of pain after a few months.
The rate of CP-associated complications such as pseudocysts
or progression of endocrine and exocrine insufficiency is not
improved. Up to 60% of the patients with CP have pancreatic
duct stones, which cause an obstruction and consecutively an
increase of the intraductal pressure. This can lead to hyper-
tension and ischemia, causing the pain attacks. Many patients
are asymptomatic though they have proven duct stones.
Extracorporal shockwave lithotripsy (ESWL) can be used in
painful, chronic, calcified pancreatitis. The median delay to
pain relief was 1.1 years, but 38% had pain relapse after
2 years. With a combination of ESWL and endoscopy (sphinc-
terotomy and fragment extraction after ESWL), the rate
increased to 45%. The mortality was 0, and the morbidity in
the endoscopy group was 3% (77).
454
Different endoscopic procedures have been used in treatment
of CP including sphincterotomy, endoscopic stone extraction
(in some trial combined with ESWL), and stenting of the
pancreatic duct.
Endoscopic pancreatic sphincterotomy in CP is technically
challenging. Indications are sphincter oddi dysfunction or
papillary stenosis/stricture. Another indication is to gain better
access to the pancreatic duct for dilatation, transpapillary
drainage, and stenting. The overall response rate was found to
be 55% to 95%, in a follow-up an improvement of pain was
found to be 60% after 14 months (78). Using the endoscopic
stenting with changes on regularly base, a complete pain relief
was found in 45% to 95% of the patients. Early complications
(pancreatitis, cholangitis) occurred in 10% to 15% and late
complications (strictures, ductal changes) in 10% to 30% of the
patients (79). In endoscopic stenting the rate of complications
was 32%, the initial pain relieve was 89% (80). In an other
small trial stenting was performed in 25 patients with low
morbidity (8–10%) and good results in 80% after 13 months
(81). In another trial pain control was achieved after stenting
in 70% in 12-month follow-up and 62% of the patients in
27-month follow-up; the morbidity was 25% overall (82).
Therefore endoscopic stenting plays a role in patients who are
unfit for surgery, but it is not recommended as definitive ther-
apy, particularly with regard to the necessity of repeated endo-
scopic interventions due to infection, stent displacement, or
stent occlusion (83,84).
A randomized controlled trial (n = 39) recently found that
patients who underwent pancreatojejunostomy (Partington–
Rochelle) had a better quality of life and better pain relief
(pain score 53 ± 21 vs. 25 ± 15) as compared to endoscopic
drainage procedures in patients without pathology of the
pancreatic head (85).
Exocrine insufficiency, mortality, and rate of complications
showed no significant differences. Since the inclusion criteria in
this trial were obstruction of the pancreatic duct but without
inflammatory mass (enlargement <4 cm), these results should be
even more true in patients suffering from inflammatory tumor
of the pancreatic head with potential organ complications such
as stenosis of the CBD and duodenal outlet obstruction (85).
In a previous trial including 72 patients comparing endos-
copy and surgery a significant advantage of the surgical group
was found in a 5-year follow-up with a rate of complete pain
relief of 33.8% compared to 15% after endoscopy. The rate of
new-onset diabetes mellitus did not show significant differ-
ences while patients in the surgical group had a higher increase
of the body weight (47.2% vs. 28.6%) (86). It is mandatory that
a good selection of patients in that endoscopic treatment for
pain relief can be considered, but endoscopy has an important
role in management of complications of CP.
indications for surgical intervention
The primary therapy for CP is conservative, symptom-related
treatment.
Surgery should be considered in patients with failure of con-
servative and endoscopic interventions. Established indication
for surgery are intractable pain, complications related to adja-
cent organs, suspicion of neoplasm, non-resolving stenosis of
 CHRONIC PANCREATITIS

duodenum or CBD, intractable pain, pseudoaneurysm, or
vascular erosion that cannot be controlled by radiological
intervention, large pancreatic pseudocysts that cannot be endo-
scopically controlled, especially in conjunction with ductal
pathology, and neither conservatively nor interventionally
tractable internal pancreatic fistula (8,9,87–89).
The indication for surgical interventions in CP has seen its
ups and downs over the last decades. Due to optimized surgical
procedures, improvements in intensive care and in selection of
the patients, the perioperative risk was reduced and the out-
come has improved. In preoperative diagnostic it is a major
challenge to differentiate a malignant tumor from an inflam-
matory mass in the pancreatic head (2). For sufficient histo-
pathological examination it is necessary to provide an adequate
specimen to exclude malignancy; only resections or limited
resections and extended drainage procedures can provide this
(8). In approximately 10% of the patients with pancreatic car-
cinoma even in experienced centers the initial diagnose of
malignancy is based on the histological specimen at the time of
operation. An optimal surgical intervention should manage the
problems and complications of the CP (Fig. 48.1). Additionally
it should guarantee a low relapse rate, preserve a maximum of
endocrine and exocrine function, and most importantly,
restore quality of life (8).
rationale for drainage procedures
Up to 60% of the patients with CP present with ductal ectasia
that may arouse suspicion of intraductal hypertension
(8,88,90,91). Therefore decompression of the pancreatic head
by drainage has become a major procedure. At the turn of the
19th century the operative removal of pancreatic stones was
described (92,93). The rationale for this operative interven-
tion was an alleviation of pain and prevention of pancreatic
atrophy (93). Coffey (94) and Link (95) were the first to
describe the drainage of the pancreas with bypass by opening
the pancreatic main duct.
The groups of DuVal (96) and Zollinger (97) independently
performed the decompression of the main pancreatic duct by
resection of the pancreatic tail and retrograde drainage of the
pancreatic duct via a termino-terminal or termino-lateral
pancreaticojejunostomy.
A new drainage procedure was described by Puestow and
Gillesby in 1956 (98). Decompression of the main pancreatic duct
was performed by a longitudinal latero-lateral pancreaticojeju-
nostomy after resection of the pancreatic tail and splenectomy. A
modification of the Puestow–Gillesby procedure, performing a
spleen-preserving longitudinal pancreaticojejunostomy without
pancreatic tail resection, was introduced by Partington and
Rochelle (99).
The procedure described by DuVal (96) and Zollinger (97)
proved to be effective only if there was a single dominant
obstruction between pancreatic tail and the ampulla of Vater. A
single dominant stricture is found rarely, especially in chronic
alcohol-induced pancreatitis, which is common among the
majority of patients in the western hemisphere. It has to be men-
tioned that recurrent episodes of severe pain were frequently
observed even after sufficient drainage of the duct system.
For many years the longitudinal pancreaticojejunostomy
introduced by Partington–Rochelle was favored in surgical
treatment of CP. Even in the presence of multiple strictures
(“chain of lakes”) the main pancreatic duct could be effectively
drained. No resection is included in this procedure, therefore
it was associated with lower perioperative morbidity and mor-
tality compared to resection procedures. The advantages of
simple drainage procedures are the maximal preservation of
pancreatic tissue. Performing drainage procedure, ruling out a
malignancy, is not possible, because no adequate specimen is
available for pathological examination.
Pain relief was found in 80% to 90% of the patients with
non alcohol-induced CP and only 50% to 60% of the patients
with alcohol-induced pancreatitis because the inflammatory
mass in the pancreatic head including its strictures as well as
the local intraductal hypertension of the ducts of second and
third order are left behind (8,91).
In the long-term follow-up the failure rate of drainage
procedure was found to be up to 45%. The reasons were inad-
equate duct decompression, biliary stenosis, and most impor-
tantly inflammatory mass of the pancreatic head. Studies
have shown that drainage procedure can prevent or delay the
loss of pancreatic function.
The rationale for the wide-spread application of drainage
procedures in CP was the considerable morbidity and mortality

Drainage
Cysto(gastro-)jejunostomy
Pancreaticojejunostomy (Partington-Rochelle)
Drainage and resection of pancreatic tail (Puestow-Mercadier)
Left-resection of the pancreas (DuVal)
Extended drainage (limited excision of pancreatic head (Frey)
Duodenum preserving resection of pancreatic head (Beger)
Pylorus-preserving partial duodenopancreatectomy
Partial duodenopancreatectomy (Whipple)
Pancreatectomy
Resection
Figure 48.1 Surgical armamentarium for the treatment of chronic pancreatitis.

455
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
rates of resectional procedures, i.e., partial pancreatoduode-
nectomy in the beginnings of pancreatic surgery. Nowadays
the only suitable indication for a simple drainage procedure
(Partington–Rochelle) with longitudinal pancreaticojejunos-
tomy is in patients with a dilated ductal diameter (>7 mm) or
“chain of lakes,” without an inflammatory mass in the pancreatic
head and a normal ductal system (8,31).
rationale for resectional procedures
Approximately 90% to 95% of the patients suffering from CP
irrespective of the width of the pancreatic duct present with a
pathology in the pancreatic head such as inflammatory mass,
neuronal or proximal duct alterations (75,100,101). Thus, the
head of the pancreas has been referred to as the pacemaker of
the disease and its complications (75,102).
The inflammatory enlargement of the pancreatic head is
found in 30% to 50% of patients with CP, causes an obstruction
of the pancreatic duct and sometimes even obstruction of the
duodenum or CBD or segmental portal hypertension (103).
Besides the mechanical disturbances the pain is thought to be
caused by alteration of the parenchyma and nerve fibers in
quality and quantity.
An inflammatory mass in the pancreatic head is considered
as a contraindication for a simple drainage procedure. The
therapeutic principle of the resection of the pancreatic head is
to eliminate the obstructive mass to drain the entire pancreatic
duct and pancreatic ducts of second or third order. Because
pain is related to hypertension of the duct and parenchyma the
inflammatory mass is resected for achieving pain relieve.
Initial the original Whipple–Kausch Procedure has been
performed, which has been replaced by the pylorus-preserving
pancreatoduodenectomy (PPPD) introduced by Longmire/
Traverso. The two procedures are basically the same except the
preservation of antrum and pylorus resulting in preservation
of the normal gastric function and prevention of biliary reflux
gastritis. The pancreatoduodenectomy is the standard proce-
dure in cancer of the pancreatic head; therefore pancreatic
centers have high experience in this procedure. Comparing
classic Whipple procedure with PPPD in a 5-year follow-up, a
significantly higher rate of pain and nausea and lower quality
of life were found (104).
PPPD is an effective procedure in treatment of CP with
improvement of the quality of life and short- and long-term
pain relief in up to 90% of the patients (105). But the major
disadvantage of the procedure is the sacrifice of the surround-
ing non-diseased organs with loss of the natural bowl continu-
ity. Additionally a significant reduction of pancreatic exocrine
and endocrine function was found. Long-term pain relief is
reported in 66% to 89% after resection of the pancreatic head
(105). After partial pancreatoduodenectomy the periopera-
tive morbidity was found to be 20% to 53% (75,106). Now-
adays the procedure can be performed with low mortality and
adequate morbidity. Resections of the distal part of the pan-
creas are often associated with endocrine insufficiency. They
offer only short pain relief. Therefore this procedure is in
obsolete in treatment of pain. The only suitable indications
are localized severe complications of the pancreatic tail such
as pseudoaneurysm.
456
duodenum-preserving resection
of the pancreatic head
In order to combine the advantages of drainage procedures
and pancreatoduodenectomy the duodenum-preserving
resection was developed. The technique was first described by
Beger in 1980 (107).
The aim of this procedure was the prevention of sacrificing
undiseased organ and achieving optimal control of the symp-
toms of the pancreatitis, especially pain. Due to minimizing the
loss of normal pancreatic tissue this procedure is aiming for a
better pancreatic function (108).
This Beger procedure consists of a subtotal resection of the
pancreatic head following transection of the pancreas above
the portal vein. In CP with an inflammatory tumor of the
pancreatic head, the transection is the most challenging part
of the operation due to displacement or compression of the
mesenterico-portal vein axis (Fig. 48.2).
The body of the pancreas is drained by an end-to-end or
end-to-side pancreatojejunostomy using a Roux-en-Y loop.
The resection cavity is drained by the same jejunal loop drains
by a side to side anastomosis to the rim of the resection cavity
of the pancreatic head.
An other advantage of this procedure is that the gastroduo-
denal passage and CBD continuity may be preserved (102,109).
Extensive resection of the pancreatic head with decompression
of the bile duct and the duodenum will allow adequate man-
agement even in cases of distal CBD stenosis or segmental
duodenal obstruction The identification of the intrapancre-
atic course of the distal bile duct can be facilitated by inser-
tion of a metal probe into the CBD through a proximal
choledochotomy (110).
The Beger procedure provides long-term pain relief in 75%
to 95% of the patients (102,103,106,111–115). The mortality
rate ranges from 0% to 3% in experienced centers
(111,112,116). The morbidity rate was found to be 15% to
32% (75,108,112).
In a randomized trial Berger’s procedure was superior in
terms of pain relief as compared with pylorus-preserving partial
pancreatoduodenectomy (75). No significant differences in pain
relief were found in randomized trails comparing duodenum-
preserving resection and partial pancreatoduodenectomy or
Figure 48.2 Beger procedure.
 CHRONIC PANCREATITIS
pylorus-preserving partial pancreatoduodenectomy after long-
term follow up (117).
A modification of the Beger procedure was presented by
Frey in 1985. The Frey procedure (115,116,118) combines a
longitudinal pancreaticojejunostomy according to Partington
and Rochelle (99) with a local excision of the pancreatic head.
It is marked by leaving a rim of pancreatic tissue across the
portal vein and superior mesenteric vein (Fig. 48.3). Therefore
this operation is easier to learn and perform; additionally only
one pancreatojejunostomy is necessary.
The drainage of the resection cavity of pancreatic head,
body, and tail is performed with a longitudinal pancreatojeju-
nostomy using a Roux-en-Y loop. The Frey procedure can be
performed without mortality (<1%) and low morbidity
(9–39%) (7,106,112). In these patients, 56% were free of pain,
and 32% had substantial pain relief. The main complications are
hemorrhage, pancreatic fistula (0–5%), and intra-abdominal
abscess. After 5 years 78% suffered from exocrine and 60%
from endocrine; 44% were professionally rehabilitated.
By preserving the duodenum, the physiological gastroduo-
denal passage and the continuity of the CBD are sustained.
Additionally exocrine and endocrine pancreatic functions are
preserved and the procedure is able to control complications of
adjacent organs such as CBD stenosis, duodenal stenosis, and
internal pancreatic fistulas comparable to the Beger procedure
(118,119).
The Hamburg procedure is a modification of the Frey pro-
cedure and was proposed by Izbicki and coworkers. The extent
of pancreatic head excision can be modified up to a subtotal
excision including the uncinate process combined with a
longitudinal V-shaped excision of the ventral aspect of the
pancreas into the pancreatic duct (Fig. 48.4). If ductal irregu-
larities are present in the pancreatic body and tail, the operation
can be extended as a drainage operation much in the way of a
Partington–Rochelle procedure into the pancreatic tail.
Therefore the major advantage of this procedure is that the
extent of the resection can be customized to the individual
morphology of the pancreas (113).
In a recently published trial, the mortality and morbidity of
the Hamburg procedure were 0% and 19.6%, respectively;
Figure 48.3 Frey procedure.
89% of the patients were free of pain in the follow-up; the
increase of the body weight was significantly better as compared
with classic PPPD (31).
The Berne procedure is combining the Frey and Beger
procedure (120). A duodenum-preserving resection of the
pancreatic head is performed according to the Beger tech-
nique. Compared to the Frey procedure the extent of the exci-
sion of the pancreatic is much larger and is therefore definitely
decompressing the CBD and preventing a potential recurrence.
According to the Frey procedure the hazardous dissection is
avoided by leaving a small shape of the pancreatic tissue on the
anterior wall of the portal vein (120,121). Performing the Berne
procedure the mortality was found to be 0% and the morbidity
20% (108).
comparison of different surgical
approaches
Recently Müller published the long-term follow-up of an RCT,
comparing Beger and PPPD, that was originally presented by
Büchler 1995 (n = 40). No significant differences were found
in terms of morbidity, mortality, and survival. After 24 months
a significant better gain of body weight was reported after
Beger procedure. Favorable results concerning loss of appetite
could be detected after 14 years. Interestingly the rate of pain-
free patients was significantly higher after Beger (75%) com-
pared to PPPD (40%) in short-term follow-up, while no
significant differences could be detected concerning the pain
score after 14 years. No significant differences were found
comparing new-onset diabetes mellitus, enzyme substitution,
and global health status (75,122).
Additionally Farkas presented the results of a 12-month
follow-up comparing Beger and PPPD in 2006 (n = 40). Sig-
nificant advantages for the Beger procedure were noticed in
terms of operating time (142.5 ± 4.9 vs. 278.5 ± 6.9 min), hos-
pital stay (8.5 ± 0.9 vs. 13.8 ± 3.9 days), morbidity (0% vs.
30%), and increase of body weight (7.8 ± 0.9 vs. 3.2 ± 0.3 kg),
while rates of pain-free patients (86% vs. 83%), mortality, and
diabetes missed significance (123).
The results of a prospective randomized trial comparing
Frey versus PPPD were presented by Izbicki 1998 including a
Figure 48.4 Hamburg procedure.
457
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 48.1 Outcome after Frey procedure and Pylorus Table 48.2 Outcome after Frey procedure and Beger
preserving pancreatoduodenectomy procedure
Pylorus- Beger procedure Frey procedure
preserving
Perioperative mortality 0% 0%
pancreatoduode-
Frey procedure nectomy Perioperative morbidity 32% 22%
30-mo follow-up
Perioperative mortality 3% 0% VAS 12 16
Perioperative morbidity 19% 53% Frequency of pain attacks 0 0
30-mo follow-up Pain medications 0 0
VAS 12 10 Inability to work 0 0
Frequency of pain attacks 12.5 12.5 Pain score 3 4
Pain medications 0 0 8-yr follow-up
Inability to work 0 50 VAS 20 20
Pain score 6.1 18.1 Frequency of pain attacks 25 25
7-yr follow-up Pain medications 0 0
VAS 20 25 Inability to work 0 0
Frequency of Pain attacks 25 25 Pain score 11.25 11.25
Pain medications 0 0 Late mortality 24% 24%
Inability to work 0 0 Late mortality (chronic 3% 6%
Pain score 17.75 18.75
pancreatitis associated)
Late mortality 20% 15% Endocrine insufficiency 56% 60%
Late mortality(chronic 3% 0% Exocrine insufficiency 88% 78%
pancreatitis associated) Reoperation 8% 12%
Endocrine insufficiency 61% 65% Professional rehabilitation 59% 38%
Exocrine insufficiency 86% 96% Source: From Refs. (12,125).
Reoperation 8% 0%
Professional rehabilitation 42% 39%
Source: From Ref. (106,124).

65 patients were treated with other operation compared to

24-month follow-up (n = 61). In terms of morbidity rate the
Frey procedure (19%) was superior to PPPD (53%). Addition-
ally the Quality of Life was significantly higher (85.7 vs. 75.1)
and the pain score better (6.1 vs. 18.1) after Frey procedure. In
the long-term follow-up recently presented by Strate the favor-
able results still exists, but statistical significance is lost. Addition-
ally no difference was found comparing late mortality, rate of
endocrine and exocrine insufficiency, and need of reoperations
(106,124) (Table 48.1).
The only randomized trial comparing Frey and Beger proce-
dure has been published by Izbicki 1995 (n = 42) (112). The
perioperative mortality was 0 in both groups, while the mor-
bidity rate was significantly lower after Frey (9%) compared to
15% after Beger procedure. In the 8-year follow-up published
by Strate 2005 the rate of endocrine and exocrine insufficiency
and rate of reoperation were comparable in both groups. No
significant differences concerning Quality of Life and pain
score were found at short-term and long-term follow-up (125)
(Table 48.2).
Recently a trial comparing Beger versus Berne modification
was published (n = 65). The quality of life measured with the
EORTC QLQ-PAN 26 was better, while no difference was
found using the EORTC QLQ C30. The duration of hospital
stay and the mean operating time were significantly shorter in
the Berne group. No significant differences were found com-
paring the rates of reoperation, complications, and need of
blood products. It had to be mentioned that the analysis was
performed on an intention to treat basis, with 14 of the
randomization due to intraoperative findings (108).
Short-term results favor the organ sparing operation, and
additionally it is the easier operation to perform (easier
to learn anyway) (106). In patients with small duct disease
(diameter <3 mm), extended resection procedures are
suggested (31).
Additionally pain, nausea, and fatigue were significantly
reduced. In terms of pain relief and quality of life and exo-
crine and endocrine function no significant differences were
detected (7,125).
small duct disease
Recently a new entity of the sclerosing ductal pancreatitis
characterized by a maximal Wirsungian duct diameter of less
than 3 mm was described (126). In literature there is a contro-
versy on the definition of a dilated pancreatic duct (90,127).
The normal diameter of the main duct is 3 to 5 mm in relation
to age (90,91).
Independently of the discussion of the definition of a dilation
of the main pancreatic ducts there is controversy concerning
surgical technique. The majority of members of the American
Pancreas Club considered a duct size of a minimum of 8 mm
sufficient to justify a pancreaticojejunostomy.
Others regarded a duct size of 5 mm as the limit to perform
a pancreatojejunostomy rather than a pancreaticojejunos-
tomy (90). An another extended drainage procedure has been
proposed for treatment of the small duct disease: a longitudi-
nal V-shaped excision of the ventral aspect of the pancreas
combined with a longitudinal pancreatojejunostomy (Fig. 48.5).

458
 CHRONIC PANCREATITIS
Figure 48.5 V-Shape.
If the pancreatitis is accompanied by an enlarged pancreatic
head a pancreatic head resection should be performed.
salvage procedures
Due to improvement of surgical technique and selection of
patients, pancreatic surgery for CP yields excellent results. In
some cases recurrence develops; most frequently in the rem-
nant of the pancreatic head indicating either insufficient sur-
gical resection of the head of the pancreas or aggressive disease.
In these patients “re-do” pancreas head resections are indi-
cated. The procedures that should be considered are the partial
pancreatoduodenectomy (Whipple procedure, PPPD) and in
selected patients (i.e. re-recurrence) even total splenopancre-
atoduodenectomy. This procedure is indicated in patients that
underwent partial pancreatoduodenectomy, and additional
interventional nerve blocks or surgical denervation fail to
achieve definitive pain relief.
In patients that previously underwent duodenum-preserving
resection of the pancreatic head or partial pancreatoduode-
nectomy with recurrence of the CP in the body or tail a V-shape
drainage procedure is indicated.
conclusion
The aim of treatment of CP is mainly pain relief and improve-
ment in the quality of life, which still poses a major challenge
today. Duodenum-preserving pancreatic head resection is the
ideal procedure for treatment of CP. If ductal pathology is
present in the pancreatic body or tail the procedure can be
combined with longitudinal duct drainage in various degrees
which allows a tailored concept. Duodenum-preserving resec-
tions of the pancreas combine high safety with high efficacy
and offer the best short-term outcome, while the long-term
results of PPPD are comparable. In small duct pancreatitis
(duct diameter <3 mm), a V-shape excision is the therapy of
choice. Pancreatic surgery bears many pitfalls and potential
complications and is technically demanding. It should be left
to experts in high-volume hospitals in order to minimize
mortality and morbidity.
references
1. Lohr JM. What are the useful biological and functional markers of early-
stage chronic pancreatitis? J Gastroenterol 2007 January; 42(Suppl 17):
66–71.
2. Mayerle J, Lerch MM. Is it necessary to distinguish between alcoholic and
nonalcoholic chronic pancreatitis? J Gastroenterol 2007 January;
42(Suppl 17): 127–30.
3. Andersen BN, Pedersen NT, Scheel J, Worning H. Incidence of alcoholic
chronic pancreatitis in Copenhagen. Scand J Gastroenterol 1982 March;
17(2): 247–52.
4. Ammann RW, Mullhaupt B. Do the diagnostic criteria differ between
alcoholic and nonalcoholic chronic pancreatitis? J Gastroenterol 2007
January; 42(Suppl 17): 118–26.
5. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and out-
come of chronic pancreatitis. Gastroenterology 1984; 86: 820–8.
6. Thorsgaard PN, Nyboe AB, Pedersen G, Worning H. Chronic pancreati-
tis in Copenhagen. A retrospective study of 64 consecutive patients.
Scand J Gastroenterol 1982 October; 17(7): 925–31.
7. Pessaux P, Kianmanesh R, Regimbeau JM, et al. Frey procedure in the
treatment of chronic pancreatitis: short-term results. Pancreas 2006
November; 33(4): 354–8.
8. Knoefel WT, Eisenberger CF, Strate T, Izbicki JR. Optimizing surgical
therapy for chronic pancreatitis. Pancreatology 2002; 2: 379–85.
9. Warshaw AL. Pain in chronic pancreatitis – patients, patience, and the
impatient surgeon. Gastroenterology 1984; 86: 987–9.
10. Kloppel G. Toward a new classification of chronic pancreatitis. J Gastro-
enterol 2007 January; 42(Suppl 17): 55–7.
11. Ammann RW. A clinically based classification system for alcoholic
chronic pancreatitis: summary of an international workshop on chronic
pancreatitis. Pancreas 1997; 14: 215–21.
12. Strate T, Knoefel WT, Yekebas E, Izbicki JR. Chronic pancreatitis: etiol-
ogy, pathogenesis, diagnosis, and treatment. Int J Colorectal Dis 2003
March; 18(2): 97–106.
13. Banks PA. Classification and diagnosis of chronic pancreatitis. J Gastro-
enterol 2007 January; 42(Suppl 17): 148–51.
14. Ammann RW. Diagnosis and management of chronic pancreatitis: cur-
rent knowledge. Swiss Med Wkly 2006 March 18; 136(11–12): 166–74.
15. Ammann RW, Akovbiantz A, Largiader F. Pain relief in chronic pancreati-
tis with and without surgery. Gastroenterology 1984; 87: 746–77.
16. Adler DG, Lichtenstein D, Baron TH, et al. The role of endoscopy in
patients with chronic pancreatitis. Gastrointest Endosc 2006; 63(7):
933–7.
17. Strate T, Yekebas E, Knoefel WT, Bloechle C, Izbicki JR. Pathogenesis and
the natural course of chronic pancreatitis. Eur J Gastroenterol Hepatol
2002; 14: 929–34.
18. Chari ST. Chronic pancreatitis: classification, relationship to acute pan-
creatitis, and early diagnosis. J Gastroenterol 2007 January; 42(Suppl 17):
58–9.
19. Malka D, Hammel P, Sauvanet A, et al. Risk factors for diabetes mellitus
in chronic pancreatitis. Gastroenterology 2000; 119: 1324–32.
20. Lankisch PG, Happe-Loehr A, Otto J, Creutzfeldt W. Natural course in
chronic pancreatitis. Pain, exocrine and endocrine pancreatic insuffi-
ciency and prognosis of the disease. Digest 1993; 54: 148–55.
21. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The
different course of early- and late-onset idiopathic and alcoholic chronic
pancreatitis. Gastroenterology 1994; 107: 1481–7.
22. Ammann RW, Buehler H, Muench R, Freiburghaus AW, Siegenthaler W.
Differences in the natural history of idiopathic (nonalcoholic) and alco-
holic chronic pancreatitis. A comparative long-term study of 287 patients.
Pancreas 1987; 2(4): 368–77.
23. Levy P, Milan C, Pignon JP, Baetz A, Bernades P. Mortality factors associ-
ated with chronic pancreatitis. Unidimensional and multidimensional
analysis of a medical-surgical series of 240 patients. Gastroenterology
1989; 96: 1165–72.
24. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and out-
come of chronic pancreatitis. Longitudinal study of a mixed medical-
surgical series of 245 patients. Gastroenterology 1984; 86: 820–88.
25. Lankisch PG. Natural course of chronic pancreatitis. Pancreatology 2001;
1: 3–14.
459
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
26. Kloppel G, Maillet B. Pathology of acute and chronic pancreatitis. Pan-
creas 1993 November; 8(6): 659–70.
27. Kloppel G, Maillet B. The morphological basis for the evolution of
acute pancreatitis into chronic pancreatitis. Virchows Arch A Pathol
Anat Histopathol 1992; 420(1): 1–4.
28. Sarles H. Epidemiology and physiopathology of chronic pancreatitis and the
role of the pancreatic stone protein. Clin Gastroenterol 1984; 13: 895–912.
29. Kloppel G. Pathology of chronic pancreatitis and pancreatic pain. Acta
Chir Scand 1990; 156(4): 261–5.
30. Lehnert P. Ätiologie und Pathogenese der chronischen Pankreatitis. Inter-
nist 1979; 20: 321–30.
31. Yekebas EF, Bogoevski D, Honarpisheh H, et al. Long-term follow-up in
small duct chronic pancreatitis: a plea for extended drainage by
“V-shaped excision” of the anterior aspect of the pancreas. Ann Surg
2006; 244(6): 940–6.
32. Ectors N, Maillet B, Aerts R, et al. Non alcoholic duct destructive chronic
pancreatitis. Gut 1997; 41: 263–8.
33. Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N.
Chronic pancreatitis caused by an autoimmune abnormality. Proposal of
the concept of autoimmune pancreatitis. Dig Dis Sci 1995 July; 40(7):
1561–8.
34. Toomey DP, Swan N, Torreggiani W, Conlon KC. Autoimmune pancreati-
tis. Br J Surg 2007; 94(9): 1067–74.
35. Choi EK, Kim MH, Lee TY, et al. The sensitivity and specificity of serum
immunoglobulin G and immunoglobulin G4 levels in the diagnosis of
autoimmune chronic pancreatitis: Korean experience. Pancreas 2007;
35(2): 156–61.
36. Kloppel G. Chronic pancreatitis, pseudotumors and other tumor-like
lesions. Mod Pathol 2007 February; 20(Suppl 1): S113–31.
37. Barkin JS, Fayne SD. Chronic pancreatitis: update 1986. Mt Sinai J Med
1986; 53(5): 404–8.
38. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is
caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;
14(2): 141–5.
39. Gorry MC, Gabbaizedeh D, Furey W, et al. Mutations in the cationic
trypsinogen gene are associated with recurrent acute and chronic pan-
creatitis. Gastroenterology 1997; 113(4): 1063–8.
40. Teich N, Mossner J, Keim V. Mutations of the cationic trypsinogen in
hereditary pancreatitis. Hum Mutat 1998; 12(1): 39–43.
41. Lowenfels AB, Maisonneuve P, DiMagno EP,et al. Hereditary pancreatitis
and the risk of pancreatic cancer. International Hereditary Pancreatitis
Study Group. J Natl Cancer Inst 1997; 89(6): 442–6.
42. Malka D, Hammel P, Maire F, et al. Risk of pancreatic adenocarcinoma in
chronic pancreatitis. Gut 2002; 51(6): 849–52.
43. Bradley EL. Long-term results of pancreatojejunostomy in patients with
chronic pancreatitis. Am J Surg 1987; 153: 207–13.
44. Glasbrenner B, Adler G. Evaluating pain and the quality of life in chronic
pancreatitis. Int J Pancreatol 1997; 22(3): 163–70.
45. Mannell A, Adson MA, McIlrath DC, Ilstrup DM. Surgical management
of chronic pancreatitis: long-term results in 141 patients. Br J Surg 1988;
75(5): 467–72.
46. Ebbehoj N, Svendsen LB, Madsen P. Pancreatic tissue pressure in chronic
obstructive pancreatitis. Scand J Gastroenterol 1984; 19: 1066–8.
47. Ebbehoj N, Borly L, Bulow J, Rasmussen SG, Madsen P. Evaluation of pan-
creatic tissue fluid pressure and pain in chronic pancreatitis. A longitudi-
nal study. Scand J Gastroenterol 1990 May; 25(5): 462–6.
48. Woolf CJ. Phenotypic modification of primary sensory neurons: the role
of nerve growth factor in the production of persistent pain. Philos Trans
R Soc Lond B Biol Sci 1996 March 29; 351(1338): 441–8.
49. Bockman DE, Buechler M, Malfertheiner P, Beger HG. Analysis of nerves
in chronic pancreatitis. Gastroenterology 1988; 94: 1459–69.
50. Di SP, Fink T, Weihe E, et al. Immune cell infiltration and growth-associ-
ated protein 43 expression correlate with pain in chronic pancreatitis.
Gastroenterology 1997; 112(5): 1648–55.
51. Foster JR, Idle JR, Hardwick JP, et al. Induction of drug-metabolizing
enzymes in human pancreatic cancer and chronic pancreatitis. J Pathol
1993; 169(4): 457–63.
52. Acheson DW, Hunt LP, Rose P, Houston JB, Braganza JM. Factors con-
tributing to the accelerated clearance of theophylline and antipyrine in
460
adults with exocrine pancreatic disease. Clin Sci (Lond) 1989; 76(4):
377–85.
53. Prinz RA, Aranha GV, Greenlee HB. Combined pancreatic duct and
upper gastrointestinal and biliary tract drainage in chronic pancreatitis.
Arch Surg 1985; 120(3): 361–6.
54. Warshaw AL. Conservation of pancreatic tissue by combined gastric, bili-
ary, and pancreatic duct drainage for pain from chronic pancreatitis. Am
J Surg 1985; 149(4): 563–9.
55. Bradley EL. Parapancreatic biliary and intestinal obstruction in chronic
obstructive pancreatitis. Is prophylactic bypass necessary? Am J Surg
1986; 151(2): 256–8.
56. Huizinga WK, Thomson SR, Spitaels JM, Simjee AE. Chronic pancre-
atitis with biliary obstruction. Ann R Coll Surg Engl 1992; 74(2):
119–23.
57. Vijungco JD, Prinz RA. Management of biliary and duodenal complica-
tions of chronic pancreatitis. World J Surg 2003; 27(11): 1258–70.
58. Wislooff F, Jakobsen J, Osnes M. Stenosis of the common bile duct in
chronic pancreatitis. Br J Surg 1982; 69(1): 52–4.
59. Uchiyama T, Yamamoto T, Mizuta E, Suzuki T. Pancreatic ascites-–a
collected review of 37 cases in Japan. Hepatogastroenterology 1989;
36(4): 244–8.
60. Runyon BA. Amylase levels in ascitic fluid. J Clin Gastroenterol 1987;
9(2): 172–4.
61. Bracher GA, Manocha AP, DeBanto JR, et al. Endoscopic pancreatic duct
stenting to treat pancreatic ascites. Gastrointest Endosc 1999 June; 49(6):
710–5.
62. Oktedalen O, Nygaard K, Osnes M. Somatostatin in the treatment of
pancreatic ascites. Gastroenterology 1990; 99(5): 1520–1.
63. Uhl W, Buchler MW, Malfertheiner P, et al. A randomised, double blind,
multicenter trial of octreotide in moderate to severe acute pancreatitis.
Gut 1999; 45: 97–104.
64. Gomez-Cerezo J, Barbado CA, Suarez I, et al. Pancreatic ascites: study
of therapeutic options by analysis of case reports and case series
between the years 1975 and 2000. Am J Gastroenterol 2003; 98(3):
568–77.
65. Saps M. Re: Gomez-Cerezo et al. Pancreatic ascites: study of therapeutic
options by analysis of case reports and case series between the years 1975
and 2000. Am J Gastroenterol 2003; 98(10): 2332–3.
66. Chebli JM, Gaburri PD, de Souza AF, et al. Internal pancreatic fistulas:
proposal of a management algorithm based on a case series analysis. J
Clin Gastroenterol 2004; 38(9): 795–800.
67. Stenger AM, Knoefel WT, Dahmen U, Blochle C, Izbicki JR. Pancreatico-
bronchial fistula with communication to a pseudoaneurysm of the arte-
ria lienalis as a rare complication in chronic pancreatitis. Z Gastroenterol
1998; 36(12): 1047–51.
68. Izbicki JR, Wilker DK, Waldner H, Rueff FL, Schweiberer L. Thoracic
manifestations of internal pancreatic fistulas: report of five cases. Am J
Gastroenterol 1989; 84(3): 265–71.
69. Kaman L, Behera A, Singh R, Katariya RN. Internal pancreatic fistulas
with pancreatic ascites and pancreatic pleural effusions: recognition and
management. ANZ J Surg 2001; 71(4): 221–5.
70. Izbicki JR, Yekebas EF, Strate T, et al. Extrahepatic portal hypertension in
chronic pancreatitis: an old problem revisited. Ann Surg 2002; 236: 82–9.
71. Little AG, Moossa AR. Gastrointestinal hemorrhage from left-sided por-
tal hypertension. An unappreciated complication of pancreatitis. Am J
Surg 1981; 141(1): 153–8.
72. Bernades P, Baetz A, Levy P, et al. Splenic and portal venous obstruction in
chronic pancreatitis. A prospective longitudinal study of a medical-surgi-
cal series of 266 patients. Dig Dis Sci 1992; 37: 340–36.
73. Malka D, Hammel P, Levy P, et al. Splenic complications in chronic pan-
creatitis: prevalence and risk factors in a medical-surgical series of
500 patients. Br J Surg 1998; 85(12): 1645–9.
74. Bloechle C, Busch C, Tesch C, et al. Prospective randomized study of
drainage and resection on non-occlusive segmental portal hypertension
in chronic pancreatitis. Br J Surg 1997; 84(4): 477–82.
75. Buchler MW, Friess H, Muller MW, Wheatley AM, Beger HG. Random-
ized trial of duodenum-preserving pancreatic head resection versus
pylorus-preserving Whipple in chronic pancreatitis. Am J Surg 1995;
169(1): 65–9.
 CHRONIC PANCREATITIS
76. Warshaw AL, Jin GL, Ottinger LW. Recognition and clinical implications
of mesenteric and portal vein obstruction in chronic pancreatitis. Arch
Surg 1987; 122: 410–45.
77. Dumonceau JM, Costamagna G, Tringali A, et al. Treatment for painful
calcified chronic pancreatitis: extracorporeal shock wave lithotripsy
versus endoscopic therapy. A randomised controlled trial. Gut 2007
Apr; 56(4): 545–52.
78. Martin RF, Hanson BL, Bosco JJ, et al. Combined modality treatment
of symptomatic pancreatic ductal lithiasis. Arch Surg 1995; 130(4):
375–9.
79. Buscaglia JM, Kalloo AN. Pancreatic sphincterotomy: technique,
indications, and complications. World J Gastroenterol 2007; 13(30):
4064–71.
80. Weber A, Schneider J, Neu B, et al. Endoscopic stent therapy for patients
with chronic pancreatitis: results from a prospective follow-up study.
Pancreas 2007; 34(3): 287–94.
81. Heyries L, Sahel J. Endoscopic treatment of chronic pancreatitis. World J
Gastroenterol 2007; 13(46): 6127–33.
82. Eleftherladis N, Dinu F, Delhaye M, et al. Long-term outcome after
pancreatic stenting in severe chronic pancreatitis. Endoscopy 2005;
37(3): 223–30.
83. Born P, Rosch T, Bruhl K, et al. Long-term results of endoscopic treat-
ment of biliary duct obstruction due to pancreatic disease. Hepatogas-
troenterology 1998; 45(21): 833–9.
84. Kahl S, Zimmermann S, Genz I, et al. Risk factors for failure of endo-
scopic stenting of biliary strictures in chronic pancreatitis: a prospective
follow-up study. Am J Gastroenterol 2003; 98(11): 2448–53.
85. Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage
of the pancreatic duct in chronic pancreatitis. N Engl J Med 2007; 356(7):
676–84.
86. Dite P, Ruzicka M, Zboril V, Novotny I. A prospective, randomized trial
comparing endoscopic and surgical therapy for chronic pancreatitis.
Endosc 2003; 35(7): 553–8.
87. Lankisch PG, Andren-Sandberg A. Standards for the diagnosis of chronic
pancreatitis and for the evaluation of treatment. Int J Pancreatol 1993;
14: 205–12.
88. Frey CF, Suzuki M, Isaji S. Treatment of chronic pancreatitis complicated
by obstruction of the common bile duct or duodenum. World J Surg
1990; 14: 59–69.
89. Saeger HD, Schwall G, Trede M. Standard Whipple in chronic pancreati-
tis. In: Beger HG, Buechler M, Malfertheimer P, eds. Standards in Pancre-
atic Surgery, 1st edn. Berlin: Springer, 1993, 385–91.
90. Frey CF. Why and when to drain the pancreatic ductal system. In: Beger
HG, Buechler MW, Ditschuneit H, Malfertheiner P, eds. Chronic Pancre-
atitis. Berlin: Springer, 1990, 415–25.
91. Markowitz JS, Rattner DW, Warshaw AL. Failure of symptomatic relief
after pancreaticojejunal decompression for chronic pancreatitis. Strate-
gies for salvage. Arch Surg 1994; 129: 374–9.
92. Gould AP. Pancreatic calculi: transactions of the Clinical Society of
London. Lancet 1898; 2: 1532.
93. Moynihan SB. Pancreatic calculus. Lancet 1902; 4: 335.
94. Coffey R. Pancreaticojejunostomy and pancreatectomy. Ann Surg 1909;
50: 1238–64.
95. Link G. Treatment of chronic pancreatitis by pancreatectomy. Ann Surg
1911; 53: 768–82.
96. DuVal MK. Caudal pancreatico-jejunostomy for chronic relapsing pan-
creatitis. Ann Surg 1954; 140: 775–85.
97. Zollinger RM, Keith LM, Ellison EH. Pancreatitis. N Engl J Med 1954;
251: 497–502.
98. Puestow CB, Gillesby WJ. Petrograde surgical drainage of pancreas for
chronic pancreatitis. Arch Surg 1958; 76: 898–906.
99. Partington PF, Rochelle REL. Modified Puestow procedure for retro-
grade drainage of the pancreatic duct. Ann Surg 1960; 152: 1037–43.
100. Izbicki JR, Bloechle C, Knoefel WT, Rogiers X, Kuechler T. Surgical treat-
ment of chronic pancreatitis and quality of life after operation. Surg Clin
North Am 1999; 79: 913–44.
101. Traverso LW, Tompkins RK, Urrea PT, Longmire WP, Jr. Surgical treat-
ment of chronic pancreatitis. Twenty-two years’ experience. Ann Surg
1979 September; 190(3): 312–19.
102. Beger HG, Buechler M. Duodenum preserving resection of the head of
the pancreas in chronic pancreatitis with inflammatory mass in the head.
World J Surg 1990; 14: 83–7.
103. Buechler M, Friess H, Isenmann R, Bittner R, Beger HG. Duodenum-
preserving resection of the head of the pancreas: the Ulm experience. In:
Beger HG, Buechler M, Malfertheimer P, eds. Standards in Pancreatic
Surgery, 1st edn. Berlin: Springer, 1993, 436–49.
104. Mobius C, Max D, Uhlmann D, et al. Five-year follow-up of a prospective
non-randomised study comparing duodenum-preserving pancreatic
head resection with classic Whipple procedure in the treatment of
chronic pancreatitis. Langenbecks Arch Surg 2007; 392(3): 359–64.
105. Schnelldorfer T, Lewin DN, Adams DB. Reoperative surgery for chronic
pancreatitis: is it safe? World J Surg 2006; 30(7): 1321–8.
106. Izbicki JR, Bloechle C, Broering DC, et al. Extended drainage versus
resection in surgery for chronic pancreatitis – Prospective randomized
trial comparing the longitudinal pancreaticojejunostomy combined
with local pancreatic head excision with the pylorus preserving pancre-
atoduodenectomy. Ann Surg 1998; 228: 771–9.
107. Beger HG, Witte C, Krautzberger W, Bittner R. Experiences with duode-
num-sparing pancreas head resection in chronic pancreatitis. Chirurg
1980; 51: 303–7.
108. Koninger J, Seiler CM, Sauerland S, et al. Duodenum-preserving pancre-
atic head resection—a randomized controlled trial comparing the origi-
nal Beger procedure with the Berne modification (ISRCTN No.
50638764). Surgery 2008; 143(4): 490–8.
109. Izbicki JR, Bloechle C, Knoefel WT, et al. Complications of adjacent
organs in chronic pancreatitis managed by duodenum-preserving resec-
tion of the head of the pancreas. Br J Surg 1994; 81(9): 1351–5.
110. Wilker DK, Izbicki JR, Knoefel WT, Geissler K, Schweiberer L.
Duodenum-preserving resection of the head of the pancreas in treat-
ment of chronic pancreatitis. Am J Gastroenterol 1990; 85(8): 1000–4.
111. Buechler MW, Friess H, Bittner R, et al. Duodenum-preserving pancre-
atic head resection: long-term results. J Gastrointest Surg 1997; 1: 13–9.
112. Izbicki JR, Bloechle C, Knoefel WT, et al. Duodenum preserving resec-
tions of the head of the pancreas in chronic pancreatitis – a prospective
randomized trial. Ann Surg 1995; 221: 350–8.
113. Izbicki JR, Bloechle C, Broering DC, Kuechler T, Broelsch CE. Longitudi-
nal V-shaped excision of the ventral pancreas for small duct disease in
severe chronic pancreatitis. Ann Surg 1998; 227: 213–19.
114. Izbicki JR, Bloechle C, Knoefel WT, et al. Drainage versus Resektion in
der chirurgischen Therapie der chronischen Kopfpankreatitis: eine ran-
domisierte Studie. Chirurg 1997; 68: 369–77.
115. Frey CF, Amikura K. Local resection of the head of the pancreas com-
bined with longitudinal pancreaticojejunostomy in the management of
patients with chronic pancreatitis. Ann Surg 1994; 220: 492–507.
116. Frey CF, Smith GJ. Description and rationale of a new operation for
chronic pancreatitis. Pancreas 1987; 2: 701–7.
117. Muller MW, Friess H, Martin DJ. Long-term follow-up of a randomized
clinical trial comparing Beger with pylorus-preserving Whipple proce-
dure for chronic pancreatitis. Br J Surg 2008 Mar; 95(3): 350–6
118. Beger HG, Krautzberger W, Bittner R, Büchler M, Limmer J. Duodenum-
preserving resection of the head of the pancreas in patients with severe
chronic pancreatitis. Surgery 1985; 97: 467–73.
119. Beger HG, Buechler M, Bittner R, Oettinger W, Roscher R. Duodenum-
preserving resection of the head of the pancreas in severe chronic pan-
creatitis. Ann Surg 1989; 209: 273–8.
120. Gloor B, Friess H, Uhl W, Buchler MW. A modified technique of the
Beger and Frey procedure in patients with chronic pancreatitis. Dig Surg
2001; 18: 21–5.
121. Koninger J, Friess H, Muller M, et al. Duodenum-preserving pancreas
head resection-an operative technique for retaining the organ in the
treatment of chronic pancreatitis. Chirurg 2004; 75(8): 781–8.
122. Muller MW, Friess H, Martin DJ, et al. Long-term follow-up of a ran-
domized clinical trial comparing Beger with pylorus-preserving Whipple
procedure for chronic pancreatitis. Br J Surg 2008; 95(3): 350–6.
123. Farkas G, Leindler L, Daroczi M, Farkas G, Jr. Prospective randomised
comparison of organ-preserving pancreatic head resection with pylorus-
preserving pancreaticoduodenectomy. Langenbecks Arch Surg 2006;
391(4): 338–42.
461
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

124. Strate T, Bachmann K, Busch P, et al. Resection vs drainage in treatment of
chronic pancreatitis: long-term results of a randomized trial. Gastroenter-
ology 2008; 134: 1406–11.
125. Strate T, Taherpour Z, Bloechle C, et al. Long-term follow-up of a
randomized trial comparing the Beger and Frey procedures for patients
suffering from chronic pancreatitis. Ann Surg 2005; 241(4):
591–8.
126. Izbicki JR, Bloechle C, Broering DC, Kuechler T, Broelsch CE. Longitudinal
V-shaped excision of the ventral pancreas for small duct disease in severe
chronic pancreatitis: prospective evaluation of a new surgical procedure.
Ann Surg 1998 February; 227(2): 213–19.
127. Delcore R, Rodriguez FJ, Thomas JH, Forster J, Hermreck AS. The role of
pancreatojejunostomy in patients without dilated pancreatic ducts. Am J
Surg 1994; 168: 598–601.

462
49 Pancreatic injury
Demetrios Demetriades, Beat Schnüriger, and Galinos Barmparas
history
The first reported case of pancreatic injury was discovered at
an autopsy in 1827, in a woman who was hit and killed by a
stagecoach (1). The first documented posttraumatic pancre-
atic fistula was published in 1905 (2). In 1904, Garre operated
successfully on a patient with a transected pancreas (3).
Advances over the next few decades led to significant improve-
ments in the diagnosis and management of pancreatic injuries.
epidemiology
Pancreatic trauma remains fairly uncommon. The overall inci-
dence in blunt trauma is reported to be 0.2% and in penetrat-
ing trauma about 1% (4–9). However, it is likely that some
injuries, especially after blunt trauma may remain undiag-
nosed. Penetrating trauma accounts for the majority of injuries
(70–80%), with gunshot wounds being the most common
mechanism (72%) (8). The location of the injury is evenly
distributed among the head/neck and body of the pancreas
(about 40% each), with the tail being less frequently injured
(about 20%) (8,10). Because of the retroperitoneal location of
the pancreas, significant force is mandated to lead to its injury.
This fact, in combination with the proximity of the pancreas
to vital structures, makes isolated pancreatic injuries rare.
Overall, about 60% of patients with blunt trauma and about
90% with penetrating trauma have associated intra-abdomi-
nal injuries (7,11–15). Pancreatic trauma should be consid-
ered as a marker of other intra-abdominal injuries. The most
commonly associated injuries in blunt trauma are of the spleen
(34%), liver (26%), and duodenum (6%). In penetrating
trauma, first is the stomach (53%), followed by the liver (51%)
(7). Associated intra-abdominal vascular injuries are of major
concern since they are the most common cause of early
mortality. More than 75% of penetrating injuries to the head
of the pancreas are associated with a major vascular injury (8).
injury grading
There are numerous classification systems for pancreatic inju-
ries. The most widely accepted grading system is the one pro-
posed by the Organ Injury Scaling Committee of the American
Association for the Surgery of Trauma (OIS-AAST) in 1990
(Table 49.1) (16). This classification scheme takes into account
the type of injury (hematoma or laceration), the presence or
absence of structural duct involvement, and the location of
pancreatic injury (proximal or distal to superior mesenteric
vein). OIS-AAST grades I and II are considered as low-grade
and grades III–V as high-grade pancreatic injuries (17). The
classification may be based on computed tomography (CT)
and intraoperative or autopsy findings. It is useful in the evalu-
ation and management of patients with pancreatic injuries,
and it is an excellent research tool for the comparison of the
safety and efficacy of the various therapeutic approaches (15).
diagnosis
Clinical Presentation
The diagnosis of penetrating pancreatic injury is usually made
intraoperatively and does not pose any significant diagnostic
problems. However, the diagnosis in blunt trauma is often
challenging. A missed or delayed diagnosis of pancreatic injury
increases morbidity and mortality (15). Because of its retro-
peritoneal location and infrequent occurrence, timely diagno-
sis of blunt pancreatic injury requires a high index of suspicion
and is a challenging task even to the most experienced sur-
geon. Clinical signs are often vague and nonspecific. Even sig-
nificant pancreatic injuries may present initially with minimal
epigastric pain, with signs of peritonitis developing many
hours or even days after the injury. The cornerstone of early
diagnosis is a combination of serial physical examinations,
laboratory tests, and imaging studies.
Laboratory Investigations
Unfortunately, no laboratory test is either sensitive or specific
enough in evaluating suspected pancreatic injuries. Serum
amylase levels have long been used as a useful marker and may
assist in the diagnosis (18,19). Takishima et al. found a time-
dependent increase of serum amylase in patients suffering
blunt pancreatic trauma (20). Elevated serum amylase was
present in all cases when the samples were collected more than
3 hours after the injury. Therefore, serum amylase on admis-
sion may be particularly unreliable and should be followed
serially. Additionally, no relation between the grade of pancre-
atic injury and the level of hyperamylasemia was found (20).
The sensitivity and specificity of serum amylase in detecting
pancreatic trauma range from 48% to 89% and 64% to 81%,
respectively (Table 49.2). When used as a screening tool after
blunt abdominal trauma, a normal serum amylase has a nega-
tive predictive value of 93% to 98% (20–24). Various other
injuries, such as brain injuries, salivary gland, duodenal, and
small bowel trauma may be associated with increased serum
amylase levels (25–28). The determination of amylase isoen-
zymes does not improve the sensitivity of specificity.
Radiologic Investigations
Plain abdominal films and ultrasonography are of limited
value in the diagnostic work-up of patients with suspected
pancreatic injury. Contrast-enhanced helical CT is considered
as the imaging study of choice for these patients (Fig. 49.1). Its
accuracy increases in parallel with the interval between the CT
study and the injury. In suspicious injuries a repeat CT scan at
least 6 to 8 hours after the initial investigation is recommended.
The timing of the intravenous contrast bolus, as well as the
experience of the radiologist involved affects the diagnostic
precision (29,30). The overall sensitivity and specificity of CT
for identification of pancreatic injuries of all grades is reported
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Table 49.1 American Association of the Surgery of Trauma

Organ Injury Scale for the Pancreas
Grade Type of injury Description of injury
I Hematoma Minor contusion without duct injury
Laceration Superficial laceration without duct
injury
II Hematoma Major contusion without duct injury
or tissue loss
Laceration Major laceration without duct injury
or tissue loss
III Laceration Distal transection or parenchymal
injury with duct injury
IV Laceration Proximal transection or parenchymal
injury with duct injury
V Laceration Massive destruction of pancreatic
head

Table 49.2 Sensitivity and Specificity of the Diagnostic

Adjunctive and Level of Evidence
Figure 49.2 MRCP with detection of a pancreatic duct disruption (white
Sensitivity Specificity Level of evidence arrow).
(%) (%) (references)
Amylase levels 48–89 64–81 III (20–24)
CT 80 80 III (10,31–33)
MRCP >95 >95 III–IV (37–39) technique for the evaluation of pancreatic injuries and ductal
ERCP >95 >95 III–IV (40,41) status (Fig. 49.2). MRCP is diagnostic in 95% to 99% of cases
of pancreatic ductal injuries, and complete visualization of
normal-sized pancreatic ducts occurs in 97% of the patients
(37–39) (Table 49.2). Secretin administration may improve
ductal visualization (39). However, MRCP is applicable only in
those patients who are hemodynamically stable and have min-
imal other injuries and does not permit therapeutic interven-
tion, such as stent placement.
Endoscopic retrograde pancreatography (ERCP) is the gold
standard in the evaluation of the pancreatic duct and may also
have therapeutic application by placement of a stent over a
ductal injury (40–43). The procedure should be performed as
early as possible, preferably within 12 to 24 hours of injury, to
prevent abdominal septic complications (44). ERCP is often
not available in an emergency setting and requires hemody-
namic stability. The procedure may cause pancreatitis and the
long-term results of stenting are still not well known (45,46).
Figure 49.1 Grade IV pancreatic injury (white circle) and concomitant grade IV
liver injury after blunt abdominal trauma. Intraoperative Exposure and Evaluation
Many patients with pancreatic injury present with peritonitis
or hemodynamic instability, requiring immediate abdominal
to be around 80%, and the positive predictive value ranges exploration, before any preoperative diagnostic evaluation. A
from 80% to 100% (10,31–33) (Table 49.2). The study tends to midline incision is the preferred approach in trauma because
underestimate the severity of pancreatic injury (34). With the it provides an optimal exposure for the evaluation of other
introduction of multidetector CT and improved techniques, associated injuries. The pancreas is explored only after control
the diagnostic accuracy is likely to improve (35,36). The sensi- of any bleeding and contamination due to a hollow viscus
tivity of detecting ductal injury with multidetector CT has injury. A pancreatic injury should be suspected by the presence
been measured in a single study at 91% (32). However, to fur- of lesser sac fluid collection, retroperitoneal bile staining, ret-
ther assess the integrity of the pancreatic duct, additional roperitoneal hematoma, and fat necrosis of the omentum and
investigations may be needed. retroperitoneum (47).
Magnetic resonance imaging (MRI) with cholangiopan- Most of the pancreas can be visualized by opening the lesser
creatography (MRCP) is a noninvasive, alternative imaging sac. This maneuver can be easily and rapidly done by dividing

464
 PANCREATIC INJURY

(A) (B)
Figure 49.3 (A,B) Opening of the lesser sac allows exposure and evalutaion of the anterior surface of the body and tail of the pancreas. Kocher maneuver allows
evaluation of the pancreatic head. Source : From Ref. 83.

the gastrocolic ligament between the stomach and the

transverse colon. This maneuver exposes the anterior, inferior,
and superior surfaces of the body and tail of the pancreas
(Fig. 49.3A). Any attachments between the pancreas and the
posterior wall of the stomach are divided. Exploration of the
posterior portion of the pancreas can be performed by an inci-
sion in the peritoneum on the inferior border of the pancreas in
the region of suspected injury. The avascular nature of the retro-
pancreatic plane allows the index finger to be carefully slipped
behind the pancreas where a laceration can often be felt.
Improved access to the posterior portion of the body and tail
can be achieved by dissecting the splenocolic, splenophrenic,
and splenorenal ligament. The plane anterior to the kidneys
usually can be developed with careful blunt dissection (48).
To assess the head and uncinate process of the pancreas and
the integrity of the duodenum and the bile duct, an extended
Kocher maneuver should be performed. This includes the
mobilization of the second and third portion of the duode-
num, pancreatic head, and distal common bile duct from their
retroperitoneal position. This procedure allows inspection and
bimanual palpation of the anterior and posterior surfaces of
the head and uncinate process (Fig. 49.3B).
Intraoperative Evaluation of the Integrity of the
Pancreatic Duct
The major determinant of morbidity and mortality related to
pancreatic trauma is the integrity of the main pancreatic duct
(49–51). Most trauma patients have normal-sized pancreatic
ducts, which can be difficult to visualize. The use of magnify-
ing glasses and administration of secretin may facilitate
visualization of the duct.
Several radiological and endoscopic methods of intraopera-
tive pancreatography have been described (52–56), but are
rarely used in trauma. If there is a low probability of ductal
injury or the patient is hemodynamically unstable, simple
drainage of the peripancreatic space is the most appropriate
Figure 49.4 Duodenotomy and catheterization of the ampulla of Vater for
intraoperative pancreatography. Source : From Ref. 83.
approach. Postoperative evaluation by means of CT or MRCP
may be considered in patients with persistent elevation of the
serum amylase or pancreatic leaks.
Intraoperative pancreatography may be considered in
selected stable patients with suspicious pancreatic head ductal
injury. It can be performed by injecting contrast medium into
the gallbladder after clamping the proximal common bile duct.
The administration of morphine to cause contraction of the
sphincter of Oddi may aid in visualizing the pancreatic duct.
In about 10% of subjects, the common bile duct and pancre-
atic duct drain separately, and the pancreatic duct is not visible
with this technique. However, the images obtained may be
useful in assessing the intrapancreatic portion of the common
bile duct and the integrity of the ampulla of Vater (57).
If the duodenum is already open, the ampulla of Vater may
be cannulated directly (Fig. 49.4). Identification of the ampulla
of Vater can be difficult, especially in the presence of edema or
hematoma, and magnifying glasses are strongly recommended
in order to identify this structure. The major duct is cannulated

465
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

using a pediatric feeding tube, and several milliliters of contrast

medium are instilled. A static radiograph or fluoroscopy is
taken to identify contrast extravasation. Amputation of the tail
to gain access to the pancreatic duct for pancreaticography is
mentioned only to condemn.
Intraoperative ERCP has been used to assess the ductal sys-
tem. This is a time-consuming approach and is rarely used,
especially in severe trauma (56).
In summary, visualization of the pancreatic duct using com-
plex techniques should be considered only if the patient is
stable and the surgeon is prepared to act on the findings and
perform major pancreatic resection if needed.

management
The rarity of these injuries precludes the development of
evidence-based guidelines. Expert opinions and small series
reports (levels III and IV evidence) constitute the major
source of the knowledge gained throughout the years.

Nonoperative Management (NOM)

Selective NOM might have a place in the management of care-
fully selected patients with blunt abdominal trauma. Only
hemodynamically stable patients without evidence of perito-
nitis are potential candidates for NOM. Experience of NOM in
pediatric population showed that this approach is safe and
effective. Keller et al. (58) in a National Pediatric Trauma Reg-
istry study reviewed 154 pancreatic injuries in children, 80%
with low-grade and 20% with high-grade injuries. NOM was
successful in about half of high-grade injuries and about 80%
of low-grade injuries. The frequency of NOM increased sig-
nificantly over the last year of the study. However, pediatric
pancreatic trauma is different from adult trauma because of
the much lower risk of pancreatic duct injury in children (less
than 1% in children, about 15% in adults). Subsequent experi-
ence in adult blunt trauma patients confirmed the safety of
this approach (58–62). In a recent study there were no failures
of NOM in grade I and 17.3% failure in grade II pancreatic
injuries (61). In summary, NOM is safe for low grade injuries
and may be acceptable in selected high-grade injuries. Early
evaluation by means of ERCP or MRCP helps to visualize the
integrity of the pancreatic duct. In addition ERCP might be
used for stent placement, which can be an excellent adjunctive
tool to NOM (63). The downside to NOM is the development
of a pseudocyst or fistulae and occasionally severe pancreatitis
(64). Most of these complications are treatable by percutanous
CT-guided drainage.
There is no evidence that the use of somatostatin analogs,
such as octreotide, increases the success rate of NOM, although
they might have a role in the treatment of posttraumatic pan-
creatic fistulae (65).
Operative Management
The surgical treatment plan of pancreatic injury should be
determined by the overall condition of the patient, the
grade and location of pancreatic injury, the concomitant
injuries, and the experience of the surgeon. The strengths
of management recommendations for pancreatic trauma
are all of level C or D.
Figure 49.5 Anastomosis of the distal pancreatic stump to a Roux-en-Y
jejunal loop. Source : From Ref. 83.
Low-grade injuries discovered intraoperatively are best man-
aged with sparse debridement of nonviable tissue, hemostasis,
and wide external drainage with closed suction drains.
Although some authors advocate repair of the pancreatic cap-
sule (66), this may lead to further parenchymal damage and
pseudocyst formation and should only be done to control
bleeding. Application of topical hemostatics on the pancreatic
laceration may facilitate hemostasis and reduce the risk of
postoperative leaks.
When dealing with high-grade injuries (AAST-OIS grades
III, IV, and V), the choice of procedure depends on the general
condition of the patient and the location of duct injury, i.e., in
the head, neck, or tail of the pancreas.
Distal ductal injuries (AAST-OIS grade III) are best treated
by distal pancreatectomy (67,68) often en bloc with the
spleen. Spleen-preserving distal pancreatectomy should be
considered in hemodynamically stable patients especially in
children (69–72). Splenic preservation is technically more
challenging and may result in increased blood loss. After com-
pletion of the distal pancreatectomy, the main pancreatic duct
is identified if possible and is suture-ligated with nonabsorb-
able suture. With the main duct ligated, the proximal paren-
chyma should be closed with a mattress sutures or a TA
stapling device. Extensive pancreatic resection to the right
side of the superior mesenteric vessels may lead to diabetes or
exocrine insufficiency. In these cases, the distal pancreas may
be preserved and anastomosed to a Roux-en-Y jejunal loop
(Fig. 49.5). Closed suction drains should be placed around the
remaining pancreas and left upper quadrant if the spleen has
been removed.

466
 PANCREATIC INJURY
Proximal ductal injuries and injuries to the head of the pancreas
(AAST-OIS grade IV) are more challenging. In the presence of
hemodynamic instability or major associated injuries, or if the
surgeon has no experience with complex pancreatic surgery, no
attempts should be made to evaluate the integrity of the duct or
perform major resections. In these cases, the safest option is
hemostasis and liberal external drainage (50,68). Damage con-
trol with packing and temporary abdominal closure may be
necessary. In destructive injuries to the head of the pancreas or
the duodenum, a pancreaticoduodenectomy may be necessary.
It should only be performed as a primary procedure in hemo-
dynamically stable patients by an experienced surgeon. In
severely compromised patients the surgeon should opt for
damage control and a two-stage procedure (73–75). Primarily,
damage control surgery should be performed to control the
hemorrhage and any intestinal spillage. Major associated vas-
cular injuries may be managed by ligation or temporary arte-
rial shunts reinforced by abdominal packing. Complex
gastrointestinal injuries may be stapled off and the common
bile duct exteriorly drained. The abdominal wall is temporar-
ily closed and the patient is transferred to the intensive care
unit for stabilization. The definitive Whipple’s procedure
should be deferred for 24 to 48 hours after restoration of the
hemodynamic status, coagulability, and normalization of body
temperature. The reconstruction, including pancreatico-jeju-
nostomy or pancreatico-gastrostomy (76,77), choledocho-
jejunostomy, and gastro-enterostomy, is similar to that in
elective cases. Insertion of a jejunal feeding tube beyond the
ligament of Treitz is strongly recommended to allow feeding in
prolonged complicated cases. Overall, pancreaticoduodenec-
tomy is rarely indicated in trauma. In a review at our center
over 7.5 years, only 16 of 214 (7.4%) patients with pancreatic
injuries required pancreaticoduodenectomy (73).
outcomes
Mortality
Many patients with pancreatic injury die from associated
exsanguinating injuries. The overall pancreas-related mortal-
ity is lower than 1% and is usually the result of sepsis and
organ failure. In pancreatico-duodenal resection the overall
mortality is about 30% to 40% (7,73).
Complications
Pancreas-related local complications occur in about 25% of
patients. The complication rate depends on the severity of
pancreatic injury and associated injuries. The most common
complications include pancreatic fistulae, peripancreatic
fluid collection, local sepsis, pseudocysts, and pancreatitis.
Most of these complications can successfully be managed
non-operatively, either expectantly or with percutaneous
drainage or endoscopic stenting of the duct.
Pancreatic Leaks and Fistulae
Early pancreatic leaks are the most common complications
after surgery for pancreatic trauma and occur in 10% to 35% of
patients (7,78). The amylase levels of this fluid should be deter-
mined to confirm the pancreatic origin. The prognosis is excel-
lent and the vast majority close spontaneously within days or
Figure 49.6 Very large posttraumatic peripancreatic pseudocyst.
weeks (79). Administration of a somatostatin analog may
accelerate the resolution of the pancreatic leaks (65). The role
of prophylactic use of somatostatin following pancreatic
trauma is controversial and there is no evidence to support its
routine use. Routine parenteral nutrition is not necessary in
this group of patients. Many of them tolerate oral or intestinal
tube feeding well, without any significant increase of the drain
output. Parenteral nutrition should only be considered in cases
where enteral feeding is associated with an increase of the out-
put. No invasive diagnostic procedures, such as ERCP, should
be considered during the early postoperative period, because of
the high rate of spontaneous healing. Specific investigations
should be considered only after persistently high output which
shows no evidence of improvement. An MRCP might delineate
the anatomy of the pancreatic duct and select those patients
who might benefit from ERCP duct stenting. The long-term
experience with stenting of posttraumatic leaks is still limited
but encouraging. Previous case series found a high incidence of
long-term ductal stricture and therefore concluded that the
role of pancreatic duct stenting remains uncertain (46). Other
investigators however, have reported successful stent place-
ment, even in complicated cases (80–82).
Peripancreatic Fluid Collection and Pseudocysts
These complications are fairly common and may occur with
either operative or non-operative management of pancreatic
injuries. They are usually diagnosed during CT scan evalua-
tion of the abdomen (Fig. 49.6). The nature of the fluid collec-
tion varies and it can be residual bleeding, serosanguinous
fluid, pancreatic exudate, or true pancreatic juice. The natural
history of truly pancreatic collections depends on the integrity
of the main pancreatic duct. If the main duct is intact, the
majority of these collections resolve spontaneously without
any intervention. If the main duct is injured, the collection
may persist and evolve to a pancreatic pseudocyst.
Asymptomatic patients with small peripancreatic collec-
tions should be managed expectantly. Symptomatic patients,
or those with large collections, may require CT-guided percu-
taneous drainage. If external drainage fails, as shown by persis-
tently high drain output without any signs of improvement, an
467
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
ERCP with duct stenting should be considered. In rare cases
operative resection or internal drainage of a pseudocyst may
be necessary.
Pancreatic Insufficiency
Endocrine and exocrine insufficiency may occur after major
pancreatic resections and the patients should be monitored on
a regular basis, at least during the first few months after the
resection.
Late Strictures
Late stricture of the choledochojejunostomy following pan-
creaticoduodenectomy for trauma is common because of the
usually small size of the common bile duct. This stricture may
manifest many months after the operation. It is strongly rec-
ommended that the liver function is monitored regularly,
especially during the early months after the injury, in order to
identify and treat the problem before liver damage occurs.
summary
Pancreatic injuries remain fairly uncommon with penetrating
trauma accounting for most cases. The diagnosis of isolated
pancreatic injury due to blunt trauma may be missed on the
initial evaluation and this delay increases morbidity and mor-
tality. The diagnosis in these cases can be made timely by a
high index of suspicion, serial clinical examinations, serial
amylase levels, and repeat CT scan evaluation. All penetrating
injuries to the pancreas require surgical interventions but a
significant number of isolated injuries due to blunt trauma
can safely be managed non-operatively, provided that the
main pancreatic duct is intact and the patient is hemodynami-
cally stable and has no signs of peritonitis. The type of opera-
tive management of the pancreatic injury depends on the
severity and site of the injury, associated injuries, hemody-
namic condition of the patient, and the experience of the sur-
geon. The majority of injuries can be managed by hemostasis
and closed suction drainage. Distal injuries are best managed
by distal pancreatectomy, with or without splenic preserva-
tion. Proximal injuries may be managed with hemostasis and
drainage or extended distal pancreatectomy. In many pancre-
atic head injuries, if the duodenum is not severely damaged,
hemostasis and external drainage may be sufficient. Pancreati-
coduodenectomy is very rarely indicated and should be
reserved only for destructive injuries to the head of pancreas
or the duodenum. Damage control procedures should be con-
sidered in hemodynamically unstable, coagulopathic patients.
Pancreas-related complications are common after severe
trauma but they can usually be managed successfully with
non-operative methods.
references
1. Travers B. Rupture of the pancreas. Lancet. 1827; 12: 384.
2. Korte W. The Pancreas: Its Surgery and Pathology. Philadelphia: Saunders,
1907.
3. Garre C. Totaler Querriss des Pankreas durch Naht geheilt. Beit Clin Chir
1904; 46: 233.
4. Wind P, Tiret E, Cunningham C, et al. Contribution of endoscopic retro-
grade pancreatography in management of complications following distal
pancreatic trauma. Am Surg 1999 Aug; 65(8): 777–83.
468
5. Tyburski JG, Dente CJ, Wilson RF et al. Infectious complications following
duodenal and/or pancreatic trauma. Am Surg 2001 Mar; 67(3): 227–30;
discussion 30–1.
6. Feliciano DV, Burch JM, Sput-Parinely V. Abdominal gunshut wounds. An
urban trauma center’s experience with 300 consecutive patients. Ann Surg
1988; 208(3): 362–70.
7. Vasquez JC, Coimbra R, Hoyt DB, Fortlage D. Management of penetrating
pancreatic trauma: an 11-year experience of a level-1 trauma center.
Injury 2001 Dec; 32(10): 753–9.
8. Asensio JA, Demetriades D, Hanpeter DE, Gambaro E, Chahwan S. Man-
agement of pancreatic injuries. Curr Probl Surg 1999 May; 36(5): 325–419.
9. Akhrass R, Yaffe MB, Brandt CP, et al. Pancreatic trauma: a ten-year
multi-institutional experience. Am Surg 1997 Jul; 63(7): 598–604.
10. Leppaniemi A, Haapiainen R, Kiviluoto T, Lempinen M. Pancreatic
trauma: acute and late manifestations. Br J Surg 1988 Feb; 75(2): 165–7.
11. Stone HH, Fabian TC, Satiani B, Turkleson ML. Experiences in the
management of pancreatic trauma. J Trauma 1981 Apr; 21(4): 257–62.
12. Graham J, Mattox K, Jordan G. Traumatic injuries of the pancreas. Am
J Surg 1978; 136: 744.
13. Sukul K, Lont HE, Johannes EJ. Management of pancreatic injuries.
Hepatogastroenterology 1992 Oct; 39(5): 447–50.
14. Sorensen V, Obeid F, Horst H. Penetrating pancreatic injuries. Am Surg
1986; 52: 354.
15. Bradley EL 3rd, Young PR Jr, Chang MC, et al. Diagnosis and initial
management of blunt pancreatic trauma: guidelines from a multiinstitu-
tional review. Ann Surg 1998 Jun; 227(6): 861–9.
16. Moore EE, Cogbill TH, Malangoni MA, et al. Organ injury scaling, II:
Pancreas, duodenum, small bowel, colon, and rectum. J Trauma 1990
Nov; 30(11): 1427–9.
17. Kao LS, Bulger EM, Parks DL, Byrd GF, Jurkovich GJ. Predictors of morbidity
after traumatic pancreatic injury. J Trauma 2003 Nov; 55(5): 898–905.
18. Naffziger HC, McCorkle HJ. The recognition and management of acute
trauma to the pancreas: with particular reference to the use of the serum
amylase test. Ann Surg 1943 Oct; 118(4): 594–602.
19. Elman R. The variations of blood amylase during acute transient disease
of the pancreas. Ann Surg 1937 Mar; 105(3): 379–84.
20. Takishima T, Sugimoto K, Hirata M, et al. Serum amylase level on
admission in the diagnosis of blunt injury to the pancreas: its significance
and limitations. Ann Surg 1997 Jul; 226(1): 70–6.
21. White PH, Benfield JR. Amylase in the management of pancreatic trauma.
Arch Surg 1972 Aug; 105(2): 158–63.
22. Olsen WR. The serum amylase in blunt abdominal trauma. J Trauma
1973 Mar; 13(3): 200–4.
23. Moretz JA 3rd, Campbell DP, Parker DE, Williams GR. Significance of
serum amylase level in evaluating pancreatic trauma. Am J Surg 1975 Dec;
130(6): 739–41.
24. Bouwman DL, Weaver DW, Walt AJ. Serum amylase and its isoenzymes: a
clarification of their implications in trauma. J Trauma 1984 Jul; 24(7): 573–8.
25. Liu KJ, Atten MJ, Lichtor T, et al. Serum amylase and lipase elevation is
associated with intracranial events. Am Surg 2001 Mar; 67(3): 215–9;
discussion 9–20.
26. Takahashi M, Maemura K, Sawada Y, Yoshioka T, Sugimoto T. Hyperamy-
lasemia in critically injured patients. J Trauma 1980 Nov; 20(11): 951–5.
27. Coleman EJ, Dietz PA. Small bowel injuries following blunt abdominal
trauma. Early recognition and management. N Y State J Med 1990 Sep;
90(9): 446–9.
28. Lawrence DM. Gastrointestinal trauma. Crit Care Nurs Clin North Am
1993 Mar; 5(1): 127–40.
29. Venkatesh SK, Wan JM. CT of blunt pancreatic trauma: a pictorial essay.
Eur J Radiol 2008 Aug; 67(2): 311–20.
30. Linsenmaier U, Wirth S, Reiser M, Korner M. Diagnosis and classification
of pancreatic and duodenal injuries in emergency radiology. Radiograph-
ics 2008 Oct; 28(6): 1591–602.
31. Cirillo RL Jr, Koniaris LG. Detecting blunt pancreatic injuries. J Gastroin-
test Surg 2002 Jul–Aug; 6(4): 587–98.
32. Teh SH, Sheppard BC, Mullins RJ, Schreiber MA, Mayberry JC. Diagnosis
and management of blunt pancreatic ductal injury in the era of high-
resolution computed axial tomography. Am J Surg 2007 May; 193(5):
641–3; discussion 3.
 PANCREATIC INJURY
33. Ilahi O, Bochicchio GV, Scalea TM. Efficacy of computed tomography in
the diagnosis of pancreatic injury in adult blunt trauma patients: a single-
institutional study. Am Surg 2002 Aug; 68(8): 704–7; discussion 7–8.
34. Akhrass R, Kim K, Brandt C. Computed tomography: an unreliable
indicator of pancreatic trauma. Am Surg 1996 Aug; 62(8): 647–51.
35. Shanmuganathan K. Multi-detector row CT imaging of blunt abdominal
trauma. Semin Ultrasound CT MR 2004 Apr; 25(2): 180–204.
36. Mullinix AJ, Foley WD. Multidetector computed tomography and blunt
thoracoabdominal trauma. J Comput Assist Tomogr 2004 Jul–Aug;
28(Suppl 1): S20–7.
37. Fulcher AS, Turner MA, Yelon JA, et al. Magnetic resonance cholangio-
pancreatography (MRCP) in the assessment of pancreatic duct trauma
and its sequelae: preliminary findings. J Trauma 2000 Jun; 48(6): 1001–7.
38. Nirula R, Velmahos GC, Demetriades D. Magnetic resonance cholangio-
pancreatography in pancreatic trauma: a new diagnostic modality?
J Trauma 1999 Sep; 47(3): 585–7.
39. Ragozzino A, Manfredi R, Scaglione M, et al. The use of MRCP in the
detection of pancreatic injuries after blunt trauma. Emerg Radiol 2003
Apr; 10(1): 14–8.
40. Hata M, Murao Y, Konobu T, Okuchi K, Nakajima Y. Laparoscopic
treatment for peripheral pancreatic duct injury after blunt abdominal
trauma: report of a case. Surg Today 2002; 32(7): 659–62.
41. Wolf A, Bernhardt J, Patrzyk M, Heidecke CD. The value of endoscopic
diagnosis and the treatment of pancreas injuries following blunt abdomi-
nal trauma. Surg Endosc 2005 May; 19(5): 665–9.
42. Varadarajulu S, Noone TC, Tutuian R, Hawes RH, Cotton PB. Predictors
of outcome in pancreatic duct disruption managed by endoscopic trans-
papillary stent placement. Gastrointest Endosc 2005 Apr; 61(4): 568–75.
43. Telford JJ, Farrell JJ, Saltzman JR, et al. Pancreatic stent placement for duct
disruption. Gastrointest Endosc 2002 Jul; 56(1): 18–24.
44. Degiannis E, Glapa M, Loukogeorgakis SP, Smith MD. Management of
pancreatic trauma. Injury 2008 Jan; 39(1): 21–9.
45. Harrell DJ, Vitale GC, Larson GM. Selective role for endoscopic retrograde
cholangiopancreatography in abdominal trauma. Surg Endosc 1998 May;
12(5): 400–4.
46. Lin BC, Liu NJ, Fang JF, Kao YC. Long-term results of endoscopic stent in
the management of blunt major pancreatic duct injury. Surg Endosc 2006
Oct; 20(10): 1551–5.
47. Olah A, Issekutz A, Haulik L, Makay R. Pancreatic transection from blunt
abdominal trauma: early versus delayed diagnosis and surgical
management. Dig Surg 2003; 20(5): 408–14.
48. Aird I, Helman P. Bilateral anterior transabdominal adrenalectomy.
Br Med J 1955 Sep 17; 2(4941): 708–9.
49. Cogbill TH, Moore EE, Kashuk JL. Changing trends in the management
of pancreatic trauma. Arch Surg 1982 May; 117(5): 722–8.
50. Degiannis E, Levy RD, Velmahos GC, et al. Gunshot injuries of the head of
the pancreas: conservative approach. World J Surg 1996 Jan; 20(1): 68–71;
discussion 2.
51. Lewis G, Krige JE, Bornman PC, Terblanche J. Traumatic pancreatic
pseudocysts. Br J Surg 1993 Jan; 80(1): 89–93.
52. Barkin JS, Ferstenberg RM, Panullo W, Manten HD, Davis RC Jr.
Endoscopic retrograde cholangiopancreatography in pancreatic trauma.
Gastrointest Endosc 1988 Mar–Apr; 34(2): 102–5.
53. Beckingham IJ, Krige JE, Bornman PC, Terblanche J. Long term outcome
of endoscopic drainage of pancreatic pseudocysts. Am J Gastroenterol
1999 Jan; 94(1): 71–4.
54. Berni GA, Bandyk DF, Oreskovich MR, Carrico CJ. Role of intraoperative
pancreatography in patients with injury to the pancreas. Am J Surg 1982
May; 143(5): 602–5.
55. Hayward SR, Lucas CE, Sugawa C, Ledgerwood AM. Emergent endoscopic
retrograde cholangiopancreatography. A highly specific test for acute
pancreatic trauma. Arch Surg 1989 Jun; 124(6): 745–6.
56. Wisner DH, Wold RL, Frey CF. Diagnosis and treatment of pancreatic
injuries. An analysis of management principles. Arch Surg 1990 Sep;
125(9): 1109–13.
57. Bornman PC, Krige JE. Management strategies in pancreatic trauma.
Johannesburg: University of the Witwatersrand Press, 2006.
58. Keller MS, Stafford PW, Vane DW. Conservative management of
pancreatic trauma in children. J Trauma 1997 Jun; 42(6): 1097–100.
59. Holmes JHt, Wiebe DJ, Tataria M, et al. The failure of nonoperative
management in pediatric solid organ injury: a multi-institutional experi-
ence. J Trauma 2005 Dec; 59(6): 1309–13.
60. Stringer MD. Pancreatic trauma in children. Br J Surg 2005 Apr; 92(4):
467–70.
61. Duchesne JC, Schmieg R, Islam S, Olivier J, McSwain N. Selective nonop-
erative management of low-grade blunt pancreatic injury: are we there
yet? J Trauma 2008 Jul; 65(1): 49–53.
62. Kouchi K, Tanabe M, Yoshida H, et al. Nonoperative management of
blunt pancreatic injury in childhood. J Pediatr Surg 1999 Nov; 34(11):
1736–9.
63. Lin BC, Fang JF, Wong YC, Liu NJ. Blunt pancreatic trauma and
pseudocyst: management of major pancreatic duct injury. Injury 2007
May; 38(5): 588–93.
64. Canty TG Sr, Weinman D. Management of major pancreatic duct injuries
in children. J Trauma 2001 Jun; 50(6): 1001–7.
65. Phelan HA, Minei JP. Pancreatic trauma: diagnostic and therapeutic
strategies. Curr Treat Options Gastroenterol 2005 Oct; 8(5): 355–63.
66. Glancy KE. Review of pancreatic trauma. West J Med 1989 Jul; 151(1):
45–51.
67. Patton JH Jr, Fabian TC. Complex pancreatic injuries. Surg Clin North
Am 1996 Aug; 76(4): 783–95.
68. Patton JH Jr, Lyden SP, Croce MA, et al. Pancreatic trauma: a simplified
management guideline. J Trauma 1997 Aug; 43(2): 234–9; discussion
9–41.
69. Cogbill TH, Moore EE, Morris JA Jr, et al. Distal pancreatectomy for
trauma: a multicenter experience. J Trauma 1991 Dec; 31(12): 1600–6.
70. Pachter HL, Hofstetter SR, Liang HG, Hoballah J. Traumatic injuries to
the pancreas: the role of distal pancreatectomy with splenic preservation.
J Trauma 1989 Oct; 29(10): 1352–5.
71. Dawson DL, Scott-Conner CE. Distal pancreatectomy with splenic
preservation: the anatomic basis for a meticulous operation. J Trauma
1986 Dec; 26(12): 1142–5.
72. Schein M, Freinkel W, D’Egidio A. Splenic conservation in distal pancre-
atic injury: stay away from the hilum! J Trauma 1991 Mar; 31(3): 431.
73. Asensio JA, Petrone P, Roldan G, Kuncir E, Demetriades D. Pancreatico-
duodenectomy: a rare procedure for the management of complex pancre-
aticoduodenal injuries. J Am Coll Surg 2003 Dec; 197(6): 937–42.
74. Koniaris LG. Role of pancreatectomy after severe pancreaticoduodenal
trauma. J Am Coll Surg 2004 Apr; 198(4): 677–8; author reply 8–9.
75. Krige JE, Beningfield SJ, Nicol AJ, Navsaria P. The management of
complex pancreatic injuries. S Afr J Surg 2005 Aug; 43(3): 92–102.
76. McKay A, Mackenzie S, Sutherland FR, et al. Meta-analysis of
pancreaticojejunostomy versus pancreaticogastrostomy reconstruction
after pancreaticoduodenectomy. Br J Surg 2006 Aug; 93(8): 929–36.
77. Nakao A, Fujii T, Sugimoto H, et al. Is pancreaticogastrostomy safer than
pancreaticojejunostomy? J Hepatobiliary Pancreat Surg 2006; 13(3):
202–6.
78. Bassi C, Dervenis C, Bultirini G. Postoperativ pancreatic fistula – an
international study group (IS6PF) definition. Surgery 2005; 138: 8.
79. Subramanian A, Dente CJ, Feliciano DV. The management of pancre-
atic trauma in the modern era. Surg Clin North Am 2007 Dec; 87(6):
1515–32, x.
80. Hsieh CH, Liu NJ, Chen RJ, Fang JF, Lin BC. Endoscopically placed
pancreatic stent in a patient with concomitant two locations of main pan-
creatic duct disruption following pancreatic trauma. Hepatogastroenter-
ology 2003 Jan–Feb; 50(49): 269–71.
81. Kim HS, Lee DK, Kim IW, et al. The role of endoscopic retrograde
pancreatography in the treatment of traumatic pancreatic duct injury.
Gastrointest Endosc 2001 Jul; 54(1): 49–55.
82. Bagci S, Tuzun A, Erdil A, et al. Endoscopic treatment of pancreatic duct
disruption due to blunt abdominal trauma: a case report. Mil Med 2007
May; 172(5): 548–50.
83. Blumgart MD, ed. Surgery of the Liver, Biliary Tract and Pancreas.
London: Elsevier, 2006.
469
50 Pancreas transplantation
Khalid Khwaja
Over the past four decades, the field of pancreas transplanta-
tion has seen much evolution, both through refinement in sur-
gical techniques and improvement in immunosuppressive
strategies. Pancreas transplantation is primarily performed in
uremic, type I diabetics in conjunction with a kidney trans-
plant, and when successful, results in freedom from exogenous
insulin therapy, amelioration, or even reversal, of diabetes-
associated complications and improved quality of life. Pan-
creas transplants, contrary to other organ transplants, are not
considered essential to patient survival. For each individual
recipient, the potential benefit of a pancreas transplant must
be carefully weighed against the risk of a major surgical opera-
tion and lifelong immunosuppression.
The first successful pancreas transplant was performed at
the University of Minnesota in 1966 (1). Early outcomes were
poor, largely due to technical and infectious complications and
the lack of effective and safe immunosuppressive regimens.
Over the next decade, the efforts of investigators at several cen-
ters in Europe and North America resulted in refinement of
surgical techniques and improvement in results. With the
introduction of cyclosporine into clinical practice, the field of
pancreas transplantation blossomed in the 1980s and out-
comes became comparable to those of other transplanted
organs. To date, over 20,000 pancreas transplants have been
performed worldwide, as reported by the International Pan-
creas Transplant Registry and about 75% of these have been in
the United States (2). In 2006 alone, 1386 pancreas transplants
were performed in the United States, with approximately 4000
people waiting for pancreas transplants at the end of that year
(Fig. 50.1) (3).
categories of pancreas transplant
Pancreas transplantation is divided into three recipient
categories as follows:
Simultaneous Kidney and Pancreas Transplant (SPK)
Pancreas transplants are most often performed in conjunction
with a simultaneous kidney transplant (Fig. 50.2). About 10%
of Type I diabetics will develop end stage renal disease (ESRD)
during their lifetime (4,5) and over 40% of ESRD cases in the
United States are due to diabetes (6). If a type I diabetic is a
candidate for a kidney transplant, it is logical to consider them
for a simultaneous pancreas transplant. Thus, two goals are
accomplished (freedom from dialysis and normalization of
glucose metabolism without exogenous insulin therapy) with
one surgical procedure and one round of induction immuno-
suppresssion. As the two organs are from the same deceased
donor, the kidney acts as a surrogate marker for pancreas
rejection, allowing for better immune monitoring. A variant of
SPK is a simultaneous pancreas and living-donor kidney
transplant (SPLK). This technique, popularized by a few
470
centers, involves performing a living-donor kidney transplant
at the same time as a deceased donor pancreas transplant (7,8).
SPK using a kidney and a partial pancreas graft and a kidney
from the same living donor has also been reported (9).
Pancreas After Kidney Transplant (PAK)
Here, the pancreas transplant is performed after the kidney
transplant in a separate operation. The benefits of preemptive
(before the initiation of dialysis) kidney transplantation have
been well established (10,11). When a uremic diabetic presents
for transplant consideration, they are candidates for either a
SPK or a living donor kidney transplant followed by a PAK.
The approach varies depending on the region of the country
and the availability of a living kidney donor. Type I diabetics
on dialysis have a waitlist mortality of almost 10% per year,
which is higher than that for people with other causes of ESRD
(12). If a living donor is available, than kidney transplant
should be performed as soon as possible, as outcomes after
transplant worsen in direct proportion to time spent on dialy-
sis (11). Some regions of the United States allocate waitlist pri-
ority to diabetics listed for SPK (over kidney alone candidates)
and in these areas, SPK may be the better option.
Pancreas Transplant Alone (PTA)
The fewest pancreas transplants are performed in this category.
A select group of non-uremic, type I diabetics who have failed
insulin therapy can be considered for solitary pancreas trans-
plantation. These patients usually have severe and life-threaten-
ing metabolic complications, such as hypoglycemia unawareness,
justifying the risk of surgery and immunosuppression.
indications for pancreas transplant
The goals of pancreas transplantation are to improve quality
of life, normalize glucose metabolism, arrest or reverse end
organ damage from diabetes, and protect the transplanted kid-
ney from the effects of hyperglycemia. It is mainly indicated
for uremic type I diabetics. However, successful outcomes have
been reported with pancreas transplants in type II diabetics
(13), but this group accounts for less than 10% of SPK trans-
plants. The American Diabetes Association (ADA) criteria for
solitary pancreas transplant (PTA) in type I diabetics are (1) a
history of frequent, acute, and severe metabolic complications
such as hypoglycemia, hyperglycemia, ketoacidosis; (2) inca-
pacitating clinical and emotional problems with exogenous
insulin therapy; and (3) consistent failure of insulin-based
management to prevent acute complications (14).
Pancreas transplant is a reasonable option for patients with
traumatic, inflammatory, or surgical loss of pancreatic func-
tion and has the added advantage in these cases of restoring
exocrine function (15). Transplantation is contraindicated in
the setting of pancreatic malignancy.

SPK PAK PTA
3000
Number of new registrations
2000
1000
0 The majority of transplanted pancreata are from deceased
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Figure 50.1 New registrations on pancreas waiting list by transplant type,
1995–2004. Data from 2007 OPTN/SRTR Annual Report. Accessed from
www.ustransplant.org December 2008. Abbreviations: SPK, simultaneous kid-
ney and pancreas; PAK, pancreas after kidney; PTA, pancreas transplant alone.
SPK PAK
1600
Number of transplants
1200
800
400
0 technical failure rates after transplant (20), and should be used
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Figure 50.2 Pancreas transplants in the United States by transplant type,
1997–2006. Data from 2007 OPTN/SRTR Annual Report. Accessed from
www.ustransplant.org December 2008.
the pancreas recipient
Pretransplant evaluation of the potential pancreas transplant
recipient is geared toward excluding occult infection, malig-
nancy, and coronary artery disease. After a thorough history
and physical exam, screening for CMV, EBV, hepatitis B and C,
HIV, syphilis, and tuberculosis is performed and vaccinations
are updated. Pancreas transplantation should not be per-
formed in the setting of active hepatitis B or C or if there is
underlying cirrhosis. HIV-positive patients who have no his-
tory of opportunistic infections, preserved CD4 counts and
low viral loads can be considered for transplantation (16).
Minimum screening for malignancy should include a CXR,
PAP smear for all women, mammogram for women over
40 years, PSA for men over 50 years, and a colonoscopy for
those over 50 years. Active malignancy is an absolute contrain-
dication to transplant, and a disease-free period of 2 to 5 years,
depending upon the type and stage of the cancer, is recom-
mended prior to transplant (17).
Diabetics frequently have asymptomatic coronary artery
disease, and should undergo baseline exercise or pharmaco-
logic stress testing. However, the sensitivities of these tests vary
and, in one study, 20% of patients with a negative dobutamine
stress echo had a cardiac event posttransplant (18). Some cen-
ters routinely perform coronary angiography in all candidates,
although this may be detrimental to those not yet on dialysis.
PANCREAS TRANSPLANTATION
All pancreas Patients with symptomatic coronary artery disease or stenoses
greater than 75% should undergo pretransplant revasculariza-
tion (19).
All candidates should have optimal management of hyper-
tension, hyperlipidemias, and be counseled on weight loss and
smoking cessation if indicated. A BMI > 30 kg/m2 is an inde-
pendent risk factor for technical graft failure (20).
the pancreas donor
donors who meet criteria for brain death. Selective use of
pancreata from donors after cardiac death (DCD) is increas-
ing, with no compromise in outcomes (21). Living donor
pancreas transplants are not widely performed. The distal half
of the donor pancreas, based on the splenic vessels, is removed
for implantation, as a segmental graft (22). However, given
the donor risk, the relatively short waiting times for solitary
PTA All pancreas pancreas transplants and the fact that these transplants are
not necessarily “life-saving,” use of live donors is hard to
justify (23).
All potential donors undergo a thorough medical evaluation
and are screened for transmissible diseases such as HIV and
hepatitis B and C. The presence of active or recent malignancy
is generally a contraindication to pancreas donation. Pancre-
ata from donors with a BMI greater than 30 kg/m2, age greater
than 45 years and a cerebrovascular cause of death have higher
very selectively. Hyperglycemia, per se, does not contraindicate
donation, as it is often related to donor stress or use of vasoac-
tive drugs or steroids. Organs from pediatric donors
(3–11 years) have been used for SPK transplants with good
long-term results (24). A donor risk index has been developed
and will allow more informed selection of donors and match-
ing with potential recipients (25).
surgical techniques
Procurement
The various methods for recovery of the pancreas from the
deceased donor have been well described (26–28). Often, mul-
tiple recovery teams are present, and careful coordination
between them is of paramount importance. Exposure is
through a long midline or cruciate incision. The infrarenal and
supraceliac aorta are controlled and looped and the pancreas is
inspected through the lesser sac. The gland is assessed for qual-
ity, in particular, presence of edema, injury, fibrosis, and fat
content. Pancreas dissection can be performed “in the warm”
(prior to crossclamp) or “in the cold’” (after crossclamp);
other surgeons prefer some form of en bloc recovery tech-
nique, with separation of the pancreas from the liver ex situ
(29,30). The supraceliac aorta is clamped and the infrarenal
aorta flushed with preservation solution. Various solutions are
available and in the United States, typically University of Wis-
consin (UW) or Histidine–Tryptophan–Ketoglutarate (HTK)
solutions are used; however, recent studies suggest that the rate
of posttransplant pancreatitis and graft failure is higher with
HTK use (31,32). After flush, the pancreas is mobilized, using
the spleen as a handle. The duodenum is maintained intact
with the gland and the mesenteric root stapled and divided
471
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 50.3 A pancreas allograft procured from a deceased donor, with the
duodenum and spleen intact.
Figure 50.4 A procured pancreas allograft. The portal vein (PV), superior
mesenteric artery (SMA), and splenic artery (SA) are preserved with the graft.
The duodenal ends and the root of the small bowel mesentery are transected
with a stapling device.
Figure 50.5 Pancreas allograft after backtable preparation. The spleen is
removed and the distal splenic vessels ligated. The inferior mesenteric vein is
ligated. The duodenal staple lines are oversewn. A donor iliac artery “Y graft”
is anastomosed to the SMA and SA.
472
away from the pancreatic head. The superior mesenteric artery
(SMA) and splenic artery (SA) are kept with the pancreas, with
the rest of the celiac axis reserved for the liver graft. The portal
vein is divided at the midhilar level, with the distal half provid-
ing venous outflow for the pancreas. A donor iliac artery is
retrieved, with its bifurcation, for subsequent vascular recon-
struction.
Living-donor pancreas procurement can be performed
through an open or laparoscopic approach (22,33). The body
and tail of the gland are mobilized while preserving the gastro-
epiploic arcade to allow preservation of the spleen. The splenic
vessels are ligated at the splenic hilum. The gland is divided at
the left border of the superior mesenteric vein (SMV), and the
pancreatic duct identified. The splenic artery is divided just
distal to its celiac origin and the splenic vein at its confluence
with the SMV, the gland flushed and submitted to the recipient
team for implantation.
backtable preparation
A carefully performed backtable preparation is probably the
single most important technical aspect of pancreas transplan-
tation. All work is carried out in a basin of preservative solu-
tion, cooled to about 4°C. The graft is received with the spleen
and duodenum intact (Figs. 50.3 and 50.4). The spleen is
removed by ligating the splenic vessels close to the distal end of
the pancreas. Loose, fatty tissue on the upper and lower bor-
ders of the pancreas is carefully tied, the inferior mesenteric
vein is ligated and the staple lines on the mesenteric stump and
duodenal ends oversewn. On the posterior surface of the
gland, the open ends of the PV, SMA, and SA are identified and
any surrounding lymphatic and ganglionic tissue removed.
The pancreatic head and duodenum will derive arterial supply
from the SMA via the inferior pancreaticoduodenal arcade
and the body and tail of the gland will be supplied by the SA.
This dual supply is united by means of a “Y-graft” fashioned
from the donor iliac vessels (Fig. 50.5), enabling a single arte-
rial anastomosis during the recipient operation.
recipient operations
The recipient operation varies with respect to graft placement
(intra- vs. extraperitoneal), venous drainage (systemic vs. por-
tal), and exocrine drainage (bladder vs. enteric). Most grafts are
placed intraperitoneally, although a few centers prefer extraper-
itoneal placement, similar to the approach used for kidney
transplantation (34,35). Intraperitoneal placement allows place-
ment of the kidney through the same incision in SPK trans-
plants and may be associated with less wound problems (36).
Systemic Venous Drainage
Most pancreas transplants are drained systemically, usually
into the iliac vein, on the right side (2). A lower midline inci-
sion is made and the cecum and right colon mobilized medi-
ally to expose the iliac vessels and ureter. The iliac vessels are
completely mobilized, and all hypogastric venous branches
ligated to allow full mobilization of the iliac vein and to reduce
tension on the subsequent venous anastomosis. The graft is
then brought into the operative field, with the head and
duodenum directed caudally. The portal vein is anastomosed
 PANCREAS TRANSPLANTATION
Figure 50.6 Transplanted[u1] pancreas allograft, just after reperfusion.
Figure 50.7 A SPK transplant. The graft PV is anastomosed to the recipient
right common iliac vein and the Y-graft to the recipient right common iliac
artery. A side-to-side enteric anastomosis is depicted. The kidney is trans-
planted to the left external iliac vessels and a standard ureteroneocystostomy is
constructed.
in an end-to-side fashion to the iliac vein and the long limb of
the “Y-graft” to the iliac artery and the graft reperfused
(Fig. 50.6). The graft duodenum is then drained into the blad-
der or bowel. Alternatively, the graft can be placed with the
head cephalad, with venous drainage directly into the cava
(37); this, however, precludes the option of bladder drainage.
In an SPK transplant, the kidney is placed on the opposite side,
either before or after the pancreas (Fig. 50.7).
Figure 50.8 Pancreas transplant with portal venous drainage and enteric anas-
tomosis. The graft PV is anastomosed, end-to-side, to the recipient superior
mesenteric vein. The graft duodenum points cephalad.
Portal Venous Drainage
About 20% to 30% of all pancreas transplants are currently
drained into the portal venous system (2). Its proponents
claim that this approach is more physiologic and associated
with lower rates of rejection (38). Indeed, systemic transplants
are associated with hyperinsulinemia, but the significance of
this is unclear (39). Disadvantages of portal drainage are a
graft that is less amenable to percutaneous biopsy and the
inability to perform bladder exocrine drainage. However, reg-
istry data show no difference in graft survival between the two
techniques (2). The author uses both methods, preferring por-
tal drainage if a difficult pelvic dissection is anticipated or
there is a prior kidney transplant on the right side.
The approach is through an upper midline incision, and the
SMV is exposed at the root of the small bowel mesentery and
dissected as far proximally as possible. The right common iliac
artery is exposed through a “window” in the mesentery. The graft
is placed with the duodenum directed superiorly, and the
graft portal vein anastomosed, end-to-side, to the SMV. The
“Y-graft,” which is kept long, is anastomosed to the iliac artery
through the mesenteric window. The graft is then reperfused and
the enteric anastomosis completed (Fig. 50.8).
Bladder Drainage
Management of exocrine drainage has been the Achilles heel
of pancreas transplantation. Over the years, numerous
473
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
Figure 50.9 Pancreas transplant with systemic venous drainage and exocrine
drainage into the bladder. The graft duodenum points caudad.
techniques have been tried, including free drainage of the
pancreatic duct into the peritoneum (40) and obliteration of
the pancreatic duct with polymer injection (41,42). Currently,
bladder or enteric drainage is the standard techniques.
Bladder drainage of pancreatic exocrine secretions was first
described in 1984 (43) and was the predominant technique in
the 1990s (44). The graft duodenum is anastomosed directly to
the dome of the bladder, using absorbable sutures (Fig. 50.9).
A stapled technique, using an EEA device, has also been
described (45). The main advantage of this technique is the
early safety (small leaks, e.g., can be managed simply by cath-
eter drainage of the bladder) and less technical failure when
compared to enterically drained grafts (2). Urinary amylase
output can also be monitored and this is a sensitive marker for
pancreatic rejection (46). However, the technique is fraught
with long-term complications, such as dehydration, metabolic
acidosis, recurrent urinary tract infections, graft pancreatitis,
and hematuria (47). About 20% to 30% of bladder drained
grafts have to be converted to enteric drainage due to these
complications (48).
Enteric Drainage
Most centers currently prefer enteric drainage, to avoid the
metabolic complications associated with bladder drainage
(2). The availability of better immunosuppressive agents
and the lower rates of acute rejection have lessened the role
of urinary amylase monitoring. The graft duodenum is
anastomosed to a loop of proximal small bowel, either
directly (Fig. 50.7) or using a Roux-en-Y technique. Techni-
cal complications are actually higher when a Roux limb is
constructed (44). If the graft duodenum does not perfuse
well or the ischemic time is long, it may be more prudent to
use a Roux or perform bladder drainage.
474
Surgical Complications
Early surgical complications are particularly relevant after
pancreas transplantation as they often lead to graft loss. Com-
mon, pancreas-specific complications are thrombosis, hemor-
rhage, infection/pancreatitis, and anastomotic leak. Graft
thrombosis accounts for over 70% of technical failures (44)
and can be arterial or venous. The incidence varies with trans-
plant category and technique and ranges from 5% to 11%
(2,44). Risk factors for thrombosis include older donor age,
cerebrovascular cause of donor death, prolonged preservation
time, retransplantation, segmental grafts, and non-standard
vascular reconstruction (49). Rarely, with early surgical inter-
vention, a graft may be salvaged after thrombosis (50). Due to
improved antibiotic prophylaxis, better surgical techniques
and more “targeted” immunosuppression, the incidence of
perigraft infections is decreasing (2,44). Most infections will
occur in the first few weeks posttransplant and are treated
aggressively with antibiotics, antifungals, and surgical washout
if necessary. Anastomotic leak rates are around 5% to 10% and
tend to be higher with bladder-drained grafts (51,52). The
most important risk factor for leaks is preservation time; when
it exceeds 24 hours, leak rates as high as 25% have been
reported (53). Bladder leaks can often be managed with drain-
age alone, whereas enteric leaks usually require aggressive sur-
gical intervention.
outcomes
Historically, SPK transplant recipients have enjoyed much bet-
ter pancreas graft survival than PAK and SPK recipients (54).
Over the last decade, the 1-year survival for solitary grafts has
been steadily improving. Current 1-year graft survivals for
SPK, PAK, and PTA transplants are 86%, 79%, and 80%,
respectively (Fig. 50.10) (3). At 10 years, 51% of SPK recipients
still have functioning grafts, compared to only 28% of PAK
recipients and 24% of PTA recipients (55). Chronic rejection
and death with a functioning graft are responsible for most
cases of late graft loss (56).
Patient survival is similar for the three categories, and ranges
from 95% to 97% at 1 year and 64% to 71% at 10 years (Fig.
50.11) (3). Recent studies have clearly demonstrated a survival
advantage with SPK transplants (57–59). However, one analy-
sis of registry data suggested that survival after pancreas trans-
plant was worse with solitary pancreas transplants, when
compared to waitlisted people who received conventional
therapy for diabetes (58). Some patients were registered on
several waitlists and counted more than once, and patients
who dropped off the list for medical reasons were censored,
biasing the outcomes of this study. When these differences
were accounted for, there was no difference in survival at
4 years between waitlisted patients and those receiving PAK or
PTA transplants (level of evidence: III) (59).
effects on secondary complications
of diabetes
To date, there have been no prospective, randomized trials
comparing the efficacy of pancreas transplant versus medical
therapy. Moreover, most recipients already have advanced sec-
ondary complications at the time of transplant, making it

100% SPK
Unadjusted graft survival (%)
80%
60%
40%
20%
0%
1-Year 3-Year 5-Year
Figure 50.10 Unadjusted pancreas graft survival by transplant type. Data from
2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org
December 2008.
100% SPK
Unadjusted patient survival (%)
80%
60%
40%
20%
0%
1-Year 3-Year 5-Year
Figure 50.11 Unadjusted pancreas patient survival by transplant type. Data
from 2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org
December 2008.
difficult to demonstrate benefit after transplant. The Diabetes
Control and Complication Trial (DCCT) clearly showed the
benefits of normalizing blood glucose concentrations in dia-
betics, with an almost 50% reduction in retinopathy, neuropa-
thy, and nephropathy (60). Several, small, non-randomized,
but controlled studies provide evidence (level IIa) of the
beneficial effects of transplant on secondary diabetic
complications.
Reversal of diabetic nephropathy was seen 10 years (but not
at 5 years) after PTA, with decreased thickness of glomerular
and tubular basement membranes and decreased mesangial
fraction volume (61). Most studies investigating the effects of
transplantation on diabetic retinopathy are limited by the
presence of advanced disease at baseline. Proteinuria also
decreases after successful PTA when compared to matched
controls at 1-year posttransplant (62). Stabilization of retinop-
athy after pancreas transplantation has been well demon-
strated (63–65) with less disease progression over time in
comparison to controls (66). There is a sustained improve-
ment in nerve conduction velocity and action potential ampli-
tude after both SPK (67,68) and solitary pancreas
transplantation (67). Recipients of SPK transplants have less
progression of coronary atherosclerosis, (69) a better athero-
sclerotic risk profile (70), and significant improvement in car-
diac geometry and function in comparison to kidney-alone
recipients (71–73). There is improvement in systolic and dia-
stolic blood pressure (74,75) and other cardiovascular param-
eters (75) after combined pancreas–kidney transplantation
PANCREAS TRANSPLANTATION
PTA PAK and a lower incidence of death from cardiovascular causes
compared to waitlisted patients (73).
Several studies have demonstrated improvement in quality
of life after pancreas transplant, using various survey instru-
ments (level of evidence IIa to III) (76).
immunosuppression
Up to 80% of pancreas recipients receive some form of induc-
tion therapy at the time of transplant, usually a T-cell deplet-
10-Year
ing agent such as thymoglobulin (77). Standard maintenance
regimen consists of a calcineurin inhibitor (tacrolimus or
cyclosporine), an antimetabolite (mycophenolate mofetil or
sirolimus), and steroids. Outcomes with tacrolimus-based
therapy are better overall (78,79) but one must be wary of the
potential of nephrotoxicity with this agent (80). Steroid avoid-
PTA PAK ance and steroid withdrawal protocols are also increasingly
used, with good short-term results (81).
Acute rejection rates in the first year after pancreas trans-
plant are currently less than 25% for SPK transplants and
somewhat higher for solitary transplants (78). A rise in serum
amylase or lipase, a fall in urinary amylase output (for bladder-
drained grafts), and hyperglycemia are suggestive of acute
rejection, and should prompt a biopsy. The histologic features
10-Year
for diagnosis and grading acute pancreas allograft rejection
were recently standardized (82).
conclusions
Combined kidney and pancreas transplant is an effective
option for uremic patients with type I diabetes. A select group
of type I diabetics, who have normal renal function, may ben-
efit from a solitary pancreas transplant. In the current era,
graft survivals are comparable to those of other solid organ
transplants. There is much enthusiasm over islet cell trans-
plantation as a less invasive alternative, but, at present, the
results are not as durable as those of whole organ transplant
(83). No doubt, both fields will continue to evolve, with
ongoing advances in techniques and immunosuppression.
references
1. Kelly WD, Lillehei RC, Merkel FK, et al. Allotransplantation of the pan-
creas and duodenum along with the kidney in diabetic nephropathy.
Surgery 1966; 61: 827–37
2. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United
States (US) and non-US cases as reported to the United Network for
Organ Sharing (UNOS) and the International Pancreas Transplant Regis-
try (IPTR) as of June 2004. Clin Transplant 2005; 19: 433–55
3. Leichtman AB, Cohen D, Keith D, et al. Kidney and pancreas transplanta-
tion in the United States, 1997–2006: the HRSA Breakthrough Collabora-
tives and the 58 DSA Challenge. Am J Transplant 2008; 8(4 Pt 2): 946–57.
4. Finne P, Reunanen A, Stenman S, et al. Incidence of end-stage renal dis-
ease in patients with type 1 diabetes. JAMA 2005; 294(14): 1782–7
5. Nishimura R, Dorman JS, Bosnyak Z, et al. Incidence of ESRD and sur-
vival after renal replacement therapy in patients with type 1 diabetes: a
report from the Allegheny County Registry. Am J Kidney Dis. 200; 42(1):
117–24.
6. Foley RN, Collins AJ. End-stage renal disease in the United States: an
update from the United States Renal Data System. J Am Soc Nephrol 2007;
18(10): 2644–8.
7. Farney AC, Cho E, Schweitzer EJ, et al. Simultaneous cadaver pancreas
living-donor kidney transplantation: a new approach for the type 1 dia-
betic uremic patient. Ann Surg 2000; 232(5): 696–703.
475
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
8. Boggi U, Vistoli F, Del Chiaro M, et al. Simultaneous cadaver pancreas-
living donor kidney transplantation. Transplant Proc 2004; 36(3): 577–9.
9. Gruessner RW, Kendall DM, Drangstveit MB, et al. Simultaneous pan-
creas-kidney transplantation from live donors. Ann Surg 1997; 226(4):
471–80
10. Becker BN, Rush SH, Dykstra DM, et al. Preemptive transplantation for
patients with diabetes-related kidney disease. Arch Intern Med 2006;
166(1): 44–8.
11. Meier-Kriesche HU, Schold JD. The impact of pretransplant dialysis on
outcomes in renal transplantation. Semin Dial 2005; 18(6): 499–504.
12. United States Renal Data System (USRDS): 2008 Annual Data Report.
www.usrds.org Accessed December 2008.
13. Nath DS, Gruessner AC, Kandaswamy R, et al. Outcomes of pancreas
transplants for patients with type 2 diabetes mellitus. Clin Transplant
2005; 19(6): 792–7.
14. Robertson P, Davis C, Larsen J, Stratta R, Sutherland DE; American Dia-
betes Association. Pancreas transplantation in type 1 diabetes. Diabetes
Care 2004; 27 Suppl 1: S105
15. Gruessner RW, Manivel C, Dunn DL, Sutherland DE. Pancreaticoduodenal
transplantation with enteric drainage following native total pancreatec-
tomy for chronic pancreatitis: a case report. Pancreas 1991; 6(4): 479–88.
16. Toso C, Berney T, Oberholzer J, et al. Kidney-pancreas transplantation in
a long-term non-progressor HIV-infected recipient. Am J Transplant
2003; 3(5): 631–3.
17. Buell JF, Beebe TM, Trofe J, et al. Donor transmitted malignancies. Ann
Transplant 2004; 9(1): 53–6.
18. Herzog CA, Marwick TH, Pheley AM, et al. Dobutamine stress echocar-
diography for the detection of significant coronary artery disease in renal
transplant candidates.Am J Kidney Dis 1999; 33(6): 1080–90.
19. Manske CL, Wang Y, Rector T, Wilson RF, White CW. Coronary revascu-
larisation in insulin-dependent diabetic patients with chronic renal fail-
ure. Lancet 1992; 340(8826): 998–1002.
20. Humar A, Ramcharan T, Kandaswamy R, et al. Technical failures after
pancreas transplants: why grafts fail and the risk factors–-a multivariate
analysis. Transplantation 2004; 78(8): 1188–92.
21. Salvalaggio PR, Davies DB, Fernandez LA, Kaufman DB. Outcomes of
pancreas transplantation in the United States using cardiac-death donors.
Am J Transplant 2006; 6(5 Pt 1): 1059–65.
22. Sutherland DE, Gruessner R, Dunn D, et al. Pancreas transplants from
living-related donors. Transplant Proc 1994; 26(2): 443–5.
23. Kumar AF, Gruessner RW, Seaquist ER. Risk of glucose intolerance and
diabetes in hemipancreatectomized donors selected for normal preopera-
tive glucose metabolism. Diabetes Care 2008; 31(8): 1639–43.
24. Fernandez LA, Turgeon NA, Odorico JS, et al. Superior long-term results
of simultaneous pancreas-kidney transplantation from pediatric donors.
Am J Transplant 2004; 4(12): 2093–101.
25. Axelrod DA, Sung RS, Meyer KH, et al. Systematic evaluation of pancreas
allograft quality, outcomes and geographic variation in utilization. Am
J Transplant 2010; 10(4): 837–45.
26. Starzl TE, Hakala TR, Shaw BW Jr., et al. A flexible procedure for multiple
cadaveric organ procurement. Surg Gynecol Obstet 1984; 158(3): 223–30.
27. Delmonico FL, Jenkins RL, Auchincloss H Jr., et al. Simultaneous pro-
curement of pancreas and liver from a single cadaveric donor. Transplant
Proc 1989; 21(3): 3521.
28. C Marsh CL, Perkins JD, Sutherland DE, et al. Combined hepatic and
pancreaticoduodenal procurement for transplantation. Surg Gynecol
Obstet 1989; 168(3): 254–8.
29. Boggi U, Vistoli F, Del Chiaro M, et al. A simplified technique for the en
bloc procurement of abdominal organs that is suitable for pancreas and
small-bowel transplantation. Surgery 2004; 135(6): 629–41.
30. Moon JI, Nishida S, Butt F, et al. Multi-organ procurement and successful
multi-center allocation using rapid en bloc technique from a controlled
non-heart-beating donor. Transplantation 2004; 77(9): 1476–7.
31. Alonso D, Dunn TB, Rigley T, et al. Increased pancreatitis in allografts
flushed with histidine-tryptophan-ketoglutarate solution: a cautionary
tale. Am J Transplant 2008; 8(9): 1942–5.
32. Stewart ZA, Cameron AM, Singer AL, et al. Histidine-tryptophan-keto-
glutarate (htk) is associated with reduced graft survival in pancreas trans-
plantation. Am J Transplant. Early online view, 2008 Nov 4.
476
33. Tan M, Kandaswamy R, Sutherland DE, Gruessner RW. Laparoscopic
donor distal pancreatectomy for living donor pancreas and pancreas-
kidney transplantation. Am J Transplant 2005; 5(8): 1966–70.
34. Adamec M, Janousek L, Saudek F, Tosenovský P. 100 pancreas transplan-
tations with extraperitoneal graft placement. Ann Transplant 2001; 6(2):
41–2.
35. Boggi U, Vistoli F, Signori S, et al. Outcome of 118 pancreas transplants
with retroperitoneal portal-enteric drainage. Transplant Proc 2005; 37(6):
2648–50.
36. Schweitzer EJ, Bartlett ST. Wound complications after pancreatic trans-
plantation through a kidney transplant incision. Transplant Proc 1994;
26(2): 461.
37. Fridell JA, Shah A, Milgrom ML, et al. Ipsilateral placement of simultane-
ous pancreas and kidney allografts. Transplantation 2004; 78(7): 1074–6.
38. Philosophe B, Farney AC, Schweitzer EJ, et al. Superiority of portal venous
drainage over systemic venous drainage in pancreas transplantation: a
retrospective study. Ann Surg 2001; 234(5): 689–96.
39. Diem P, Abid M, Redmon JB, et al. Systemic venous drainage of pancreas
allografts as independent cause of hyperinsulinemia in type I diabetic
recipients. Diabetes 1990; 39(5): 534–40.
40. Sutherland DE, Baumgartner D, Najarian JS. Free intraperitoneal drain-
age of segmental pancreas grafts: clinical and experimental observations
on technical aspects. Transplant Proc 1980; 12(4 Suppl 2): 26–32.
41. Dubernard JM, Traeger J, Neyra P, et al. A new method of preparation of
segmental pancreatic grafts for transplantation: trials in dogs and in man.
Surgery 1978; 84(5): 633–9.
42. Little JM, Lauer C, Hogg J. Pancreatic duct obstruction with an acrylate
glue: a new method for producing pancreatic exocrine atrophy. Surgery
1977; 81(3): 243–9.
43. Sollinger HW, Cook K, Kamps D, et al. Clinical and experimental experi-
ence with pancreaticocystostomy for exocrine pancreatic drainage in pan-
creas transplantation. Transplant Proc 1984; 16(3): 749–51.
44. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United
States (US) cases reported to the United Network for Organ Sharing
(UNOS) and non-US cases reported to the International Pancreas Trans-
plant Registry (IPTR) as of October, 2000. Clin Transpl 2000: 45–72.
45. Pescovitz MD, Dunn DL, Sutherland DE. Use of the circular stapler in
construction of the duodenoneocystostomy for drainage into the bladder
in transplants involving the whole pancreas. Surg Gynecol Obstet 1989;
169(2): 169–71.
46. Prieto M, Sutherland DE, Fernandez-Cruz L, et al. Experimental
and clinical experience with urine amylase monitoring for early diag-
nosis of rejection in pancreas transplantation. Transplantation 1987;
43(1): 73–9.
47. Baktavatsalam R, Little DM, Connolly EM, et al. Complications relating
to the urinary tract associated with bladder-drained pancreatic transplan-
tation. Br J Urol 1998; 81(2): 219–23.
48. West M, Gruessner AC, Metrakos P, et al. Conversion from bladder to
enteric drainage after pancreaticoduodenal transplantations. Surgery
1998; 124(5): 883–93.
49. Humar A, Kandaswamy R, Drangstveit MB, et al. Surgical risks and out-
come of pancreas retransplants. Surgery 2000; 127(6): 634–40.
50. Boggi U, Vistoli F, Signori S, et al. Surveillance and rescue of pancreas
grafts. Transplant Proc 2005; 37(6): 2644–7.
51. Gruessner RW, Sutherland DE, Troppmann C, et al. The surgical risk of
pancreas transplantation in the cyclosporine era: an overview. J Am Coll
Surg 1997; 185(2): 128–44.
52. Sollinger HW, Messing EM, Eckhoff DE, Pirsch JD, et al. Urological com-
plications in 210 consecutive simultaneous pancreas-kidney transplants
with bladder drainage. Ann Surg 1993 Oct; 218(4): 561–8
53. Humar A, Kandaswamy R, Drangstveit MB, et al. Prolonged preservation
increases surgical complications after pancreas transplants. Surgery 2000;
127(5): 545–51.
54. Gruessner A, Sutherland DE. Pancreas transplant results in the United
Network for Organ Sharing (UNOS) United States of America (USA)
Registry compared with non-USA data in the International Registry. Clin
Transpl 1994: 47–68.
55. Sutherland DE, Gruessner AC. Long-term results after pancreas
transplantation. Transplant Proc 2007; 39(7): 2323–5.
 PANCREAS TRANSPLANTATION
56. Humar A, Khwaja K, Ramcharan T, et al. Chronic rejection: the next
major challenge for pancreas transplant recipients. Transplantation 2003;
76(6): 918–23.
57. Ojo AO, Meier-Kriesche HU, Hanson JA, et al. The impact of simultane-
ous pancreas-kidney transplantation on long-term patient survival.
Transplantation 2001; 71(1): 82–90.
58. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas
transplantation in patients with diabetes and preserved kidney function.
JAMA 2003; 290(21): 2817–23.
59. Gruessner RW, Sutherland DE, Gruessner AC. Mortality assessment for
pancreas transplants. Am J Transplant 2004; 4(12): 2018–26.
60. The Diabetes Control and Complications Trial Research Group. the effect
of intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N Engl J
Med 1993; 329: 977–86
61. Fioretto P, Steffes MW, Sutherland DER, et al. Reversal of lesions of dia-
betic nephropathy after pancreas transplantation. N Engl J Med 1998;
339; 69–75.
62. Coppelli A, Giannarelli R, Boggi U, et al. Disappearance of nephrotic syn-
drome in type 1 diabetic patients following pancreas transplant alone.
Transplantation 2006; 81(7): 1067–8.
63. Konigsrainer A, Miller K, Steurer W, et al. Does pancreas transplantation
influence the course of diabetic retinopathy? Diabetologia 1991; 34(S1):
S86–8.
64. Koznarova R, Saudek F, Sosna T, et al. Beneficial effect of pancreas and
kidney transplantation on advanced diabetic retinopathy. Cell Transplant
2000; 9: 903–8.
65. Giannarelli R, Copelli A, Sartini MS, et al. Early improvement of unstable
diabetic retinopathy after solitary pancreas transplantation. Diabetes
Care 2002; 25: 2358–9.
66. Ramsey RC, Goetz FC, Sutherland DE, et al. Progression of diabetic reti-
nopathy after pancreas transplantation for insulin-dependent diabetes
mellitus. N Engl J Med 1998; 318: 208–14.
67. Navarro X, Sutherland DE, Kennedy WR. Long-term effects of pancreatic
transplantation on diabetic neuropathy. Ann Neurol 1997; 42: 727–36.
68. Allen RD, Al-Harbi IS, Morris JG, et al. Diabetic neuropathy after pan-
creas transplantation: determinants of recovery. Transplantation 1997; 63:
830–8.
69. Jukema J, Wouter MD, Smets YF, et al. Impact of simultaneous pancreas
and kidney transplantation on progression of coronary atherosclerosis in
patients with end-stage renal failure due to type 1 diabetes. Diabetes Care
2002; 25: 906–11.
70. Fiorina P, La Rocca E, Venturini M, et al. Effects of kidney-pancreas
transplantation on atherosclerotic risk factors and endothelial func-
tion in patients with uremia and type 1 diabetes. Diabetes 2001; 50(3):
496–501.
71. Gaber AO, Wicks MN, Hathaway DK, Burlew BS. Sustained improvement
in cardiac geometry and function following kidney-pancreas transplanta-
tion. Cell Transplant 2000; 9: 913–8.
72. Fiorina P, La Rocca E, Astorri E, et al. Reversal of left ventricular diastolic
dysfunction after kidney-pancreas transplantation in type 1 diabetic ure-
mic patients. Diabetes Care 2000; 23: 1804–10.
73. La Rocca E, Fiorina P, Di Carlo V, et al. Cardiovascular outcomes after
kidney-pancreas and kidney-alone transplantation. Kid Int 2001; 60:
1964–71.
74. Elliot MD, Kapoor A, Parker MA, et al. Improvement in Hypertension in
patients with diabetes mellitus after kidney/pancreas transplantation.
Circulation 2001; 104: 563–9.
75. Coppelli A, Giannarelli R, Mariotti R, et al. Pancreas Transplant alone
determines early improvement of cardiovascular risk factors and cardiac
function in type 1 diabetic patients. Transplantation 2003; 76: 974–6.
76. Joseph JT, Baines LS, Morris MC, Jindal RM. Quality of life after kidney
and pancreas transplantation: a review. Am J Kidney Dis 2003; 42(3):
431–45.
77. Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, et al. Immunosuppres-
sion: evolution in practice and trends, 1994–2004. Am J Transplant 2006;
6(5 Pt 2): 1111–31.
78. Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned from
more than 1,000 pancreas transplants at a single institution. Ann Surg
2001 Apr; 233(4): 463–501.
79. Saudek F, Malaise J, Boucek P, Adamec M; Euro-SPK Study Group. Effi-
cacy and safety of tacrolimus compared with cyclosporin microemulsion
in primary SPK transplantation: 3-year results of the Euro-SPK 001 trial.
Nephrol Dial Transplant 2005; 20(Suppl 2): ii3–10, ii62.
80. Ojo AO. Renal disease in recipients of nonrenal solid organ transplanta-
tion. Semin Nephrol 2007; 27(4): 498–507
81. Cantarovich D, Vistoli F. Minimization protocols in pancreas transplanta-
tion. Transpl Int 2008 Aug 15.
82. Drachenberg CB, Odorico J, Demetris AJ, et al. Banff schema for grading
pancreas allograft rejection: working proposal by a multi-disciplinary
international consensus panel. Am J Transplant 2008; 8(6): 1237–49.
83. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the
Edmonton protocol for islet transplantation. N Engl J Med 2006;
355(13): 1318–30.
477
51 Pediatric HPB disorders
Maureen McEvoy and Michael P. La Quaglia
introduction
Advances in surgical technique have led various treatment
options for patients with hepatobiliary and pancreatic disor-
ders. There have also been advances in the understanding of
pathogenesis and clinical behavior of specific diseases. This
chapter addresses the common hepatobiliary and pancreatic
disorders with a focus on surgical treatment modalities.
biliary atresia ⁽ba⁾
Classification
BA is an obstructive condition of the bile ducts. It is of
unknown etiology but results from a progressive obliterative
process of variable extent. It has a worldwide incidence of
1 in 5000 to 18,000 live births, and it is more common in
girls than in boys (1,2). Two clinical forms are described:
acquired and embryonic (3). The acquired form accounts
for 80% of affected infants. They are asymptomatic and
anicteric at birth and develop jaundice in the first postnatal
weeks. These otherwise normal infants are born with a pat-
ent biliary system which undergoes progressive inflamma-
tion and fibro-obliteration initiated by a perinatal insult.
Infants with the embryonic form have no jaundice-free
interval and suffer from one or more congenital anomalies,
such as interruption of the suprarenal segment of the infe-
rior vena cava with azygous continuation, preduodenal por-
tal vein, midline symmetric liver, intestinal malrotation,
situs anomalies, bronchial anomalies, and polysplenia or
asplenia (2,4).
Pathology
BA can be classified by using macroscopic appearance and
cholangiography findings according to three main catego-
ries. Types I, II, and III are defined as atresia at the site of the
common bile duct, at the site of the hepatic duct, and up to
the porta hepatis, respectively. Type III is most common. A
patent duct that can be anastomosed to the intestine at the
porta hepatis is present in 5% of cases. In more than 90% of
cases, no normal ductal structures are seen at the porta
hepatis (5).
Early in the course the liver is enlarged. There are portal
tract edema, bile duct proliferation, portal and periductal
inflammation, and associated areas of hepatic cell injury.
This process develops into end stage cirrhosis. The patho-
logic changes are generally considered to be panductal,
affecting intrahepatic as well as extrahepatic structures (6–8).
The degree of damage present in the intrahepatic biliary sys-
tem is responsible for much of the morbidity after hepatic
portoenterostomy (HPE). Paucity or absence of intralobular
bile ducts along with architectural disturbances, even in
jaundice-free infants after successful HPE, has been observed
by some (9).
478
Clinical Features
Signs and symptoms include jaundice, clay-colored stools, and
hepatomegaly. In infancy, jaundice that persists beyond
2 weeks is no longer considered physiologic. The differential
for neonatal cholestasis is presented in Table 51.1. The first
step in diagnosis in an infant is to identify conjugated hyper-
bilirubinemia with prolonged jaundice, pale stools, or dark
urine. A conjugated bilirubin greater than 20% of an elevated
total serum bilirubin is diagnostic of homeostasis. Table 51.2
lists the diagnostic evaluation appropriate for the homeostatic
neonate. Several authors consider liver biopsy to be the most
reliable test for establishing the diagnosis (10,11). Liver biopsy
can correctly predict extra hepatic biliary obstruction in more
than 90% of cases (1,12). Ultrasound is safe and noninvasive
and should be performed in all jaundiced infants as in initial
evaluation.
Treatment
The surgical procedure of choice is the HPE, first described by
Kasai in 1959 (13). The procedure has three components: (1)
abdominal exploration and cholangiography to confirm the
diagnosis, (2) dissection of the porta hepatis and transection
of biliary tissue remnants at the portal plate, and (3) establish-
ment of biliary drainage through the construction of a 40 to
50 cm Roux-en-Y jejunal conduit. Success in obtaining bile
flow is better if HPE is done when the patient is between 60
and 90 days old. The sequential use of HPE followed by liver
transplantation is the standard surgical paradigm followed
around the world (14–16).
Outcomes
Left untreated, an infant with BA has a life expectancy of
approximately 1 year. Following a Kasai procedure, 5-year sur-
vival rates with native liver have ranged between 48% and 60%.
With the sequential treatment of a Kasai portoenterostomy and
secondary liver transplant, if required, overall survival rate is
approximately 90% (17). Outcomes of BA following Kasai HPE
and liver transplant from various centers are summarized in
Table 51.3. Survival with the native liver after the Kasai opera-
tion is approximately 30% at 10 years and 14% to 23% at
20 years (18–21). The largest North American long-term experi-
ence with HPE demonstrated survival with the native liver of
35% at 10 years and 21% at 20 years (22). A recent series of 755
BA patients listed for liver transplantation from North America
reported a 3-year graft survival rate of 88% and a patient sur-
vival rate of 80% (23). Thus the current use of HPE followed by
liver transplantation in children who subsequently develop
cirrhosis provides excellent long-term survival for a disease that
is fatal without surgery. Complications include cholangitis,
cessation of bile flow, portal hypertension, intrahepatic cysts,
hepatopulmonary syndrome, and others.
 PEDIATRIC HPB DISORDERS

Table 51.1 Differential Diagnosis of Neonatal Cholestasis

1. Extrahepatic causes
A. Biliary atresia
B. Choledochal cyst
C. Bile duct stenosis, strictures, or cholelithiasis
D. Spontaneous perforation of the common bile duct
E. Tumors or masses (extrinsic or intrinsic compression of bile ducts)
2. Intrahepatic causes
A. Infectious: cytomegalovirus, rubella, herpes simplex, human herpesvirus 6, varicella zoster, adenovirus, enterovirus, parvovirus B19,
hepatitis B virus, human immunodeficiency virus, toxoplasmosis, syphilis, tuberculosis, listeriosis, bacterial sepsis, and urinary tract
infection
B. Metabolic: alpha-1 antitrypsin deficiency, cystic fibrosis, galactosemia, hereditary tyrosinemia, hereditary fructose intolerance,
glycogen storage disease type IV, Niemann-Pick type C, Gaucher’s disease, Wolman’s disease, cholesterol ester storage disease,
panhypopituitarism, hypothyroidism, bile acid synthesis defects, peroxisomal disorders, arginase deficiency, and mitochondrial
respiratory chain deficiencies
C. Genetic: Alagille syndrome, Turner syndrome, trisomy 21, arthrogryposis-renal dysfunction-cholestasis syndrome, Aagenaes syn-
drome (cholestasis with lymphedema), progressive familial intrahepatic cholestasis (FIC1, BSEP, and multiple drug resistance 3 gene
deficiencies), North American Indian childhood cirrhosis (cirrhin deficiency), congenital hepatic fibrosis/autosomal recessive
polycystic kidney disease, Caroli’s disease, and neonatal Dubin–Johnson syndrome
D. Toxic: total parenteral nutrition-associated, endotoxin from gram-negative infection, choral hydrate and other medications, and
aluminum
E. Cholangiopathies: nonsyndromic paucity of interlobular bile ducts and neonatal sclerosing cholangitis
F. Miscellaneous: idiopathic neonatal hepatitis, congenital lupus, ischemia-reperfusion injury, histiocytosis X, erythrophagocytic
lymphohistiocytosis, veno-occlusive disease, erythroblastosis fetalis (inspissated bile syndrome), and neonatal iron storage disease
Source: Reprinted from Ref. (105).

The incidence is 1 in 13,000 to 15,000 in western countries, but

Table 51.2 Diagnostic Evaluation in the Cholestatic Neonate
rates as high as 1 in 1000 have been described in Japan (24).
Basic evaluation Choledochal cyst can be categorized according to their
Serum aspartate aminotransferase and Serum alanine anatomic appearance into five types (25,26):
aminotransferase
γ-glutamyl transferase I. Cystic or diffuse fusiform dilatation of the extrahe-
Bilirubin—indirect and direct patic bile duct
Prothrombin time/International normalized ratio II. Diverticulum of the extrahepatic bile duct
Albumin level III. Choledochocele
Complete blood count IV. Multiple cysts of the intra- or extrahepatic ducts (or
Initial diagnostic evaluation
both)
Blood and urine cultures
Urine for reducing substances (if infant on a V. Single or multiple intrahepatic cysts
galactose-containing diet)
Type I accounts for at least 75% of all cases, and type IV
Galactose-1-phosphate uridyl transferase
accounts for most of the remainder. The other varieties are
Urine succinylacetone
Thyroid-stimulating hormone/T4 rare (27,28).
Cortisol
Hepatobiliary ultrasound Pathology
Secondary diagnostic evaluation
Histologic sections of the wall of extrahepatic choledochal
A1AT level and genotype
Cystic fibrosis screen
cysts have demonstrated a thick-walled structure of dense
Liver biopsy connective tissue interlaced with strands of smooth muscle. In
Hepatobiliary scintigraphy most instances, some degree of inflammatory reaction is
MRCP or ERCP (depending on facility) noted. The degree of histologic damage and the rate of epithe-
Source: Reprinted from Ref. (106). lial metaplasia and dysplasia are related to the age of the
patient (29). In a newborn, the histologic appearance of the
liver is usually normal or having mild bile duct proliferation
consistent with chronic biliary obstruction. Occasionally in
choledochal cyst older patients mild periportal fibrosis is noted.
Classification Choledochal cysts are congenital. There is predominance in
Choledochal cysts are congenital anomalies of the biliary tract females, suggesting a sex-linked defect, as well as a much
manifested by cystic dilatation of the extra hepatic biliary tree. higher incidence in Asian populations.

479
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Table 51.3 Contemporary Outcome of Biliary Atresia Following Kasai Hepatoportoenterostomy (HPE) and Liver
Transplantation
Country, year, and Number of Median age Survival with Survival after liver Overall survival
number of centers patients at HPE native liver transplantation of patients
Japan, 1989–1999, 1381 61–70 days 5 years: 59.7% (actual) _ 5 years: 75.5% (actual)
93 centers
UK and Ireland, 93 54 days 5 years: 30.1% (actuarial) 2.4 years: 89% (actual) 5 years: 85% (actuarial)
1993–1995, 15 centers
USA, 1997–2000, 9 centers 104 61 days 2 years: 55.8% (actual) 2 years: 88% (actual) 2 years: 91.3% (actual)
France, 1997–2002, 271 57 days 4 years: 42.7% (actuarial) 4 years: 88.8% (actuarial) 4 years: 87.1% (actuarial)
22 centers
England and Wales, 148 54 days 4 years: 51% (actuarial) 2 years: 89% (actuarial) 4 years: 89% (actuarial)
1999–2002, 3 centers
Source: Adapted from Ref. (107).

The most plausible etiology is obstruction of the distal
common bile duct.
Clinical Features
In the infantile form, patients present with obstructive jaun-
dice, acholic stools, and hepatomegaly at 1 to 3 months of age
(30). Patients do not tend to have abdominal pain of palpable
mass. Infants do not ordinarily become jaundiced until 1 to
3 weeks after birth. In the adult forms, the clinical manifesta-
tions do not become evident until the patient is 2 years old;
and most of these patients have fusiform deformities of the
common duct without high grade or complete obstruction.
The classic triad of abdominal pain, a palpable abdominal
mass, and jaundice may be noted (31). Only partial obstruc-
tion occurs in the adult form, so the symptoms are intermit-
tent. The pattern of pain has been described as similar to that
of recurrent pancreatitis.
Imaging
Ultrasonography may be the only screening required in
infants. If a choledochal cyst is suspected on US, 99Tc-
di-isopropylphenylcarbamoyl-methylimidodiacetic acid (DIS-
IDA) scintigraphy can confirm the diagnosis and provide
information about drainage, obstruction, and hepatic func-
tion. Prenatal ultrasonography of fetal choledochal cyst has
been reported by a number of investigators (32–34). A key
question after prenatal diagnosis is the appropriate timing of
surgical correction. Redkar suggests that asymptomatic
patients are best operated around 3 months of age (35). Suita
et al. noted that patients who undergo surgery within a month
of life have a lower incidence of hepatic fibrosis than those
operated on later (36).
Treatment
In 1970, Kasai et al. and Ishida et al. reported favorable results
with cyst excision and Roux-en-Y jejunostomy (37,38).
Outcome
Radical cyst excision and hepaticojejunostomy yield consis-
tently good results, even in small infants (27). In a large
Japanese series of 200 children followed for a mean of
11 years, Roux-en-Y hepaticojejunostomy was performed in
188 patients. No operative mortality occurred, and 9% had
complications including cholangitis, intrapancreatic termi-
nal CBD calculi, pancreatitis, and bowel obstruction (39).
gallbladder disease
Cholelithiasis
The prevalence of gallstones in children varies according to
geography and age. The predominant factors in gallstone for-
mation are biliary stasis, excess bilirubin pigment, and litho-
genic bile. Hemolytic disorders, fasting and TPN, ileal
resection/disease, cystic fibrosis, Down syndrome, childhood
cancer, bone marrow transplantation, cardiac transplantation,
spinal surgery, dystrophia myotonica, and chronic intestinal
pseudo-obstruction have all been associated with increased
incidence of cholelithiasis in children (40).
Gallstones in infants occasionally resolve spontaneously.
Early surgery can be deferred in the asymptomatic infant with
gallbladder calculi. Management of asymptomatic cholelithia-
sis in older children is controversial. In children without
hemolytic disorders, a conservative approach is recommended
(41). Cholecystectomy is the standard treatment for symptom-
atic or complicated gallbladder stones.
Hemolytic Cholelithiasis
In the past, the usual cause of gallstones in children was hemo-
lytic disease. Hereditary spherocytosis, sickle cell anemia, and
thalassemia are the most common hemolytic disorders result-
ing in the development of gallstones. In patients with sphero-
cytosis, ultrasound is indicated prior to splenectomy. If stones
are present, cholecystectomy is performed. In sickle cell dis-
ease, only symptomatic patients require cholecystectomy,
which should be preformed electively rather than emergently
during a hemolytic crisis (42).
Congenital Deformities
Congenital deformities include a variety of abnormal configu-
rations and locations of the gallbladder, such as gallbladder
agenesis, duplication, bilobation, floating gallbladder, diver-
ticula, and ectopia. They are usually of no clinical relevance; if

480
 PEDIATRIC HPB DISORDERS
they are of clinical relevance, the symptoms are from gallblad-
der emptying, and cholecystectomy is recommended.
hepatoblastoma
Incidence
Hepatoblastoma is the most common malignant hepatic
tumor. Liver cancers constitute 0.5% to 2% of all pediatric solid
tumors and about 5% of abdominal tumors in childhood (43).
Hepatoblastomas are the most common primary hepatic
tumors of childhood constituting 43% to 64% of all hepatic
neoplasms in one large series (43–45). Approximately two-
thirds of all liver masses occurring in children are malignant.
Eighty percent of 123 children in the United States registered
with malignant liver tumors in 2000 had hepatoblastoma and
they accounted for 91% of primary hepatic malignancies in
children less than 5 years of age (46). There are approximately
50 to 70 new cases per year in the United States with a male to
female ratio of 1.7:1 (47). The median age at diagnosis is
about 18 months, and most cases occur before age 2½ to
3 years (48).
Hepatoblastoma may occur in siblings (49–51). It is most
strongly associated with familial polyposis (52,53), Gardner’s
syndrome (54), and Beckwith–Wiedemann syndrome (55,56).
Pathology
The five histologic subtypes observed in hepatoblastoma are
fetal, embryonal, mixed mesenchymal, macrotubular, and
anaplastic or small cell. The importance of subtyping in hep-
atoblastoma is the association between prognostic risk and
subtype (57,58). Patients with small cell undifferentiated
tend to do worse. Figure 51.1 illustrates imaging and patho-
logy of a child with Beckwith-Wiedemann syndrome with
hepatoblastoma.
Clinical Features
The most common presenting sign of hepatoblastoma is an
asymptomatic abdominal mass. A mild anemia with a mark-
edly elevated platelet count is observed in most patients at
diagnosis. The cause is probably secondary to abnormal cyto-
kine release. In an abstract from the 1993 Annual Meeting of
the American Society of Clinical Oncology, Van Tournet et al.
stated that measurement of serum alpha-fetoprotein is well
established as an initial tumor marker in the diagnosis of hep-
atoblastoma and a means of monitoring the therapeutic
response. The normal level in most laboratories is less than 20
ng/ml whereas the AFP level at diagnosis in hepatoblastoma
patients can range from normal to 7.7 × 106 ng/ml. It is esti-
mated that the AFP is elevated in 84% to 91% of patients with
hepatoblastoma (58). In comparison, the mean in pediatric
patients with HCC was about 200,000 ng/ml (59).
Imaging
The first imaging study is usually an abdominal ultrasound.
Computed tomography (CT) is useful to identify pulmonary
metastases, identify diffuse hepatic involvement, and deter-
mine respectability. MRI is useful for evaluating hepatic lesions
and their relationship to vascular structures (60). It can show
the hepatic veins, the vena cava, and bile ducts.
Staging
Most studies to date have used the clinical grouping defined by
the Children’s Cancer Group and the Pediatric Oncology
Group, which is presented in Table 51.4.
Treatment
Most studies support the effectiveness of systemic chemother-
apy combined with complete surgical resection of the primary
hepatic tumor (61,62). Survival depends on removal of the pri-
mary liver tumor in most cases. The first clinical decision is
whether to initial neoadjuvant chemotherapy or proceed with
resection. A completely resected tumor without the presence of
metastatic disease is deemed stage I. If after resection pathology
shows pure fetal histology, close observation ensues. For all
other histologies and for stage II disease, four cycles of combi-
nation cisplatin, 5-fluorouracil, and incrusting are given. For a
tumor deemed unrespectable at diagnosis (stage III) or a
patient with metastatic disease (stage IV), current therapy con-
sists of four cycles of chemotherapy with either resection or
liver transplantation after cycle 4 followed by two more cycles.
Extensive tumors usually shrink with chemotherapy, facilitat-
ing resection, whereas chemotherapy might be lessened or
avoided in some patients by resection at diagnosis. About 46%
of hepatic malignancies are resectable at diagnosis (59).
Outcome
Overall survival of 60% to 70% is achievable with non-stage
IV hepatoblastoma except for with the very aggressive small
cell variant. Approximately 50% of patients who present with
pulmonary metastasis are curable. If gross disease remains in
the primary site, survival falls to zero. Some patients with
microscopic residual tumor are curable with continued che-
motherapy and may benefit from external-beam radiotherapy
to the primary hepatic site. In a multivariate analysis, factors
that have been independent predictors of worsened prognosis
include high TNM stage, unresectable tumor, bilobar involve-
ment and multifocality, AFP less than 100 ng/ml or more than
105 ng/ml, distant metastases, embryonal versus fetal histology,
and vascular invasion (63).
hepatocellular carcinoma ⁽hcc⁾
Incidence
HCC accounts for 23% of pediatric liver tumors (64). The
incidence is bimodal with an early peak that occurs before
5 years and a second peak that occurs between 13 and 15 years.
HCC is the most common hepatic malignancy of adolescence
(65). There is a male predominance of 1.3 to 3.2:1. Hepatitis B
and C correlate with the incidence of HCC. In Asia 85% of
these patients (adults and children) are hepatitis B surface
antigen positive, whereas this is found in only 10% to 25% of
patients in the United States. The relative risk for the develop-
ment of HCC is 250:1 for patients with chronic active hepatitis
compared with patients without hepatitis surface antigen posi-
tivity (66). Other conditions associated with the development of
HCC include cirrhosis, α1-antitrypsin deficiency, tyrosinemia,
aflatoxin ingestion, hemochromatosis, hepatic venous obstruc-
tion, androgen and estrogen exposure, Alagille syndrome, and
thorotrast administration (67).
481
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A) (B)

(C) (D)

(E)

Figure 51.1 Ten-month-old female with Beckwith–Wiedemann syndrome. (A,B) The hepatoblastoma is centered on the middle hepatic vein, with an extension
into the right hepatic vein (arrow in A) and an encasement of the left hepatic vein (arrow in B). (C,D) Preoperative chemotherapy resulted in shrinkage of the
tumor, with apparent involvement of a clear plane between the tumor and the right hepatic vein (arrow in C); panel D demonstrates the tumor encasing the left
portal vein. An attempted extended left hepatic lobectomy was abandoned because of the presence of an occult tumor involvement of the right hepatic vein noted
at surgery. (E) The patient underwent hepatic transplantation. Source: Reprinted from Ref. (104).

Pathology Clinical Features

HCCs are highly invasive and often multicentric at diagnosis,
with frequent hemorrhage and necrosis. Invasiveness, especially
vascular invasion, is a hallmark of these tumors. Extrahepatic
dissemination to portal lymph nodes, lungs, and bones is
frequent at diagnosis and strongly affects survival.
Children and adolescents with HCC frequently present (68)
with palpable abdominal masses (40%), but many are asymp-
tomatic at diagnosis. Pain is common (38%) and may occur in
the absence of an obvious mass. Constitutional disturbances
such a as anorexia, malaise, nausea and vomiting, and significant

482
 PEDIATRIC HPB DISORDERS

When encountered at laparotomy, they should usually be

Table 51.4 Children’s Oncology Group Staging
excised unless this would entail significant risk of morbidity.
for Hepatoblastoma
Stage I Complete resection Annular Pancreas
Favorable histology Purely fetal histology with a low Annular pancreas is thought to be due to a faulty rotation of the
mitotic index ventral pancreatic bud in its course around the posterior aspect
Other histology All other stage I tumors of the duodenal anlage during the sixth week of gestation. The
Stage II Gross total resection with duodenum is encircled by and obstructed with normal pancre-
microscopic residuals or total atic tissue containing normal functioning acini, ducts, and islets
resection with preoperative or of Langerhans (79,80). The theory is that half the ventral bud
intraoperative rupture
migrates anteriorly and half migrates posteriorly. Duodenal atre-
Stage III Unresectable tumors as
determined by the attending
sia and stenosis, intestinal malrotation, and trisomy 21 can often
surgeon, partially resected be found in combination with annular pancreas (81). The clini-
tumors with macroscopic cal symptoms relate to duodenal obstruction with bilious vomit-
residual, or any tumor with ing. Radiographic studies reveal the classic finding of the “double
lymph node involvement bubble” sign (82). Management consists of surgical bypass of the
Stage IV Measurable metastatic disease to obstructing lesion with a duodenoduodenostomy. Resection or
lungs or other organs division of the annular pancreas should not be carried out.
Source: Reprinted from Ref. (104).
Pancreas Divisum
Failure of the duct of Wirsung and the duct of Santorini to
weight loss occur with greater frequency. AFP is elevated in unite from the dorsal and ventral pancreas during development
approximately 85% of patients, with most levels greater than results in the anatomic variant known as pancreas divisum. In
1000 ng/ml (69). this disorder the duct of Wirsung is very small, and the duct of
Santorini becomes the major ductal system and communicates
Treatment with the duodenum through the minor papilla. If the orifice of
Long-term survival is impossible without complete resection. the accessory papilla is stenotic, pancreatitis can occur. The
However, because of the high incidence of multifocality within goal of treatment is to establish adequate drainage of the duct
the liver, extrahepatic extension to regional lymph nodes, vas- of Santorini. Several reports show that adequate drainage can
cular invasion, and distant metastases, complete resection is be obtained with accessory papilla sphincteroplasty (83).
often impossible. Unresectable HCCs can be palliated with
embolization with or without added chemotherapeutic agents Acute Pancreatitis
or radioisotopes (70). Percutaneous intralesional injection of The causes of acute pancreatitis include trauma, biliary tract
ethanol also has been of palliative benefit when lesions are stone disease, choledochal cyst, ductal developmental anoma-
small (71). Radiofrequency ablation of these tumors, percuta- lies, drugs, such as retrovirals, diuretics, anticonvulsants, as well
neously or at laparoscopy/laparotomy, has been associated as some chemotherapeutic agents, metabolic derangements,
with tumor resolution and prolonged survival (72–75). and infections. In children, trauma is the most common cause.
Pancreas divisum is an anomaly present in 10% of the popu-
Outcome lation, resulting from failure of the dorsal duct to fuse with the
The overall survival from HCC in childhood approaches zero ventral duct. This relative obstruction may cause recurring
and it remains a therapeutic problem. Occasionally, resection episodes of pancreatitis (84). These patients should undergo a
of localized lesions results in long-term survival. The trend is sphincteroplasty of the minor papilla. The pathogenesis
to separate HCC from hepatoblastoma in clinical studies entails the inappropriate activation of proenzymes, leading to
because of its greatly differing biologic behavior. autodigestion of the pancreas.
Acute pancreatitis usually presents with the acute onset of
pancreas midepigastric pain associated with back pain, severe vomiting,
Congenital Anomalies and low-grade fever (85,86). In severe cases of necrotizing or
Ectopic Pancreatic Rests hemorrhagic pancreatitis, hemorrhage may dissect from the
The incidence of ectopic pancreatic rests in autopsy ranges pancreas along tissue plans appearing as ecchymosis either in
from 1% to 2% (76) and is frequently encountered along fore- the flanks (Grey–Turner sign) or at the umbilicus (Cullen’s
gut derivatives, such as the stomach and duodenum, as well as sign). Lipase levels have been proposed as a more specific test of
jejunum, ileum, and colon (77). They represent the most com- pancreatic tissue damage, although intestinal perforation does
mon anomaly of the gastric antrum and may cause a gastric cause an elevation of lipase throughout reabsorption via the
outlet obstruction (78). Their origin is unknown, but one pos- peritoneum. Lipase is produced only in the pancreas and its
sible explanation suggests an aberrant epithelial–mesenchymal measurement is particularly helpful for distinguishing pancre-
interaction, leading to trans-differentiation of heterotrophic atic trauma from salivary trauma (87). CT scan offers better
embryonic epithelium into pancreatic epithelium. Ectopic rests resolution than other modalities to determine size of pancreas,
are usually asymptomatic and found incidentally at laparotomy. degree of edema, and the presence of fluid collections (88). It

483
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
can also distinguish areas of necrosis. ERCP has been shown to
have higher complication rates in children than in the adult
population; however, it may be helpful with an impacted stone
or in trauma patients with a pseudocyst (89). MRCP is a non-
invasive, nontherapeutic technique to evaluate the biliary tree
and pancreas. MRCP is currently the initial imaging study of
choice in evaluation of pancreatic ductal anatomy in children
with pancreatitis (90). Treatment requires aggressive fluid
replacement and low threshold for transferring the patient to
an intensive care unit (91,92). Surgical intervention in acute
pancreatitis is not often necessary and is reserved for patients
with severe necrotizing pancreatitis needing debridement or
patients with pancreatic abscess (93,94).
Pancreatic Abscess
A pancreatic abscess may result from infection of necrotic
pancreatic tissue or a peripancreatic fluid collection. Pancre-
atic abscess increases the mortality rate of pancreatitis three-
fold and is an absolute indication for surgical therapy (95,96).
Diagnosis is made by Gram stain and culture of the suspected
abscess by CT-guided needle aspiration. The indication is
fever and leukocytosis persisting more than 7 to 10 days after
onset of pancreatitis. Surgery consists of debridement of
clearly necrotic tissue and placement of large sump suction
drains.
Pancreatic Pseudocyst
Pancreatic pseudocysts result from damage of the pancre-
atic ductal system. The extravasated pancreatic enzymes
and digested tissue are contained by the formation of a cav-
ity composed of fibroblastic reaction and inflammation;
however, there is no epithelial lining. Pseudocysts may be
acute or chronic. Acute pseudocysts have an irregular wall
on CT, and about 50% resolve without therapy. Chronic
pseudocysts are spherical with a thick wall and rarely resolve
on their own. In children, pseudocysts tend to resolve more
frequently with medical therapy alone (97). Persistent pseu-
docysts require internal drainage, excision, or external
drainage.
Chronic Pancreatitis
Chronic pancreatitis differs from acute pancreatitis in the irre-
versibility of the changes associated with the inflammation
(98). Chronic pancreatitis is either calcifying or obstructive.
The calcifying form is more common in children and is usually
caused by hereditary pancreatitis, and is associated with intra-
ductal pancreatic stones, pseudocysts and a more aggressive
scar formation with significant damage. The obstructive type
is associated with anatomic obstructions and is less severe.
Chronic pancreatitis is uncommon in children, and the most
common cause in North America is hereditary or familial pan-
creatitis (99). The inheritance is autosomal dominant with
incomplete penetrance. The majority of patients express one
of two mutations in the trypsinogen gene leading to altera-
tions that prevent deactivation of trypsin within the pancreas
causing autodigestion. The diagnosis of chronic pancreatitis
depends on characteristic pain, diminished pancreatic func-
tion, and changes in radiographic appearances. Therapy is
484
directed toward palliation of symptoms. Surgical or endoscopic
therapy is indicated for bile or pancreatic duct obstruction or
for pancreatic pseudocyst complications (100).
Persistent Hyperinsulinemic Hypoglycemia of Infancy
The defect in patients with persistent hyperinsulinemic
hypoglycemia of infancy (PHHI) is related to four genes
responsible for the ability of the beta-cell to regulate insulin
secretion. Mutations prevent the normal feedback regulation
of insulin production by serum glucose. Patients typically
have hypoglycemia shortly after birth. It is critical to measure
serum insulin levels and glucose levels simultaneously
because the ratio is important. Initial treatment should con-
sist of frequent feedings, with the addition of intravenous
glucose as needed. Initial medical treatment should include
antisecretory drugs such as diazoxide or a long-acting soma-
tostatin analog. In patients with diffuse-type PHHI, adequate
surgical treatment consists of a 90% to 95% pancreatectomy,
leaving a residual remnant of the pancreas on the common
bile duct (101). It is important to examine the tissue for ade-
noma. Approximately 75% of patients develop diabetes
occurs after a 95% pancreatectomy (102). The long-term
outcome for these patients depends on the age at onset,
which relates to severity of disease. Most patients seem to
outgrow the disease after several years, perhaps due to dimin-
ished activity of the beta-cell.
Adenocarcinoma
In general, pancreatic cancers in children are rare. Acinar cell
adenocarcinoma has been seen in children and tends to be
less aggressive with a better prognosis. Treatment is complete
surgical resection. Another variant of adenocarcinoma seen
in younger children has been termed pancreatoblastoma. This
is the most common exocrine tumor of the pancreas in chil-
dren. It is more often seen in boys and is thought to be of
embryonic origin. These tumors are low malignancy and
often arise in the head of the pancreas (103). Metastases are
reported in one-third of cases, with the liver and lung being
the most common sites. The prognosis is relatively good with
a complete resection. As recurrence is common, close follow-up
is required.
KEY POINTS
Biliary atresia is marked by obstruction of the bile ducts.
In infancy, jaundice that persists beyond 2 weeks is
physiologic. Signs and symptoms include jaundice,
clay-colored stools, and hepatomegaly. Treatment is a
hepatic portoenterostomy.
Choledochal cysts are congenital anomalies of the biliary
tract. There are five types. They present with obstructive
jaundice. Treatment is cyst excision and Roux-en-Y
jejunostomy.
Cholelithiasis, hemolytic cholelithiasis, and congenital
deformities are gallbladder diseases seen in pediatrics.
Treatment varies for each and depends on symptoms.
 PEDIATRIC HPB DISORDERS
Hepablastoma is the most common malignant hepatic
tumor. There are five histologic subtypes. Patients with
small cell undifferentiated have worse prognosis. It
generally presents as an asymptomatic abdominal mass.
Treatment is with systemic chemotherapy and complete
surgical resection.
Hepatocellular carcinoma is the most common hepatic
malignancy of adolescence. It is highly invasive and
generally presents with an asymptomatic abdominal
mass. Treatment is complete resection; however, this is
often difficult, and thus embolization may be helpful.
Congenital anomalies consist of annular pancreas and
pancreas divisum. Pancreatitis is rare, but both acute and
chronic types are seen. Adenocarcinoma is rare in
children.
references
1. Mack CL, Sokol RJ. Unraveling the pathogenesis and etiology of biliary
atresia. Pediatr Res 2005; 57: 87R–94R.
2. Carmi R, Magee CA, Neill CA, et al. Extrahepatic biliary atresia and asso-
ciated anomalies: etiologic heterogeneity suggested by distinctive pat-
terns of associations. Am J Med Genet 1993; 45: 683–93.
3. Perlmutter DH, Shepherd RW. Extrahepatic biliary atresia: a disease or a
phenotype? Hepatology 2002; 35: 1297–304.
4. Silveira TR, Salzano FM, Howard ER, et al. Congenital structural abnor-
malities in biliary atresia: evidence for etiopathogenic heterogeneity and
therapeutic implications. Acta Paediatr Scand 1991; 80: 1192–9.
5. O’Neill JA, Rowe MI, Grosfeld JL, et al. Pediatric Surgery. 5th edn. St.
Louis, MO: Mosby, 1998.
6. Raweily EA, Gibson AA, Burt AD. Abnormalities of intrahepatic bile
ducts in extrahepatic biliary atresia. Histopathology 1990; 17: 521–7.
7. Lilly JR, Altman RP. Hepatic portoenterostomy (the Kasai operation) for
biliary atresia. Surgery 1975; 78: 76–86.
8. Ito T, Horisawa M, Ando H. Intrahepatic bile ducts in biliary atresia--a
possible factor determining the prognosis. J Pediatr Surg 1983; 18:
124–30.
9. Sherlock S. The syndrome of disappearing intrahepatic bile ducts. Lancet
1987; 2: 493–6.
10. Balistreri WF. Neonatal cholestasis. J Pediatr 1985; 106: 171–84.
11. Brough AJ, Bernstein J. Conjugated hyperbilirubinemia in early infancy.
A reassessment of liver biopsy. Hum Pathol 1974; 5: 507–16.
12. Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of
cholestatic jaundice in infants: recommendations of the North American
Society for Pediatric Gastroenterology, Hepatology and Nutrition. J
Pediatr Gastroenterol Nutr 2004; 39: 115–28.
13. Kasai M, Suzuki S. A new operation for “non-correctable” biliary atresia:
hepatic portoenterostomy. Shujjutsu 1959; 13: 733–9.
14. Shteyer E, Ramm GA, Xu C, et al. Outcome after portoenterostomy in
biliary atresia: pivotal role of degree of liver fibrosis and intensity of stel-
late cell activation. J Pediatr Gastroenterol Nutr 2006; 42: 93–9.
15. Azarow KS, Phillips MJ, Sandler AD, et al. Biliary atresia: should all
patients undergo a portoenterostomy? J Pediatr Surg 1997; 32: 168–72;
discussion 72–4.
16. Lang T, Kappler M, Dietz H, et al. Biliary atresia: which factors predict
the success of a Kasai operation? An analysis of 36 patients. Eur J Med
Res 2000; 5: 110–4.
17. Davenport M, De Ville de Goyet J, Stringer MD, et al. Seamless man-
agement of biliary atresia in England and Wales (1999–2002). Lancet
2004; 363: 1354–7.
18. Chardot C, Carton M, Spire-Bendelac N, et al. Prognosis of biliary atresia
in the era of liver transplantation: French national study from 1986 to
1996. Hepatology 1999; 30: 606–11.
19. Laurent J, Gauthier F, Bernard O, et al. Long-term outcome after surgery
for biliary atresia. Study of 40 patients surviving for more than 10 years.
Gastroenterology 1990; 99: 1793–7.
20. Lykavieris P, Chardot C, Sokhn M, et al. Outcome in adulthood of biliary
atresia: a study of 63 patients who survived for over 20 years with their
native liver. Hepatology 2005; 41: 366–71.
21. Okazaki T, Kobayashi H, Yamataka A, et al. Long-term postsurgical out-
come of biliary atresia. J Pediatr Surg 1999; 34: 312–5.
22. Altman RP, Lilly JR, Greenfeld J, et al. A multivariable risk factor analysis of
the portoenterostomy (Kasai) procedure for biliary atresia: twenty-five years
of experience from two centers. Ann Surg 1997; 226: 348–53; discussion
53–5.
23. Utterson EC, Shepherd RW, Sokol RJ, et al. Biliary atresia: clinical pro-
files, risk factors, and outcomes of 755 patients listed for liver transplan-
tation. J Pediatr 2005; 147: 180–5.
24. McEvoy CF, Suchy FJ. Biliary tract disease in children. Pediatr Clin North
Am 1996; 43: 75–98.
25. Todani T, Watanabe Y, Narusue M, et al. Congenital bile duct cysts: Clas-
sification, operative procedures, and review of thirty-seven cases includ-
ing cancer arising from choledochal cyst. Am J Surg 1977; 134: 263–9.
26. Todani T, Watanabe Y, Toki A, et al. Co-existing biliary anomalies and
anatomical variants in choledochal cyst. Br J Surg 1998; 85: 760–3.
27. Miyano T, Yamataka A, Kato Y, et al. Hepaticoenterostomy after excision
of choledochal cyst in children: a 30-year experience with 180 cases. J
Pediatr Surg 1996; 31: 1417–21.
28. Stringer MD, Dhawan A, Davenport M, et al. Choledochal cysts: lessons
from a 20 year experience. Arch Dis Child 1995; 73: 528–31.
29. Tan CE, Howard ER, Driver M, et al. Non-communicating multiseptate
gall bladder and choledochal cyst: a case report and review of publica-
tions. Gut 1993; 34: 853–6.
30. Davenport M, Betalli P, D’Antiga L, et al. The spectrum of surgical jaun-
dice in infancy. J Pediatr Surg 2003; 38: 1471–9.
31. Alonso-Lej F, Rever WB Jr., Pessagno DJ. Congenital choledochal cyst, with
a report of 2, and an analysis of 94, cases. Int Abstr Surg 1959; 108: 1–30.
32. Howell CG, Templeton JM, Weiner S, et al. Antenatal diagnosis and early
surgery for choledochal cyst. J Pediatr Surg 1983; 18: 387–93.
33. Lugo-Vicente HL. Prenatally diagnosed choledochal cysts: observation
or early surgery? J Pediatr Surg 1995; 30: 1288–90.
34. Mackenzie TC, Howell LJ, Flake AW, et al. The management of prenatally
diagnosed choledochal cysts. J Pediatr Surg 2001; 36: 1241–3.
35. Redkar R, Davenport M, Howard ER. Antenatal diagnosis of congenital
anomalies of the biliary tract. J Pediatr Surg 1998; 33: 700–4.
36. Suita S, Shono K, Kinugasa Y, et al. Influence of age on the presentation
and outcome of choledochal cyst. J Pediatr Surg 1999; 34: 1765–8.
37. Ishida M, Tsuchida Y, Saito S, et al. Primary excision of choledochal cysts.
Surgery 1970; 68: 884–8.
38. Kasai M, Asakura Y, Taira Y. Surgical treatment of choledochal cyst. Ann
Surg 1970; 172: 844–51.
39. Yamataka A, Ohshiro K, Okada Y, et al. Complications after cyst excision
with hepaticoenterostomy for choledochal cysts and their surgical man-
agement in children versus adults. J Pediatr Surg 1997; 32: 1097–102.
40. Stringer M. Gallbladder disease and cholelithiasis. In: Howard ER,
Stringer MD, Columbani PM, eds. Surgery of the Liver, Bile Ducts and
Pancreas in Children. 2nd edn. London, UK: Arnold; 2002: 189–208.
41. Bruch SW, Ein SH, Rocchi C, et al. The management of nonpigmented
gallstones in children. J Pediatr Surg 2000; 35: 729–32.
42. Ware R, Filston HC, Schultz WH, et al. Elective cholecystectomy in chil-
dren with sickle hemoglobinopathies. Successful outcome using a preop-
erative transfusion regimen. Ann Surg 1988; 208: 17–22.
43. Weinberg AG, Finegold MJ. Primary hepatic tumors of childhood. Hum
Pathol 1983; 14: 512–37.
44. Stocker JT. Hepatoblastoma. Semin Diagn Pathol 1994; 11: 136–43.
45. Mann JR, Kasthuri N, Raafat F, et al. Malignant hepatic tumours in chil-
dren: incidence, clinical features and aetiology. Paediatr Perinat Epide-
miol 1990; 4: 276–89.
46. Darbari A, Sabin KM, Shapiro CN, et al. Epidemiology of primary
hepatic malignancies in U.S. children. Hepatology 2003; 38: 560–6.
47. Lampkin BC, Wong KY, Kalinyak KA, et al. Solid malignancies in chil-
dren and adolescents. Surg Clin North Am 1985; 65: 1351–86.
48. Exelby PR, Filler RM, Grosfeld JL. Liver tumors in children in the par-
ticular reference to hepatoblastoma and hepatocellular carcinoma:
American Academy of Pediatrics Surgical Section Survey—1974. J Pedi-
atr Surg 1975; 10: 329–37.
485
 SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS
49. Fraumeni JF Jr., Rosen PJ, Hull EW, et al. Hepatoblastoma in infant sis-
ters. Cancer 1969; 24: 1086–90.
50. Napoli VM, Campbell WG Jr. Hepatoblastoma in infant sister and
brother. Cancer 1977; 39: 2647–50.
51. Taat F, Bosman DK, Aronson DC. Hepatoblastoma in a girl with biliary
atresia: coincidence or co-incidence. Pediatr Blood Cancer 2004; 43: 603–5.
52. Giardiello FM, Petersen GM, Brensinger JD, et al. Hepatoblastoma and APC
gene mutation in familial adenomatous polyposis. Gut 1996; 39: 867–9.
53. Iwama T, Mishima Y. Mortality in young first-degree relatives of patients
with familial adenomatous polyposis. Cancer 1994; 73: 2065–8.
54. Hartley AL, Birch JM, Kelsey AM, et al. Epidemiological and familial
aspects of hepatoblastoma. Med Pediatr Oncol 1990; 18: 103–9.
55. Koishi S, Kubota M, Taniguchi Y, et al. Myelodysplasia in a child with Beck-
with–Wiedemann syndrome previously treated for hepatoblastoma with
multi-agent chemotherapy. J Pediatr Hematol Oncol 1996; 18: 419–20.
56. Tsai SY, Jeng YM, Hwu WL, et al. Hepatoblastoma in an infant with Beck-
with–Wiedemann Syndrome. J Formos Med Assoc 1996; 95: 180–3.
57. Gonzalez-Crussi F, Upton MP, Maurer HS. Hepatoblastoma. Attempt at
characterization of histologic subtypes. Am J Surg Pathol 1982; 6: 599–612.
58. Lack EE, Neave C, Vawter GF. Hepatoblastoma. A clinical and pathologic
study of 54 cases. Am J Surg Pathol 1982; 6: 693–705.
59. Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of unresectable
or metastatic hepatoblastoma with cisplatin and continuous infusion
doxorubicin chemotherapy: a report from the Childrens Cancer Study
Group. J Clin Oncol 1991; 9: 2167–76.
60. Ohnuma N, Takahashi H, Tanabe M, et al. The role of magnetic reso-
nance imaging for treatment in children with malignant solid tumor.
Nippon Geka Gakkai Zasshi 1991; 92: 1143–6.
61. Gauthier F, Valayer J, Thai BL, et al. Hepatoblastoma and hepatocarci-
noma in children: analysis of a series of 29 cases. J Pediatr Surg 1986;
21: 424–9.
62. von Schweinitz D, Hecker H, Harms D, et al. Complete resection before
development of drug resistance is essential for survival from advanced
hepatoblastoma–a report from the German Cooperative Pediatric Liver
Tumor Study HB-89. J Pediatr Surg 1995; 30: 845–52.
63. von Schweinitz D, Hecker H, Schmidt-von-Arndt G, et al. Prognostic fac-
tors and staging systems in childhood hepatoblastoma. Int J Cancer
1997; 74: 593–9.
64. Finegold MJ. Tumors of the liver. Semin Liver Dis 1994; 14: 270–81.
65. Katzenstein HM, Krailo MD, Malogolowkin MH, et al. Hepatocellular
carcinoma in children and adolescents: results from the Pediatric Oncol-
ogy Group and the Children’s Cancer Group intergroup study. J Clin
Oncol 2002; 20: 2789–97.
66. Bower M, Newlands ES, Habib N. Fibrolamellar hepatocellular carci-
noma responsive to platinum-based combination chemotherapy. Clin
Oncol (R Coll Radiol) 1996; 8: 331–3.
67. Wegmann W, Evison J, Schaub N, et al. [Liver cell carcinoma as a late
complication of Alagille syndrome (arterio-hepatic dysplasia)]. Leber
Magen Darm 1996; 26: 157–8, 61–3.
68. Ni YH, Chang MH, Hsu HY, et al. Hepatocellular carcinoma in child-
hood. Clinical manifestations and prognosis. Cancer 1991; 68: 1737–41.
69. Brower ST. Pancreatic cancer, hepatobiliary cancer, and neuroendocrine
cancers of the GI tract. In: Padzur R, Hoskins WJ, Lawrence C, Wagman
L, eds. Cancer Management: A Multidisciplinary Approach. 2nd edn.
Huntington, NY: PRR, 1998: 113–48.
70. Maini CL, Scelsa MG, Fiumara C, et al. Superselective intra-arterial
radiometabolic therapy with I-131 lipiodol in hepatocellular carcinoma.
Clin Nucl Med 1996; 21: 221–6.
71. Ryu M, Shimamura Y, Kinoshita T, et al. Therapeutic results of resection,
transcatheter arterial embolization and percutaneous transhepatic etha-
nol injection in 3225 patients with hepatocellular carcinoma: a retro-
spective multicenter study. Jpn J Clin Oncol 1997; 27: 251–7.
72. Inamori H, Ido K, Isoda N, et al. Laparoscopic radiofrequency ablation
of hepatocellular carcinoma in the caudate lobe by using a new laparo-
scopic US probe with a forward-viewing convex-array transducer. Gas-
trointest Endosc 2004; 60: 628–31.
73. Koda M, Ueki M, Maeda Y, et al. Percutaneous sonographically guided
radiofrequency ablation with artificial pleural effusion for hepatocellular
carcinoma located under the diaphragm. AJR 2004; 183: 583–8.
486
74. Raut CP, Izzo F, Marra P, et al. Significant long-term survival after radio-
frequency ablation of unresectable hepatocellular carcinoma in patients
with cirrhosis. Ann Surg Oncol 2005; 12: 616–28.
75. Santambrogio R, Podda M, Zuin M, et al. Safety and efficacy of laparo-
scopic radiofrequency ablation of hepatocellular carcinoma in patients
with liver cirrhosis. Surg Endosc 2003; 17: 1826–32.
76. Filippou DK, Vezakis A, Filippou G, et al. A rare case of ectopic pancreas
in the ampulla of Vater presented with obstructive jaundice. Ann Ital
Chir 2006; 77: 517–9.
77. Nakajima H, Kambayashi M, Okubo H, et al. Annular pancreas accom-
panied by an ectopic pancreas in the adult: a case report. Endoscopy
1995; 27: 713.
78. Ozcan C, Celik A, Guclu C, et al. A rare cause of gastric outlet obstruc-
tion in the newborn: Pyloric ectopic pancreas. J Pediatr Surg 2002; 37:
119–20.
79. Brambs HJ. Developmental anomalies and congenital diseases of the
pancreas. Radiologe 1996; 36: 381–8.
80. Skandalakis JE, Gray SW, Ricketts R. The pancreas. In: Skandalakis JE,
Gray SW, eds. Embrylology for Surgeons. 2nd edn. Baltimore: Lippincott,
1994: 381.
81. Sencan A, Mir E, Gunsar C, et al. Symptomatic annular pancreas in new-
borns. Med Sci Monit 2002; 8: CR434–7.
82. Berrocal T, Torres I, Gutierrez J, et al. Congenital anomalies of the upper
gastrointestinal tract. Radiographics 1999; 19: 855–72.
83. Adzick NS, Shamberger RC, Winter HS, et al. Surgical treatment of pan-
creas divisum causing pancreatitis in children. J Pediatr Surg 1989; 24:
54–8; discussion 8.
84. Stimec B, Bulajic M, Korneti V, et al. Ductal morphometry of ventral
pancreas in pancreas divisum. Comparison between clinical and
anatomical results. Ital J Gastroenterol 1996; 28: 76–80.
85. Beger HG, Rau B, Mayer J, et al. Natural course of acute pancreatitis.
World J Surg 1997; 21: 130–5.
86. Waldemar H, Buchler U, Buchler MW. Classification and severity staging
of acute pancreatitis. Ann Ital Chir 1995; 66: 171–9.
87. Sternby B, O’Brien JF, Zinsmeister AR, et al. What is the best biochemical
test to diagnose acute pancreatitis? A prospective clinical study. Mayo
Clin Proc 1996; 71: 1138–44.
88. Fujiwara T, Takehara Y, Ichijo K, et al. Anterior extension of acute pan-
creatitis: CT findings. J Comput Assist Tomogr 1995; 19: 963–6.
89. Prasil P, Laberge JM, Barkun A, et al. Endoscopic retrograde cholangio-
pancreatography in children: a surgeon’s perspective. J Pediatr Surg 2001;
36: 733–5.
90. Neblett WW 3rd, O’Neill JA Jr. Surgical management of recurrent
pancreatitis in children with pancreas divisum. Ann Surg 2000; 231:
899–908.
91. Ihse I, Andersson R, Andren-Sandberg A, et al. Conservative treatment in
acute pancreatitis. Ann Ital Chir 1995; 66: 181–5.
92. Kaufmann P, Hofmann G, Smolle KH, et al. Intensive care management
of acute pancreatitis: recognition of patients at high risk of developing
severe or fatal complications. Wien Klin Wochenschr 1996; 108: 9–15.
93. Hwang TL, Chiu CT, Chen HM, et al. Surgical results for severe acute
pancreatitis--comparison of the different surgical procedures. Hepato-
gastroenterology 1995; 42: 1026–9.
94. Beger HG, Rau B. Necrosectomy and postoperative local lavage in necro-
tizing pancreatitis. Ann Ital Chir 1995; 66: 209–15.
95. Wilson C. Management of the later complications of severe acute pan-
creatitis – pseudocyst, abscess and fistula. Eur J Gastroenterol Hepatol
1997; 9: 117–21.
96. Bittner R. Clinical significance and management of pancreatic abscess
and infected necrosis complicating acute pancreatitis. Ann Ital Chir
1995; 66: 217–22.
97. Kisra M, Ettayebi F, Benhammou M. Pseudocysts of the pancreas in children
in Morocco. J Pediatr Surg 1999; 34: 1327–9.
98. Shimizu M, Hirokawa M, Manabe T. Histological assessment of chronic
pancreatitis at necropsy. J Clin Pathol 1996; 49: 913–5.
99. Sidhu SS, Tandon RK. The pathogenesis of chronic pancreatitis. Postgrad
Med J 1995; 71: 67–70.
100. Dite P, Zboril V, Cikankova E. Endoscopic therapy of chronic pancreatitis.
Hepatogastroenterology 1996; 43: 1633–7.
 PEDIATRIC HPB DISORDERS
101. Soliman AT, Alsalmi I, Darwish A, et al. Growth and endocrine function
after near total pancreatectomy for hyperinsulinaemic hypoglycaemia.
Arch Dis Child 1996; 74: 379–85.
102. Taguchi T, Suita S, Ohkubo K, et al. Mutations in the sulfonylurea
receptor gene in relation to the long-term outcome of persistent hyper-
insulinemic hypoglycemia of infancy. J Pediatr Surg 2002; 37: 593–8.
103. Murakami T, Ueki K, Kawakami H, et al. Pancreatoblastoma: case report and
review of treatment in the literature. Med Pediatr Oncol 1996; 27: 193–7.
104. Finegold MJ, et al. Liver tumors: pediatric population. Liver Transpl
2008; 14(11): 1545–56
105. Sokol RJ, et al. Screening and outcomes in biliary atresia: summary of a
National Institutes of Health workshop. Hepatology 2007; 46(2): 566–81
106. Bassett MD, Murray KF, Biliary atresia: recent progress. J Clin Gastroenterol
2008; 42(6): 720–9.
107. Chardot C, Serinet MO. Prognosis of biliary atresia: what can be further
improved? J Pediatr 2006; 148(4): 432–5
487
Index
AAST. See American Association for Surgery
of Trauma
Abdominal compartment syndrome, 274
Abdominal pain, 451
Ablative techniques, 57–58
ABO-incompatible liver, 291
ACC. See Acinar cell carcinoma
Acinar cell carcinoma, 432
pancreatic lesions, 107
ACS. See Abdominal compartment
syndrome
Acute and chronic liver failure
auxiliary liver transplantation
auxiliary whole orthotopic liver
transplantation, 294–295
immunosuppression, 295
outcome of, 295
donor selection
ABO-incompatible liver, 291
donation after cardiac death, 290–291
donors with infection, 290
donors with malignancy, 290
elderly donors, 289–290
hepatitis B core antibody positive
donors, 290
hepatitis C infection donors, 290
split-liver, 290
steatosis and abnormal liver
function, 289
future perspectives
hepatocyte transplantation, 297
immune tolerance, 297
liver support devices, 295, 297
orthotopic liver transplantation
immunosuppression, 292–293
operative technique of, 292
outcomes in, 293–294
post-operative management, 292–293
recipient selection
with acute liver failure, 288
end-stage liver disease, 288
with HIV, 288–289
with viral hepatitis, 288
retrieval of deceased donor liver graft
donation after cardiac death
retrieval, 292
standard retrieval, 291
splitting of deceased donor liver graft, 292
Acute cholangitis, gallstone disease, 374
Acute cholecystitis
bile duct injuries, 360–362
gallstone disease, 373
Acute pancreatitis
congenital anomalies, 483–484
early management of, 439–441
etiology of, 439
gallstone disease, 374–375
laparoscopy, 443
necrosis management, 441
radiological assessment, 441
role for specific interventions, 440
surgical intervention
endoscopic drainage, 443, 445
laparotomy/debridement, 441–443
open surgery, 441
percutaneous catheter drainage, 443–444
percutaneous necrosectomy, 443, 446
Acute variceal hemorrhage, 282
ADA. See American Diabetes Association
Adenocarcinoma, congenital anomalies, 484
Adenosquamous carcinoma, 432–434
Adjuvant chemotherapy, 391–393
hepatic metastasectomy, 58–59
Adjuvant intra-arterial chemotherapy, 123
Adjuvant regional chemotherapy, 141–142
Adjuvant systemic chemotherapy
after liver resection, 141
colorectal liver metastases, 122
Adjuvant therapy
gallbladder cancer, 331
laparoscopically discovered
disease, 204–205
Adult hemangioma, 262
Adulthood, choledochal cyst
clinical presentation, 354
complications, 355
diagnosis, 354–355
etiology and classification, 354
incidence and pathophysiology, 354
treatment, 355–358
Advanced cholangiocarcinoma
combined liver and portal vein
resection, 339–340
hepatopancreatoduodenectomy, 340
Aging, 46
AIP. See Autoimmune pancreatitis
AJCC. See American Joint Committee on
Cancer
ALT. See Auxiliary liver transplantation
Amebiasis, 253
Amebic liver abscess
diagnosis of, 253–254
epidemiology of, 253
outcomes of, 255
pathogenesis of, 253
treatment of, 254–255
American Association for Surgery of
Trauma, 271–272
American Diabetes Association, 470
American Joint Committee on Cancer,
192, 198
American Pancreas Club, 458
American Society of Anesthesiology, 47
American Society of Clinical Oncology, 137
Anatomic right trisectionectomy, 339
Anatomical hepatectomies, 5–6
Anatomical hepatic resection, 276–277
Anatomy of pancreas
arterial anatomy
anterior and posterior inferior
pancreaticoduodenal arteries, 19
caudal and great pancreatic arteries, 20
dorsal pancreatic artery, 19–20
inferior pancreaticoduodenal
artery, 19
posterior superior
pancreaticoduodenal artery, 18–19
superior pancreaticoduodenal
artery, 18
venous drainage of pancreas, 20–21
ductal anatomy of, 17
innervation of, 22
lymphatic drainage, 21–22
topography of, 17
Angioembolization, 275
Angiography, hydatid cyst, 313
Angiomyolipoma, 267
Annular pancreas, congenital
anomalies, 483
Anti-angiogenic therapies, 219–220
ASA. See American Society of
Anesthesiology
ASC. See Adenosquamous carcinoma
Aschoff–Rokitansky sinuses, 40
Ascites, 280, 284–285
ASCO. See American Society of Clinical
Oncology
Aspiration sclerotherapy, 301–302
laparoscopic surgery, 303
open surgery, 303
surgical treatment, 302–303
Associated intra-abdominal vascular
injuries, 463
Autoimmune pancreatitis
chronic pancreatitis, 452
rare tumors, 436–437
Auxiliary liver transplantation
auxiliary whole orthotopic liver
transplantation
recipient selection criteria, 294
surgical technique, 294–295
immunosuppression, 295
outcome of, 295
Auxiliary whole orthotopic liver
transplantation
recipient selection criteria, 294
surgical technique, 294–295
AWOLT. See Auxiliary whole orthotopic
liver transplantation
BA. See Biliary atresia
Backtable preparation, 472
BCS. See Budd–Chiari syndrome
BD. See Biliary drainage
489

Benign cystic diseases
aspiration sclerotherapy, 301–303
polycystic liver disease, 303–304
rare lesions, 305
simple biliary hepatic cysts, 301
Benign disease, 24
Benign inflammatory pseudotumors, 370
Benign solid tumors
adult hemangioma, 262
capillary hemangioma, 262
cavernous hemangioma
imaging features of, 263
management of, 263
pathology of, 262
classification of, 262
congenital hepatic fibrosis, 267
focal nodular hyperplasia
imaging features of, 264
management of, 264
pathology of, 263
telangiectatic, 263
hepatocellular adenoma
imaging features of, 265
management of, 265
pathology of, 264–265
hepatocellular adenomatosis
management of, 266–267
pathology of, 265–266
nodular regenerative hyperplasia, 266
pseudolipoma
hereditary hemorrhagic
telangiectasia, 268
heterotopic tissue, 268
inflammatory pseudotumor, 268
miscellaneous rare benign solid liver
lesions, 268
peliosis hepatic, 267–268
Benzimidazole, 321
Bevacizumab, 140, 176, 220
Bile duct
hamartomas, 305
ultrasound applications, 39–41
Bile duct injuries
noniatrogenic bile duct strictures
benign inflammatory
pseudotumors, 370
biliary strictures secondary to
pancreatitis, 369–370
calculous disease, 370
sclerosing cholangitis, 370
patient-related factors
acute cholecystitis, 360–362
congenital abnormalities, 362–363
procedure-related factors
critical view technique, 365
misidentification concepts, 363–365
technical problems, 365
surgeon/hospital-related factors
laparoscopic equipment, 366
learning curve effect, 366
psychology of human error, 366
Bile ducts and liver, surgical anatomy
490
INDEX
anatomical hepatectomies, 5–6 presentation, 65
anatomy of biliary exposure, 12–13 prevention, 63–65
arterial blood supply of, 11–12 Body habitus, 363
biliary anatomy, 10–11 Borderline tumors, 385
biliary tract, 6 Brachytherapy, malignant biliary
caudate lobe, surgical approach, 6 obstruction, 349–350
cystic duct, 9–10 Breast cancer, 54
early application of functional anatomy, 1 noncolorectal, nonneuroendocrine
extrahepatic biliary anatomy, 8–9 metastases, 166
falciform ligament, 14 British Society of Gastroenterology, 346
gallbladder, 9–10, 14 BSG. See British Society of Gastroenterology
hepatic veins, 13 Budd–Chiari syndrome, 280
intrahepatic biliary anatomy, 7–8
ligamentum venosum, 14
CA19-9. See Carbohydrate antigen 19-9
morphological anatomy, 1
Cambridge Classification of Chronic
portal system, 13–14
Pancreatitis, 451
radiological anatomy of, 13
Capecitabine, 173
segmental anatomy of, 1–5
Capillary hemangioma, 262
Bile fistula, 367
Carbamates, 321
Bile leak, hepatectomy
Carbohydrate antigen 19-9, 382
incidence, 65
Carcinoid symptom severity scale, 157
prevention, 65
Carcinoid tumors, 154
risk factors, 65–66 Carcinoma
Bile pigment stone, 373 fibrolamellar, 104
Biliary adenoma, 267 gallbladder, 104
Biliary atresia hepatocellular, 104
classification, 478 Caroli’s disease, 357
clinical features, 478 Caspofungin, 259
outcomes, 478 Caudal pancreatic artery, 20
pathology, 478 Caudate lobe, surgical approach, 6
surgical treatment, 478 Caval injury, 276
Biliary colic, 373 Cavernous hemangioma
Biliary decompression imaging features of, 263
nonoperative technique, 402 management of, 263
operative technique, 402 pathology of, 262
Biliary drainage, 333–334 CCA. See Cholangiocarcinoma
Biliary dyspepsia, 375 CECT. See Contrast-enhanced
Biliary hamartoma, 266–267 computerized tomography
Biliary injuries Central pancreatectomy, 85
avoidance of, 366–367 Cetuximab, 137, 176
classification of, 360 CgA. See chromogranin A
iatrogenic, 360 Charcot’s Triad of symptoms, 374
incidence Chemical ablation, 195
laparoscopic versus open Chemical splanchnicectomy, 403–404
cholecystectomy, 360 Chemo-embolization, 216–218
population-based studies, 360 Chemotherapeutic agents
management of capecitabine, 173
intraoperative recognition, 367–368 irinotecan, 135
operative technique, 368–369 oxaliplatin, 135
preoperative preparation, 368 Chemotherapeutic regimens, 173
types of injuries, 368 Chemotherapy
outcome of treatment, 369 neuroendocrine tumors, 161
post-transplantation, 369 non-functional islet cell tumors, 428
Biliary stricture, 356 Chemotherapy-associated hepatotoxicity
after hepatectomy diagnosis, 176–177
incidence of, 66 monoclonal antibodies, 176
management of, 66 nonalcoholic fatty liver disease
Bladder drainage, 473–474 sinusoidal obstruction
Bland embolization, 216–218 syndrome, 174–176
Bleeding, hepatectomy steatohepatitis, 174
incidence, 63 steatosis, 173–174
investigation and treatment, 65 preoperative chemotherapy, 178

prevention, 177
Chemotherapy-associated nonalcoholic
fatty liver disease
diagnosis of, 173
sinusoidal obstruction syndrome, 174–176
steatohepatitis, 174
steatosis, 173–174
CHF. See Congenital hepatic fibrosis
Child–Turcotte–Pugh Score, 289
Chlorozotocin, 428
Cholangiocarcinoma
liver and biliary tract lesions, 104
liver transplantation
neoadjuvant chemoradiotherapy,
229–231
organ allocation, 231
Cholecystenteric fistula, 374
Choledochal cysts
adulthood
clinical presentation, 354
complications, 355
diagnosis, 354–355
etiology and classification, 354
incidence and pathophysiology, 354
treatment, 355–358
classification, 479
clinical features, 480
imaging, 480
outcomes, 480
pathology, 479–480
surgical treatment, 480
Choledochoduodenostomy, 91
Choledocholithiasis, 370
Choledochotomy, 90–91
Cholelithiasis, 480
Cholestatic neonate, diagnostic evaluation
in, 479
Cholesterol stones, 373
chromogranin A, 154
Chronic pancreatitis
classification of, 451
comparison of different surgical
approaches, 457–458
complications of, 453–454
congenital anomalies, 484
conservative treatment, 454
definition of, 451
duodenum-preserving resection
Beger procedure, 456–457
Berne procedure, 457
Hamburg procedure, 457
quality of life, 458
etiology pathomorphological
findings, 452
indications for surgical
intervention, 454–455
interventional treatment, 454
natural course of, 451
pathogenesis of pain, 452–453
rationale for drainage
procedures, 455–456
rationale for resectional procedures, 456
salvage procedures, 459
INDEX
small duct disease, 458–459
ultrasound findings in, 41
Ciliated foregut cysts, 305
Cirrhosis, 356
Cirrhotic liver, 266
cisPlatin, Interferon, Adriamycin,
and 5-Fluorouracil, 219
Clinical risk score, 56
metastatic colorectal cancer, 120–121
Clonorchis sinensis, 242
CMC. See Conventional Milan Criteria
Color Doppler, 36
Colorectal cancer, 47–48
Colorectal liver metastases, 47–48
clinical risk scores, 120–121
hepatic arterial infusion, 136–137
multimodal strategies
chemotherapy and surgery, 149–150
computed tomography, 148–149
magnetic resonance imaging, 149
management strategies, 150–152
multidisciplinary team, 148
positron emission tomography, 149
preoperative staging, 148
resectability of, 149
resection margins, 149
strategies to improve respectability, 149
surgery, 149
tumor ablation, 150
natural history of, 118
patient evaluation
patient selection, 118
preoperative imaging, 118–119
tumor resectability, 118
postoperative management
adjuvant intra-arterial
chemotherapy, 123
adjuvant systemic chemotherapy, 122
nonresectable metastatic
disease, 124–126
outcomes of resection, 123–124
repeat liver resection, 129–130
resectability techniques, 126–129
prognostic factors, 119–120
resectable management
preoperative management, 121
surgery approaches, 121–122
thermal ablation
CLOCC study, 184
cryotherapy, 180–181
edge cryotherapy, 181
limitations of, 180
microwave coagulation, 183–184
percutaneous ethanol injection, 184
radiofrequency ablation, 181–183
Combined liver and portal vein
resection, 339–340
Common bile duct (CBD) stenosis, 453
Common bile duct stones
non-surgical management
drug dissolution therapy, 377
endoscopic removal of bile duct
stones/biliary stenting, 377
lithotripsy, 377
surgical management
laparoscopic common bile duct stone
removal, 378
open choledocholithotomy, 377
Computed tomography
choledochal cyst, 355
colorectal liver metastases, 148–149
hydatid cyst, 311
liver and biliary tract lesions
cholangiocarcinoma, 104
cross-sectional anatomy, 100
fibrolamellar carcinoma, 104
focal nodular hyperplasia, 102
gallbladder carcinoma, 104
hepatic hemangioma, 102
hepatocellular adenoma, 102, 104
hepatocellular carcinoma, 104
metastatic cancer to liver, 104
liver metastases, 109–110
localization of insulinomas, 415
neuroendocrine tumors, 155
pancreatic ductal adenocarcinoma,
382–383
pancreatic injuries, 463
pancreatic lesions
acinar cell carcinoma, 107
cross-sectional anatomy, 100
metastatic cancer to pancreas, 107
pancreatic adenocarcinoma, 107
pancreatic neuroendocrine tumors, 106
solid pseudopapillary tumor, 106–107
scanning, radiological anatomy of liver, 13
Congenital abnormalities, bile duct injuries,
362–363
Congenital anomalies
acute pancreatitis, 483–484
adenocarcinoma, 484
annular pancreas, 483
chronic pancreatitis, 484
ectopic pancreatic rests, 483
pancreas divisum, 483
pancreatic abscess, 484
pancreatic pseudocyst, 484
persistent hyperinsulinemic
hypoglycemia of infancy, 484
Congenital deformities, 480–481
Congenital hepatic fibrosis, 267
CONKO-1, randomized controlled
trail, 391–392
Contrast-enhanced computerized
tomography, 192
Contrast-enhanced ultrasound, liver
metastases, 109
Conventional Milan Criteria, 193
Covered stents, 349
CP. See Central pancreatectomy; Chronic
pancreatitis
CRLM. See Colorectal liver metastases
Cross-sectional imaging. See CT imaging,
MRI characteristics
CRS. See Clinical risk score
Cryoablation, neuroendocrine tumors, 160
491

Cryotherapy, 126
thermal ablation, 180–181
Cryptogenic abscess, 256
CT. See Computed tomography
Curative surgical resection, 394
Cyst aspiration, 301
Cyst fluid analysis, 411
Cystic dilatation. See Choledochal cyst
Cystic fibrosis, 380–381
Cystic lesions, 36–37
Cystic metastases, 113
Cystic pancreatic neoplasms, 41
Cystic tumors
clinical scenarios
presentation and diagnostic
evaluation, 407
treatment, 412
diagnostic evaluation, 411
pathologic sub-types and clinical
behavior
intraductal papillary mucinous
neoplasm, 409–410
mucinous cystic neoplasm, 410–411
pancreatic pseudocyst, 407
serous cystadenoma, 407–409
treatment recommendations
intraductal papillary mucinous
neoplasm, 412
mucinous cystic neoplasm, 412
DCCT. See Diabetes Control and
Complication Trial
DCD. See Donation after cardiac death
DDLT. See Deceased donor liver
transplantation
Deceased donor liver graft
retrieval of
donation after cardiac death
retrieval, 292
standard retrieval, 291
splitting of, 292
Deceased donor liver transplantation,
208–213
Delayed gastric emptying, 81, 389
Detectable metastases, 401
Dexamethasone, 136
DGE. See Delayed gastric emptying
Diabetes Control and Complication
Trial, 475
Diabetic nephropathy, 475
Diagnostic laparoscopy
palliation of pancreas cancer, 401–402
pancreatic ductal adenocarcinoma,
383, 385
Diagnostic radiography, 402
Diarrhea, 417, 421
Diet, 380
Diffuse liver disease
liver, 36
pancreas, 41
Diffusion-weighted MR imaging, 111
Direct cholangioscopy, 346
endoscopic therapy, 347
492
INDEX
methods of therapy, 347
percutaneous drainage of jaundice, 348
Distal cholangiocarcinoma, 336–337
Distal ductal pancreatic injuries, 466
Distal pancreatectomy, 73–74, 416
Distal splenorenal shunt, 283–284
Donation after cardiac death, 290–291
Donor, pancreas, 471
Doppler ultrasound, 329
Dorsal liver dissection, 338
Dorsal pancreatic artery, 19–20
DPPHR. See Duodenum-preserving
pancreatic head resection
Drug dissolution therapy
common bile duct stones, 377
gallstone disease, 375
Drug-eluting microspheres, 218
DSRS. See Distal splenorenal shunt
Ductal anatomy of pancreas, 17
Duodenal outlet obstruction, 402
Duodenal tumors, 419
Duodenum-preserving pancreatic head
resection, 75–76. See also Chronic
pancreatitis
Dysplastic nodules, 266
Eastern Cooperative Oncology Group, 421
EBRT. See External beam radiotherapy
ECD. See Extended/Expanded
criteria donor
Echinococcal cysts, 102
ECOG. See European Cooperative
Oncology Group
Ectopic insulinomas, 414
Ectopic pancreatic rest, 483
Edge cryotherapy, thermal ablation, 181
EHD. See Extrahepatic disease
Elderly patients, liver surgery
age-related liver changes, 46–47
colorectal liver metastases, 47–48
financial cost, 50
hepatocellular carcinoma, 48–50
surgical risk evaluation, 47
ELTR. See European Liver Transplant
Registry
Empyema, 373–374
Endogenic vesiculation, 308
Endoluminal ultrasound
cystic tumors, 411
pancreatic ductal adenocarcinoma, 383
Endoscopic assessment, malignant biliary
obstruction
causes of, 343
covered vs. uncovered stents, 349
CT scanning, 343
direct cholangioscopy, 346
endoscopic therapy, 347
methods of therapy, 347
percutaneous drainage of
jaundice, 348
endoscopic intervention, 344
endoscopic retrograde
cholangio-pancreatography, 344–346
ERCP vs. PTC vs. surgery, 348
hilar strictures
disease modifying treatment, 349
unilateral versus bilateral, 349
MR scanning, 343–344
plastic vs. metal, 348–349
radiological diagnostic imaging, 343
radiotherapy
brachytherapy, 349–350
photodynamic therapy, 350
ultrasound, 343
Endoscopic drainage, 443, 445
Endoscopic pancreatic sphincterotomy, 454
Endoscopic retrograde
cholangiopancreatography
acute pancreatitis
antibiotics, 440
nutrition, 440
specific pharmacological
intervention, 440
surgical intervention, 440
cystic tumors, 411
gallbladder cancer, 329
gallstone disease, 377
malignant biliary obstruction, 344–346
pancreatic ductal adenocarcinoma,
383, 385
Endoscopic retrograde
pancreatography, 464
Endoscopic therapy, 282–283
Endoscopic ultrasound, 415–416
malignant biliary obstruction, 344
Endoscopic variceal ligation, 282
End-stage liver disease, 288
Enteral feeding, 391
Enteric drainage, 474
Enucleation, 76–77, 416
EORTC. See European Organization for
Research and Treatment of Cancer
EPIC. See Erbitux Plus Irinotecan in
Colorectal Cancer
Erbitux Plus Irinotecan in Colorectal
Cancer, 137
ERCP. See Endoscopic retrograde
cholangio-pancreaticography
ESLD. See end-stage liver disease
ESPAC-1, randomized controlled trail,
391–393
ESWL. See Extracorporal shockwave
lithotripsy
European Cooperative Oncology
Group, 137
European Liver Transplant Registry, 233
European Organization for Research and
Treatment of Cancer, 141
EUS. See Endoluminal ultrasound
EVL. See Endoscopic variceal ligation
Exogenous vesiculation, 308, 310
Extended lymphadenectomy, 84–85, 387
Extended resections, 387
Extended/Expanded criteria donor
ABO-incompatible liver, 291
donation after cardiac death, 290–291

donors with infection, 290
donors with malignancy, 290
elderly donors, 289–290
hepatitis B core antibody positive
donors, 290
hepatitis C infection donors, 290
split-liver, 290
steatosis and abnormal liver
function, 289
Extensive locoregional disease, 401
External beam radiotherapy, 230
Extracorporal shockwave lithotripsy, 454
Extrahepatic biliary anatomy, 8–9
Extrahepatic cholangiocarcinoma
operative procedures
combined liver and portal vein
resection, 339–340
distal cholangiocarcinoma, 336–337
hepatobiliary resection for hilar
cholangiocarcinoma, 337–339
hepatopancreatoduodenectomy, 340
pancreatoduodenectomy, 336–337
preoperative management
biliary drainage, 333–334
portal vein embolization, 334
staging of cholangiocarcinoma, 333
synbiotics treatments with bile
replacement, 334–336
surgical anatomy of bile duct, 333
Extrahepatic disease, 181–183
Extrahepatic portal hypertension, 453
[18F] 2-fluoro-2-deoxyglucose, 111–112
Familial pancreatic cancer syndrome, 380
Familial predisposition, 380
FAST. See Focused Assessment for
Sonographic examination of
Trauma patient
FDA. See Food and Drug Administration
FDG. See [18F] 2-fluoro-2-deoxyglucose;
Fluorine-18-labeled
fluoro-deoxyglucose
Fertile cyst, 315
Fibrolamellar carcinoma, 104
Fine needle aspiration, 383, 440
FISH. See Fluorescent in situ hybridization
FLC. See Fibrolamellar carcinoma
Floxuridine, 136–137
FLR. See Future liver remnant
Fluorescent in situ hybridization, 229
Fluorine-18-labeled fluoro-deoxyglucose, 329
Fluorouracil, 135
5-Fluorouracil, 58–59
FNA. See Fine needle aspiration
FNH. See Focal nodular hyperplasia
FNH-like lesions, 264
Focal fatty variants, 267
Focal hepatic lesions
ultrasound applications
cystic lesions, 36–37
solid liver lesions, 37–39
Focal nodular hyperplasia
imaging features of, 264
INDEX
liver and biliary tract lesions, 102
management of, 264
pathology of, 263
telangiectatic, 263
Focused Assessment for
Sonographic examination
of Trauma patient, 271
FOLFIRI, 121
FOLFOX, 121
Food and Drug Administration, 176, 218
FPC. See Familial pancreatic cancer
syndrome
FUDR. See Floxuridine
Functional endocrine tumors
comparison of, 415
definition, 414
Functional islet cell tumors
definition of, 414
gastrinomas
management of, 419
precise localization of, 417
preoperative evaluation, 418
sensitivity of invasive
and non-invasive imaging
studies, 418
symptoms of, 417
glucagonomas, 419–420
insulinoma
biochemical diagnosis of, 415
ectopic, 414
endoscopic ultrasound, 415–416
intraoperative ultrasonography, 416
localization modalities for, 415–416
symptoms, 415
somatostatinomas, 421
VIPomas, 420–421
Fungal liver abscess, 258–259
Future liver remnant, 67, 177
Gallbladder cancer
adjuvant therapy, 331
clinical presentation and work-up,
329–330
history of, 329
laparoscopically discovered disease
adjuvant therapy, 204–205
clinical presentation of, 199–200
epidemiology of, 197–198
palliative management, 205
pathology of, 198
patterns of spread, 198
radiologic workup, 200
staging systems, 198–199
surgical management, 201–204
liver and biliary tract lesions, 104
outcomes, 331
palliative care, 331–332
surgical management, 330–331
ultrasound applications, 39–41
Gallbladder disease
cholelithiasis, 480
congenital deformities, 480–481
hemolytic cholelithiasis, 480
Gallstone
acute cholangitis, 374
acute cholecystitis, 373
acute pancreatitis, 374–375
biliary colic, 373
biliary dyspepsia, 375
cholecystenteric fistula, 374
classification of, 373
empyema, 373–374
gallstone ileus, 374
ileus, 374
Mirrizi’s syndrome, 375
mucocele, 374
non-surgical management
analgesia for biliary colic/
cholecystitis, 375
drug dissolution therapy, 375
percutaneous cholecystostomy, 375
obstructive jaundice, 374
surgical management, cholecystectomy
laparoscopic cholecystectomy, 376
open cholecystectomy, 375–376
operative technique, 376–377
Gastric cancer, noncolorectal,
nonneuroendocrine
metastases, 167–168
Gastric decompression
nonoperative technique, 402–403
operative technique, 403
Gastric outlet obstruction, 401–402
Gastrinomas
management of, 419
precise localization of, 417
preoperative evaluation, 418
sensitivity of invasive and non-invasive
imaging studies, 418
symptoms of, 417
Gastrointestinal cancers, 55
Gastrojejunostomy, 402
isoperistaltic, 403
palliative, 403
Gelfoam, 216
Genitourinary tumors, 55
Giant cell tumors, 435
Giant hemangiomas, 37
β-Glucuronidase, 242
Glucagonomas, 419–420
Grade A fistulas, 389
Grade B fistulas, 389
Grade C fistulas, 389–390
Great pancreatic artery, 20
Gynecological tumors, 166
HAE. See Hepatic artery embolization
HAI. See Hepatic arterial infusion
HALT. See Heterotopic auxiliary liver
transplantation
HAS. See Hepatic hemangiosarcoma
HBV. See Hepatitis B Virus
HCC. See Hepatocellular carcinoma
Head and neck tumors, 168
HEHE. See Hepatic epithelioid
hemangioendothelioma
493

Hemangioma, 37
adult, 262
Hemolytic cholelithiasis, 480
Hemorrhage, 273–274
Hepatectomy, 5–6
bile leak
consequences of, 66
incidence, 65
management of, 66
presentation, 66
prevention, 65
risk factors, 65–66
biliary stricture
incidence of, 66
management of, 66
bleeding
incidence, 63
investigation and treatment, 65
presentation, 65
prevention, 63–65
cardiac complications, 69
hepatic insufficiency
incidence, 66
optimization of venous drainage, 67
portal vein embolization, 67
prevention, 67
treatment, 67–68
intra-abdominal infection
abdominal drainage, 68
factors affecting, 68
pain relief, 68–69
renal failure
consequences of, 69–70
etiology of, 69
renal impairment, 70
respiratory complications, 68–69
wound complications, 70
Hepatic abscess. See Liver abscess
Hepatic arterial infusion, 136–137
Hepatic arterial infusional
chemotherapy, 59
Hepatic artery embolization, 427
neuroendocrine tumors, 156–158
Hepatic cryoablation, 160
Hepatic epithelioid
hemangioendothelioma, 233–235
Hepatic hemangioma, 102
Hepatic hemangiosarcoma, 237–238
Hepatic infantile hemangioendothelioma,
235–237
Hepatic metastasectomy
adjuvant chemotherapy, 58–59
colorectal metastases, 53
neuroendocrine metastases, 53
noncolorectal metastases, 54–55
nonneuroendocrine metastases, 54–55
patient selection
colorectal metastases, 55
neuroendocrine tumors, 56
noncolorectal tumors, 56
nonneuroendocrine tumors, 56
resection techniques
ablative techniques, 57–58
494
INDEX
morbidity and mortality, 57
segmental resections, 57
wedge resections, 56–57
Hepatic metastases, neuroendocrine tumors
clinical features, 154
cryoablation, 160
diagnostic imaging, 155
hepatic artery embolization, 156–158
hepatic resection, 156
laboratory investigation, 154
liver transplantation, 160–161
medical treatment, 161
radiofrequency ablation, 158, 160
radionuclide therapy, 161
WHO classification of, 155
Hepatic portoenterostomy, 478
Hepatic radiofrequency ablation, 158, 160
Hepatic resection
basic principles
anesthetic techniques, 25
benign disease, 24
malignant disease, 24
patient selection, 24–25
preoperative imaging, 25
basic techniques
exposure, 25
mobilization, 25–27
positioning, 25
skin incision, 25
left hemihepatectomy, 32
left lateral sectionectomy, 32–33
left trisectionectomy, 32
neuroendocrine tumors, 156
renal failure after
consequences of, 69–70
etiology of, 69
right hemihepatectomy, 30–31
right trisectionectomy, 31
vascular isolation
inflow control, 27–28
outflow control, 28–29
parenchymal transaction, 29
wedge vs. segmental resection
central hepatectomy, 34
segment 4, 33
segmentectomy I, caudate resection, 33
segments 2/3, 33
segments 5 and 8, anterior sector, 33
segments 6 and 7, posterior
sector, 33–34
Hepatic steatosis, 36
Hepaticojejunostomy, 337
Hepatitis B virus, 208
Hepatobiliary resection for hilar
cholangiocarcinoma, 337–339
Hepatoblastoma
clinical features, 481
imaging, 481
incidence, 481
outcomes, 481
pathology, 481
staging, 481
surgical treatment, 481
Hepatocellular adenoma
imaging features of, 265
liver and biliary tract lesions, 102, 104
management of, 265
pathology of, 264–265
Hepatocellular adenomatosis
management of, 266–267
pathology of, 265–266
Hepatocellular carcinoma
advanced stage, 195
diagnosis, 192
early stages
chemical ablation, 195
liver resection, 193–195
liver transplant, 195
thermal ablation, 195
intermediate stage, 195
liver and biliary tract lesions, 104
liver surgery, in elderly patients, 48–50
liver transplantation
in Asia, 208
pretransplant neoadjuvant
therapy, 211–212
recurrence treatment, 212–213
selection criteria and outcomes,
209–211
local regional therapies
arterial embolization, 216
bland embolization, 216–218
chemo-embolization, 216–218
drug-eluting microspheres, 218
percutaneous chemical/thermal
ablation, 218–219
radio-embolization, 218
pediatric hepato-pancreato-biliary
disorders
clinical features, 482–483
incidence, 481
outcomes, 483
pathology, 482
surgical treatment, 483
staging systems, 192
systemic therapies
advanced cirrhosis treatment, 220
anti-angiogenic therapies, 219–220
cisPlatin, interferon, adriamycin, and
5-fluorouracil, 219
future developments, 220–221
historical background, 219
treatment options, 192–193
ultrasound applications, 38
variceal bleeding, 281
Hepatocyte transplantation, 297
Hepatopancreatoduodenectomy, 340
Hepatopulmonary syndrome, 285
Hepatotomy, 275–276
Hereditary chronic pancreatitis, 452
Hereditary hemorrhagic
telangiectasia, 268
Hereditary pancreatitis, 380
Hereditary tumor syndromes, 380
Heterotopic auxiliary liver
transplantation, 295

Heterotopic tissue, 268
HHT. See Hereditary hemorrhagic
telangiectasia
5-HIAA. See 5-Hydroxyindoleacetic acid
High-affinity somatostatin receptors, 424
High-grade pancreatic injuries, 466
HIHE. See Hepatic infantile
hemangioendothelioma
Hilar cholangiocarcinoma
anatomic right trisectionectomy, 339
intrahepatic cholangiojejunostomy, 339
left trisectionectomy, 338
left-sided hepatectomy, 337
liver transplantation
neoadjuvant chemoradiotherapy,
229–231
organ allocation, 231
right hepatectomy, 338–339
right trisectionectomy, 338
Hilar strictures, malignant biliary
obstruction
disease modifying treatment, 349
unilateral vs. bilateral, 349
Histidine–Tryptophan–Ketoglutarate, 471
“Hockey stick” incision, 25
HPD. See Hepatopancreatoduodenectomy
HPE. See Hepatic portoenterostomy
HPS. See Hepatopulmonary syndrome
HT. See Hepatocyte transplantation
HTK. See Histidine–Tryptophan–
Ketoglutarate
5-HTP. See 5-Hydroxytryptophan
Human error, psychology of, 366
Hydatid cyst, 102
biological basis of surgery, 308
complications
infection, 313
rupture, 313–314
conservative procedures, 316–317
diagnostic imaging
angiography, 313
computed tomography, 311
magnetic resonance imaging, 311
radioisotope imaging, 313
ultrasonography, 311
intraoperative approach, 315–316
laparoscopy, 320
medical therapy, 321
pathological basis of surgery, 308
puncture aspiration injection
reaspiration, 320–321
radical procedures, 317–320
serology of, 313
structure of, 308–310
topography, 314–315
treatment, 315
5-Hydroxyindoleacetic acid, 154
5-Hydroxytryptophan, 424
Hyperglycemia, 471
Hypersplenism, 280
Hypervascular metastases, 113
Hypoechoic halo, 38
Hypoechoic liver, 39
INDEX
Iatrogenic biliary injuries, 360
ICC. See Intrahepatic cholangiocarcinoma
IG-ICC. See Intraductal growth type of
intrahepatic cholangiocarcinoma
Immune tolerance, 297
Immunosuppression, 475
Indocyanine green (ICG) test, 67, 334
Infants, gallstones, 480
Inferior pancreaticoduodenal artery, 19
Inflammatory pseudotumor, 268
Infundibular technique, 364
Injury grading, 463
Institutional factors, 85
Insulinoma
biochemical diagnosis of, 415
ectopic, 414
endoscopic ultrasound, 415–416
intraoperative ultrasonography, 416
laparoscopic enucleation, 93
localization modalities for, 415–416
symptoms, 415
Interferon, 161
International Pancreas Transplant
Registry, 470
International Registry of Hepatic
Metastases of Colorectal Cancer, 123
International Union against Cancer, 21
Intraabdominal abscesses, 390
Intra-abdominal infection, hepatectomy
abdominal drainage, 68
factors affecting, 68
Intra-arterial chemotherapy, 125–126
Intra-arterial infusion therapies
bland embolization, 216–218
chemo-embolization, 216–218
radio-embolization, 218
Intrabiliary metastases, 113
Intraductal growth type of intrahepatic
cholangiocarcinoma, 223
Intraductal papillary mucinous neoplasm,
385, 409–410, 412
Intrahepatic biliary anatomy, 7–8
Intrahepatic cholangiocarcinoma,
resection of
adjuvant therapy, 226
classification and terminology, 223
epidemiology, 223
pre-operative diagnosis, 223–224
prognosis factors, 225–226
risk factors, 223
surgical strategy, 224–225
Intrahepatic cholangiojejunostomy, 339
Intrahepatic gallbladder, 363
Intrahepatic portal hypertension, 267, 280
Intraoperative cholangiography, 364–365
Intraoperative pancreatography
pancreatic injuries, 465–466
Intraoperative ultrasonography, 416
Intraoperative ultrasound, 42–43
colorectal liver metastases, 122
Intravenous erythromycin, 389
IOC. See Intraoperative cholangiography
IOUS, Intraoperative ultrasound
IPMN. See Intraductal papillary mucinous
neoplasm
Irinotecan, 135
Isolated liver metastases, 109
Isolated pancreatic metastases, 435
Isoperistaltic gastrojejunostomy, 403
Japan Integrated Staging score, 192
Jaundice, 367
Juxtahepatic injury, 276
Laparoscopic cholecystectomy, 89
common bile duct stones, 378
gallstone disease, 376
Laparoscopic common bile duct
exploration
choledochoduodenostomy, 91
choledochotomy, 90–91
transcystic flushing, 89
transcystic stone extraction, 89–90
Laparoscopic cystgastrostomy, 443
Laparoscopic distal pancreatectomy, 93
Laparoscopic enucleation, 93
Laparoscopic liver resection, 93–95
Laparoscopic palliative bypass, 92
Laparoscopic pancreatectomy, 85, 92–93
Laparoscopic pancreaticoduodenectomy, 93
Laparoscopic port sites, 204
Laparoscopic staging, 91–92
Laparoscopically discovered gallbladder
cancer
adjuvant therapy, 204–205
clinical presentation of, 199–200
epidemiology of, 197–198
palliative management, 205
pathology of, 198
patterns of spread, 198
radiologic workup, 200
staging systems, 198–199
surgical management
advanced tumors, 202
complications, 204
laparoscopic port sites, 204
liver resection, 203–204
lymph node dissection, 204
re-resection after laparoscopic
cholecystectomy, 202–203
tumor invading into the subserosal
layer, 201–202
tumors confined to the muscular
propria, 201
Laparotomy/Debridement
with closed lavage, 443
closed packing, 441
with drainage, 441
laparostomy with open packing, 441, 443
minimally invasive approaches, 443
Laser lithotripsy, 377
Late stricture, of choledochojejunostomy, 468
LDLT. See Living donor liver transplantation
l-DOPA. See l-Dihydroxyphenylalanine
Learning curve effect, 366
Left hemihepatectomy, 32
495

Left lateral sectionectomy, 32–33
Left trisectionectomy
hepatic resection, 32
hilar cholangiocarcinoma, 338
Left-sided hepatectomy, 337
Lexipafant, 440
LGSW. See Liver gunshot wounds
Ligasure device, 94
Lipase, 483
Lipoma, 267
Lithotripsy, 377
Liver
and bile ducts, surgical anatomy
anatomical hepatectomies, 5–6
anatomy of biliary exposure, 12–13
arterial blood supply of, 11–12
biliary anatomy, 10–11
biliary tract, 6
caudate lobe, surgical approach, 6
cystic duct, 9–10
early application of functional
anatomy, 1
extrahepatic biliary anatomy, 8–9
falciform ligament, 14
gallbladder, 9–10, 14
hepatic veins, 13
intrahepatic biliary anatomy, 7–8
ligamentum venosum, 14
morphological anatomy, 1
portal system, 13–14
radiological anatomy of, 13
segmental anatomy of, 1–5
and biliary tract lesions, CT and MRI
imaging
cholangiocarcinoma, 104
cross-sectional anatomy, 100
fibrolamellar carcinoma, 104
focal nodular hyperplasia, 102
gallbladder carcinoma, 104
hepatic hemangioma, 102
hepatocellular adenoma, 102, 104
hepatocellular carcinoma, 104
metastatic cancer to liver, 104
hydatid cyst
biological basis of surgery, 308
complications, 313–314
conservative procedures, 316–317
diagnostic imaging, 311, 313
intraoperative approach, 315–316
laparoscopy, 320
medical therapy, 321
pathological basis of surgery, 308
puncture aspiration injection
reaspiration, 320–321
radical procedures, 317–320
serology of, 313
structure of, 308–310
topography, 314–315
treatment, 315
ultrasound applications
diffuse liver disease, 36
focal hepatic lesions, 36–39
Liver abscess, 356
496
INDEX
amebic abscess selection criteria and outcomes,
diagnosis of, 253–254 209–211
epidemiology of, 253 hilar cholangiocarcinoma
outcomes of, 255 neoadjuvant chemoradiotherapy,
pathogenesis of, 253 229–231
treatment of, 254–255 organ allocation, 231
fungal abscess, 258–259 neuroendocrine tumors, 160–161
pyogenic abscess stages of hepatocellular carcinoma, 195
diagnosis of, 256–257 variceal bleeding, 284
epidemiology of, 255 Liver trauma
microbiology of, 256 anatomical hepatic resection, 276–277
outcomes of, 258 classification of, 271
pathogenesis of, 255–256 complications of non-operative
treatment of, 257–258 management, 273–274
Liver biopsy, 478 definitive surgical procedures, 275
Liver Cancer Study Group of Japan, 223 early decision making during
Liver failure, 48 laparotomy, 275
Liver gunshot wounds, 274–275 hepatotomy, 275–276
Liver metastases liver gunshot wounds, 274–275
computed tomography, 109–110 liver injuries, 274
contrast-enhanced ultrasound, 109 manouevres, 276
detection, 114–115 non-anatomic liver resection, 276
imaging findings non-operative management of liver
cystic metastases, 113 injury, 272–273
hypervascular metastases, 113 perihepatic packing, 275
intrabiliary metastases, 113 refractory bleeding, 275
pitfalls and limitations, 113 selective vascular ligation, 275–276
magnetic resonance imaging, 110–111 LiverMetSurvey, 123
perfusion imaging, 112 Living donor liver transplantation, 208–213
positron emission Living-donor pancreas procurement, 472
tomography, 111–112 Local regional therapies
preoperative staging, 115–116 arterial embolization, 216
ultrasound techniques, 109 bland embolization, 216–218
Liver resection chemo-embolization, 216–218
laparoscopically discovered gallbladder drug-eluting microspheres, 218
cancer, 203–204 percutaneous chemical/thermal
stages of hepatocellular carcinoma, ablation, 218–219
193–195 radio-embolization, 218
types of, 122 Low-grade pancreatic injuries, 466
Liver support devices, 295, 297 LPSP. See Lymphoplasmacytic sclerosing
Liver surgery, elderly patients pancreatitis
age-related liver changes, 46–47 LT. See Liver transplantation
colorectal liver metastases, 47–48 l–Dihydroxyphenylalanine, 424
financial cost, 50 Lymph node dissection, 337
hepatocellular carcinoma, 48–50 laparoscopically discovered gallbladder
surgical risk evaluation, 47 cancer, 204
Liver transplantation Lymphadenopathy, 343
for acute and chronic liver failure Lymphatic drainage of pancreas, 21–22
auxiliary liver transplantation, 294–295 Lymphoplasmacytic infiltration, 452
donor selection, 289–291 Lymphoplasmacytic sclerosing
future perspectives, 295, 297 pancreatitis, 436
orthotopic liver transplantation,
292–294 Macrocystic mucinous tumors, 41
recipient selection, 288–289 Magnetic resonance cholangiography, 245
retrieval of deceased donor liver Magnetic resonance
graft, 291–292 cholangiopancreaticography
splitting of deceased donor liver cystic tumors, 411
graft, 292 malignant biliary obstruction, 344
in Asia, 208–209 pancreatic ductal adenocarcinoma, 383
hepatocellular carcinoma pancreatic injuries, 464
pretransplant neoadjuvant Magnetic resonance imaging
therapy, 211–212 colorectal liver metastases, 149
recurrence treatment, 212–213 hydatid cyst, 311

liver and biliary tract lesions
cholangiocarcinoma, 104
cross-sectional anatomy, 100
fibrolamellar carcinoma, 104
focal nodular hyperplasia, 102
gallbladder carcinoma, 104
hepatic hemangioma, 102
hepatocellular adenoma, 102, 104
hepatocellular carcinoma, 104
metastatic cancer to liver, 104
liver metastases, 110–111
neuroendocrine tumors, 155
pancreatic lesions
acinar cell carcinoma, 107
cross-sectional anatomy, 100
metastatic cancer to pancreas, 107
pancreatic adenocarcinoma, 107
pancreatic neuroendocrine tumors, 106
solid pseudopapillary tumor, 106–107
Malignant biliary obstruction
causes of, 343
covered vs. uncovered stents, 349
CT scanning, 343
direct cholangioscopy, 346
endoscopic therapy, 347
methods of therapy, 347
percutaneous drainage of
jaundice, 348
endoscopic intervention, 344
endoscopic retrograde
cholangio-pancreatography, 344–346
ERCP vs. PTC vs. surgery, 348
hilar strictures
disease modifying treatment, 349
unilateral vs. bilateral, 349
MR scanning, 343–344
operative vs. nonoperative palliation
of, 404
plastic vs. metal, 348–349
radiological diagnostic imaging, 343
radiotherapy
brachytherapy, 349–350
photodynamic therapy, 350
ultrasound, 343
Malignant disease, 24
Malignant gastroduodenal obstruction, 404
Malignant insulinomas, 416
Marseille–Rome classification of chronic
pancreatitis, 451
Mass-forming type of intrahepatic
cholangiocarcinoma, 223
Mayo Clinic protocol, 230
MCN. See Mucinous cystic neoplasm
MCT. See Microwave coagulation
MdCT. See Multidetector computed
tomography
Mebendazol, 321
Medullary carcinoma, 436
Melanoma, 54–55
noncolorectal, nonneuroendocrine
metastases, 169
Memorial Sloan-Kettering
Cancer Center, 201
INDEX
MEN-1 syndrome, 423
“Mercedes” incision, 25
Mesenchymal hamartoma, 268, 305
Mesh hepatorrhaphy technique, 275
Metastasis resections, 78–79
Metastatic cancer
to liver, 104
to pancreas, 107
Metastatic colorectal cancer
clinical risk scores, 120–121
patient evaluation
patient selection, 118
preoperative imaging, 118–119
tumor resectability, 118
postoperative management
adjuvant intra-arterial
chemotherapy, 123
adjuvant systemic chemotherapy, 122
nonresectable metastatic disease,
124–126
outcomes of resection, 123–124
repeat liver resection, 129–130
resectability techniques, 126–129
prognostic factors, 119–120
resectable management
preoperative management, 121
surgery approaches, 121–122
unresectable liver disease
coverting to resection, 138–140
regional chemotherapy, 136–137
systemic chemobiologic therapy,
137–138
systemic chemotherapy, 135–136
systemic therapy, 140–141
Metastatic disease, pancreas, 434–435
Metronidazole, 246
MF-ICC. See Mass-forming type of
intrahepatic cholangiocarcinoma
MIBG. See Radiolabeled
metaiodobenzylguanidine
Microsatellite instability, 436
Microwave ablation, 183–184
Microwave coagulation, 183–184
Mild postpancreatectomy hemorrhage, 391
Mirrizi’s syndrome, 375
Misidentification injuries, 367
Mixed stones, 373
Monoclonal antibodies, 176
MRCP. See Magnetic resonance
cholangiopancreaticography
MRI. See Magnetic resonance imaging
MSI. See Microsatellite instability
MSKCC. See Memorial Sloan-Kettering
Cancer Center
Mucinous cystic neoplasm, 410–412
Mucocele, 374
Multidetector computed tomography
cystic tumors, 411
pancreatic ductal adenocarcinoma, 383
Multimodal strategies, colorectal liver
metastases
chemotherapy and surgery, 149–150
computed tomography, 148–149
magnetic resonance imaging, 149
management strategies, 150–152
multidisciplinary team, 148
positron emission tomography, 149
preoperative staging, 148
resectability of, 149
resection margins, 149
strategies to improve respectability, 149
surgery, 149
tumor ablation, 150
Multiple single antibiotics, 257
Multivesicular cyst, 315
Multivisceral resections, 78
NAFLD. See Nonalcoholic fatty liver disease
National Cancer Database, 198
National Cancer Institute of Canada, 137
National Pediatric Trauma Registry, 466
Natural orifice transabdominal endoscopic
surgery, 91
NCIC. See National Cancer Institute of
Canada
Necrosis, acute pancreatitis, 441
Neoadjuvant chemoradiotherapy
liver transplantation, hilar
cholangiocarcinoma, 229–231
Neoadjuvant chemotherapy, 121
Neoadjuvant systemic chemotherapy, 139
Neonatal cholestasis, 479
NETs. See Neuroendocrine tumors
Neuroendocrine metastases, 53
Neuroendocrine tumor hepatic metastasis
clinical features, 154
cryoablation, 160
diagnostic imaging, 155
hepatic artery embolization, 156–158
hepatic resection, 156
laboratory investigation, 154
liver transplantation, 160–161
medical treatment, 161
radiofrequency ablation, 158, 160
radionuclide therapy, 161
WHO Classification of, 155
Neuroendocrine tumors, 41, 56, 154
Nodular regenerative hyperplasia, 239, 266
NOMLI. See Non-operative management of
liver injury
Nonalcoholic fatty liver disease, 173
Non-anatomic liver resection, 276
Nonanatomical hepatectomies, 5
Noncolorectal metastases, 54–55
Noncolorectal, nonneuroendocrine
metastases
breast cancer, 166
gastric cancer, 167–168
gynecological tumors, 166
head and neck tumors, 168
melanoma, 169
pancreatic cancer, 167
predictive factors determining clinical
outcome, 169–170
renal cell cancer, 166–167
respiratory tract, 168
497

Noncolorectal, nonneuroendocrine
metastases (Continued)
sarcoma, 168–169
Noncolorectal tumors, 56
Non-functional islet cell tumors, 421–422
clinical presentation of, 422–423
curative resection and survival, 426
curative surgery treatment
for metastatic disease, 426–427
for the primary tumor, 425–426
extent of disease and localization, 423–424
location of, 422
prognosis, 428
surgical palliation and survival, 427
treatment
chemotherapy, 428
octreotide, 428
palliative surgery, 427
radiation therapy, 428
Non-functioning islet cell tumors, 414
Noniatrogenic bile duct strictures
benign inflammatory pseudotumors, 370
biliary strictures secondary to
pancreatitis, 369–370
calculous disease, 370
sclerosing cholangitis, 370
Nonneuroendocrine metastases, 54–55
Nonneuroendocrine tumors, 56
Non-operative management of liver
injury, 272–273
Nonparasitic simple hepatic cysts, 102
Nonresectable metastatic disease
intra-arterial chemotherapy, 125–126
management of, 124
systemic chemotherapy, 124–125
NOTES. See Natural orifice transabdominal
endoscopic surgery
NRH. See Nodular regenerative
hyperplasia
Nutrition, 440
Obesity, 363
Obstructive chronic pancreatitis, 452
Obstructive jaundice, 334, 374, 401
Octreotide, 84
non-functional islet cell tumors, 428
Octreotide acetate, 420
Ocular melanoma, 55
OGTP. See osteoclast-like giant cell tumor
of pancreas
OIS-AAST. See Organ Injury Scaling
Committee of the American
Association for the Surgery of
Trauma
Okuda Classification, 192
OLT. See Orthotopic liver transplant
Open cholecystectomy
common bile duct stones, 377
gallstone disease, 375–376
Organ Injury Scaling Committee of the
American Association for the
Surgery of Trauma, 463–464
Oriental cholangiohepatitis, 370
498
INDEX
Orthotopic liver transplantation, 192–195
for acute and chronic liver failure
immunosuppression, 292–293
operative technique of, 292
outcomes in, 293–294
post-operative management, 292–293
Osteoclast-like giant cell tumor of
pancreas, 435
Oxaliplatin, 135
Oxaliplatin-associated neurotoxicity, 140
Pain, 367
palliation of, 403–405
Painless jaundice, 381
PAIR. See Puncture aspiration injection
reaspiration
PAK. See Pancreas after kidney transplant
Palliation
indications for, 401–402
nonoperative techniques
biliary decompression, 402
gastric decompression, 402–403
operative techniques
biliary decompression, 402
gastric decompression, 403
vs. nonoperative techniques, 404–405
of pain, 403–405
Palliative gastrojejunostomy, 403
Palliative surgery, non-functional islet cell
tumors, 427
Palliative therapy, laparoscopically
discovered disease, 205
Pancreas after kidney transplant, 470
Pancreas divisum, congenital
anomalies, 483
Pancreas transplant alone, 470
Pancreas transplantation
effects on secondary complications of
diabetes, 474–475
immunosuppression, 475
indications, 470–471
outcomes, 474
pancreas donor, 471
pancreas recipient, 471
recipient categories
pancreas after kidney transplant, 470
pancreas transplant alone, 470
simultaneous kidney and pancreas
transplant, 470
recipient operations
bladder drainage, 473–474
enteric drainage, 474
portal venous drainage, 473
surgical complications, 474
systemic venous drainage, 472–473
surgical techniques
backtable preparation, 472
procurement, 471–472
Pancreatectomy
bile leak, 82
death, 83
delayed gastric emptying, 81
factors affecting complication rates
extended lymphadenectomy, 84–85
institutional factors, 85
laparoscopic pancreatectomy, 85
octreotide, 84
pancreatic duct management following
resection, 83–84
patient factors, 85
peritoneal drainage, 84
pylorus-preserving
pancreaticoduodenectomy, 84
resection of contiguous
structures, 84–85
total and central pancreatectomy, 85
pancreatic anastomotic leak, 81
pancreatic fistula, 81
postpancreatectomy hemorrhage, 81–82
Pancreatic abscess, congenital
anomalies, 484
Pancreatic adenocarcinoma, 107
Pancreatic anastomotic leak, 81
Pancreatic cancer
common symptoms, 401
diet as risk factor, 380
dietary factors, 381
noncolorectal, nonneuroendocrine
metastases, 167
randomized controlled trials, 382–383
Pancreatic duct, integrity of, 465–466
Pancreatic duct management following
resection, 83–84
Pancreatic ductal adenocarcinoma
adjuvant treatment, 391–394
clinical presentation, 381
diagnosis and staging, 381–385
epidemiology of, 380
etiology of, 380–381
management of, 385
mortality and morbidity, 387–399
delayed gastric emptying, 389
intraabdominal abscesses, 390
postoperative pancreatic
fistula, 389–390
postpancreatectomy hemorrhage,
390–391
neoadjuvant treatment, 387
postoperative treatment, 391
preoperative biliary drainage, 385
prognosis, 394
risk factors, 380–381
surgical resection
extended lymphadenectomy, 387
extended resections, 387
pancreatic–enteric anastomosis,
386–387
standard vs. pylorus-preserving
pancreatoduodenectomy, 385–386
symptoms, 381
Pancreatic endocrine tumors
classification, 414
functional islet cell tumors
gastrinomas, 417–419
glucagonomas, 419–420
insulinoma, 414–416

somatostatinomas, 421
VIPomas, 420–421
non-functioning islet cell tumors
clinical presentation of, 422–423
curative resection and survival, 426
curative surgery treatment, 425–427
extent of disease and localization,
423–424
location of, 422
prognosis, 428
surgical palliation and survival, 427
treatment, 427–428
Pancreatic exocrine secretions, 474
Pancreatic fistula, 81
Pancreatic fluid, 389
Pancreatic inflammation, 439
Pancreatic injury
diagnosis
clinical presentation, 463
intraoperative exposure
and evaluation, 464–465
intraoperative pancreatography, 465–466
laboratory investigations, 463
radiologic investigations, 463–464
epidemiology of, 463
injury grading, 463
nonoperative management, 466
operative management
distal ductal injuries, 466
high-grade injuries, 466
low-grade injuries, 466
proximal ductal injuries, 467
outcomes
complications, 467
late stricture, 468
mortality, 467
pancreatic insufficiency, 468
pancreatic leaks and fistulae, 467
peripancreatic fluid collection, 467–468
pseudocysts, 467–468
Pancreatic ischemia, 453
Pancreatic leaks, 467
Pancreatic lesions, CT and MRI imaging
acinar cell carcinoma, 107
cross-sectional anatomy, 100
metastatic cancer to pancreas, 107
pancreatic adenocarcinoma, 107
pancreatic neuroendocrine tumors, 106
solid pseudopapillary tumor, 106–107
Pancreatic lymphoma, 434
Pancreatic main duct stenosis, 452
Pancreatic neoplasms, 41–42. See also
Non-functioning islet cell tumors
Pancreatic neuroendocrine tumors, 435
pancreatic lesions, 106
Pancreatic polypeptideoma, 423
Pancreatic pseudocyst, 407
congenital anomalies, 484
Pancreatic pseudocysts, 91
Pancreatic resections
distal pancreatectomy, 73–74
duodenum-preserving pancreatic head
resection, 75–76
INDEX
enucleation, 76–77
metastasis resections, 78–79
multivisceral resections, 78
recurrence resections, 78
segmental resections, 76
total pancreatectomy, 74–75
vessel resections, 77–78
Whipple resection, 73
Pancreatic trauma, 463
Pancreaticopleural fistulas, 453
Pancreatic–enteric anastomosis, 386–387
Pancreatitis, choledochal cyst, 356
Pancreatoduodenectomy vs.
pylorus-preserving
pancreatoduodenectomy, 336–337
Panitumumab, 137
Parasympathetic innervation, 22
Partial pancreaticoduodenectomy, 73
Partial surgical shunts, 283
Patient-related factors, bile duct injury
acute cholecystitis, 360–362
congenital abnormalities, 362–363
Paucity, 478
PBD. See Preoperative biliary drainage
PCLD. See Polycystic liver disease
PDAC. See Pancreatic ductal
adenocarcinoma
PDT. See Photodynamic therapy
Pediatric hepato-pancreato-biliary
disorders
biliary atresia, 478
choledochal cysts, 479–480
congenital anomalies, 483–484
gallbladder disease, 480–481
hepatoblastoma, 481
hepatocellular carcinoma, 481–483
PEI. See Percutaneous ethanol injection
Peliosis hepatic, 267–268
Percutaneous catheter drainage, 443–444
Percutaneous chemical/thermal
ablation, 218–219
Percutaneous cholangio-drainage, 385
Percutaneous cholecystostomy, 375
Percutaneous drainage of jaundice, 348
Percutaneous ethanol injection, 184
Percutaneous necrosectomy, 443, 446
Percutaneous transhepatic biliary
drainage, 247–248
Percutaneous transhepatic
cholangiography, 348, 367
Perfusion imaging, 112
Perihepatic packing, 275
Peripancreatic fluid collection, 467–468
Peritoneal drainage, 84
Peroral cholangioscopy, 333
Persistent hyperinsulinemic hypoglycemia
of infancy, 484
PET. See Positron emission tomography
PET-CT. See Positron emission tomography
with CT
Pharmacologic therapy, 282–283
PHHI. See Persistent hyperinsulinemic
hypoglycemia of infancy
Photodynamic therapy, 350
Photofrin®, 350
PIAF. See cisPlatin, Interferon, Adriamycin,
and 5-Fluorouracil
Pleomorphic giant cell carcinoma, 435
PNET. See Pancreatic neuroendocrine
tumors
POC. See Peroral cholangioscopy
Polycystic liver disease
clinical presentation, 303–304
Gigot classification of, 304
novel treatments, 305
surgical treatment, 304–305
POPF. See Postoperative
pancreatic fistula
Portal hypertension
causes of, 281
clinical manifestations
ascites, 280
hepatocellular carcinoma, 281
hypersplenism, 280
pulmonary syndromes, 280–281
variceal bleeding, 280
etiology of, 280
evaluation, 281
and general surgeon, 285–286
pathophysiology of, 280
Portal vein embolization, 67, 334
tumor respectability, 126
Portal venous drainage, 473
Portopulmonary syndromes, 285
Positron emission tomography
colorectal liver metastases
multimodal approaches, 149
with computer tomography, 383
gallbladder cancer, 329
liver metastases, 111–112
neuroendocrine tumors, 155
Posterior inferior pancreaticoduodenal
artery, 19
Posterior superior pancreaticoduodenal
artery, 18–19
Posthepatectomy infections, 68
Postoperative bile leak
consequences of, 66
management of, 66
presentation, 66
Postoperative pancreatic fistula
definition, 390
grade A fistulas, 389
grade B fistulas, 389
grade C fistulas, 389–390
pancreatic fluid, 389
Postoperative treatment, pancreatic ductal
adenocarcinoma, 391
Postpancreatectomy hemorrhage, 81–82
intraluminal and extraluminal, 390
mild, 391
severe, 391
PPH. See Portopulmonary syndromes;
Postpancreatectomy hemorrhage
PPL. See Primary pancreatic lymphoma
PPoma. See Pancreatic polypeptideoma
499

Ppower Doppler, 36
ppPD. See Pylorus-preserving
pancreatoduodenectomy
Preoperative biliary drainage, 385
Primary pancreatic lymphoma, 434
Primary prophylaxis, 281–282
Primary resection therapy, 194
Primary sclerosing cholangitis
cholangiocarcinoma, 324–325
diagnosis of, 324
endoscopic treatment, 325
medical treatment, 325
natural history of, 324
surgical management, 325–327
Procedure-related factors, bile duct injury
critical view technique, 365
misidentification concepts, 363–365
technical problems, 365
Procurement surgical technique, 471–472
Prophylactic octreotide, 84
Proton pump inhibitors, 417
Proximal ductal pancreatic injuries, 467
PSC. See Primary sclerosing cholangitis
Pseudocysts, 467–468
Pseudolipoma
hereditary hemorrhagic telangiectasia, 268
heterotopic tissue, 268
inflammatory pseudotumor, 268
miscellaneous rare benign solid liver
lesions, 268
peliosis hepatic, 267–268
PTA. See Pancreas transplant alone
PTC. See Percutaneous trans-hepatic
cholangiography
PTCD. See Percutaneous cholangio-drainage
Pulmonary syndromes, 280–281
Puncture aspiration injection reaspiration,
320–321
PVE. See Portal vein embolization
Pylorus-preserving
pancreaticoduodenectomy, 84,
385–386
Pyogenic liver abscess
diagnosis of, 256–257
epidemiology of, 255
microbiology of, 256
outcomes of, 258
pathogenesis of, 255–256
treatment of, 257–258
Pyrexia, 440
Radiation therapy, 428
Radiochemotherapy, 391
Radio-embolization, 218
Radiofrequency ablation, 126
thermal ablation, 181–183
Radioisotope imaging, hydatid cyst, 313
Radiolabeled metaiodobenzylguanidine, 155
Radionuclide therapy, neuroendocrine
tumors, 161
Randomized controlled trail
operative vs. nonoperative palliation
malignant biliary obstruction, 404
500
INDEX
malignant gastroduodenal
obstruction, 404
pancreatic ductal adenocarcinoma
CONKO-1, 391–392
ESPAC-1, 391–393
Rapamycin, 235
Rare benign cystic lesions, 305
Rare benign solid liver lesions, 268
Rare tumors
acinar cell carcinoma, 432
adenosquamous carcinoma, 432–434
autoimmune pancreatitis, 436–437
giant cell tumors, 435
medullary carcinoma, 436
metastatic disease, pancreas, 434–435
pancreatic lymphoma, 434
renal cell carcinoma, 434
solid pseudopapillary neoplasm, 432
Von Hippel–Lindau syndrome, 435
Rare vascular liver tumors
hepatic epithelioid
hemangioendothelioma, 233–235
hepatic hemangiosarcoma, 237–238
hepatic infantile
hemangioendothelioma, 235–237
nodular regenerative hyperplasia, 239
RCC. See Renal cell carcinoma
Recurrence resections, 78
Recurrent metastatic disease, 129–130
Recurrent pyogenic cholangitis
acute management, 246–247
clinical presentation, 244–245
complications, 250
definitive management, 247
definitive surgery, 248–250
hematological and biochemical
investigations, 245–246
minimal access approach, 247–248
pathogenesis of, 242–243
pathology of, 243–244
Recurrent variceal bleeding, 282
Refractory bleeding, 275
Regenerative nodules, 266
Regional chemotherapy, 136–137
Renal cell cancer, 166–167, 434
Repeat liver resection, 129–130
Resectable liver disease, systemic therapy,
140–141
Resectable tumors, 385
Resection of contiguous structures, 84–85
Respiratory tract, 168
Retroperitoneal laparostomy, 447
RFA. See Radiofrequency ablation
Right hemihepatectomy, 30–31
Right hepatectomy, 338
Right trisectionectomy
hepatic resection, 31
hilar cholangiocarcinoma, 338–339
Routine arteriography, 416
RPC. See Recurrent pyogenic cholangitis
Sarcoma, 54
noncolorectal, nonneuroendocrine
metastases, 168–169
SCA. See Serous cystadenoma
Sclerosing cholangitis, 370
Segmental resections, 57, 76
Selective surgical shunts, 283
Selective vascular ligation, 275–276
Self-expanding metal stents, 349
SEMS. See Self-expanding metal stents
Sepsis, 367
Serous cystadenoma, 407–409, 412
Serum amylase, 463
Severe postpancreatectomy hemorrhage, 391
sFLR. See Standardized future liver remnant
Short-term biliary stenting, 377
Simple biliary hepatic cysts, 301
Simple cystenterostomy, 357
Simultaneous kidney and pancreas
transplant, 470
Sinusoidal obstruction syndrome, 174–176
SLT. See Split-liver transplantation
SMA. See Superior mesenteric artery
Small duct disease, 458–459
Small solitary hepatic metastases. See
Hepatic metastasectomy
SMV. See superior mesenteric vein
Solid liver lesions, 37–39
Solid pseudopapillary neoplasm, 432
Solid pseudopapillary tumor, 106–107
Somatostatin analogs, 391
Somatostatin receptor scintigraphy, 424, 435
neuroendocrine tumors, 155
Somatostatinomas, 421
Sorafenib, 220
Special dedicated high-frequency
transducers, 42
Spectral Doppler, 36
Spironolactone, 285
SPK. See Simultaneous kidney and pancreas
transplant
Split-liver transplantation, 290
SPPN. See Solid pseudopapillary neoplasm
SPT. See Solid pseudopapillary tumor
Spyglass™, 347
SRS, Somatostatin receptor scintigraphy
SSTR-targeted therapy, 161
Staging laparoscopy, 91–92
Standard lymphadenectomy, 387
Standard vs. pylorus-preserving
pancreatoduodenectomy, 385–386
Standardized future liver remnant, 177
Stapling devices, 94
Steatohepatitis, 174
Steatorrhea, 421
Steatosis, 173–174
Sterile cyst, 315
Streptozotocin, 420
Streptozotocin plus doxorubicin, 428
Streptozotocin plus fluorouracil, 428
Sunitinib, 220
Superior mesenteric artery, 381
Superior mesenteric vein, 381
Superior pancreaticoduodenal artery, 18
Surgeon/hospital-related factors
laparoscopic equipment, 366

Surgeon/hospital-related factors (Continued)
learning curve effect, 366
psychology of human error, 366
Surgical resection, pancreatic ductal
adenocarcinoma, 385–387
extended lymphadenectomy, 387
extended resections, 387
pancreatic–enteric anastomosis, 386–387
standard vs. pylorus-preserving
pancreatoduodenectomy, 385–386
Surgical shunts, 283–284
Sympathetic innervation, 22
Symptom palliation, 401
Symptomatic hepatocellular carcinoma, 192
Synchronous liver metastases
neoadjuvant chemotherapy, 130–131
surgery, 131
Systemic chemobiologic therapy, 137–138
Systemic chemotherapy
nonresectable metastatic disease, 124–125
unresectable liver disease, 135–136
Systemic therapies
advanced cirrhosis treatment, 220
anti-angiogenic therapies, 219–220
cisPlatin, interferon, adriamycin, and
5-fluorouracil, 219
future developments, 220–221
historical background, 219
unresectable liver disease, 140–141
Systemic venous drainage, 472–473
TACE. See Transarterial chemo-embolization;
Trans-catheter arterial
chemo-embolization
TachoSil®, 65
Telangiectatic focal nodular hyperplasia, 263
Tenting injuries, 366–367
TFNH. See Telangiectatic focal nodular
hyperplasia
Therapeutic packing, 275
Thermal ablation
CLOCC study, 184
cryotherapy, 180–181
edge cryotherapy, 181
limitations of, 180
microwave ablation, 183–184
percutaneous ethanol injection, 184
radiofrequency ablation, 181–183
stages of hepatocellular carcinoma, 195
Thermal injuries, 366–367
TIPS. See Transjugular intrahepatic
portosystemic shunt
INDEX
“Top-Down” cholecystectomy, 365
Total cyst excision, 356
Total pancreatectomy, 74–75, 85
Total surgical shunts, 283
Total vascular exclusion, 128–129
TP. See Total pancreatectomy
Trans-abdominal ultrasonography, 383
choledochal cyst, 355
Trans-abdominal ultrasound, 441
malignant biliary obstruction, 343
Transarterial chemo-embolization, 195
Trans-catheter arterial
chemo-embolization, 216–217
Transcystic flushing, 89
Transcystic stone extraction, 89–90
Transjugular intrahepatic portosystemic
shunt, 283
Tumor ablation
multimodal approaches, 150
techniques, 126
Tumor respectability
definition of, 118
portal vein embolization, 126
total vascular exclusion and
cooling, 128–129
tumor ablation techniques, 126
two-stage hepatectomy, 127–128
TVE. See Total vascular exclusion
Two-stage hepatectomy, 127–128
Two-stage liver resection, 127
Type B juxtahepatic injuries, 276
UCDA. See Ursodeoxycholic acid
UCSF. See University of California at San
Francisco
UICC. See International Union against
Cancer
Ultrasonography
hydatid cyst, 311
transabdominal, 382–383
Ultrasound
gallbladder and bile ducts, 39–41
intraoperative, 42–43
liver
diffuse liver disease, 36
focal hepatic lesions, 36–39
liver metastases, 109
malignant biliary obstruction, 343
pancreas
diffuse pancreatic diseases, 41
pancreatic neoplasms, 41–42
radiological anatomy of liver, 13
University of California at San Francisco,
209–210
Univesicular cyst, 315
Unresectable liver disease
coverting to resection, 138–140
regional chemotherapy, 136–137
systemic chemobiologic therapy, 137–138
systemic chemotherapy, 135–136
systemic therapy, 140–141
Unusual functional islet cell
tumors, 421
Urine, 154
Ursodeoxycholic acid, 377
Vagotomy, 403
Variceal bleeding
acute variceal hemorrhage, 282
clinical manifestations, 280
devascularization procedures, 284
endoscopic therapy, 282–283
liver transplantation, 284
pharmacologic therapy, 282–283
primary prophylaxis, 281–282
recurrent, 282
surgical shunts, 283–284
transjugular intrahepatic portosystemic
shunt, 283
Variceal decompression, 283
Vascular endothelial growth factor, 137
Vascular injuries, 360
Vasoactive intestinal peptide, 420
VEGF. See Vascular endothelial growth
factor
Venous bleeding, 95
Venous drainage of pancreas, 20–21
Vessel resections, 77–78
VIPomas, 420–421
Von Hippel–Lindau (VHL)
syndrome, 435
Watery diarrhea, hypokalemia, and
achlorhydria, 420
WDHA. See Watery diarrhea,
hypokalemia, and achlorhydria
Wedge resections, 56–57
Whipple resection, 73
Y-graft, pancreas transplants, 473
ZES. See Zollinger–Ellison syndrome
Zollinger–Ellison syndrome, 416–417
501
Surgical Management of Hepatobiliary

Poston • D’Angelica • Adam

With a Foreword by
and Pancreatic Disorders Yuji Nimura, MD, President
of the Aichi Cancer Center,
Japan, and Past President
Second Edition of the IHPBA
Edited by Graeme J. Poston, Michael D’Angelica, and René Adam This book

Surgical
demonstrates the
About the book
wisdom of the
Hepato-Pancreato-Biliary (HPB) surgery is now firmly established within the repertoire
of modern general surgery. This new edition has been completely rewritten by
new knowledge

Management of
world-leading surgeons to reflect the considerable advances made in the surgical and technical skills
management of HPB disorders since the highly successful first edition.
of these diverse
This new edition includes: disciplines where

Hepatobiliary
• An in-depth coverage of benign and malignant disorders of the liver, pancreas, and cooperative efforts

and Pancreatic Disorders

Surgical Management of Hepatobiliary
bile ducts and gallbladder
• A comprehensive section on anatomy, imaging, and surgical technique
contribute toward
• Over 20 new chapters, including a complete account of pediatric HPB disorders the benefit of the
• Almost 300 high-resolution images, many in full color patients with HPB

and Pancreatic
Surgical Management of Hepatobiliary and Pancreatic Disorders, Second Edition, disorders.
comprehensively covers the full spectrum of common HPB diseases and associated
surgical techniques to assist not only the general surgeon in regular practice,
but also surgical trainees and those in related specialties of oncology, radiology, Also Available
gastroenterology, and anesthesia.
Hepatocellular Carcinoma:
A Practical Approach

Disorders
About the Editors Edited by Bandar Al Knawy, K. Rajendra Reddy
and Luigi Bolondi
Graeme j. Poston, MS, FRCS (Eng), FRCS (Ed), is Director of Surgery and Hepatobiliary ISBN: 9780415480802
Surgeon, University Hospital Aintree, Liverpool, UK. He is the President of the Association e-ISBN: 9780203092880
of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS), President-
Elect of the European Society of Surgical Oncology (ESSO), Past President of the British Improved Outcomes in Colon
Association of Surgical Oncology (BASO), and author of numerous publications and and Rectal Surgery
national/international guidelines relating to the practice of HPB surgery. Edited by Charles B. Whitlow, David E. Beck, David A.
Margolin, Terry C. Hicks and Alan E. Timmcke

Second Edition
Michael D’Angelica, MD, is an Associate Attending at Memorial Sloan-Kettering ISBN: 9781420071528
Cancer Center and an Associate Professor at Cornell University/Weill Medical Center. e-ISBN: 9781420071535
He is currently the Program Chairman of the American Hepato-Pancreato-Biliary
Association and a writing member of the National Comprehensive Cancer Network Textbook of Surgical Oncology
(NCCN) practice guidelines for hepatobiliary malignancy. Edited by Graeme J. Poston, R. Daniel Beauchamp,
and Theo J. M. Rogers
René Adam, MD, PHD, is Hepatobiliary Surgeon and Professor of Surgery, Hôpital Paul ISBN: 9781841845074
Brousse, Université Paris-Sud, Villejuif, France. e-ISBN: 9780203003220

Second
Edition
Edited by
Graeme J. Poston
Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK Michael D’Angelica
52 Vanderbilt Avenue, New York, NY 10017, USA

www.informahealthcare.com René Adam